Human 

Adaptation 

to Spaceflight:

The Role of 

Food and 

Nutrition

Second Edition

Scott M. Smith 

Sara R. Zwart

Grace L. Douglas 

Martina Heer

National Aeronautics and

 Space Administration

HUMAN ADAPTATION TO SPACEFLIGHT:

THE ROLE OF FOOD AND NUTRITION

Second Edition

Scott M. Smith 

Nutritionist; 

Manager for Nutritional Biochemistry 

Nutritional Biochemistry Laboratory 

Biomedical Research and 

Environmental Sciences Division

Human Health and Performance 

Directorate

NASA Johnson Space Center

Houston, Texas USA

Sara R. Zwart

Senior Scientist; 

Deputy Manager for Nutritional 

Biochemistry

Nutritional Biochemistry Laboratory 

Biomedical Research and 

Environmental Sciences Division

Human Health and Performance 

Directorate

NASA Johnson Space Center

Houston, Texas USA

&

Preventive Medicine and 

Population Health

University of Texas Medical Branch

Galveston, Texas USA 

National Aeronautics and 

Space Administration

Grace L. Douglas

Advanced Food Technology Lead Scientist;

Manager for Exploration Food Systems

Space Food Systems Laboratory

Human Systems Engineering and 

Integration Division

Human Health and Performance 

Directorate

NASA Johnson Space Center

Houston, Texas USA

Martina Heer

Nutritionist;

Program Director Nutritional Sciences

IU International University of 

Applied Sciences

Bad Reichenhall, Germany 

&

Adjunct Professor of Nutrition Physiology

Institute of Nutritional and Food Sciences

University of Bonn, Germany
i

Table of Contents

Preface .......................................................................................................................... vi

1. Introduction...............................................................................................................1

Stressors of Spaceflight ............................................................................................2

Microgravity or Partial Gravity ..............................................................................2

Radiation...............................................................................................................2

Isolation ................................................................................................................2

Environment..........................................................................................................3

Duration ................................................................................................................3

References for Chapter 1 ..........................................................................................5

2. Nutritional Requirements for Space Explorers......................................................7

Requirements Definition and Evolution ....................................................................7

Food Provisioning and Standard Menu ....................................................................9

References for Chapter 2 ........................................................................................11

3. Space Food Systems .............................................................................................13

International Space Station Food System...............................................................14

Food System Requirements....................................................................................15

Nutrition ..............................................................................................................15

Acceptability and Variety ....................................................................................16

Preference and Behavior ....................................................................................17

Safety..................................................................................................................19

Stability...............................................................................................................20

Resource Minimization .......................................................................................21

Food System Considerations for Future Exploration Missions ...............................21

The Moon: Artemis (Orion/Gateway/Lunar)........................................................21

Mars and other Deep Space Exploration ...........................................................22

References for Chapter 3 ........................................................................................24

4. Energy......................................................................................................................27

Energy Intake...........................................................................................................28

Implications for Inadequate Energy Intake .........................................................30

Fuel Sources............................................................................................................33

Carbohydrate (and Fiber)....................................................................................33

Fat (and Fatty Acids)...........................................................................................35

Protein ................................................................................................................37
ii iii

Nutrients Associated with Energy Metabolism........................................................38

Vitamin B6 ...........................................................................................................38

Thiamin ...............................................................................................................38

Riboflavin............................................................................................................39

Niacin..................................................................................................................40

Pantothenic acid.................................................................................................41

Iodine..................................................................................................................41

Manganese .........................................................................................................41

Chromium ...........................................................................................................42

References for Chapter 4 ........................................................................................42

5. Fluid .........................................................................................................................51

Fluid Intake ..............................................................................................................51

Fluid Homeostasis...................................................................................................51

Diuresis and Dehydration ........................................................................................52

References for Chapter 5 ........................................................................................54

6. Bone.........................................................................................................................57

Bone Biochemistry ..................................................................................................58

Ground Analogs and Animal Models of Spaceflight-Induced Bone Loss...............59

Renal Stone Risk .....................................................................................................60

Urine Processing and Water Reclamation..........................................................62

Bone Loss Countermeasures ..................................................................................63

Exercise ..............................................................................................................63

Gravity ................................................................................................................67

Vibration..............................................................................................................67

Pharmacological Agents.....................................................................................68

Nutritional Countermeasures..............................................................................70

Nutrients Associated with Bone Health...................................................................71

Energy.................................................................................................................71

Calcium...............................................................................................................71

Vitamin D ............................................................................................................72

Vitamin K ............................................................................................................75

Vitamin C ............................................................................................................76

Sodium and Chloride..........................................................................................76

Protein ................................................................................................................81

Iron......................................................................................................................83

Phosphorus ........................................................................................................87

Magnesium .........................................................................................................88

Copper................................................................................................................90

Zinc (and Lead)...................................................................................................91

References for Chapter 6 ........................................................................................93

7. Muscle ...................................................................................................................115

Protein Biochemistry .............................................................................................115

Ground Analog Studies .........................................................................................116

Muscle Loss Countermeasures.............................................................................117

Mechanical .......................................................................................................117

Pharmacological...............................................................................................119

Nutritional .........................................................................................................122

Nutrients Associated with Muscle Health..............................................................124

Potassium.........................................................................................................125

References for Chapter 7 ......................................................................................126

8. Cardiovascular......................................................................................................137

Nutrients Associated with Cardiovascular Health .................................................139

Energy...............................................................................................................139

Magnesium .......................................................................................................140

Antioxidants and Oxidative Stress....................................................................140

Omega-3 Fatty Acids........................................................................................140

Overall Diet Effects on Cardiovascular Health.......................................................140

References for Chapter 8 ......................................................................................142

9. Brain ......................................................................................................................147

Radiation and Central Nervous System, Behavior/Performance, 

and Sensorimotor Function...................................................................................147

Nutrition Countermeasures ...................................................................................149

References for Chapter 9 ......................................................................................150

10. Ocular..................................................................................................................153

Spaceflight Associated Neuro-ocular Syndrome ..................................................153

Spaceflight Associated Neuro-ocular Syndrome, Vitamins, 

and One Carbon Biochemistry ..............................................................................155

How could one-carbon pathway function contribute 

to optic disc edema and SANS? ......................................................................157

Nutrients Associated with Ocular Health...............................................................162

Folate................................................................................................................162

Vitamin B12 ........................................................................................................163
iv v

Riboflavin..........................................................................................................164

Vitamin A...........................................................................................................164

References for Chapter 10 ....................................................................................165

11. Immune................................................................................................................173

Diet, Gastrointestinal Microbiota, and Immune Response....................................173

Skin........................................................................................................................175

Nutrients Associated with Immune and Dermatologic Health...............................175

Energy...............................................................................................................175

Protein and Amino Acids ..................................................................................176

Vitamin D ..........................................................................................................177

Vitamin B12 ........................................................................................................178

Riboflavin..........................................................................................................179

Vitamin B6 .........................................................................................................179

Biotin.................................................................................................................179

Sodium .............................................................................................................179

Vitamin A...........................................................................................................180

Vitamin C ..........................................................................................................180

Vitamin E...........................................................................................................181

Copper..............................................................................................................181

Zinc...................................................................................................................181

Selenium...........................................................................................................182

Polyphenols ......................................................................................................182

Iron....................................................................................................................183

Polyunsaturated Fatty Acids.............................................................................184

References for Chapter 11 ....................................................................................185

12. Oxidative Stress..................................................................................................195

Radiation Exposure ...............................................................................................195

Reactive Oxygen Species and Exercise................................................................195

Oxidative Damage Markers during Spaceflight and in Ground Analogs...............196

Nutrients Associated with Antioxidant Protection and Oxidative Stress...............196

Selenium...........................................................................................................196

Vitamin E...........................................................................................................197

Vitamin C ..........................................................................................................197

Folate................................................................................................................198

References for Chapter 12 ....................................................................................199

13. Supplements, Foods, and Pharmaceuticals ....................................................203

Dietary Factors ......................................................................................................205

Metabolism of Nutrients ........................................................................................205

Monoamine Oxidase Inhibitors..............................................................................206

Antacids and Proton Pump Inhibitors ...................................................................206

Anti-Hypertensives: Angiotensin-Converting Enzyme Inhibitors...........................207

Oral Contraceptives...............................................................................................207

Pharmacology and Drug-Nutrient Interactions......................................................207

References for Chapter 13 ....................................................................................208

14. Conducting Space Research.............................................................................211

Flight Research......................................................................................................211

Blood Collection ...............................................................................................211

Urine Collection ................................................................................................212

Frozen Storage .................................................................................................213

Sample Return..................................................................................................214

Dietary Intake Recording During Spaceflight ...................................................214

Body Mass Measurement.................................................................................217

Ground-based Analogs .........................................................................................217

References for Chapter 14 ....................................................................................220

15. Summary .............................................................................................................223

References for Chapter 15 ....................................................................................224

16. Appendices .........................................................................................................225

Authors ................................................................................................................ 225

Acknowledgments.................................................................................................226

List of Figures ........................................................................................................228

Acronyms and Abbreviations.................................................................................237

Index......................................................................................................................240
1

vi

Preface

This book marks our third effort to review available literature regarding the role of 

nutrition in astronaut health. In 2009, we reviewed the existing knowledge and history 

of human nutrition for spaceflight, with a key goal of identifying additional data that 

would be required before NASA could confidently reduce the risk of an inadequate 

food system or inadequate nutrition to as low as possible in support of human 

expeditions to the Moon or Mars. We used a nutrient-by-nutrient approach to address 

this effort, and we included a brief description of the space food systems during 

historical space programs. This previous review is available for free download, most 

recently at https://www.nasa.gov/hhp/education. 

In 2014, we published a second volume of the book, which was not so much a second 

edition, but rather a view of space nutrition from a different perspective. Also available 

at the link mentioned above, this volume updated research that had been published 

in the intervening 6 years and addressed space nutrition with a more physiological 

systems-based approach.

The current version is an expanded, updated version of that second book, providing 

both a systems approach overall, but also including details of nutrients and their roles 

within each system. As such, this book is divided into chapters based on physiological 

systems (e.g., bone, muscle, ocular); highlighted in each chapter are the nutrients 

associated with that particular system. We provide updated information on space food 

systems and constraints of the same, and provide dietary intake data from International 

Space Station (ISS) astronauts.

We present data from ground-based analog studies, designed to mimic one 

or more conditions similar to those produced by spaceflight. Head-down tilt bed 

rest is a common analog of the general (and specifically musculoskeletal) disuse of 

spaceflight. Nutrition research from Antarctica relies on the associated confinement 

and isolation, in addition to the lack of sunlight exposure during the winter months. 

Undersea habitats help expand our understanding of nutritional changes in a confined 

space with a hyperbaric atmosphere. We also review spaceflight research, including data 

from now “historical” flights on the Space Shuttle, data from the Russian space station 

Mir, and earlier space programs such as Apollo and Skylab. The ISS, now more than 

20 years old, has provided (and continues to provide) a wealth of nutrition findings from 

extended-duration spaceflights of 4 to 12 months. We review findings from this platform 

as well, providing a comprehensive review of what is known regarding the role of human 

nutrition in keeping astronauts healthy.

With this book, we hope we have accurately captured the current state of the field 

of space food and nutrition, and that we have provided some guideposts for work 

that remains to be done to enable safe and successful human exploration beyond 

low-Earth orbit.

Scott M. Smith

Sara R. Zwart

Grace L. Douglas

Martina Heer

The importance of nutrition in exploration has been documented repeatedly throughout 

history, on voyages across oceans, on expeditions across polar ice, and on treks across 

unexplored continents (1-5). Scurvy is a prime example of an exploration-induced 

nutritional discovery. Although most people now understand that scurvy is associated 

with vitamin C deficiency, and that this was an issue for sailors centuries ago, few realize 

the magnitude of this problem. Over the roughly 400-year period between Christopher 

Columbus’ voyage in 1492 and the invention of the steam engine, scurvy resulted in the 

deaths of more sailors than did all other causes of death combined (2). Ships that sailed 

with a crew of hundreds often returned with tens. It is estimated that more than 2 million 

sailors perished from scurvy during this time (2). Although in the last 100 years we have 

gained significant nutritional knowledge that can benefit food system planning, a key 

difference between past journeys and space exploration is that astronauts are not likely 

to find food along the way. Thus, understanding the nutritional requirements of space 

travelers, the role of nutrition in human adaptation to microgravity, and the food system 

requirements over long durations are as critical to crew safety and mission success as 

any of the mechanical systems of the spacecraft itself (6).

More basic concerns during spaceflight include loss of body mass and depletion 

of body nutrient stores because of inadequate food supply, inadequate food intake, 

increased metabolism, and/or irreversible loss or degradation of nutrients in the food 

supply. Physiological changes associated with spaceflight (e.g., bone and muscle loss, 

cardiovascular degradation, ophthalmic pathologies, impaired immune function) may 

have nutritional underpinnings as well, potentially as cause and/or effect. Environmental 

issues, including radiation exposure and the cabin environment (e.g., oxygen [O2

], and 

carbon dioxide [CO2], temperature, humidity) can have profound effects on nutritional 

requirements. Nutrients could serve as countermeasures to these stressors. Food and 

nutrition also have profound effects on behavior and performance. 

All these elements become critical in a closed spacecraft that has a limited food system 

and a limited ability for resupply or return to Earth. Food and nutrition are essential to 

support astronaut health and performance and therefore mission success.

Introduction 1
2 3

lived in a hermetically sealed habitat for 

520 days had measurable effects in the 

microstructure of their brain’s white matter, 

as determined using diffusion tensor 

imaging (20). This finding suggested 

changes in underlying processes of myelin 

plasticity during the 520 days of isolation 

and confinement.

Environment 

The spacecraft environment can also 

affect crewmembers’ health, performance, 

dietary intake, and nutritional status. 

The cabin pressure, gas mixture 

(i.e., percentages of O2 and CO2) in the 

cabin air, temperature, and humidity can 

all have profound effects on physiology, 

behavior and performance, and food and 

nutrition. Given that the concentrations 

of CO2 on the ISS are approximately 

10 times greater than those on Earth 

(21-23), it is possible that this could 

affect crew behavior and performance 

(e.g., cognition, sleep, headaches) (22-26), 

bone and calcium loss (27, 28), 

metabolism (29), cerebral blood flow 

(21, 30), and ophthalmic pathologies (31). 

As of this writing, studies are planned 

to further examine how a proposed 

exploration vehicle atmosphere of 

32% oxygen at 8 psi (pounds per 

square inch, compared to sea level: 

21% O2 at 14.7 psi) affects crew health 

(32), including how this atmosphere affects 

nutritional status, immune system function, 

and oxidative stress and damage.

When crewmembers are outside the 

spacecraft (i.e., on extravehicular activities 

[EVAs], also referred to as spacewalks), 

the spacesuit becomes their spacecraft. 

Nutritional concerns could arise (high O2

exposure, limited water availability, inability 

to eat for up to 8 to 10 hours at a time 

while in the suit). These limitations have 

generally been acceptable on missions 

to date because relatively few (2-6) EVAs 

occur during a 6-month ISS mission. 

However, the increased frequency and 

intensity of spacewalks on the lunar 

or Martian surface will be much more 

demanding, requiring the suits to include 

nutrition, or allowing crewmembers 

to get in and out of the suit quickly for 

meal breaks.

Duration 

The duration of exposure to spaceflightassociated stressors defines the limits of 

what can feasibly be accomplished on any 

given mission. Space Shuttle missions, 

which lasted from a few days to 2 weeks, 

were in many ways seen as camping trips. 

Although nutrition was not a significant 

factor on these missions, maintaining 

hydration and dietary intake continue to 

be important for many aspects of health 

on short or long missions. Hydration is 

important for performance and cognitive 

function, and for minimizing the risk of 

developing renal stones (which occurred 

even on short-duration missions), among 

other concerns.

Dietary intake and nutritional status 

became more important on what could 

be considered medium-duration 

missions—2- to 6-month ISS expeditions. 

Loss of body mass became problematic, 

exacerbating muscle and bone loss and 

cardiovascular decrements. The Earth 

provides some protection against radiation 

on vehicles in low-Earth orbit; however, 

radiation exposure remains a careerlimiting factor for astronauts. During 

18 months of spaceflight, astronauts are 

exposed to levels of radiation that are 

roughly equivalent to the maximum lifetime 

levels allowed for terrestrial radiation 

workers. The physiological changes that 

occur during the span of an ISS mission 

are typically not associated with chronic 

disease incidence, although concerns 

clearly exist with regard to accelerating 

risks of bone loss and other diseases.

Missions in the coming decade will be 

the same duration as a mission on the 

ISS (i.e., up to 1 year); however, they will 

involve operations in lunar orbit and on 

the lunar surface. Periodic cargo vehicles 

Stressors of Spaceflight 

Microgravity or Partial Gravity 

Entry into weightlessness (technically 

referred to as microgravity) is associated 

with a shift of fluids from the lower 

extremities into the thorax and head. 

Astronauts often experience “puffy” faces 

in the initial days of flight. This effect 

lasts much longer in some individuals 

than in others. This individual variability 

in response is not well characterized; 

however, it might involve genetic influence 

on ophthalmic pathologies. 

This headward shift of fluids is associated 

with a negligible (≈1% of body mass) 

reduction in total body water observed 

as soon as within the first hours of flight, 

and is accompanied by a 10% to 15% 

reduction in blood volume that takes about 

2 weeks to stabilize (7-9). The associated 

reduction in circulating red blood cells 

(RBCs) affects iron requirements and iron 

stores and can have downstream effects 

on oxidative stress (10).

Scientists often speculate as to whether 

the partial gravity of the Moon (0.16 g) 

or of Mars (0.38 g) will affect human 

physiology. Bone researchers typically 

assert that gravity levels of more than 

0.5 g are required to stimulate enough 

bone loading to mitigate bone and 

calcium loss; however, proving this 

experimentally is difficult in terrestrial 

analogs. Partial gravity would likely affect 

fluid redistribution to some degree, with 

potential implications for cardiovascular 

health and cerebrovascular fluid dynamics. 

Regardless, partial gravity on a planetary 

surface should be less problematic than 

microgravity conditions in a spacecraft 

(i.e., providing means to perform 

loading exercises will be easier on 

a planetary surface).

Radiation 

Long-duration exploration missions 

beyond low-Earth orbit will be 

accompanied by high-linear energy 

transfer (LET) galactic cosmic rays 

consisting of high-energy protons and 

high-charge, high-energy nuclei (11, 12). 

High-LET radiation deposits part of its 

energy in ion tracks known as cores, and 

the remaining energy is dispersed 

randomly outside of the core by energetic 

electrons. By contrast, low-LET ionizing 

radiation, including x-rays or gamma rays, 

deposit energy uniformly (13). In addition 

to galactic cosmic rays, solar particle 

events comprised mainly of low- to 

medium-energy protons periodically 

bombard the solar system. The timing 

of these events is difficult to predict; 

however, they are more prevalent during 

periods of the solar cycle when the Sun is 

at maximum activity (14). Galactic cosmic 

radiation exposures during exploration 

missions to Mars will be about 10 times 

higher than exposures on the International 

Space Station (ISS) (15). These higher 

radiation doses will increase the 

astronauts’ risk of both short- and 

long-term health effects.

Isolation 

Isolation and confinement during space 

missions can increase an astronaut’s risk 

of developing symptoms of depression 

(16, 17), which can lead to nutritional 

issues (e.g., over or under consumption 

of food). Available data from early 

spaceflights indicate that neurological 

incidents do occur; however, the etiologies 

are typically unknown. Two psychiatric 

events were reported among seven NASA 

astronauts who carried out long-duration 

increments on Mir between 1995 and 

1998 (18); at least one of these events 

was accompanied by a significant 

reduction in dietary intake and weight loss. 

A crewmember who flew on the ISS for 

1 year had some cognitive decline during 

and after flight (19), along with significant 

weight loss. The risk of depression or 

cognitive changes will undoubtedly be 

greater as mission durations extend 

to several years. While participating in 

the MARS-500 project, six people who 
4 5

that deliver fresh fruits and vegetables 

will no longer be possible, as they are 

for ISS missions, and the foods will 

likely be prepositioned given logistics 

issues. Prepositioning will not support 

provisioning of individual-preference foods 

due to the potential for late crew changes, 

thus resulting in less variety and choice, 

and a greater risk of menu fatigue and 

reduced consumption. The astronauts of 

these missions will be exposed to higher 

doses of radiation compared to exposures 

on the ISS, thereby incurring significantly 

greater risk despite the similar durations.

Mars-class missions will be altogether 

more challenging than lunar missions, 

and will include greater challenges 

from a food and nutrition perspective. 

Exposures to radiation, isolation, etc. for 

the expected nominal 2.5-year prototype 

missions will be profound. The stability 

of food for the required shelf life is at this 

point untenable. This issue represents 

one of the four “red risks” for Mars 

missions: Food, Radiation, Psychological 

Issues, and Ophthalmic Pathologies 

(currently dubbed SANS, SpaceflightAssociated Neuro-ocular Syndrome) 

(33). It is possible that missions of this 

duration could accelerate the incidence of 

chronic diseases, which will be difficult to 

discriminate from diseases that astronauts 

might have developed on Earth anyway. 

Regardless, nutrition provides the greatest 

potential for mitigating chronic diseases 

such as osteoporosis, sarcopenia, cancer, 

dementia, neuropathy, atherosclerosis, 

and cardiovascular disease, to name 

a few. Although nutrition will not be a 

panacea and is by no means advocated 

as the end to spaceflight maladies, food 

and nutrition can improve or optimize 

health and mitigate disease, or they can 

worsen health and exacerbate disease, 

as they do on Earth. 

References for Chapter 1 

1. Smith SM, Zwart SR, Kloeris V, Heer M. Nutritional biochemistry of space flight. New York: Nova Science 

Publishers; 2009.

2. Bown SR. Scurvy. New York: St. Martin's Press; 2003.

3. De Luca LM, Norum KR. Scurvy and cloudberries: a chapter in the history of nutritional sciences. J Nutr. 

2011;141:2101-5.

4. Stuster JW. Bold endeavors: behavioral lessons from polar and space exploration. Gravit Space Biol Bull. 

2000;13:49-57.

5. McIntosh EN. The Lewis and Clark Expedition: Food, Nutrition, and Health Rock Island, IL: Center for Western 

Studies, Augustana College; 2003.

6. Douglas GL, Zwart SR, Smith SM. Space food for thought: Challenges and considerations for food and nutrition 

on exploration missions. J Nutr. 2020;150:2242-4.

7. Leach CS, Alfrey CP, Suki WN, Leonard JI, Rambaut PC, Inners LD, Smith SM, Lane HW, Krauhs JM. 

Regulation of body fluid compartments during short-term spaceflight. J Appl Physiol (1985). 1996;81:105-16.

8. Alfrey CP, Udden MM, Huntoon CL, Driscoll T. Destruction of newly released red blood cells in space flight. 

Med Sci Sports Exerc. 1996;28:S42-4.

9. Alfrey CP, Udden MM, Leach-Huntoon C, Driscoll T, Pickett MH. Control of red blood cell mass in spaceflight. 

J Appl Physiol (1985). 1996;81:98-104.

10. Zwart SR, Morgan JLL, Smith SM. Iron status and its relations with oxidative damage and bone loss during 

long-duration space flight on the International Space Station. Am J Clin Nutr. 2013;98:217-23.

11. Norbury JW, Slaba TC, Aghara S, Badavi FF, Blattnig SR, Clowdsley MS, Heilbronn LH, Lee K, Maung KM, 

Mertens CJ, Miller J, Norman RB, Sandridge CA, Singleterry R, Sobolevsky N, Spangler JL, Townsend LW, 

Werneth CM, Whitman K, Wilson JW, Xu SX, Zeitlin C. Advances in space radiation physics and transport 

at NASA. Life Sci Space Res (Amst). 2019;22:98-124.

12. Sobel A, Duncan R. Aerospace environmental health: Considerations and countermeasures to sustain 

crew health through vastly reduced transit time to/from Mars. Front Public Health. 2020;8:327.

13. Cekanaviciute E, Rosi S, Costes SV. Central nervous system responses to simulated galactic cosmic rays. 

Int J Mol Sci. 2018;19.

14. Kiffer F, Boerma M, Allen A. Behavioral effects of space radiation: A comprehensive review of animal studies. 

Life Sci Space Res (Amst). 2019;21:1-21.

15. Krukowski K, Feng X, Paladini MS, Chou A, Sacramento K, Grue K, Riparip LK, Jones T, Campbell-Beachler M, 

Nelson G, Rosi S. Temporary microglia-depletion after cosmic radiation modifies phagocytic activity and prevents 

cognitive deficits. Sci Rep. 2018;8:7857.

16. Palinkas LA, Johnson JC, Boster JS. Social support and depressed mood in isolated and confined environments. 

Acta Astronaut. 2004;54:639-47.

17. Gemignani A, Piarulli A, Menicucci D, Laurino M, Rota G, Mastorci F, Gushin V, Shevchenko O, Garbella E, 

Pingitore A, Sebastiani L, Bergamasco M, L'Abbate A, Allegrini P, Bedini R. How stressful are 105 days of 

isolation? Sleep EEG patterns and tonic cortisol in healthy volunteers simulating manned flight to Mars. 

Int J Psychophysiol. 2014;93:211-9.

18. National Academy of Sciences Institute of Medicine. Safe passage: Astronaut care for exploration missions: 

The National Academies Press: Washington DC2001.

19. Garrett-Bakelman FE, Darshi M, Green SJ, Gur RC, Lin L, Macias BR, McKenna MJ, Meydan C, Mishra T, 

Nasrini J, Piening BD, Rizzardi LF, Sharma K, Siamwala JH, Taylor L, Vitaterna MH, Afkarian M, Afshinnekoo E, 

Ahadi S, Ambati A, Arya M, Bezdan D, Callahan CM, Chen S, Choi AMK, Chlipala GE, Contrepois K, Covington M, 

Crucian BE, De Vivo I, Dinges DF, Ebert DJ, Feinberg JI, Gandara JA, George KA, Goutsias J, Grills GS, 

Hargens AR, Heer M, Hillary RP, Hoofnagle AN, Hook VYH, Jenkinson G, Jiang P, Keshavarzian A, Laurie SS, 

Lee-McMullen B, Lumpkins SB, MacKay M, Maienschein-Cline MG, Melnick AM, Moore TM, Nakahira K, 

Patel HH, Pietrzyk R, Rao V, Saito R, Salins DN, Schilling JM, Sears DD, Sheridan CK, Stenger MB, 

Tryggvadottir R, Urban AE, Vaisar T, Van Espen B, Zhang J, Ziegler MG, Zwart SR, Charles JB, Kundrot CE, 

Scott GBI, Bailey SM, Basner M, Feinberg AP, Lee SMC, Mason CE, Mignot E, Rana BK, Smith SM, 

Snyder MP, Turek FW. The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight. 

Science. 2019;364.

Expedition 34 crew fruit and vegetables within a Cargo Transfer Bag. Photo Credit: NASA. 
6 7

Requirements Definition and Evolution

The first concerted effort to define 

nutritional requirements for astronauts 

came in 1991, as NASA prepared to send 

crews on 90- to 180-day missions to the 

planned Space Station Freedom (34), 

which would eventually evolve to be the 

ISS. For these flights, the panel of the 

1991 conference recommended terrestrial 

nutritional requirements with specific 

modifications and suggestions based on 

known losses of bone and muscle tissue 

and assumed increased stress levels in 

astronauts. The panel noted “nutritional 

status should absolutely be assessed 

before and after flight, and if at all 

possible during flight.” (34). The panel 

recommended nutrients be provided 

in the form of foods, as opposed to 

supplements, and specifically advocated 

against iron supplementation given “that 

serum ferritin levels increase with age...”. 

The 1991 panel report was codified into 

a NASA requirements documents in 

1993 (35) aimed at Freedom missions 

and planned 30- to 90-day Space Shuttle 

missions, which never came to fruition.

The next set of nutritional requirements 

came during the joint U.S.-Russian 

Shuttle-Mir and NASA-Mir Programs of 

the early and mid-1990s. NASA defined 

a bilateral set of nutritional requirements 

in 1996 (36) (Table 1) that were based 

largely on the previously defined 

requirements but were targeted for 

missions of up to 360 days on the ISS 

(Figure 1). A multilateral group with 

representation from all the ISS partner 

agencies—Canada, Europe, Japan, 

Russia, and the United States— 

reevaluated these requirements in 1999; 

however, no formal documentation of 

these discussions were ever published.

In 2005, NASA defined a set of nutritional 

requirements for future exploration 

missions (37) (Table 1). These were not 

intended to affect the ISS requirements. 

However, they offered a first look at 

potential missions outside of low-Earth 

orbit; i.e., the Moon, Mars, or an asteroid 

in between.

In 2016, a panel of nutrition experts 

was invited to the Johnson Space Center 

to evaluate the current data regarding 

nutrition and space, and to define an 

updated set of nutritional requirements 

for exploration missions up to 1 year. 

These nutritional requirements, 

documented in 2020 (38) (Table 1), 

were intended to cover planned missions 

outside low-Earth orbit, namely Orion, 

Lunar Gateway, and Artemis/Human 

Landing System missions to the Moon. 

The panel suggested that requirements 

be based on terrestrial nutritional 

requirements, with a few exceptions.

2 Nutritional Requirements for 

Space Explorers

20. Brem C, Lutz J, Vollmar C, Feuerecker M, Strewe C, Nichiporuk I, Vassilieva G, Schelling G, Choukér A. 

Changes of brain DTI in healthy human subjects after 520 days isolation and confinement on a simulated 

mission to Mars. Life Sci Space Res (Amst). 2020;24:83-90.

21. Frey MA, Sulzman FM, Oser H, Ruyters G. The effects of moderately elevated ambient carbon dioxide levels 

on human physiology and performance: a joint NASA-ESA-DARA study--overview. Aviat Space Environ Med. 

1998;69:282-4.

22. Law J, Watkins S, Alexander D. In-flight carbon dioxide exposures and related symptoms: Association, 

susceptibility, and operational implications. Houston, TX: National Aeronautics and Space Administration 

Lyndon B. Johnson Space Center. 2010. Report No.: NASA/TP-2010-21626.

23. Law J, Young M, Alexander D, Mason SS, Wear ML, Mendez CM, Stanley D, Ryder VM, Van Baalen M. 

Carbon dioxide physiological training at NASA. Aerosp Med Hum Perform. 2017;88:897-902.

24. Manzey D, Lorenz B. Joint NASA-ESA-DARA Study. Part three: effects of chronically elevated CO2

on mental performance during 26 days of confinement. Aviat Space Environ Med. 1998;69:506-14.

25. Law J, Van Baalen M, Foy M, Mason SS, Mendez C, Wear ML, Meyers VE, Alexander D. Relationship between 

carbon dioxide levels and reported headaches on the international space station. J Occup Environ Med. 

2014;56:477-83.

26. Gundel A, Parisi RA, Strobel R, Weihrauch MR. Joint NASA-ESA-DARA Study. Part three: characterization 

of sleep under ambient CO2

-levels of 0.7% and 1.2%. Aviat Space Environ Med. 1998;69:491-5.

27. Davies DM, Morris JE. Carbon dioxide and vitamin D effects on calcium metabolism in nuclear submariners: 

a review. Undersea Biomed Res. 1979;6 Suppl:S71-80.

28. Drummer C, Friedel V, Borger A, Stormer I, Wolter S, Zittermann A, Wolfram G, Heer M. Effects of elevated 

carbon dioxide environment on calcium metabolism in humans. Aviat Space Environ Med. 1998;69:291-8.

29. Bishop PA, Lee SM, Conza NE, Clapp LL, Moore AD, Jr., Williams WJ, Guilliams ME, Greenisen MC. 

Carbon dioxide accumulation, walking performance, and metabolic cost in the NASA launch and entry suit. 

Aviat Space Environ Med. 1999;70:656-65.

30. Sliwka U, Krasney JA, Simon SG, Schmidt P, Noth J. Effects of sustained low-level elevations of carbon dioxide 

on cerebral blood flow and autoregulation of the intracerebral arteries in humans. Aviat Space Environ Med. 

1998;69:299-306.

31. Stenger MB, Tarver WJ, Brunstetter T, Gibson CR, Laurie SS, Macias BR, Mader TH, Otto C, Smith SM, Zwart SR. 

Evidence Report: Risk of spaceflight associated neuro-ocular syndrome (SANS) [online]. National Aeronautics and 

Space Administration. https://humanresearchroadmap.nasa.gov/evidence/reports/SANS.pdf. 2017.

32. Norcross J, Norsk P, Law J, Arias D, Conkin J, Perchonok M, Menon A, Huff J, Fogarty J, Wessel JH, Whitmire S. 

Effects of the 8 psia / 32% O2 atmosphere on the human in the spaceflight environment. Hanover, MD: 

National Aeronautics and Space Administration Center for AeroSpace Information. 2013.

33. Patel ZS, Brunstetter TJ, Tarver WJ, Whitmire AM, Zwart SR, Smith SM, Huff JL. Red risks for a journey 

to the red planet: The highest priority human health risks for a mission to Mars. NPJ Microgravity. 2020;6.

The obvious, primary role of any space food system is to deliver requisite nutrients 

to the astronauts. Defining and meeting astronaut nutritional requirements has been 

an ongoing challenge since the dawn of human spaceflight. The foods provided to 

astronauts for short-duration missions (i.e., days to weeks) generally follow terrestrial 

nutritional requirements. These missions are often considered analogous to camping 

trips, where the duration is assumed to be short enough to negate any effects of 

inadequate nutritional intakes during the mission.
8 9

Terrestrial nutritional requirements are 

typically used as the starting point for 

spaceflight requirements, with exceptions 

in cases where evidence leads to a 

different requirement. The Food and 

Nutrition Board of the National Academies 

of Science, Engineering, and Medicine 

recommend requirements that are 

designed to mitigate nutrient deficiency 

in the vast majority of the population. 

That is, the nutritional requirements are 

not designed to prevent chronic diseases, 

even though many of these diseases 

(e.g., cancer, osteoporosis, sarcopenia, 

dementia) have nutritional underpinnings. 

Although there has been much discussion 

and initial attempts to expand recent 

nutritional requirements to address 

disease (39), much more needs to be 

known before this can be fully 

implemented on Earth. For space 

travel, especially on longer missions 

beyond low-Earth orbit, it will be critical 

that nutrition not only prevent nutrient 

deficiency, but also serve as a 

countermeasure against the many 

negative effects on human physiology. 

This represents a major gap in our 

understanding of the role of nutrition 

in spaceflight.

Food Provisioning and Standard Menu 

Food provision during early ISS missions 

followed the same plan as was initiated 

during the NASA-Mir missions: the 

Russian Space Agency provided 

approximately half of the space food, 

Nutrient ISS Requirements 

(1996)

Exploration 

Requirements (2005)

Exploration 

Requirements (2020)

Energy Based on World Health 

Organization equations 

(40) 

Based on Dietary Reference Intake (DRI) equations (41)Based on DRI equations 

(41)

Protein 12% – 15% of total daily 

energy intake, and the 

ratio of animal:vegetable 

protein no higher than 

60:40

0.8 g/kg body weight, < 

35% of total daily energy 

intake, and the ratio of 

animal:vegetable protein 

is about (2/3):(1/3)

1.2 – 1.8 g/kg body 

weight, and the ratio of 

animal:vegetable protein 

no higher than 60:40

Carbohydrate 50% – 55% of the total 

daily energy intake 

< 10% of energy from 

added sugars

50% – 55% of the total 

daily energy intake

45% – 65% of the total 

daily energy intake

<10% of energy from 

added sugars

Fat 30%– 35% of the total 

daily energy intake

25% – 35% of the total 

daily energy intake

20% – 35% of the total 

daily energy intake

Omega-6 Fatty Acids N/A 14 g Women: 12 g

Men: 17g

Omega-3 Fatty Acids N/A 1.1 – 1.6 g Women: 1.1 g 

Men: 1.6g

Saturated Fat Polyunsaturated: monounsaturated: saturated = 

1:1.5 – 2:1

as low as possible ALARA, <10% of total 

calories 

Trans Fatty Acids N/A as low as possible ALARA, < 1% of total 

calories 

Cholesterol N/A as low as possible < 300 mg

Fiber N/A 10 – 14 g/1000 kcal Women: 25 g

Men: 38 g

Fluid 1 – 1.5 ml/kcal 1 – 1.5 ml/kcal 32 mL/kg body weight

>2000 ml > 2000 ml Women: > 2100 ml

Men: > 2500 ml 

Vitamin A 1000 μg RE 700 – 900 μg RE Women: 700 μg RE

Men: 900 μg RE

Vitamin D 10 μg 25 μg 1000 IU (25 μg)

Vitamin K 80 μg Women: 90 μg

Men: 120 μg

Women: 90 μg

Men: 120 μg

Vitamin E 20 mg Tocopherol 

Equivalents

15 mg Tocopherol 

Equivalents

15 mg Tocopherol 

Equivalents

Vitamin C 100 mg 90 mg Women: 110 mg

Men: 125 mg

Vitamin B12 2.0 μg 2.4 μg 2.4 μg

Vitamin B6 2.0 mg 1.7 mg 1.3 mg

Thiamin 1.5 mg Women: 1.1 mg

Men: 1.2 mg

Women: 1.1 mg

Men: 1.2 mg

Riboflavin 2.0 mg 1.3 mg Women: 1.1 mg

Men: 1.3 mg

Folate 400 μg 400 μg 400 μg

Niacin 20 mg NE 16 mg NE Women: 14 mg NE

Men: 16 mg NE

Biotin 100 μg 30 μg 30 μg

Pantothenic Acid 5 mg 30 mg 5 mg

Choline N/A N/A Women: 425 mg

Men: 550 mg

Calcium 1,200 – 2,000 mg 1,200 – 2,000 mg 1,000 – 1,200 mg

Phosphorus ≤ 1.5 x calcium intake 700 mg, and ≤ 1.5 x 

calcium intake

700 mg, and ≤ 1.5 x 

calcium intake

Magnesium 350 mg Women: 320 mg

Men: 420 mg

Women: 320 mg

Men: 420 mg

< 350 mg from supplements per day< 350 mg from supplements per day

Sodium 1,500 – 3,500 mg 1,500 – 2,300 mg 1,500 – 2,300 mg

Potassium 3,500 mg 4.7 g Women: 2600 mg

Men: 3400 mg

Iron < 10 mg 8 – 10 mg 8 mg/d for men and 

women, 18 mg/d for 

women under 50 who do 

not pharmacologically 

suppress menstruation

Copper 1.5 – 3.0 mg 0.5 – 9 mg 900 μg

Manganese 2 – 5 mg Women: 1.8 mg

Men: 2.3 mg

Women: 1.8 mg

Men: 2.3 mg

Fluoride 4.0 mg Women: 3 mg

Men: 4 mg

Women: 3 mg

Men: 4 mg

Zinc 15 mg 11 mg Women: 8 mg

Men: 11 mg

Selenium 70 μg 55 – 400 μg 55 μg

Iodine 150 μg 150 μg 150 μg

Chromium 100 – 200 μg 35 μg Women: 25 μg 

Men: 35 μg

Chloride N/A N/A 2300 mg

Molybdenum N/A N/A 45 μg

Table 1. Nutritional Requirements Defined for ISS and Exploration Missions. Adapted from (36-38).
10 11

In addition to the standard food set, 

crewmembers were provided with a set 

of “preference containers.” A 6-month 

mission included nine preference 

containers (not counting coffee/tea 

preference containers) that augmented 

the nominal food system with the 

astronauts’ selections of their choice. 

It should be noted that, although 

nutritional requirements were defined and 

documented, the ISS food system was 

largely the same as the Space Shuttle food 

system, with some exclusions of food with 

shorter shelf life because food was often 

pre-positioned. As a result, the ISS food 

system was very high in sodium and iron. 

References for Chapter 2 

34. National Aeronautics and Space Administration Johnson Space Center. Nutritional requirements for 

Space Station Freedom crews. NASA Conference Publication #3146 Houston, TX, 1991.

35. National Aeronautics and Space Administration Johnson Space Center. Nutritional requirements for 

Extended Duration Orbiter missions (30-90 d) and Space Station Freedom (30-120 d). Report No.: JSC-32283. 

Houston, TX: National Aeronautics and Space Administration Lyndon B. Johnson Space Center, 1993.

36. National Aeronautics and Space Administration Johnson Space Center. Nutritional requirements for 

International Space Station (ISS) missions up to 360 days. Report No.: JSC-28038. Houston, TX: 

National Aeronautics and Space Administration Lyndon B. Johnson Space Center, 1996.

37. National Aeronautics and Space Administration Johnson Space Center. Nutrition requirements, standards, 

and operating bands for exploration missions. Report No.: JSC-63555. Houston, TX: Lyndon B. Johnson 

Space Center; 2005.

38. National Aeronautics and Space Administration Johnson Space Center. Nutrition requirements for exploration 

missions up to 365 days. Report No.: JSC-67378. Houston, TX: Lyndon B. Johnson Space Center; 2020.

39. National Academies of Sciences, Engineering, and Medicine. Dietary Reference Intakes for sodium and 

potassium. Washington, DC: The National Academies Press. 2019.

40. World Health Organization. Energy and protein requirements. Report of a joint FAO/WHO/UNU expert 

consultation. Geneva, Switzerland: World Health Organization; 1985.

41. Institute of Medicine. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, 

protein, and amino acids (macronutrients). Washington, DC: National Academy Press; 2002.

and NASA provided the other half. 

This covered ISS missions from 2000 

(Expedition 1) until approximately 2007 

(Expedition 16), when the ISS crew 

complement expanded to six, and it 

was easier logistically for each agency 

to provide food for their respective crews 

(although, mathematically, both agencies 

were still providing half of the food). 

During this period, NASA also opted for 

a “standard menu” for food provision, as 

opposed to individual-preference menus. 

This came about because the vagaries of 

launch schedules and slippages made it 

complicated to ensure each crewmember’s 

specific food was on board at the same 

time they were. The phrase “standard 

menu” is in quotes because there is no 

menu defined for crewmembers; rather, 

they receive a standard set of food 

containers from which to eat over a 

specified number of days, typically 7 to 

9 days. The “standard menu” is one way 

to select from those containers to make 

a menu; however, that information is not 

provided to crewmembers (unless they 

specifically ask for it), and astronauts are 

not required to follow that menu. In other 

words, it is an idealized menu created 

from the standard food containers to 

assess to what degree crewmembers 

could meet nutritional requirements from 

the food system. 

Throughout this book, reported intakes 

are shown alongside the content of this 

idealized “standard menu.” Key points in 

considering this is that the “standard 

menu" is expected to provide, on average, 

approximately 2300 to 2400 kcals/d, 

and crews are expected to consume only 

80% to 90% of their daily intake from the 

standard food containers, with the rest 

coming from preference containers. 

These estimates are just that, in part 

because the allowed rate of food usage 

is increased or decreased depending on 

the estimated requirements for the crew 

on board at any given time. Individual 

astronaut requirements will affect the 

percent contribution of the standard 

food system to their intake.

Figure 1. The ISS as seen from the last Space Shuttle mission. Photo Credit: NASA.
12 13 3 Space Food Systems Astronauts Julie Payette, Koichi Wakata, Frank De Winne, 

and Michael Barratt enjoy a meal in the ISS Node 1 during 

Expedition 20. Photo Credit: NASA.

A space food system, developed and provisioned to deliver all the defined nutritional 

requirements, should be available on every human mission as an essential countermeasure to health and performance decrements. However, resources are limited on 

every mission. The adequacy of the food system may be impacted by how resources 

are distributed and prioritized across life support and vehicle systems. The first edition 

of this book included a review of food systems from the Apollo Program through the 

beginning of the ISS Program (1). This edition focuses on the factors essential to 

providing an adequate food system for spaceflight, upcoming challenges, and the 

known and unknown risks that future exploration missions may introduce as resources 

are prioritized for missions to the Moon and Mars. Nutrition is only one facet of the food 

system. Acceptability, safety, shelf life, and resource requirements are equally important, 

and require integrated solutions for spaceflight. As missions become longer, and 

alternative food systems (such as growing foods) are considered, many other factors 

must also be considered in trades between food systems and other resources such 

as hardware, crew time, and system acceptability. 

NASA maintains a set of human-system standards (42, 43) as a starting point for all 

mission scenarios. Standards for a basic food system framework include nutritional 

content (e.g., as defined in Chapter 1, Table 1), acceptability, hot and cold water, 

food-warming capability, time for meals, and microbiological testing requirements. 

Although these standards provide a baseline for an adequate food system, they do not 

guarantee an optimal solution. As mentioned in Chapter 2, nutritional requirements have 

been established to mitigate deficiency, not to prevent disease or promote performance 

(44). Some standards may not become requirements on every spacecraft or during every 

mission scenario due to resource restrictions. For instance, although Apollo astronauts 

rated hot water as non-negotiable (45), neither hot water nor the ability to heat food 

may be available on every segment of every future mission due to resource constraints. 

Foods are considered more acceptable at their expected serving temperature, and 

the ability to quickly and easily heat foods is associated with increased food intake 

(46, 47). Heating also improves rehydration of some freeze-dried foods. The impact 

that the inability to heat foods and beverages will have on intake over multiple days 

of high-tempo missions is currently unknown. In fact, despite the central link between 

food and nutrition and every aspect of physiology (44), many of the physiological 

and behavioral outcomes that have been reported in spaceflight, such as immune 

dysregulation, increased incidence of rashes and headaches, and increased stress, 

have yet to be formally investigated in relation to food intake during spaceflight (48, 49). 

Given the central role that food and nutrition have on astronaut health and performance, 

and therefore mission success, it is imperative to assess the risks of implementing 

variations of the food system standards to effectively inform mission risk and resource 

trades before exploration missions commence.

Although past spaceflight food systems will not be reviewed in detail here, specific 

points need to be highlighted. NASA met food system challenges at the beginning of 

the space food program more than 60 years ago by focusing more on resources and 

safety than on nutrition and acceptability. Even on short missions during the Mercury, 
14 15

International Space Station 

Food System 

Astronauts in the United States Operating 

Segment (USOS; includes International 

Partners from the European Space Agency 

[ESA], Canadian Space Agency [CSA], and 

the Japan Aerospace Exploration Agency 

[JAXA]) on the ISS share a standard 

food set of shelf-stable foods, described 

previously (1, 50). These standard foods 

provide a commonly accepted set of foods 

to the crew regardless of resupply delays 

or late crew changes, which preference 

menus cannot accommodate. Meal 

items include retort thermostabilized, 

irradiated, or freeze-dried products, 

low- and intermediate-moisture fruits 

and snacks, and powdered beverages. 

Products are developed and produced by 

NASA when a food item is not available 

commercially (based on required nutrition, 

shelf life, and food type), or an item is 

procured commercially and repackaged 

for spaceflight use, as necessary. All items 

are packaged as individual servings in 

lightweight flexible laminates, from which 

foods are directly consumed. The only 

preparation capability on the ISS is the 

addition of hot or ambient temperature 

water through a septum adapter assembly 

attached to freeze-dried packages 

and beverage bags, or heating via a 

conduction oven (Figure 2). A small chiller 

is available for condiments and for cooling 

a limited number of foods, if preferred, 

prior to consumption. The bulk supply of 

foods is stored under ambient conditions.

Astronauts select their own meals from 

standard containers, stowed pantry-style, 

which rotate based on the number of 

crewmembers sharing the set (e.g., 7- to 

9-day rotation cycle for three astronauts). 

Currently, more than 200 standard 

foods and beverages are available for 

consumption on the ISS, and products 

continue to be developed to increase 

availability of acceptable, healthy, shelfstable options and to replace items 

that are less popular. The current 

system provides a lot of variety in each 

container but few replicates of each item 

(1 to 3 servings of a particular item in a 

rotation cycle). Astronaut preferences vary 

from crew to crew, which changes the 

items that are in high demand and those 

that are less preferred in each increment. 

The dynamic of changing preferences 

is alleviated on the ISS by regular crew 

changes and resupply vehicles; however, 

the supply chain requires food to be ready 

for launch several months in advance. 

In addition, a multi-month supply of food 

must always be maintained on the ISS. 

Therefore, the food system on the ISS 

is, by necessity, a mostly closed system, 

meaning astronauts are restricted to the 

foods that are available, and logistically 

the oldest food must be consumed first. 

Preference containers, known as Crew 

Specific Menu (CSM) containers, are 

delivered to the ISS, typically on cargo 

vehicles. These containers provide 

astronauts with around 10% to 20% 

of their foods, depending on individual 

astronaut requirements. Although 

Russian crewmembers are provisioned 

separately (i.e., by the Russian Space 

Agency) from USOS crew, NASA, CSA, 

ESA, and JAXA crews can choose 

some Russian and some international 

partner foods, as available, as part of 

their CSM food supply. Astronauts can 

also share food with their crewmates at 

their own discretion. Astronauts on the 

ISS also receive a small supply of fresh 

foods (e.g., apples, oranges, carrots) 

and limited shelf life foods (e.g., pizza 

kits) on resupply vehicles, which have 

increased in occurrence with the regularity 

of commercial vehicles in recent years. 

Although limited, these fresh produce, 

crew-specific foods, international partner 

foods, foods in crew care packages, 

and even occasional cold supply foods 

(e.g., ice cream and cheese) have greatly 

increased the variety and quality of the 

food system on the ISS. The actual 

quantity of non-standard foods consumed 

may be 20% to 25% for some astronauts. 

During debriefs, astronauts comment 

regularly on the importance of CSM 

foods, and the variety of foods in general 

during 6-month ISS missions. Despite the 

increased variety of foods, astronauts still 

comment that they would like more crewspecific food and more fresh food than 

is available (50). Although the wide variety 

of preference foods helps to support 

caloric intake, many of these foods might 

not be available on future missions that 

are longer and farther from Earth because 

resupply will be unlikely during these 

missions. Currently, no food system exists 

to meet the nutrition, acceptability, safety, 

and resource challenges of extendedexploration missions, such as a mission 

to Mars. 

Food System Requirements

Food has both a nutritional role and a 

social role in supporting physical and 

behavioral health and performance. 

Many requirements must be met to 

support both of these roles, described 

in detail here, reviewed in (6), and 

depicted in Figure 3.

Nutrition

A good approach to supporting adequate 

nutritional intake is to provide a variety 

of high-quality whole foods for the length 

of the mission. A balanced diet of whole 

foods provides all essential nutrients 

and thousands of bioactive compounds. 

Many previous studies have shown that 

Gemini, and Apollo Programs, foods were underconsumed and astronauts lost weight 

(1, 50). Although the food system has advanced with every NASA program, as previously 

described, astronauts in general still do not consume enough food to maintain body 

weight (1, 50). Multiple factors besides food acceptability have the potential to contribute 

to underconsumption, and research is needed to further investigate these factors. 

Based on anecdotal reports, potential contributors to underconsumption during flight 

could include factors such as physiological changes, time allotted for meals, and menu 

fatigue. The degree of underconsumption may vary by individual and with mission length 

(50-52). This chapter describes considerations for product development, acceptability 

of food and mealtime factors, and menu fatigue. Physiological factors that may be 

associated with underconsumption are discussed in detail in Chapter 4.

Figure 2. The ISS Galley in the USOS includes a conduction food warmer and a Potable Water 

Dispenser with metered hot or ambient temperature water. NASA astronaut Christina Koch is 

heating pizzas, part of the limited shelf life foods that may be included in some resupply provisions 

to the ISS. Inset: Example of a food package during rehydration. Photo Credits: NASA.
16 17

the complex synergistic benefits provided 

by whole foods cannot be replicated by 

supplements (53-57). Nutrients provided 

by foods have a direct impact at the 

biochemical level, and also an influence 

on the composition and metabolism 

of the microbiome, which converts 

metabolites that human digestion 

cannot break down (58). The metabolites 

produced from human digestion and from 

the microbiome are used throughout the 

body, providing the required substrates to 

maintain all physiological systems (44, 59). 

Nutrients and metabolites can be essential 

or beneficial to factors such as immunity, 

sleep, performance, mood, and cognition 

(60-65). Metabolites can also affect the 

brain and behavioral health through 

interaction via the gut-brain axis (66). 

An adequate diet can stave off deficiency, 

an exceptional diet can promote health 

and performance, and a deficient diet 

can result in health and performance 

decrements that, if extended long 

enough, could end with loss of life 

and the mission (44, 67).

In addition to the complex synergistic 

benefits of whole foods, they have several 

other advantages over supplements. 

First, over-supplementation of some 

nutrients can result in toxicity or even 

death (68, 69). Second, supplements 

cannot effectively support adequate 

caloric and macro-nutritional intake 

over time. These points are discussed 

further in Chapter 13.

Acceptability and Variety

Caloric intake may be affected by the 

acceptability of the food system, and 

acceptability may be affected by variety 

and choice (70), quality after storage 

(71), and menu fatigue over time (72). 

Food acceptability is critical to support 

consistent consumption throughout the 

mission. Astronauts receive no benefit 

from nutritious foods that they are 

unwilling to consume. It is commonly 

assumed that high-performing groups 

of people, such as astronauts, will 

“eat anything” to successfully complete 

a mission. On the contrary, military, 

spaceflight, and test data show that if 

the food is not considered acceptable 

for the length of the mission, then body 

mass and nutritional intake will not be 

maintained (50, 73, 74). In the military, 

the risk to health and performance 

from consuming meals-ready-to-eat 

for extended periods has resulted in a 

policy to limit their continuous use to 

21 days (73, 75). However, limiting the 

use of shelf-stable food is not an option 

for spaceflight because no alternative is 

currently available, and continued work is 

warranted to understand and ensure that 

an acceptable food system is provisioned 

for all missions.

Standard spaceflight foods are developed 

based on several factors, including 

crew feedback, safety and shelf life 

requirements, allocation of spacecraft 

mass and volume, capabilities for 

preparing food, and the variety and 

nutrition of the menu complement. 

Because foods are provided as a standard 

set and crewmembers change regularly, 

foods are developed to provide nutritional 

variety that most consumers will find 

acceptable. A greater variety of meal 

options can prevent menu fatigue that 

may occur from consuming the same 

foods repeatedly, which may impact 

consumption (72).

Providing all nutritional needs and 

promoting adequate consumption 

within a processed, shelf-stable system 

is a challenge. On Earth, fruits and 

vegetables are generally refrigerated or 

stored in a freezer before being consumed; 

current and planned spacecraft are not 

able to accommodate these storage 

methods. Additionally, many Earth-based 

processed foods are high in sugar or 

sodium, which promotes acceptability 

with the flavor and texture changes 

that occur during processing. Given the 

concern regarding the high concentrations 

of sodium in space food (as reviewed in 

other chapters of this book), the sodium 

content of the space food system was 

reduced by about a third during the last 

decade by reformulating many of the 

foods (76). Reformulations focused 

on high-quality ingredients, flavor 

combinations, and spices, while 

maintaining or even increasing 

acceptability of individual items. 

It is important to note that the sodium 

reformulation was the only opportunity, 

to date, for significant nutritional 

change to the food system. Prior to 

this, the majority of foods were acquired 

commercially and further processed or 

repackaged as necessary for compatibility 

with spaceflight. Although the sodium 

reformulation provided an opportunity 

to develop healthier choices, many 

commercially available foods are still used, 

and many are fortified. The standard food 

set, and suggested standard menu, were 

developed to meet nutritional requirements 

within these limitations, which is an 

important consideration throughout this 

book. When possible, healthier choices 

are developed and evaluated for potential 

addition to the standard food set.

After the foods are developed, they 

are evaluated for sensory acceptability. 

All foods selected for spaceflight must 

receive an acceptability score of a 6.0 

or higher on a 9-pt hedonic scale, as 

evaluated by a panel of Johnson Space 

Center (JSC) volunteers that includes 

astronauts (50). These requirements 

and evaluations mean that the food 

provisioned to the ISS has acceptable 

sensory attributes; however, several 

factors besides appearance, aroma, 

flavor, and texture of individual foods 

can affect consumption. The behavioral 

factors that affect food consumption 

can be more challenging to solve in 

a resource-limited environment that 

contains a closed food system.

Preference and Behavior

Food familiarity, choice, and the social 

aspects surrounding food (time and 

space to gather and consume meals 

together [Figures 4 and 5]) become more 

important with extended isolation, 

confinement, and distance from 

Earth (51). Beyond the effects on health 

and performance, the adequacy of the 

food system may become a factor in 

crewmembers’ moods, and the dynamics 

and cohesion of the team (77). Food was 

Figure 3. Space food system requirements. Adapted from (6).
18 19

or even vegetables) this also restricts 

the remaining food selections for their 

crewmates. This could impact nutritional 

intake for the whole crew, or even 

negatively affect team dynamics. 

Another concern may be dishonorable 

food practices, such as eating 

a crewmate’s food, which can 

lead to feelings of resentment (78).

These scenarios were evident in groundbased chamber studies with closed or 

semi-closed food systems, where 

crewmembers did not get enough 

nutrients despite the food system 

containing enough of each nutrient. 

For example, during the ESA Experimental 

Campaign for the European Manned 

Space Infrastructure (EXEMSI) study, 

a 60-day closed food system provided 

all nutrient requirements; however, 

crewmembers’ actual vitamin intake 

(vitamins B1

 and B6 in particular) was 

below the dietary requirements, indicating 

that they were not selecting completely 

nutritionally balanced meals (80). In yet 

another example, during a 105-day 

chamber study in Russia, subjects that 

intentionally excluded specific food items 

became protein deficient and lost body 

mass (81). During the Mars 500 mission, 

it was reported that “food became 

probably the greatest problem in isolation,” 

likely impacted by a lack of variety in 

general, and a lack of culturally familiar 

foods for all crew (82). 

Several of these factors become more 

concerning as distance from Earth and 

mission duration increases and the ability 

to resupply food is not possible. It is likely 

that food will be prepositioned ahead of 

missions, before the crewmembers have 

been assigned, thus eliminating the 

opportunity for crewmembers to select 

their preference. Therefore, preference 

foods may not be available for these 

missions. A food system without 

preference diets will not support 

individuals with food allergies or 

restrictions, even on near-term missions. 

In addition, crew timelines, and therefore 

mealtimes, may be constrained during 

some mission scenarios. If crew timelines are constricted and food must be 

consumed quickly, then food must be 

packaged so that it can be prepared 

quickly and still be acceptable to 

support adequate consumption. 

This can be essential to morale (51).

Further work will be warranted to 

determine acceptable food factors (e.g., 

variety, choice, social requirements) that 

support adequate intake as mission 

duration increases. More on this topic 

is discussed in Chapter 14.

Safety 

Safety is another critical factor that 

includes physical, chemical, and 

microbiological risks. Because limited 

one of the top 10 items discussed by 

the astronauts who participated in the 

Journals experiment, which entailed 

crewmembers recording general feelings 

about their daily activities and their fellow 

crewmembers during long-duration space 

missions on the ISS (4, 78, 79). To quote 

from Dr. Stuster’s final report of the 

Journals experiment:

“Food assumes added importance 

when access to friends, family, 

leisure pursuits and other normal 

sources of gratification are denied. 

The importance of food during 

isolation and confinement is 

well-known to the managers of oil 

rigs, commercial ships, Antarctic 

research stations and nuclear 

submarines, all of whom serve 

large quantities and varieties of 

high-quality food daily.” (79)

The quality, variety, and availability of 

food, the stability of nutrients, the ease 

of preparation, the timing of meals, and 

the ability to warm or chill food have the 

potential to affect both nutrient intake 

and behavioral health, as have been 

observed previously during spaceflight, 

Antarctic and sea explorations, and 

military deployments (4, 73, 79). However, 

resources, and the ability to support 

variety, choice, and even cold storage, 

are more limited in space exploration 

than they are in most remote Earth-based 

deployments, as discussed below, which 

adds an additional challenge to supporting 

these psychosocial factors.

Self-selection or avoidance of food 

items in a closed food system has the 

potential to unintentionally affect nutrient 

intake. If a crewmember over- or underconsumes certain items (e.g., dairy, meat, 

Figure 4. The Expedition 50 crewmembers share a meal during the Christmas holidays. 

Back row (left to right): Cosmonauts Sergei Ryzhikov, Andrei Borisenko, Oleg Novitskiy. 

Front row (left to right): ESA astronaut Thomas Pesquet (wearing Santa cap), NASA astronauts 

Shane Kimbrough, Peggy Whitson. Food, and gatherings around the table, are important to 

celebrations and holidays in spaceflight, just as they are on Earth. Photo Credit: NASA.

Figure 5. NASA astronaut Sandra Magnus, 

Expedition 18 flight engineer, experiments with 

mixing food in weightlessness while preparing 

a Christmas meal at the Galley in the Zvezda 

Service Module. Photo Credit: NASA. 
20 21

medical capability is available on a 

spacecraft, an incidence of foodborne 

illness could result in loss of a mission, 

and even loss of life as distance from 

Earth increases. NASA, U.S. Army 

Natick Soldier Research, Development 

& Engineering Center, and Pillsbury 

collaborated to develop The Hazard 

Analysis Critical Control Point for the 

spaceflight food system. Because this 

system was so successful in improving 

the safety of spaceflight food, it was 

implemented throughout the food industry 

(83). The safety of the current, shelfstable food system is managed on Earth 

(50) through processing, packaging, and 

microbiological testing. Flight orbital 

debris, which can become a hazard to 

spacecraft systems and to humans in 

microgravity, is mitigated by food 

selection or by preparing foods 

to minimize or eliminate crumbs. 

These processing, packaging, and 

testing capabilities require substantial 

resources that are not available in 

current or planned spacecraft. 

Stability

Some nutritional and quality factors in 

spaceflight foods degrade during storage, 

and many foods and some critical 

nutrients reach unacceptable levels 

within 1 to 3 years (71, 84) (Figure 6). 

Recently, three NASA space foods—

brown rice, split pea soup, and barbeque 

beef—were tested at three different 

storage temperatures to determine 

whether degradation of thiamin depends 

on the matrix (85). Levels of thiamin 

rapidly decreased in the barbeque beef, 

suggesting that food matrix is very 

important. Packaging and preservation 

method, and the compatibility of these 

factors, are also central to shelf stability 

(86). A processing technology that 

produces high-quality products may not 

maintain the quality through the required 

shelf life if the compatible packaging 

does not provide an adequate oxygen 

and moisture barrier, as is the case to 

date with Microwave Assisted Thermal 

Sterilization (50).

The nutritional status of astronauts and 

the nutritional content of space food 

should continue to be monitored as 

we begin to embark on longer missions, 

including the 1-year missions on 

the ISS planned for 2021 onward. 

Supplements would not solve the 

issue of nutritional degradation because 

nutrients also degrade in supplement 

form (87). Supplement inadequacy is 

discussed further in Chapter 13.

The current shelf life of space food 

is sufficient for ISS missions because 

food is regularly resupplied. For some 

upcoming missions, food will be launched 

with the crew or could be prepositioned for 

no more than a year. However, preventing 

nutritional and quality degradation will be 

a greater challenge for missions lasting 

more than a year. It is important to note 

that shelf-stable processed foods will 

remain safe to eat well after the quality 

and nutritional value have degraded if 

the foods are stored in a dry, controlled 

room temperature environment and the 

packaging remains intact.

Resource Minimization

The limited resources available on a 

spacecraft often conflict with the goals 

of providing a nutritious, acceptable 

variety of safe foods. Resources include 

mass, volume, power, water, crew time, 

and waste management that must have 

a dedicated system, as well as resources 

that impact other systems (e.g., heat load 

or volatile management). Mass, volume, 

and power limitations have eliminated 

refrigerators, freezers, and microwaves 

from all spaceflight programs to date, 

except during the Skylab Program when 

cold storage was provided. Mass and 

volume limitations have also necessitated 

a shift from cans and rigid packaging 

to lightweight, flexible laminates, which 

further limit the commercially available 

products that are compatible with 

spaceflight. As missions get longer and 

farther from Earth, and greater propulsion 

is needed to provide the same quantity 

of supplies, it will be important to minimize 

resources for every system. As such, 

providing an adequate food system 

will become a greater challenge.

Food System Considerations for 

Future Exploration Missions

The Moon: Artemis 

(Orion/Gateway/Lunar)

Although the ideal scenario for nearterm Orion, Gateway, and lunar missions 

is to launch food with the crew to 

accommodate preference food and 

shorten the storage durations, some 

food may need to be prepositioned 

due to mass and volume constraints. 

This will limit those prepositioned foods 

to a standard set. In addition, astronauts 

will be performing high-tempo EVAs 

that will require an increase in caloric 

intake during these missions, and these 

increased calories must be provided 

within the resource limitations. 

The use of meal replacement bars could 

reduce the mass and volume of the food 

system, but it will also reduce choice, 

which may affect caloric intake and 

behavior even over short durations (74). 

Weight loss, even on short missions, can 

impact crew status; weight loss has been 

associated previously with cardiovascular 

Figure 6. Nutrient stability over 3 years of study. 

Data are presented based on the content 

(after processing) of each nutrient as included 

in the standard menu. Although there is an 

expectation that crews will consume at least 

10% (and often 20% to 25%) of their food from 

CSM containers, the content of vitamin D, 

vitamin K, calcium, and potassium start below 

nominal recommendations. Thiamin and vitamin 

C degrade to inadequate amounts over the 

3-year study period. Other nutrients (vitamins A, 

B6

, and B12) degrade, but remain above required 

minimums. Adapted from Cooper et al. (84). Figure 7. Depiction of Orion, Gateway, and Artemis mission profile. Image Credit: NASA.

Thiamin

Vit B6

Vit B12

Vit C

Vit AVit DVit K

Calcium

Potassium

0

50

100

150

200

250

300

350

400

% of the Recommended Daily IntakeDelivered by the ISS Standard Menu

 Inital

 One Year

 Three Years
22 23

changes that could affect crew health 

and performance (88).

Increasing the fat content of food could 

potentially reduce the mass and volume 

of the food system by increasing energy 

density of the food. Calories could also 

be consumed quicker in an energydense food system, which may be 

useful during short meal timelines. 

However, a high-fat diet could also 

introduce unacceptable physiological 

outcomes, such as gastrointestinal (GI) 

complaints (89, 90) that may impact 

high-tempo EVA schedules. Alternatively, 

if astronauts try to avoid GI issues, this 

could result in inadequate energy intake. 

High-fat diets may also induce some 

cognitive effects, even over short durations 

(91-93). The type of fat consumed will 

influence any associated health effects; 

however, healthier unsaturated fats are 

more unstable and not as compatible with 

shelf life requirements for spaceflight food 

systems (94). Although multiple factors 

may influence the onset of performance 

decrements, such as the initial nutritional 

status of an individual (89), the issues 

described above highlight the need to 

evaluate and understand the risks of 

imposing each potential food system 

solution in the intended mission scenarios. 

Once quantified, risks to human health 

and performance from the proposed food 

system could be appropriately evaluated 

and prioritized with other vehicle and 

mission risks.

Mars and other Deep Space Exploration 

Currently, no food system exists that 

meets the nutrition, acceptability, 

safety, and resource challenges of 

extended-exploration missions, such 

as a Mars mission (95). Logistics may 

require a processed food system to be 

prepositioned in space or on the Martian 

surface before the crew departs from 

Earth, resulting in a food system that is 

5 to 7 years old by the end of the mission. 

Several critical nutrients and quality 

factors in the shelf-stable spaceflight 

food system will degrade to unacceptable 

levels well before 5 years of storage 

under current ambient temperatures, 

and solutions to ensure a nutritious and 

adequate food system for extended 

durations are needed (71, 84). 

Shelf-stable foods still have many 

advantages; they are safe, familiar, 

and easy to prepare. Evaluation of 

novel processing and packaging, or 

alternative storage temperatures, may 

identify solutions to extend the shelf life 

of these foods; however, all cold storage 

solutions, whether the passive cold of 

space or active refrigeration, require 

resources and infrastructure. Shelf-stable 

foods also require significant mass and 

volume when launched from Earth.

Alternative food systems, or combinations 

of food systems, may provide options. 

However, additional challenges will be 

introduced if current methods to produce 

or process foods on Earth are used during 

spaceflight or on an extraterrestrial surface 

(6). Much is still unknown regarding even 

more-advanced systems, such as food 

crop production in space (96).

The first challenge is resources. Although 

it is commonly believed that producing 

food during spaceflight will require 

less resources than supplying a readily 

available food source, this has yet to 

be confirmed. The requirements of an 

alternative food system in a closed-loop 

environment is still unknown, including 

the required equipment, crew time, 

cleaning and sanitizing, substrates 

and ingredients, storage conditions of 

ingredients, power, volume, water, and 

waste processing. For example, even if 

water is recycled, more water may be 

required for processing, cleaning, and 

sanitizing food, which would increase 

the resources required for the mission. 

A second challenge is reliability, or the 

risk of food scarcity. If astronauts rely 

on a system that produces a portion of 

their nutrition, then loss of that system 

could result in loss of the mission and 

loss of life. The effects of radiation add 

an additional unknown to risk of food 

scarcity. All ingredients and equipment 

for producing food may need to be 

prepositioned, requiring a 5- to 7-year 

shelf life. Although the data available to 

date indicate that deep space radiation 

may have no significant effect on shelfstable foods (87), the effects of radiation 

on food growth are currently unknown. 

Opportunities to understand radiation 

effects are limited to space missions 

and to Earth-based facilities that simulate 

deep space radiation conditions (97). 

A third challenge is acceptability 

of food production and human factors. 

If a system requires extensive crew time 

or is difficult to use, then it may be less 

likely to be used, thereby generating 

a risk of inadequate food availability 

and underconsumption. Food growth 

and processing may be more suited 

to longer planetary residences than 

to exploration-class missions. On nearterm exploration missions, astronauts will 

not have the time or the skills to produce 

food. Similar to food production on Earth, 

food production in space must be 

something that a person will want to 

come home and do after a long day of 

work, an enjoyable activity that efficiently 

produces a meal. If the end-to-end 

process of preparing food is generally 

unacceptable to most people, then it 

is unlikely to be a successful candidate 

for exploration missions; however, the 

fourth challenge, which is food production 

and preparation equipment, may also 

be a factor. The food preparation 

equipment currently available for 

spaceflight adds only water or heat. New, 

efficient, and acceptable equipment that 

produces a variety of nutritious and 

acceptable food options, while keeping 

the entire food system within resource 

requirements, could revolutionize both a 

Mars exploration food system and food 

sustainability on Earth. However, 

additional equipment will factor into 

resource trades for mass, volume, 

power, crew time, cleaning and 

sanitizing, and maintenance resources.

The fifth challenge is safety. Unlike 

prepackaged foods where safety is 

confirmed on Earth, producing food in 

space will introduce new food safety 

challenges. For example, cleaning and 

sanitizing the equipment could produce 

volatile compounds that will need to 

be removed from the air, supplies for 

microbiological testing will introduce mass 

and waste, and mechanical safety (touch 

temperatures) will need to be addressed, 

while fitting everything within the resource 

limitations of the mission.

The sixth challenge is cost and schedule 

feasibility. These are not clear for many 

alternative food systems. Finally, even if 

a food system is successfully developed 

with acceptable resource trades, the risks 

to crew health and performance of any 

planned food system must be evaluated 

in realistic mission scenarios—either on 

Earth or on a lunar base—before being 

implemented on a mission to Mars, where 

there will be no opportunity for early crew 

return and no possibility for resupply.
24 25

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4Energy

Adequate energy intake is perhaps the single most important aspect of astronaut 

nutrition, not only because energy in and of itself is more important than other nutritional 

factors, but because if enough food is consumed to meet energy needs, then generally 

other nutrients (i.e., vitamins and minerals) will also be consumed in reasonable 

amounts. This assumes that the food system provides a balanced set of food 

choices, because plenty of diets provide adequate caloric intake but are associated 

with undernutrition. 

Many facets are involved in maintaining eucaloric intake during spaceflight, including: 

energy requirements; potential physiological changes in taste and satiety; scheduling 

issues of allotting time for meal preparation, consumption, and cleanup; food quality; 

and preference for the available food. Little research has been done on differences in 

fuel components (i.e., protein, carbohydrate, fat) during spaceflight, or on cofactors 

(e.g., vitamins) of energy use. We review these here, highlighting what has been done 

as well as potential areas of future research.

Total energy expenditure (TEE) is the sum of the energy needed to maintain the body’s 

function and physiological homeostasis at rest plus the energy needed for any physical 

activity. Energy expenditure has long been hypothesized to be lower during flight than 

on the ground because of the presumed relative hypokinesia during spaceflight (98). 

An early example that supports this is that lower energy expenditure was observed 

during EVA on the lunar surface than during similar activities at 1g (99). This was 

determined through indirect calorimetry in the space suit. However, Space Shuttle 

crewmembers’ energy expenditure during EVA was no different than their energy 

expenditure before flight (100).

Studies have documented that Space Shuttle astronauts’ energy expenditure during 

flight was unchanged from their preflight levels (101). In cases where the crewmember 

performed intensive exercise during the mission, their energy expenditure during 

flight was higher than before flight (102). For these studies, the doubly labeled water 

(i.e., water enriched with deuterium and 18O) technique was used to determine oxygen 

consumption (103). The benefits of this technique are that it is noninvasive, and it 

accounts for the energy cost of all activities over a period of several days. The drawback 

of the method is that it cannot be used to determine individual variation of TEE during 

specific activities, such as rest, sleep, and exercise, which would be important to 

assess given the inter-individual differences in intake and body mass loss. Although it 

is assumed that moving the body mass around the cabin requires less expenditure of 

energy during weightlessness than at 1g, other metabolic activities, such as maintaining 

resting metabolic rate and responding to stress, may require increased energy 

expenditure during weightlessness. 

In ground-based bed rest studies, an analog of microgravity, resting energy expenditure 

did not change; however, TEE was less during bed rest than before bed rest (104). 

Because TEE during flight is unchanged (101) or increased (102) from preflight levels, 

the lower TEE during bed rest may indicate that bed rest is not an appropriate model 

for studies of energy metabolism during flight. One possible explanation for this 
28 29

Energy Intake 

Historically, inadequate energy intake and 

subsequent loss of body mass have been 

considered hallmarks of spaceflight, and 

they have occurred on many missions 

and programs (1, 7, 101, 110-120). 

From Apollo through the Space Shuttle 

Program, dietary intakes during flight 

averaged about 70% of predicted 

requirements (111) (Figure 8), and intakes 

on the ISS have averaged about 80% of 

requirements. There are exceptions to this 

finding, including the Skylab missions during

the early 1970s (121, 122), European 

flights to the Mir (123) and, more recently, 

some of the ISS missions (124). In the 

Skylab and Mir examples, crew participation

in metabolic experiments required that 

they consume balanced, controlled, 

eucaloric diets. As a result, crewmembers 

met their recommended energy intake 

requirements. It is difficult to determine 

whether the intakes on Skylab were related 

more to the requirement to consume the 

food or to the fact that the food was more 

palatable because of the additional variety 

available with frozen foods; however, 

increased palatability is obviously beneficial.

The ISS has accommodated 4- to 

6-month missions dating back to 2000. 

Many aspects of these missions have 

evolved during this time, and new 

exercise equipment, reformulations of 

many space food items, and international 

foods from all partner agencies have 

debuted. These factors, coupled with 

the passage of lessons learned from 

one crew to the next, may have been 

responsible for our observation that many 

of the ISS crewmembers now consume 

recommended dietary intakes of energy, 

and also maintain body mass (111, 124).

Many potential explanations have 

been proposed in cases where energy 

intakes do not meet requirements, 

absent definitive causes (98, 114, 128). 

Appetite may vary significantly, as 

indicated in a Russian study in which 

40% of Mir crewmembers reported 

decreased appetite, 40% reported no 

change, and 20% reported increased 

appetite (129). 

Anecdotal reports exist of changes in the 

taste of food during flight (52, 130, 131). 

One hypothesis is that fluid shifts and 

congestion associated with the first days 

of introduction into microgravity can alter 

perception of taste and smell. The lack 

of convection in microgravity, along with 

competing odors from living in a relatively 

small, confined, and closed volume 

may affect food aromas. There has 

been speculation about other potential 

impacts on olfaction during flight, 

including higher concentrations of CO2

, 

or compounds in the recycled water on 

board, which might alter taste perception 

after rehydrating food (132, 133). Other 

possibilities exist as well, including effects 

of other atmospheric contaminants, stress, 

radiation, and psychological factors (52). 

To date, research has not been able to 

clearly document changes in taste or 

olfaction during spaceflight or during 

head-down-tilt bed rest (52, 134, 135). 

When taste perception was measured 

before, during, and after 30 days of 

–6° head-down bed rest, subjects 

reported decreased appetite and lack 

of taste early in the bed rest phase 

(135, 136). By day 13 of the bed rest 

phase, the sensitivity threshold for almost 

all tastes (i.e., sweet, salt, acidic, bitter) 

had increased. In contrast, a bed rest 

study in the 1990s found no changes 

in odor or taste perception after 

14 days of head-down bed rest (137). 

Current food strategies focus on providing 

astronauts with as much variety and 

choice as possible, and with condiments 

to tailor foods during flight. In lowEarth orbit, these approaches can be 

implemented in the resource-restricted 

spaceflight environment, and they receive 

positive feedback in debriefs. If groundbased or in-flight research is pursued to 

assess contributions of factors, such as 

potential changes in taste and smell, to 

inadequate energy consumption, then 

carefully designed and executed studies 

would be required. A large number of 

subjects would likely be required to 

determine whether perception of taste 

and odor are altered for any, or many, 

individuals, and to delineate the 

physiological or environmental factors 

that contribute to these changes.

Flight-related changes in GI function may 

also occur. Fluid shifts, in combination 

with reduced fluid intake, would tend to 

decrease GI motility. GI transit time has 

not been systematically studied during 

difference between bed rest and spaceflight is the lack of a metabolic response to stress 

during bed rest (105). Attempts have been made to improve the utility of bed rest studies 

by administering a metabolic stressor (such as triiodothyronine or cortisol) to provide a 

better ground-based model than bed rest alone for the metabolic effects of spaceflight 

on energy and fuel metabolism (106). Another explanation for the difference between 

bed rest and spaceflight could be that physical activity is the main driver for changes 

of TEE in spaceflight, because the level of physical activity is very different for space 

travelers during missions and for bed rest subjects. 

Energy requirements for early ISS missions were typically estimated using standard 

equations, including the World Health Organization (WHO) (40) equation and the 

Dietary Reference Intake (DRI) equation (41), and using a “moderately active” 

or “active” adjustment for activity level for these two equations, respectively. 

The DRI equation includes the effects of age, sex, weight, and height in estimating 

energy requirements. More recently, a direct method—namely, indirect calorimetry—

has been used to determine individual astronaut’s actual resting energy expenditure 

before flight. These data can then be used to more accurately estimate the individual’s 

energy expenditure levels. However, the actual energy expenditure of individual physical 

activity, which might cause large variations in TEE (107), is not measured and this 

might be the next step to more accurately determine TEE.

In a recent study on the ISS, core body temperature was shown to increase by 

about 1°C during rest in microgravity (108). Changes in core body temperature have 

a significant effect on TEE. A reduction of 0.25°C in postmenopausal women induces 

a 3.25% reduction in energy expenditure (109). Presuming that temperature induced 

changes in energy expenditure are linear, the 1°C increase in core body temperature 

in space travelers would increase TEE by 13%, resulting in the need for about 350 kcal 

more per day for a space traveler with a TEE of 2700 kcal/d. However, this change of 

TEE during space travel needs to be confirmed by directly measuring TEE during flight. 

An ESA-sponsored experiment, initiated in 2012, aims to do this by determining energy 

expenditure during 6-month missions on the ISS. These data will help us understand 

whether any adaptation effect occurs on these longer missions, and thus may be 

important in estimating energy requirements for exploration missions (i.e., missions 

beyond low-Earth orbit).

Figure 8. In-flight energy intake of 

crewmembers in different space programs. 

Data are expressed as percentage of energy 

requirements predicted by the World Health 

Organization equation (40) and are mean ± 

SD. Apollo and Skylab data are from Bourland 

et al. (125). Figure is adapted from earlier 

publications (1, 126), with additional published 

data included (111, 124, 127). Energy Intake (% Requirement)

Apollo

Skylab

Shuttle

ISS (E1-7)

ISS (E8-16)

ISS (E17-21)

ISS (E22-28)

ISS (E29-35)

ISS (E36-43)

ISS (E44-51)

ISS (E52-56)

0

10

20

30

40

50

60

70

80

90

100

110
30 31

document the relationship between energy 

intake and weight loss (Figure 10).

Data that relate reduced dietary intake 

during semi-starvation to loss of body 

mass were collected in two ground-based 

studies not related to spaceflight. In the 

first study (155), subjects who consumed 

580 kcal/d lost 7% of their body mass 

in 12 days, and subjects who consumed 

1010 kcal/d lost 11% of their body mass 

in 24 days. In the second study, starved 

subjects lost 9% of their body mass after 

11 days, 15% by day 18, and 18% by 

day 43 (156).

Only about 1% of the loss of body mass 

can be explained by loss of body water (7); 

most of the observed loss of body mass 

is accounted for by loss of muscle and fat 

tissue (100, 157). The water loss may be 

confounded by lean tissue loss, because 

metabolic water loss is associated with 

depletion of glycogen stores and protein 

catabolism, both of which occur with 

inadequate energy intake. Inadequate 

energy intake is associated not only with 

loss of fat tissue, but also with decreased 

protein synthesis (158) (during spaceflight), 

increased protein catabolism (159) (during 

bed rest), and subsequent loss of lean 

tissue mass.

Besides the obvious concerns about 

loss of body mass and dehydration (160), 

existing data suggest that many systems 

are affected by inadequate nutrient 

intake, including the muscle, bone, 

cardiovascular, and immune systems. 

The German Institute of Aerospace 

Medicine at the German Aerospace Center 

conducted a study jointly with the ESA 

to evaluate the impact of hypocaloric 

nutrition on multiple systems. They used 

a crossover design, with hypocaloric 

and eucaloric phases, and bed rest and 

ambulatory phases. Data from this study 

document that undernutrition exacerbates 

the negative effects of bed rest on 

musculoskeletal and cardiovascular 

systems, and on energy metabolism 

(159, 161, 162).

Undernutrition can also impair cardiovascular performance (orthostatic 

tolerance) in controlled bed rest settings 

(161) and after spaceflight (88) (see 

additional information in Chapter 8). 

The mechanism for this energycardiovascular connection has been 

hypothesized to involve multiple functions 

of many endocrine factors, including 

insulin, leptin, and growth hormone (163).

Anecdotal reports from crewmembers 

on long-duration missions indicate that 

crewmembers who had lost a significant 

amount of body mass on orbit had an 

excess amount of rebound weight gain 

after landing. In general, however, the 

data do not support these reports (1).

Deficiency of dietary energy intake 

leads to wasting and ultimately tissue 

breakdown, or even death. The loss 

of lean body mass during spaceflight 

is significant and is associated with 

increased proteolysis and catabolism 

related to metabolic stress (164). 

Inadequate energy intake can also 

have negative effects on bone, and is 

exacerbated by exercise-induced energy 

expenditure (165, 166). This highlights 

the interaction between systems, and 

the fact that exercise regimens must 

be coordinated with energy provision. 

It is difficult to predict the effects of 

suboptimal (or lack of) energy intake 

on otherwise healthy individuals. 

spaceflight; however, during 10 days of 

–6° head-down bed rest, mouth-to-cecum 

transit time was significantly longer than 

it was during ambulatory control periods 

(138). In a 520-day isolation study (MARS500), the 13C-octanoic breath test was 

successfully used to determine that 

confinement had no effect on GI motility 

(139). However, because the Skylab 

astronauts and others were able to 

maintain a eucaloric diet in space, 

hypotheses about inability to consume 

the requisite amount of food because of 

stomach fullness or other factors are not 

likely to fully explain decreased dietary 

intake during flight. Russian studies of GI 

function in humans and in animal models 

during actual and simulated spaceflight 

have been reviewed (140). A common 

cause of reduced dietary intake during 

the first days of a mission (141) is 

space motion sickness (131, 141-144). 

The effects of space motion sickness 

typically pass after the first several days 

of flight; however, the decreased dietary 

intake can extend well beyond the first 

week (128). Hypoxia was investigated in 

a recent series of bed rest studies and 

was not found to affect body mass or fat 

mass loss, nor did it affect resting energy 

expenditure (145). Levels of oxidative 

stress were increased, which could be 

countered by exercise (146).

Implications for Inadequate 

Energy Intake 

The obvious and immediate reason for 

concern about reduced dietary intake is 

the risk of losing body mass and, more 

specifically, loss of lean mass and bone 

tissue. Body mass losses of 1% to 5% of 

preflight body mass have been typical in 

the history of spaceflight, although some 

crewmembers have been able to maintain 

body mass (111, 124, 147). In-flight body 

mass data from ISS crews are shown in 

Figure 9. Documented weight losses have 

occurred on short- and long-duration 

flights in both the U.S. and Russian space 

programs (114, 148-150). Indeed, all 

crewmembers on Gemini, Apollo, Skylab, 

and Apollo-Soyuz Test Project missions 

lost body mass (151); thus, ingestion of the 

prescribed energy intake on the U.S. Skylab

missions did not ensure maintenance of 

body mass (121). In one study of 13 male 

Space Shuttle crewmembers, body mass 

losses ranged from 0 to 3.9 kg (101). 

Body mass losses of more than 10% 

of preflight body mass were recorded on 

Mir (152). Crewmembers on the ISS have 

similar patterns of mass loss during flight 

(153). An extrapolation of all the data of 

body weight changes in spaceflight up 

to now gives an average loss of 2.4% 

of body weight per 100 days (107). 

Data from Apollo missions clearly 

Figure 9. Body mass during flight. The left panel shows body mass in 49 male (blue line, 

open symbols) and 12 female (gold line, solid symbols) ISS astronauts during and after flight 

as a percent of preflight. In the right panel, each point represents the lowest point for each 

crewmember as compared to preflight. Three percent of astronauts (2 of 79) lost >10% body 

mass, whereas 57% (45 of 79) lost 5% to 10% of preflight mass.

Pre Mean

FD15

FD30

FD60

FD120

FD180

R+0

R+30

-10

-8

-6

-4

-2

0

2

4

Body Mass

(%

D from preflight)

-15

-10

-5

0

5

Body mass loss in mission

(%

D from preflight)

Figure 10. Relationship between energy 

intake (kcal/kg body mass/d) and weight loss 

(change in body mass/d, kg) during Apollo 

missions. N=33. Data are courtesy of William 

Carpentier, as previously published. (154).

10 15 20 25 30 35 40

0.0

0.2

0.4

0.6

0.8

1.0

kcal/kg/d

D Body Mass/day

y = -0.0247x + 1.10134

r = -0.71 (p<0.001)
32 33

One issue is that the energy equivalent 

of the lost mass changes with time 

because different body fuels are used 

at different times during semi-starvation 

(155, 167). It is reasonable to expect that 

a person could survive for more than 

4 to 6 months on partial rations (e.g., 

1000 kcal/d), and potentially longer if the 

metabolic rate were to decrease because 

of decreased intake. If energy availability 

were restricted further, survivability would 

range from 4 to 6 months; without food, 

survivability from 1 to 2 months would 

be possible. These projections obviously 

include many assumptions, unknowns, 

and extrapolations. Data from 10 Irish 

Republican Army hunger strikers, who 

consumed water ad libitum but no 

energy, vitamins, or minerals, indicate 

that an average 25-year-old male could 

survive no longer than 60 days without 

energy (168, 169). Although a crew 

may survive a short period under these 

conditions, the associated physical and 

cognitive performance capability might 

be severely degraded. A high-stress 

contingency situation during transit or 

on a planetary surface, and any need to 

perform, would likely exacerbate the basic 

effects of limited rations and may shorten 

projections of survivability estimated from 

ground-based studies. Other possible 

effects, such as decreased motor and 

cognitive function, could impair an 

astronaut’s ability to perform work-related 

tasks necessary for landing. According 

to military survival studies, astronauts 

on limited rations would be expected to 

experience early decreases in endurance, 

and a later decrease in strength that would 

parallel the decrease in lean body mass 

(170). During total fasting, degradation 

of coordination, speed, and cognitive 

function would be evident within the 

first 2 weeks (170).

The metabolic condition of ketosis, 

which would be expected to result from 

starvation, would not only have metabolic 

effects (including decreased appetite) 

but might also affect other aspects 

of the mission (e.g., the life-support 

systems might be unable to remove 

the ketones from the air). Ketoacidosis 

can have negative effects on acid-base 

balance, which in turn can affect bone, 

muscle, and other systems. 

Insufficient dietary intake and subsequent 

loss of body mass are significant not only 

for crew health; medical operations and 

research studies will also be affected 

because clear interpretation of essentially 

all physiological data is impossible in 

malnourished subjects. As such, virtually 

all human research data collected on 

the Space Shuttle, Mir, and many ISS 

missions are confounded by inadequate 

dietary intake. Investigators who have 

studied bone and muscle, cardiovascular 

function, immune response, and other 

systems during spaceflight cannot say to 

what degree undernutrition affected and 

confounded their findings.

A key question is: What level of negative 

energy balance—i.e., energy expenditure 

exceeding energy intake—can be tolerated 

while preserving physical performance? 

In a systematic review, the military tried 

to find the threshold of energy deficit that 

impairs performance, i.e., declines in 

lower-body power and strength (171). 

The authors showed that the combination 

of the degree and the duration of negative 

energy balance correlated with the 

decline in lower-body performance. 

Their regression model determined that 

the negative energy balance for an entire 

operation should be limited to -5,686 to 

-19,109 kcal, corresponding to a total 

body mass loss of < 3.3% of baseline, 

to prevent or limit decline in physical 

performance. They determined that 

moderate to large declines in physical 

performance would occur with a negative 

energy balance of -39,243 to -59,377 kcal, 

corresponding to a body weight loss of 

>7.7 % (171). When projecting the average 

body weight loss of 2.4% per 100 days for 

spaceflight crewmembers (107), moderate 

to large loss of physical performance 

could occur within 1 year of space travel; 

however, this estimate does not consider 

the additional effect of microgravity.

Although research may be warranted 

to better understand why astronauts 

typically do not consume 100% of their 

recommended intakes, recent data from 

ISS crewmembers clearly document that 

intakes can be met during spaceflight 

(124). In addition to maintaining energy 

intake and vitamin D status, in conjunction 

with exercise, these crewmembers 

maintained body mass, came home leaner, 

with less fat, and maintained bone mineral 

density (BMD) at preflight levels (124). 

Additional details are provided in Chapter 6. 

A key decision when designing bed rest 

studies is whether to provide subjects with 

ad libitum calories or whether to regulate 

caloric intake to maintain body mass or 

to maintain body composition. At least 

two approaches can be used to control 

body mass and composition while 

studying human adaptation to bed rest: 

maintaining body mass, or allowing 

subjects to lose total mass while keeping 

fat mass constant (and thus losing lean 

tissue). Although this latter approach 

sounds intriguing, implementing it 

has proven very challenging given the 

difficulties in measuring fat mass and 

adapting intake in a timely manner. 

Nonetheless, Biolo and colleagues have 

reported data suggesting that the more 

the fat mass increases during bed rest, 

the more lean tissue is lost, and that 

this loss is confounded by increases 

in oxidative and inflammatory damage 

markers (172). Altered fuel homeostasis 

has been documented in other bed 

rest studies (173-175) and in animal 

studies (176, 177), but remains to be 

fully elucidated in bed rest or spaceflight 

(177, 178).

Fuel Sources 

Carbohydrate (and Fiber) 

Carbohydrates play an important role 

in the body because they supply the 

primary, readily available source of 

energy. This energy is oxidized and used 

by various organs and cells in the body, 

particularly the brain and RBCs, which 

depend solely on carbohydrate for energy. 

The human body stores about 150 to 

500 g of carbohydrates as glycogen 

in the liver and skeletal muscle (179). 

Most of the body’s glycogen is in skeletal 

muscle. Stores of muscle glycogen are 

used mainly by muscle, whereas the 

smaller glycogen stores in the liver are 

used to maintain, store, and export blood 

glucose. Glycogen stores, especially 

those in the liver, fluctuate greatly during 

the day in response to food intake, and 

these fluctuations may be involved in the 

regulation of food intake (180). Stores of 

glycogen in the liver are depleted after 

12 to 18 hours of fasting (179). In skeletal 

muscle, glycogen synthesis is triggered 

by a rise in insulin after the consumption 

of carbohydrates. De novo synthesis of 

glucose from non-carbohydrate precursors 

occurs in the body, if needed, allowing the 

liver to maintain adequate blood glucose 

concentrations. Insulin is required for the 

uptake of glucose into cells, and various 

transporter systems are found in different 

types of tissues that use glucose.

Requirements for carbohydrates during 

spaceflight are thought to be similar 

to those on Earth. However, to date, 

few investigations have been conducted 

to assess how microgravity affects the 

metabolism of dietary carbohydrate, and 

those studies have had conflicting results.

Studies that German investigators 

conducted on the Space Shuttle showed 

no effect of 7 days of flight on glucose 

tolerance tests (181). A Russian study 

documented a reduction in fasting plasma 

glucose after 60 or 88 days of flight on 

a Salyut-Soyuz spacecraft complex, 

and a reduced peak of blood glucose in 

glucose tolerance tests (182, 183). Insulin 

resistance (i.e., lack of sensitivity to insulin) 

can result in humans who are exposed to 

simulated weightlessness (i.e., during bed 

rest) (173, 184-188), and in animals that 

are flown in space (189). Using C-peptide 

excretion as a proxy for insulin secretion, 

Stein, et al. found evidence of insulin 
34 35

resistance during actual and simulated 

spaceflight (190). After 3 weeks of bed 

rest, glucose tolerance was altered for 

more than 4 days after re-ambulation 

(191). In another bed rest study, subjects 

took whey protein supplements to improve 

their reduced insulin sensitivity; however, 

the higher protein intake was unable to 

prevent impaired insulin sensitivity during 

bed rest. (188). 

A first study of insulin resistance on the 

ISS demonstrated that insulin resistance 

increased—with a more pronounced 

increase in men than women—after 

about 3 to 5 months in microgravity (192). 

Data from bed rest studies indicate that 

a decrease in mitochondrial respiration 

may contribute to the increase in insulin 

resistance (187). Efforts continue to 

maintain muscle mass during spaceflight 

(and presumably correct the insulin 

resistance); however, little research has 

been done to understand the implications 

of insulin resistance, or methods to 

counteract it. 

Suboptimal carbohydrate intake 

before and during spaceflight may 

affect the crewmember’s productivity 

and impede their ability to respond in 

emergency situations (193). Deficiency 

of carbohydrate leads to ketosis. 

A ketotic state would likely impair 

performance of crewmembers, as seen 

in studies conducted by the military 

(170), and could increase renal stone 

risk secondary to reduced urinary pH 

(194-196). In a review by Cai et al. on 

safety and tolerability of ketogenic diets, 

the authors found more than 40 categories of adverse events in 45 studies. 

The adverse events included constipation, 

GI disturbances, vomiting, hyperlipidemia 

and hyperuricemia, acidosis, weight 

loss, and hypoglycemia (197). Although 

hypoglycemia resulting from a ketogenic 

diet might counteract the onset of insulin 

resistance in microgravity, other adverse 

effects of a ketogenic diet could occur, 

including exacerbating loss of body 

mass and musculoskeletal losses. 

A ketogenic diet could also put other 

aspects of the mission at risk (e.g., the 

life-support systems may be unable to 

remove exhaled ketones from the air). 

At the other extreme, impacts of very high 

carbohydrate have not been well studied, 

although it would likely be an issue only 

because it would displace other nutrients 

(i.e., protein and fat) from the diet.

Although few data are currently available 

to assess the impact of spaceflight on 

carbohydrate metabolism, the subtle 

changes observed in insulin secretion, 

insulin resistance, and glucose intolerance 

during spaceflight and ground-based bed 

rest studies make it critically important 

to consider its likelihood, nature, and 

consequences during exploration missions 

(185, 186, 198, 199) (187, 188, 192). 

Dietary fiber is important for GI health 

and microbiome maintenance (described 

in detail in Chapter 11). An analysis of 

dietary intake from ISS astronauts revealed 

that the standard menu did not provide, 

nor did crewmembers select, foods to 

meet recommended daily intakes of fiber 

(Figure 11).

Fat (and Fatty Acids)

Fat is the most energy-dense of 

all the nutrients, and therefore is 

a major energy source for the body. 

Chemically, dietary fat is mainly in the 

form of triacylglycerols, which contain 

a glycerol backbone with as many as 

three fatty acids attached. Many types 

of fatty acids exist, including saturated, 

monounsaturated, polyunsaturated, and 

trans. Dietary fat assists in the absorption 

of fat-soluble vitamins and supplies the 

body with the two essential fatty acids— 

linoleic acid and linolenic acid. These 

essential fatty acids are necessary for 

growth and development as well as many 

other biochemical processes, including 

production of eicosanoids (physiologically 

active substances derived from arachidonic

acid). Lipids, in the form of phospholipids, 

make up a large proportion of the structural

components of the cellular membrane 

bilayer. Energy stored as fat is released 

in the process of fatty acid oxidation, 

and fat supplies more energy than any 

other macronutrient because of its 

higher content of carbon-to-hydrogen 

bonds. According to case studies, 

people following fat-free diets can 

exhibit symptoms of essential fatty acid 

deficiencies after only 1 month (200, 201).

Future missions outside of low-Earth orbit 

will include constraints of volume and mass

that will impinge on the food system (6). 

A more energy-dense food system would 

be one solution to reduce the mass of the 

food system; however, higher fat diets are 

a concern for many reasons, as discussed 

in Chapter 3.

The ISS “standard menu” and crew-selected

diets are generally higher in cholesterol 

and saturated fat than recommendations 

(Figure 12). These intakes were associated 

with higher circulating lipids during flight. 

Voluminous data from routine medical 

examinations conducted before and 

after spaceflight, along with annual 

medical exams, were reviewed previously 

(1). Contrary to the typical lipoprotein 

response to weight loss, low-density 

lipoprotein concentrations tended to 

increase in crewmembers who lost 

weight during long-duration flights. 

This relationship seemed to return 

to normal by the subsequent nominal 

medical exam (1).

Alterations in fuel homeostasis and 

regulatory hormones have been noted 

during spaceflight and in groundbased studies. Bed rest studies 

have documented alterations in fuel 

homeostasis (202), including gender 

differences (173). Specifically, lipogenesis 

increased during bed rest, more so in 

women than in men. Additionally, men had 

increased carbohydrate oxidation (173). 

Figure 11. Dietary fiber intake in 27 astronauts 

and the ISS "standard menu." Green shaded 

area represents intakes meeting the daily 

requirement. Each symbol represents a 

day’s intake during flight. Circles are male 

astronauts, and triangles are females. 

These represent crewmembers who recorded 

dietary intake with the ISS FIT App or kept a 

detailed food log. The black lines represent 

mean ± SD for each crewmember.

Figure 12. Dietary cholesterol (left panel) and saturated fat (right panel) intake in 27 astronauts 

and the ISS "standard menu." Green shaded area represents intakes meeting the recommended 

intakes. Each symbol represents a day’s intake during flight. Circles are male astronauts, and 

triangles are females. These represent crewmembers who recorded dietary intake with the ISS 

FIT App or kept a detailed food log. The black lines represent mean ± SD for each crewmember.

1 234 5 6 78 9

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Dietary Fiber Intake (g/d)

1 2 3 4 5 6 7 8 9

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Cholesterol Intake (mg/d)

123 4 56789

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Saturated Fat Intake (% kcal/d)
36 37

The capacity of an organism to adapt fuel 

oxidation to fuel availability was originally 

defined by Kelley and Mandarino as 

‘metabolic flexibility’ (203). However, 

Rynders et al. contend that a broader 

definition that includes physical activity 

and inactivity be considered in the 

definition of metabolic flexibility (204). 

Physical inactivity, such as during bed rest, 

decreases the switch from fat oxidation to 

carbohydrate oxidation in the fed state—

i.e., physical inactivity causes metabolic 

inflexibility, even in neutral energy balance. 

Physical inactivity is also accompanied 

by fatty acid infiltration into the muscle, 

which, together with the metabolic 

inflexibility, might support the 

development of insulin resistance 

(188, 205). Reduction in glucose oxidation 

in an insulin-stimulated state is often 

accompanied by a triglyceride 

accumulation in myocytes, which is also 

seen in insulin resistance. Other studies 

have reported inflammatory changes in 

sedentary bed rest subjects, along with 

insulin resistance, leading to increased 

body fat and altered fatty acid metabolism 

(206). Given these data, and the changes 

in insulin, leptin, and other endocrines 

noted during bed rest and spaceflight 

(105, 207-210), changes in fuel 

homeostasis and metabolic inflexibility 

in bed rest clearly warrant additional 

investigation. 

Omega-3 fatty acids have multiple roles 

in physiology and biochemistry, with 

generally accepted positive health 

benefits. The role of omega-3 fatty acids 

in preventing radiation-induced cancer 

has been investigated in animal models 

(211, 212). Not only do omega-3 fatty 

acids (in combination with pectin) show 

promise in alleviating cancer risk (211-

215), these fatty acids also have welldocumented cardiovascular benefits (216). 

Abundant data show that eicosapentaenoic 

acid can successfully prevent muscle 

atrophy in other muscle-wasting 

circumstances, such as cancer or sepsis 

(217-225), as well as in muscle wasting 

induced by a single leg immobilization 

(226). During a 14-day single leg 

immobilization study, omega-3 fatty 

acid supplements prevented changes in 

mitochondrial content, function, and lipid 

metabolism, which might have helped 

maintain muscle mass and strength in the 

immobilized leg (226). These observations 

indicate a high likelihood that eicosapentaenoic acid has similar beneficial 

effects on muscle atrophy during 

spaceflight or in ground-based analogs 

of spaceflight including bed rest.

Increased dietary intake of omega-3 fatty 

acid protects bone in the general population

(227-230) and in spaceflight analog studies,

including bed rest and cell cultures (231). 

Although omega-3 fatty acids have not 

been studied in a controlled fashion during 

actual spaceflight, a positive correlation 

was found between fish intake and bone 

maintenance in astronauts (231). That is, 

those who ate more fish lost less bone 

(Figure 13). These data provide additional 

evidence of the potential importance of 

fish oils as a countermeasure for loss of 

muscle and bone, and for the health risks 

of radiation exposure during spaceflight. 

Studies showing positive effects of 

omega-3 fatty acids typically look at intake 

of fish or other food sources of these 

nutrients (232-234). Studies of fish oil 

supplements that are added to typical 

diets often fail to document any benefit 

(235-237), thus highlighting the need for 

dietary modification, and not simply 

supplementation.

Protein

As the major structural component of 

all cells in the body, protein includes 

molecules that perform many essential 

physiological functions, serving as 

enzymes, hormones, transporters, and 

other important molecules. The total 

energy contribution of protein to the 

average diet is about 15%. The nitrogen 

core of amino acids contributes to 

protein structure, along with nucleic 

acids, one of the major nitrogencontaining macromolecules.

Protein is one of the most important 

limiting factors when the body is deprived 

of energy, because essential amino acids 

are neither stored in the body nor can they 

be synthesized by the body. A complete 

depletion of energy and protein reserves 

is said to be the cause of death from 

starvation. It is estimated that when 33% 

to 50% of total body protein is lost, death 

results (238). Loss of more than 40% to 

50% of initial body mass is not compatible 

with life (170, 239). In one case report, 

individuals on a hunger strike lost 30% 

of their total body mass and 19% of total 

body protein before they died (168, 169).

Maintaining a proper protein intake is vital 

because both low-protein and high-protein 

diets can cause harm (and, at the extreme, 

death). A low-protein diet (i.e., below the 

recommended dietary allowance) for up to 

4 weeks can decrease calcium absorption 

and cause increased secretion of parathyroid hormone in otherwise healthy 

subjects (240, 241). Low-protein diets 

are associated with loss of bone density 

(242, 243) and as reviewed in (244).

Provision of protein and intake during 

spaceflight typically exceed the recommendations (1), Chapter 2, Table 1, and 

Figure 14. European studies have shown 

that on long-duration missions, reaching 

(or exceeding) nominal protein intakes is 

common; however, on short flights (e.g., 

Space Shuttle missions), protein intake is 

less than the recommended amount 

because of insufficient food intake (113). 

On ISS missions, protein intake, on 

average, is more than adequate 

(Figure 14, Figure 15).

Figure 13. Relationship between fish intake 

during long-duration flight and loss of 

whole-body BMD after flights on the ISS. 

Figure adapted from (231).

Figure 14. Protein intake during spaceflight on 

ISS missions. Each point represents the reported 

average intake for an individual crewmember 

over the course of their mission. Green dashed 

line represents the US Recommended Dietary 

Allowance (41), and the range of protein intakes 

(1.2.-1.7 g/kg) recommended by the American 

Dietetic Association, Dietitians of Canada, and 

American College of Sports Medicine for highintensity athletes (245).

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(% change from preflight)

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(g/kg BW; mission avg)

0.5

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Figure 15. Protein intake for 27 ISS astronauts 

and the "standard menu." Each symbol 

represents a day’s intake during flight. 

Circles are male astronauts, and triangles are 

females. These represent crewmembers who 

recorded dietary intake with the ISS FIT App 

or kept a detailed food log. Standard menu 

data are calculated for an 83 kg individual—

i.e., the average male astronaut’s body mass. 

The black lines represent mean ± SD for each 

crewmember. Dashed lines are as described 

in Figure 14.

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38 39

(NADH2) and flavin-adenine dinucleotide 

(FADH2), which leads to the synthesis 

of adenosine triphosphate (ATP) in the 

respiratory chain. We previously reviewed 

the basics of thiamin function (1). Thiamin 

is a therapeutic option for mitochondrial 

diseases because it supports the 

availability of mitochondrial electron 

transport chain substrate and the activity 

of pyruvate dehydrogenase, leading 

to increased catabolism of pyruvate to 

acetyl-CoA, (260). 

In a study of 17 astronauts on ISS 

missions, estimated thiamin intake 

during flight was 1.87 ± 0.60 mg/d (249), 

approximately 50% higher than the 

recommended intake of 1.2 mg/d for 

men, and 1.1 mg/d for women. Thiamin 

has been shown to be one of the more 

unstable nutrients in food during storage 

(84) (Figure 6), as discussed earlier, and it 

will be essential to establish stability for 

exploration missions.

No change in the activity of erythrocyte 

transketolase, an index of thiamin status 

(261), was detected before and after 

spaceflight (Figure 16). Similarly, no 

changes were observed in erythrocyte 

transketolase activation after a 30-day bed 

rest study (262). 

Riboflavin 

Riboflavin is a water-soluble B vitamin 

(vitamin B2

). In its role in the mitochondrial 

electron transport chain, riboflavin acts 

as a cofactor (flavin mononucleotide and 

flavin adenine dinucleotide) to metabolize 

fat, protein, and carbohydrate into energy. 

The basics of riboflavin function have been 

reviewed previously (1). Because riboflavin 

is required to synthesize flavoproteins, 

and flavoproteins are involved in lipid 

metabolism, deficiency of riboflavin 

primarily affects lipid metabolism 

and consequently ATP synthesis. 

Hence, symptoms such as skin 

dyscrasias, which are associated 

with deficiencies in essential fatty acids, 

are also seen with marginal riboflavin 

deficiencies (263). Riboflavin is also 

required to maintain reduced glutathione, 

an endogenous antioxidant; therefore, 

the antioxidant defense mechanism 

is also affected by riboflavin deficiency 

(263). Riboflavin status is analyzed by 

measuring the activation of erythrocyte 

glutathione reductase. 

Deficiencies of riboflavin are rare but can 

be present in individuals who consume 

a poor diet, have malabsorption issues, 

or have reached an advanced age (264). 

Veganism, alcoholism, and certain 

medications (e.g., birth control pills, 

chemotherapeutic agents, antibiotics) 

can also lower riboflavin status (265).

To date, no studies have reported 

changes in the activation of erythrocytes 

glutathione reductase during spaceflight 

(Figure 17). In a study of 17 astronauts 

on the ISS, riboflavin intake was estimated 

at 2.16 ± 0.69 mg/d (249), well above 

the 1.1 and 1.3 mg/d recommended 

for women and men, respectively (38, 

266). In 3-week (254) and 30-day (262) 

bed rest studies, no change occurred 

in erythrocytes glutathione reductase 

activation. Nonetheless, riboflavin levels 

could degrade in food that is stored during 

future longer-duration exploration missions, 

and it will be important to establish the 

supply needs for these missions.

Too much dietary protein and too high 

dietary acid loads may lead to a transient 

low-grade metabolic acidosis, which 

consequently may increase osteoclasts 

activity and lead to lower BMD over time 

(246). If protein intake reaches levels of 

1.6-1.8 g/kg body weight/d during physical 

inactivity (bed rest or spaceflight) when 

osteoclasts are already activated, this 

may exaggerate the bone resorbing 

effect (247-249).

Some data suggest that during the 

recovery period after short-duration 

Space Shuttle flights, protein was a 

limiting nutrient, and that competition 

for substrate to replenish plasma 

proteins and muscle mass strains the 

system (250). This has not been tested 

experimentally; however, obviously, 

good nutrition is required for rapid 

return to optimal health.

Nutrients Associated with Energy 

Metabolism

Many micronutrients—vitamins and 

minerals—are involved in energy 

homeostasis, including thiamin, 

riboflavin, niacin, pantothenic acid, 

iodine, manganese, and even chromium. 

We previously reviewed sources of these 

nutrients, their functions, deficiency 

symptoms, and concerns for spaceflight 

for these nutrients (1). In general, few 

data are available on these nutrients with 

respect to effects of spaceflight, or on 

the availability and stability of these 

nutrients in the space food system. 

No specific concerns have been raised 

at this point; however, we must ensure 

that astronauts consume adequate 

amounts of these nutrients and understand 

their metabolism during spaceflight, and 

the nutrients must remain stable in the 

food system during exploration missions 

(see additional discussion in Chapter 3). 

Although B vitamins are associated with 

energy metabolism, they are also linked 

to the development of optic disc edema—

a disorder associated with spaceflight. 

Changes in vitamin B status in space 

travelers are reviewed in detail in 

Chapter 10.

Vitamin B6

Vitamin B6 comprises a group of three 

compounds and their 5-phosphates (P): 

pyridoxal (PL) and PLP; pyridoxine (PN) 

and PNP; and pyridoxamine (PM) and 

PMP (251). We previously reviewed the 

basics of vitamin B6 function, sources, 

and deficiency symptoms (1). 

Weightlessness has been shown 

to reduce the cross-sectional area 

of muscle fibers and is associated with 

a change from type I to type II muscle 

fibers (252). Because vitamin B6 is stored 

mainly in muscle tissue (253), a decrease 

in muscle cross-sectional area could 

reduce the amount of the vitamin that is 

stored. Increased excretion of 4-pyridoxic 

acid (4-PA) during bed rest, a finding 

observed in short- (254) and long-duration 

bed rest studies (255), likely reflects this 

loss of muscle stores of vitamin B6.

Given the changes observed in vitamin 

B6 metabolism during bed rest, vitamin 

B6 status during and after long-duration 

spaceflight warrants further attention. 

Deficiency of vitamin B6 causes a 

decrease in the synthesis of serotonin 

and catecholamines, which has been 

shown to be associated with depression 

(256). Excess vitamin B6 can lead to 

neuropathy (257-259), which can be 

of concern given the very high content 

of this vitamin in many supplements 

and energy drinks.

Thiamin 

Thiamin functions as a coenzyme in 

the metabolism of carbohydrates and 

branched-chain amino acids. This process 

is mediated by enhancing the activity of 

pyruvate dehydrogenase and thereby 

reducing generation of the cofactors 

nicotinamide-adenine dinucleotide 

Figure 16. Erythrocyte transketolase 

activation before and after flight in ISS 

astronauts. Data are mean ± SD of 49 

male astronauts (blue line) and 12 female 

astronauts (gold line). The black dashed line 

represents the normal range (i.e., <15% is 

considered adequate thiamine status).

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Niacin 

Niacin is a precursor of nicotinamide 

adenine dinucleotide (NAD), which 

functions in most energy-producing 

reactions that metabolize carbohydrates, 

fats, proteins, and alcohol. Unlike other 

water-soluble vitamins, niacin can be 

synthesized in limited amounts from 

the indispensable amino acid tryptophan. 

In its reduced form, NADH is used 

as substrate to generate ATP in the 

respiration chain in mitochondria. 

The basics of niacin function have been 

reviewed previously (1). Although niacin 

could degrade in foods stored long-term 

in a microgravity and space radiation 

environment, niacin does not appear 

to be of concern (84). One study 

demonstrated that niacin concentration 

was preserved in freeze-dried black 

tomato powder, a fruit rich in watersoluble vitamins, for up to 274 days 

during spaceflight (267).

Niacin status in astronauts is assessed 

with the ratio of erythrocyte NAD:NADP 

(268), and, in general, crews are in good 

status (Figure 18). Given the processing 

required for this test, the niacin status may 

only be evaluated before and after flight.

Niacin intake in a study of 17 astronauts 

was estimated at 25.6 ± 9.3 mg niacin 

equivalents/d (249), more than the 

requirement of 14 and 16 mg/d for women 

and men, respectively. The ISS “standard 

menu” often exceeds this estimate, 

as do astronauts, depending on their 

food (and, in some cases, supplement) 

selections (Figure 19). Although there is 

no upper limit for natural sources of niacin, 

consumption of niacin from supplements 

and fortification should not exceed 

35 mg/d, given risks of vasodilatory 

effects, i.e., flushing as a critical adverse 

effect, along with risk of headaches, 

which are likely secondary to increased 

intracranial blood flow (266).

Pantothenic acid 

Pantothenic acid is required for the 

synthesis of coenzyme A, which is 

essential—with regard to energy 

metabolism—for metabolizing and 

synthesizing fatty acids (269). 

Hence, pantothenic acid is mandatory 

for synthesis of acetyl-CoA, the substrate 

that enters the citric acid cycle to convert 

the reduced cofactors NADH and FADH2 

to energy rich substances. The basics 

of pantothenic acid function have 

been reviewed previously (1, 270). 

Deficiency of pantothenic acid is very 

rare and is only observed in rare cases 

of severe malnutrition. 

Pantothenic acid intake in a study 

of 17 astronauts was estimated at 

6.63 ± 2.93 mg/d (249), more than 

the requirement of 5 mg/d for both 

women and men. Space food, 

however, is rather balanced with 

regard to supply of pantothenic 

acid, and thus further research 

on this topic is not considered 

a high priority at this time.

Iodine 

The mineral iodine is essential for 

synthesizing thyroid hormones 

(triiodothyronine [T3] and thyroxin [T4]), 

which are required to regulate basal 

energy metabolism and control metabolic 

processes such as energy production, 

lipolysis and glycolysis. Iodine excretion 

in 24-hour urine collections is a valid 

method to judge iodine intake because 

most dietary intake is excreted in urine. 

In general, when the range of urinary 

iodine excretion lies between 0.8 and 

1.6 μmol/L the iodine intake is 

considered sufficient. 

Iodine excretion was determined in 

two ISS experiments—the Nutrition 

Supplemental Medical Objective (SMO) 

and Biochemical Profile—and, with the 

exception of a few outliers, generally 

are within normal range (Figure 20). 

Data from the 1-year twin study 

demonstrate that iodine intake was 

sufficient during spaceflight, at least 

for that astronaut, being on average 

2.6 μmol/day (19). Iodine deficiency can 

lead to insufficient synthesis of T3 and 

T4. Within the thyroid gland, associated 

increases in cell development can cause 

enlargement of the gland. Additionally, 

iodine deficiency decreases basal 

metabolic rate leading to lower TEE.

Manganese 

Manganese is a micronutrient that 

functions as a cofactor for enzymes 

involved in energy production in the 

human body, mainly in the metabolism 

of carbohydrates and amino acids 

(271, 272). For instance, pyruvate 

carboxylase and phosphoenolpyruvate 

carboxykinase are enzymes involved in 

gluconeogenesis from non-carbohydrate 

sources such as amino acids. Through 

these enzymes, manganese plays a 

role in regulating blood glucose levels 

Figure 17. Erythrocyte glutathione reductase 

activation before and after flight in ISS 

astronauts. Data are mean ± SD of 49 male 

astronauts (blue line) and 12 female astronauts 

(gold line). The black dashed line represents 

the normal range (i.e., <40% is consider 

adequate riboflavin status). 

Figure 18. NAD:NADP in 23 ISS astronauts 

before and after flight. An NAD:NADP ratio 

>1.0 is considered to reflect adequate 

niacin status.

Figure 20. Urine iodine excretion in male 

(blue line) and female (gold line) ISS 

astronauts. Black dashed line represents 

normal limits.

Figure 19. Niacin intake in 27 astronauts 

and the ISS "standard menu." Each symbol 

represents a day’s intake during flight. Circles 

are male astronauts, and triangles are females. 

These represent crewmembers who recorded 

dietary intake with the ISS FIT App or kept a 

detailed food log. The black lines represent 

mean ± SD for each crewmember. Dashed 

lines represent required intakes for men 

(blue line) and women (purple line), red line 

represents the upper limit for niacin intake 

from supplements or fortification (266).

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40

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EGR (% activation)

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42 43

(271). The basics of manganese function 

have been reviewed previously (1, 271). 

Dietary manganese should be provided 

in adequate amounts, considering 

the likelihood of developing glucose 

intolerance during exploration missions.

In a study of 17 ISS astronauts, 

manganese intake was 5.17 ± 1.67 mg/d, 

compared to the recommended intake 

of 1.8 and 2.3 mg/d for women and 

men, respectively (273, 274). Manganese 

status is difficult to assess, and has 

not been attempted in astronauts, to 

our knowledge.

Chromium 

Chromium is a trace element that 

is involved in energy metabolism by 

improving the efficiency of insulin. 

Scientists do not have a clear 

understanding of how chromium might 

affect glucose metabolism, but a widely 

accepted hypothesis is that this is 

achieved through the involvement of 

an oligopeptide named chromodulin, 

which binds chromium (275). Chromodulin 

is thought to cause an insulin-sensitive 

stimulation of the insulin receptor, thereby 

amplifying the insulin signaling (276). 

Because no symptoms of chromium 

deficiency have been established, 

in 2014, the European Food and Safety 

Authority concluded that there was 

insufficient evidence demonstrating 

a beneficial effect of chromium, and 

that defining an adequate intake of 

chromium therefore was not appropriate 

(277). Animal studies, however, have 

demonstrated beneficial effects on 

glucose tolerance and insulin resistance 

(278). Future research is necessary to 

investigate whether chromium could play 

a role in mitigating this effect, considering 

that insulin resistance could develop in 

exploration missions.

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50 51

Fluid Intake

Adequate fluid intake is necessary to 

maintain the body’s normal hemodynamic 

state and normal fluid osmolality, which 

are important for cardiovascular health 

and for maintenance of fluid and 

electrolyte homeostasis. Water is a 

structural component of the body and 

the solvent for transportation of nutrients 

and waste. Fluid and electrolytes can be 

lost from the body by a variety of routes 

and for a variety of reasons. They are 

excreted in sweat, urine, and feces. 

In abnormal situations, excessive 

amounts can be lost by these routes 

and others. Significant losses may 

occur through the GI tract as a result 

of diarrhea, vomiting, or gastric drainage. 

Loss through the skin increases with 

fever, increased metabolism, sweating, 

and burns (279).

Fluid Homeostasis 

Total body water makes up about 

50% to 70% of body mass (280). 

Fluid requirements increase with 

metabolic rate and heat stress. 

Death from dehydration can occur 

within days to weeks of depriving 

the body of all water (281). Fluid and 

electrolyte homeostasis are significantly 

altered during spaceflight, and this 

has been extensively reviewed 

(7, 123, 282-290). The originally 

proposed hypothesis to explain 

this suggested that when entering 

weightlessness, the human body would 

experience a headward shift of fluids, 

with subsequent diuresis and dehydration.

A series of flight experiments were 

conducted to assess fluid and electrolyte 

homeostasis during spaceflight; the 

most comprehensive of these took place 

on the 2 Spacelab Life Sciences missions 

in the early 1990s. Despite much research, 

the hypothesis of diuresis and subsequent 

dehydration secondary to the headward 

fluid shifts has never been confirmed 

during actual spaceflight (7, 287, 289, 

291-293). 

A reduction in volume of both plasma and 

extracellular fluid occurs within hours of 

the onset of weightlessness (the earliest 

available data point), accompanied by 

the “puffy” faces typically observed early 

during spaceflight (7, 294). Initially, the 

decrement in plasma volume (~17%) is 

larger than the decrement in extracellular 

fluid volume (~10%), suggesting that 

interstitial fluid volume (the other fourfifths of extracellular fluid) is conserved 

proportionally more than plasma volume 

(7). Indication that interstitial fluid volume 

is conserved is supported by rapid 

decreases in total circulating protein, 

specifically albumin (7), suggesting that 

protein, and associated oncotic pressure, 

shifts from the intravascular to the 

extravascular space. This would facilitate 

the initial changes in plasma volume (7).

5Fluid

Fluid intake and fluid homeostasis are important elements for health. Given the 

physiological changes that occur in microgravity, these two elements take on an 

even greater importance. Adequate fluid intake must be assured to maintain hydration 

and reduce renal stone risk. Fluid shifts during spaceflight can also have implications.

SpaceX Crew-1 Pilot and Expedition 64 Flight 

Engineer Victor Glover of NASA sips on a water 

bag during his first week aboard the ISS.

Photo Credit: NASA.
52 53

After the initial adaptation, extracellular 

fluid volume further decreases between 

the first days of flight and 8 to 12 days 

after launch, from the initial ~10% below 

preflight levels to ~15% below preflight 

levels (7). Plasma volume is partially 

restored during this period, from the 

initial ~17% below preflight levels to 

~11% below preflight levels (7), and it 

remains 10% to 15% below preflight 

levels even for extended-duration 

flights (295).

Leach et al. (7) and Norsk et al. (292) 

have hypothesized that the shift of 

protein and fluid to the extravascular 

space represents an adaptation to 

weightlessness, and that after several 

days, some of the extravascular albumin 

has been metabolized, resulting in a loss 

of oncotic force and a subsequent 

decrease in extracellular fluid volume 

and increase in plasma volume. 

This loss of extracellular protein 

(intra- and extravascular) and the 

associated decrease in oncotic 

potential probably play a role in 

postflight orthostatic intolerance, 

which may partly result from reduced 

plasma volume at landing (296). 

Furthermore, the loss of protein may 

in part explain why fluid loading alone 

does not restore circulatory volume 

(297, 298), because additional solute 

load cannot maintain the fluid volume. 

Another (or perhaps partial) explanation 

for the failure of fluid loading could be 

due to the high levels of sodium in the 

astronauts’ diets; additional salt cannot 

further increase plasma or extracellular 

fluid volumes. This explanation has 

been documented in metabolic ward 

studies (299).

The effect of spaceflight on total body 

water has been evaluated to assess 

hydration. Space Shuttle and Skylab 

astronauts experienced decreases 

of about 1% in total body water during 

flight (7, 300, 301), and the percentage 

of body mass represented by water 

did not change. Thus, the often-proposed 

weightlessness-induced dehydration does 

not exist. European investigations during 

Space Shuttle and Mir missions have also 

shown this (287, 292, 293, 302, 303).

Diuresis and Dehydration 

Diuresis is also typically not observed 

during flight (157, 282, 289, 292, 293, 

302, 304-306), for several possible 

reasons. Operational constraints have 

made it difficult to document urine volume 

accurately on the first day of spaceflight; 

however, on the Spacelab Life Sciences 

missions, urine volume on the first 3 days 

of flight was significantly less than preflight 

volume, and urine volume tended to be 

less than preflight volume throughout the 

flight (7). Urine volumes on a week-long 

flight on Mir were also less than preflight 

volumes (305). During the first week of 

the 59- and 84-day Skylab flights (122), 

urine volume was less than it was before 

flight, and it remained at preflight levels for 

the remainder of the flight. Decreased fluid 

intake likely accounted for the decreased 

urine volume, which was accompanied 

by little or no change in total body water. 

Adequate urine volume during flight is 

important for reducing the risk of renal 

stone formation (307-310).

As mentioned above, the percentage 

of body mass represented by total 

body water is relatively unchanged during 

flight (7). However, on a volume basis, 

the change in extracellular fluid volume 

was greater than the change (or lack 

of change) in total body water (7). 

Thus, intracellular fluid volume increased 

during spaceflight. This had been 

previously hypothesized from groundbased studies (615) and observed in 

postflight studies of Apollo crewmembers 

(59). The mechanism for a spaceflightinduced increase in intracellular fluid 

volume is unknown. One possible 

explanation is that a shift in fuel use results 

in increased glycogen storage—a condition 

known to increase cellular water content.

Diuresis has been observed in bed rest 

studies (311-313). Urinary albumin, 

a marker of kidney function, is reduced 

both in spaceflight (relative to before flight) 

and in bed rest (relative to the ambulatory 

state) (314-316). However, spaceflight, 

but not bed rest, results in reduced urine 

flow rates (293). Taken together, these 

data suggest that differences in fluid 

metabolism exist between analog studies 

and actual spaceflight (287, 291-293, 

303, 306, 313). Such differences do not 

seem to be a simple effect of abnormal 

renal function, and thus require further 

investigation (317).

Although no spaceflight-induced 

dehydration occurs, care must be taken 

to ensure adequate fluid intake and 

hydration status. Inadequate fluid intake 

increases the risk of dehydration and renal 

stone formation. Fluid intake during flight 

is typically less than preflight intake, and 

often below the recommended quantity, 

as evidenced in Figure 21. Water is often 

a limiting resource in closed flight 

vehicles; however, rationing of water 

should be avoided.

Deficiency of fluid leads to dehydration 

and can ultimately lead to death. 

However, chronic mild hypohydration 

can lead to cardiovascular disease risk, 

along with altered performance, cognition, 

thermoregulation, and endocrine 

function (318). Despite variability among 

studies, dehydration impairs cognitive 

performance, particularly for tasks 

involving attention, executive function, 

and motor coordination when water 

deficits exceed 2% body mass loss 

(319, 320). Likewise, an excess of fluid 

intake leads to water intoxication and 

ultimately death. Obviously, the risk 

of water intoxication occurring during 

spaceflight, where water is a limited 

commodity, is extremely low. 

Decreased fluid intake during spaceflight 

may be a consequence of reduced thirst 

during flight (193); however, the reason 

for reduced thirst is unknown. Because 

studies have documented that total body 

water is unchanged during flight (7), this 

has led to the hypothesis that there is 

a shift of fluid from the extracellular to 

the intracellular compartment. If this does 

indeed occur, it would be important to 

assess cell size and cell function (such 

as how change in the density of receptors 

on cell membranes affects cell function), 

because this may contribute to some 

of the microgravity-induced changes 

that have been noted in other systems 

(e.g., endocrine, cardiovascular, 

immune systems).

Figure 21. Hydration status of astronauts by two measures: urine osmolality (left panel) and 

serum sodium concentration (right panel). Forty percent of ISS astronauts met the sports 

medicine definition of dehydration with urine osmolality above 700 mOsm/kg (above the red 

dashed line, left panel). 8.7% of astronauts met the clinical definition of dehydration (serum 

Na >145 mmol/L, above the red dashed line, right panel).

All data Inflight

0

200

400

600

800

1000

1200

Urine Osmolality

(mOsm/kg)

All Data Inflight

120

125

130

135

140

145

150

155

160

165

Serum sodium

(mmol/L)
54 55

References for Chapter 5 

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Regulation of body fluid compartments during short-term spaceflight. J Appl Physiol (1985). 1996;81:105-16.

122. Leach CS, Rambaut PC. Biochemical responses of the Skylab crewmen: an overview. In: Johnston RS, 

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284. Leach CS. An overview of the endocrine and metabolic changes in manned space flight. Acta Astronaut. 

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285. Leach CS. Fluid control mechanisms in weightlessness. Aviat Space Environ Med. 1987;58:A74-9.

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287. Drummer C, Gerzer R, Baisch F, Heer M. Body fluid regulation in micro-gravity differs from that on Earth: 

an overview. Pflugers Arch. 2000;441:R66-72.

288. De Santo NG, Christensen NJ, Drummer C, Kramer HJ, Regnard J, Heer M, Cirillo M, Norsk P. Fluid balance 

and kidney function in space: introduction. Am J Kidney Dis. 2001;38:664-7.

289. Smith SM, Krauhs JM, Leach CS. Regulation of body fluid volume and electrolyte concentrations in spaceflight. 

Adv Space Biol Med. 1997;6:123-65.

290. Leach CS, Cintron NM, Krauhs JM. Metabolic changes observed in astronauts. J Clin Pharmacol. 1991;

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291. Gerzer R, Heer M. Regulation of body fluid and salt homeostasis--from observations in space to new 

concepts on Earth. Curr Pharm Biotechnol. 2005;6:299-304.

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hypothesis and future perspectives. Am J Kidney Dis. 2001;38:696-8.

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Lancet. 2000;356:1577-8.

294. Nicogossian AE, Sawin CF, Huntoon CL. Overall physiologic response to space flight. In: Nicogossian AE, 

Huntoon CL, Pool SL, editors. Space physiology and medicine. 3rd ed. Philadelphia, PA: Lea & Febiger; 

1994. p. 213-27.

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Administration; 1977. p. 235-41.

296. Bungo MW, Johnson PC, Jr. Cardiovascular examinations and observations of deconditioning during 

the space shuttle orbital flight test program. Aviat Space Environ Med. 1983;54:1001-4.

297. Vernikos J, Convertino VA. Advantages and disadvantages of fludrocortisone or saline load in preventing 

post-spaceflight orthostatic hypotension. Acta Astronaut. 1994;33:259-66.

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and saline. Aviat Space Environ Med. 1977;48:120-4.

299. Heer M, Frings-Meuthen P, Titze J, Boschmann M, Frisch S, Baecker N, Beck L. Increasing sodium intake 

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300. Thornton W, Ord J. Physiological mass measurements on Skylab 1/2 and 1/3. Acta Astronaut. 1975;2:103-13.

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306. Gerzer R, Heer M, Drummer C. Body fluid metabolism at actual and simulated microgravity. 

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& microgravity on renal fluid excretion. J Gravit Physiol. 1998;5:P81-4.

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56 57

6 Bone

Bone health and bone loss during spaceflight has been a leading concern dating 

back to before humans had even left the planet (321, 322). Multiple risks are 

associated with spaceflight-induced bone loss, including the risk of developing 

renal stones during the mission, and the concern that astronauts will have an 

increased risk of bone fracture after flight (323). This topic has been reviewed 

many times with respect to both spaceflight (324-348) and ground-based analogs 

of spaceflight that include musculoskeletal disuse in humans and animal models 

(324, 326, 336, 337, 343, 349-351). 

Bone is lost during spaceflight, primarily from the weight-bearing bones (333). This was 

first documented in astronauts after they returned from Skylab missions (352, 353), and 

later after Mir (354-358) and ISS missions. On average, about 1% to 1.5% of total bone 

is lost per month of spaceflight (330, 335, 339, 356, 357, 359), roughly similar to the rate 

of postmenopausal bone loss over a year. Losses of BMD at landing after 6-month ISS 

missions are estimated to range between 2% and 9% for different bone sites (330, 360-

362), with significant site-to-site and individual-to-individual variability (327, 335, 356). 

The subject-to-subject variability seems a characteristic of spaceflight-induced bone 

loss (330, 335, 336, 359), and may provide insight into a means to mitigate this loss; 

that is, astronauts can be evaluated to determine what they did differently that caused 

them to lose more (or less) bone than did other astronauts (e.g., exercise, diet). 

Long-term follow-up data on bone recovery are far from complete (361, 363, 364). 

Assessments using calcium tracer kinetic data (112, 152) estimate that after flights 

of up to about 6 months, it would take 2 to 3 times the mission duration to recover the 

lost bone (327, 329). Analysis of bone recovery using dual-energy x-ray absorptiometry 

(DXA) suggests that although regional differences in recovery exist, the half-life 

of bone recovery after 6 months of spaceflight is on the order of 5 to 9 months 

(330, 361). Quantitative computerized tomography (QCT) assessments performed 

long after flight show that overall bone density can recover by 2 to 4.5 years after 

5- to 6-month ISS missions, although trabecular bone takes even longer to recover (364). 

For longer exploration missions, however, the usefulness of these assumptions comes 

into question because very little spaceflight data are available for durations greater 

than 6 months. The 1-year Twins study evaluated bone and biochemistry; however, 

the astronaut changed exercise habits mid-mission, which confounded the results (19). 

Beyond BMD, changes to bone architecture and bone strength, and the recovery of 

these losses, also remain unknown. Additionally, concern has been expressed that 

DXA assessments of bone density do not provide an accurate picture, and that 

3-dimensional analysis using QCT is required to better understand bone responses 

to spaceflight (330, 362, 365).

Negative calcium balance was observed in astronauts after they returned from the 

Skylab (122, 352, 366-370) and Mir (112, 152) missions. During the 84-day Skylab 

4 mission, calcium balance averaged negative 200 mg/d (366, 370, 371); increased 

excretion of calcium in urine and feces accounted for most of the deficit (112, 122, 

152, 310, 352, 366, 367, 369). Multiple studies using various techniques suggest 

Tim Kopra of NASA is carried to a medical tent after he and Tim Peake of the European Space 

Agency and Yuri Malenchenko of Roscosmos landed in their Soyuz TMA-19M spacecraft after 

six months onboard the ISS. Photo Credit: NASA.
58 59

spaceflight, the lower amount of calcium 

absorption during flight suggests that 

increasing calcium intake is not a viable 

countermeasure for weightlessnessinduced bone loss, a fact that was 

proven in bed rest studies (390, 391).

The increased level of bone resorption 

in microgravity is associated with the 

release of calcium (and other minerals) 

into the circulation. Calcium is filtered by 

the kidneys as the body regulates blood 

calcium concentration, and this results 

in increased urinary calcium (and mineral) 

excretion—a process that increases the 

risk of developing kidney stones (147, 

194, 195, 210, 307, 309, 310, 392) 

(see Renal Stone section below).

Ground Analogs and Animal Models 

of Spaceflight-Induced Bone Loss

Bed rest is the most common way to 

simulate spaceflight-induced bone loss 

in humans (336, 393-396), and to evaluate 

countermeasures (described in a separate 

section below). Studies have shown that 

bed rest induces effects on bone and 

calcium homeostasis similar to those 

induced during spaceflight, whereas 

quantitative effects were generally less. 

Although biologically relevant changes 

in bone density (i.e., greater than 

measurement error) are more evident 

after 2 months of bed rest, and for 

only some skeletal sites, many studies 

substantiate that biochemical markers 

may serve as harbingers of changes in 

bone mass (397-400). Bone loss has 

been assessed during horizontal bed 

rest as opposed to head-down tilt, which 

induces more cardiovascular effects (401). 

As with any research, it is important to 

understand the details of study design 

and the controls because these vary 

widely from study to study.

Bed rest induces loss of bone mass 

and bone density (402-411), and this is 

associated with negative calcium balance 

(412), decreased calcium absorption (413), 

and increased urinary excretion of calcium 

(321, 367, 399, 408, 410, 412, 414, 415). 

Bone resorption, the result of osteoclast 

activity, increases during bed rest. 

This has been documented using 

histomorphometry (404, 416), and has 

been detected extensively using bone 

biochemical markers. Excretion of 

hydroxyproline, an imperfect marker 

of bone resorption, is increased during 

bed rest (412, 413, 415, 417, 418). 

Collagen crosslinks, including 

N-telopeptide (NTX) and/or C-telopeptide 

(CTX), are also excreted in higher amounts 

during bed rest (262, 385, 398, 399, 

405, 406, 408, 413, 419-424); levels 

are elevated about 50% from pre-bed 

rest levels in untreated controls. 

For comparison, crosslink excretion 

during actual spaceflight typically 

increases more than 100% compared 

to preflight levels (112, 152, 385).

Biochemical markers indicate that bone 

formation is unresponsive during bed rest. 

BSAP is perhaps the most commonly 

studied formation marker (262, 399, 

403, 408, 413, 419, 420, 422-424), 

although amino-terminal propeptide 

Figure 22. Calcium intake in 27 crewmembers 

and the ISS "standard menu.“ Each symbol 

represents a day’s intake during flight. 

Circles are male astronauts, and triangles 

are females. These represent crewmembers 

who recorded dietary intake with the ISS 

FIT App or kept a detailed food log. 

The black lines represent mean ± SD for 

each crewmember. Dashed lines represent 

the DRI and exploration mission requirement 

of 1000 mg calcium/d.

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Bone Biochemistry

Bone is a metabolically active tissue, 

constantly undergoing turnover through 

breakdown (resorption) and formation 

processes. When these two processes 

are in balance, no net loss (or gain) of 

bone occurs. Alterations in either, or both, 

of these processes can be problematic. 

Biochemical markers of these processes, 

and their associated regulatory factors, 

can provide tremendous insight into 

bone physiology.

Historically, bone resorption has been 

difficult to quantify. Hydroxyproline 

excretion is often used as a marker 

of bone resorption. However, data are 

confounded by dietary intake of the many 

foods that contain collagen (e.g., meat). 

Nonetheless, studies have shown that 

plasma concentrations of hydroxyproline 

were elevated during Skylab flights 

(122, 352, 366, 376), and even during 

short-duration Space Shuttle flights (377).

In the late 1980s, collagen crosslinks were 

identified as markers of bone resorption 

(378-383). Collagen crosslinks—posttranslational chemical linkages that give 

mature collagen its strength—are released 

during the bone resorption process and 

are not metabolized before renal excretion, 

thus they present a valuable urine test 

that can reflect changing trends in bone 

resorption. Many commercially available 

variants of this assay are based on 

immunoassay techniques that bind 

to different portions of the crosslink. 

This analytical tool clearly shows 

increased excretion of collagen crosslinks, and thus bone resorption, during 

spaceflight (112, 152, 210, 358, 377, 

384-386). Calcium tracer kinetic studies, 

which involve more complex detection 

techniques than those required to assess 

collagen crosslinks, also provided data 

indicating that bone resorption increased 

about 50% during flight relative to preflight 

(112, 152) levels.

Without countermeasures, levels of bone 

formation either remain unchanged or 

decrease during spaceflight (112, 152, 

358). Serum concentrations of bonespecific alkaline phosphatase (BSAP) 

and osteocalcin indicate that the level 

of bone formation was unchanged during 

Mir flights, but increased 2 to 3 months 

after landing (112, 152). Trends toward 

decreased levels of bone formation 

markers were noted in two subjects 

who each participated in a Mir mission 

(358, 386). Calcium tracer techniques 

examining bone formation in three 

Mir crewmembers (112, 152) were 

equivocal (i.e., formation was unchanged 

or decreased). 

Together, increased levels of bone 

resorption and decreased or unchanged 

levels of bone formation during spaceflight 

yield an overall negative calcium balance 

and result in bone loss. The exact 

triggering mechanism for these changes 

in bone metabolism during spaceflight 

has yet to be identified; however, 

physiological and endocrine responses 

to these changes are as expected, and 

meet longstanding theories of bone 

loading (and unloading) responses 

(387). The release of calcium from 

bone suppresses parathyroid hormone 

(PTH) (358, 388, 389) and results in 

lower levels of activated vitamin D 

(1,25-dihydroxyvitamin D) (384), which 

then leads to a reduction in calcium 

absorption from the GI tract (112, 152, 

384). Although it remains important 

to maintain calcium intake during 

that about 250 mg of bone calcium is lost per day during spaceflight (112, 152, 366, 

372). When this rate of loss may slow down is not yet known; however, it does not 

appear to be within the first 6 months of flight. For comparison, bone loss after spinal 

cord injury is profound, yet seems to stabilize after about 6 to 12 months (342, 373-375), 

which is around the duration of many ISS missions.
60 61

of type I collagen is another formation 

marker reflecting little systemic change 

in bone formation during bed rest 

(399, 406, 408). Sclerostin is a factor 

produced in the osteocyte, which is 

considered the “gravity sensing” cell, 

and serves to inhibit osteoblast activity. 

Circulating concentrations of sclerostin 

are increased during bed rest (406). 

Conversely, histomorphometry data from 

bone biopsies show that bone formation 

decreases during bed rest (404, 414, 

416). This seeming discrepancy between 

BSAP (no change) and histomorphometry 

(decrease) likely reflects the difference 

between site-specific (biopsy) and 

systemic (biochemical markers) indices 

of bone formation. Once ambulation 

begins after bed rest, bone formation 

generally increases (403, 413). 

Recent evidence indicates that during 

longer periods of bed rest (e.g., 90 days), 

bone formation markers tend to increase 

(405, 419). Likewise, in the initial ISS 

reports (124), serum concentrations 

of the bone formation marker BSAP 

did not change significantly over time; 

however, later studies of a larger number 

of astronauts did document statistically 

significant increases in BSAP (210).

Endocrine adaptations to bed rest 

include decreased serum concentrations 

of parathyroid hormone (262, 408, 414, 

419, 420, 423-425), and a subsequent 

decrease in 1,25 dihydroxyvitamin D 

(262, 413, 414, 423, 426). 

Only a few studies have evaluated 

how demographic factors relate to 

bone metabolism during bed rest. 

Sex differences in baseline bone mass 

and metabolism exist; however, men 

and woman had the same response 

to bed rest (427). Similar findings have 

been documented in ground-based 

animal studies (428). One study found 

that although younger (23 years old, 

n=8) and older (60 years old, n=16) 

men had similar responses to bed 

rest, bone turnover was lower in the 

older subjects (425). 

Dry immersion is another model used to 

mimic the effects of spaceflight on human 

physiology (429-431). This has most 

commonly been implemented in Russia, 

and involves the subject lying on top of 

a plastic sheet over water. The few dry 

immersion studies that have assessed 

bone markers have been relatively short 

(3-7 days), but have found similar effects 

as those induced during bed rest (432). 

Animal models have been studied 

extensively to evaluate changes to 

bone during real and simulated (e.g., 

tail suspension) spaceflight (351, 428, 

433-438). Early animal studies, which 

used growing rats, suggested that the 

primary change in bone metabolism was 

related to decreased bone formation with 

no change in resorption during spaceflight 

(439-446). When additional studies were 

conducted using adult animals, results 

were similar to the findings in humans; 

that is, bone resorption increases and 

bone formation decreases or does 

not change significantly during actual 

or simulated spaceflight (428, 447-

449). These findings substantiate that 

spaceflight disrupts the balance between 

bone resorption and formation, which 

can lead to a net loss in bone mass.

Renal Stone Risk

Bone demineralization and calcium loss 

is associated with an increased risk of 

developing kidney stones. Renal stone 

risk is elevated during and after spaceflight 

(195, 210, 307, 309, 310, 392, 450-454) as 

part of routine Medical Operations Clinical 

Nutritional Assessment testing (455) and 

has been evaluated during and after bed 

rest (427, 456-459). A renal stone risk 

profile is generated based on urine volume 

and chemistry, including determinations of 

urinary oxalate, uric acid, citrate, calcium, 

sodium, magnesium, sulfate, potassium, 

pH, and phosphorus. These data are used 

to determine the risk of supersaturation, 

which could lead to one or more of several 

types of kidney stones (e.g., calcium 

oxalate, brushite [calcium phosphate], 

sodium urate, uric acid, and struvite 

[magnesium ammonium phosphate]) (460). 

Calcium oxalate risk in ISS crewmembers 

between 2006 and 2018 are shown in 

Figure 23. Collection of urine samples 

for analysis of renal stone risk during 

flight ceased in 2018 with the end of 

the Biochemical Profile project. 

Astronauts have significant variability for 

different elements of the renal stone profile 

(154). For example, some crewmembers 

had a very high risk of developing brushite 

or calcium oxalate supersaturation during 

spaceflight, whereas others did not. 

Environmental and dietary factors can 

greatly affect the risk of developing renal 

stones, and fluid intake and related urine 

volume are critical elements (450, 454). 

Exposure to microgravity with concomitant 

bone loss and hypercalciuria increases 

urinary sodium and decreases urinary 

output, thus further increasing the risk 

of a renal stone forming during spaceflight.

As provided by the Lifetime Surveillance of 

Astronaut Health team, 29 astronauts and 

payload specialists have reported renal 

stone events as of 2020, and the majority 

of these events occurred after their 

mission (Table 2). 

Table 2. Incidents of Urinary Tract Stones 

in Astronauts (as of December-2020)

Time

Total # Events

(Post LD # 

Events)

Comments

Before flight 5 No previous 

flight experience

0–90 days after 

spaceflight

1 (1)

90–180 days 

after spaceflight *

3 (1)

180–270 days 

after spaceflight *

1

270 –360 days 

after spaceflight *

2

Between Flights 4 (1) >360 days, and 

flew again

Post Flight 

Career

26 (1) >360 days, did 

not fly again

Total 43 (4)

Data from U.S. astronauts and payload 

specialists (n=371). Total number of astronauts 

and payload specialist reporting events = 29. 

Post LD- After Long Duration Spaceflight Post 

flight career - includes both active and retired 

crewmembers. * None of these crewmembers 

had any record of preflight events. 

Data provided by the Lifetime Surveillance 

of Astronaut Health program.

Figure 23. Calcium oxalate relative supersaturation risk before (left panel) and during (right panel) 

flight. Each symbol represents a 24-hour urine pool. The box/error bars reflect the group mean 

and SD. Data are shown over the course of Nutrition SMO and Biochemical Profile projects on 

ISS (2006-2018), n=61. The red dashed line is the point above which the risk is greater than in 

the non-stone-forming population. Data adapted and expanded from (210). Calcium oxalate relative supersaturation before flight

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Potassium citrate (KCit) and potassium 

magnesium citrate supplements have 

successfully reduced the number of 

incidents of renal stones during bed 

rest (196) and on the ISS (453). 

This countermeasure strategy has 

been “transitioned to operations,” 

meaning that KCit is now available 

on the ISS for use at the flight surgeon’s 

discretion, if clinically indicated. 

KCit increases the pH of urine, increasing 

the solubility of calcium and thereby 

decreasing the risk that a calcium oxalate 

stone will form. The dosage of KCit must 

be carefully prescribed to avoid increasing 

the risk of developing brushite stones due 

to elevated urinary pH. However, given that 

maintaining hydration by fluid intake is an 

easy, non-pharmacologic countermeasure 

(210, 454), and some concerns exist 

regarding the side effects of potassium 

supplementation, NASA decided not to 

routinely provide KCit to crewmembers. 

Magnesium and citrate can both mitigate 

the risk of developing calcium-containing 

renal stones; however, they do not mitigate 

the risk of developing sodium urate kidney 

stones (154). Thus, taking KCit or KMgCit 

should not be perceived as a panacea to 

remove kidney stone risk. 

Urine Processing and Water 

Reclamation

The ability to reclaim water from urine 

will be an absolute requirement for 

exploration-class missions. Installation 

of the Urine Processor Assembly (UPA) 

on the ISS in 2009 was a significant first 

step toward this goal. Unfortunately, 

after just a few months of use, the 

device clogged with what was later 

found to be calcium sulfate precipitate. 

Twenty-four-hour urine volume is 

about 17% lower and urinary calcium 

concentration is 50% greater during flight 

than before flight (461). This increased 

urinary calcium concentration during 

flight was identified as the primary reason 

for the UPA failure. New recommendations 

for water recovery and fluid intakes 

were made because of those findings. 

Specifically, fluid intakes above 

32 ml/kg were associated with 

urinary calcium concentrations below 

the threshold concentration for 

precipitation (Figure 25). 

Based on analysis conducted in 2012 

and the recommended higher fluid intakes, 

a decision was made to increase the 

amount of water recovered from urine, 

saving the ISS Program from launching 

an estimated >80 L of water per year. 

These findings have been employed as 

an educational tool for astronauts because 

the chemistry that caused the UPA to clog 

and fail is the same chemistry that causes 

kidney stones. The fact that both can 

be alleviated by increased fluid intake 

is important to remember.

During the UPA troubleshooting, many 

suggestions were made for ways to 

mitigate high calcium concentrations 

in the system. One of these suggestions 

was to exclude the first morning void from 

the system, based on the assumption 

that this is typically more concentrated 

than other voids throughout the day. 

Another suggestion was to administer 

bisphosphonates to all crewmembers 

to reduce calcium excretion. Data from 

the in-flight single-void analyses showed 

that neither of these suggestions are likely 

to mitigate high calcium concentrations 

in the UPA (154, 461). 

Bone Loss Countermeasures

Exercise

Exercise is typically the first countermeasure

considered to counteract spaceflightinduced deconditioning, and to counter 

bone loss in particular (334, 345, 360, 

462-468). Bungee cords were used on 

Gemini and Apollo missions, more to 

relieve muscle stiffness in the cramped 

capsule than for conditioning (469). 

In-flight exercise to mitigate deconditioning

during spaceflight was first implemented 

on Skylab missions, largely because this 

was the first vehicle with enough room 

for exercise; however, these exercises 

were not effective for protecting bone 

(352, 366). Similarly, exercises using the 

treadmill and cycle devices available on 

Mir (462) did not prevent loss of bone 

and calcium (112, 152, 334, 357, 470). 

The general assumption was that 

resistance exercise that loads bones 

Figure 24. Liquid salt and pepper dispensers 

float on the Space Shuttle Columbia’s 

middeck during STS-94. Photo Credit: NASA.

Figure 25. Fluid intake in relation to the 

concentration of calcium in the urine. 

The green dashed line represents the 

concentration above which precipitation 

would be expected. The vertical line at 

32 ml/kg represents the level of fluid 

intake recommended to mitigate this risk.

Figure 26. NASA astronauts Michael Finke and Chris Ferguson hold beverages with notes 

written on them: TODAY'S COFFEE and YESTERDAY'S COFFEE. Eric Boe and Donald Pettit 

are in the background. Photo Credit: NASA.

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64 65

would be required to mitigate bone loss 

(465, 471). For treadmill exercise, the 

inability to generate sufficient groundreaction force in weightlessness negated 

its effectiveness as a bone countermeasure

(472, 473).

Astronauts used the interim resistance 

exercise device (iRED) (Figure 27) to 

perform resistance exercise on early 

ISS missions (474). This initial—and 

aptly named—interim device was 

deployed on the inaugural ISS expedition, 

when time and other constraints did 

not permit development of all desired 

hardware requirements before this 

expedition was launched. Thus, the 

intent was to use the iRED until a moreadvanced device capable of allowing 

heavier loads could be developed, tested, 

and launched to the ISS. Unfortunately, 

the iRED provided no additional benefit 

over the Mir equipment (i.e., bungee 

cords) (124, 475).

In late 2008, the Advanced Resistance 

Exercise Device (ARED) was launched 

to the ISS (476) (Figure 27). This device 

accommodated additional exercise 

protocols and had almost twice the 

loading capability of the iRED (124, 466, 

477). Comparing crewmembers exercising 

with the iRED vs the ARED was initially 

somewhat confounded, given that early 

crews using the ARED maintained their 

energy intake and body mass and had 

better vitamin D status than earlier 

crews who used the iRED. These betternourished crewmembers exercising with 

the ARED maintained body mass during 

flight (and came back leaner, with less 

body fat) (Figure 28), and, as assessed 

by DXA whole-body scans (124, 329), 

maintained mineral density in most 

bone regions (124) (Figure 29). A followon evaluation of 42 astronauts (33 male, 

9 female) documented that the flightinduced BMD response was the same 

for men and women (147) (Figure 30). 

Three-dimensional bone densitometry 

assessments using QCT showed that 

some astronauts who exercised using 

the ARED maintained (volumetric) BMD, 

whereas others did not (478). In fact, 

some of these crewmembers maintained 

higher BMD than some others who took 

bisphosphonates and also used the ARED 

(discussed in more detail later).

Although exercise on the ARED protected 

BMD, albeit better in some astronauts 

than others, this exercise protocol did 

not mitigate the typical spaceflightinduced increase in bone breakdown. 

Rather, resistance exercise was associated 

with increased bone formation (124, 210, 

478). ARED exercise also did not have 

a significant effect on the levels 

of serum total calcium or urinary calcium. 

The slow increase in bone formation over 

time during flight is likely related to the 

fact that the astronauts’ conditioning 

and strength trainers were initially reluctant 

to have crewmembers exercise too hard 

with the ARED, to minimize the risk of 

injury. This slow and steady increase 

in bone formation over time (124, 210) 

is different from results of the bed rest 

study, where formation markers plateaued 

at 6 weeks of bed rest, the first blood 

collection during the bed rest study (479).

Although this exercise-induced bone 

remodeling, with increases in both bone 

resorption and bone formation, maintained 

BMD, concerns remained that it may 

Figure 27. Left: NASA astronaut Sunita Williams uses the iRED. The iRED was launched in 2000 

with the first ISS crew. The Advanced Resistive Exercise Device (ARED) replaced it in late 2008. 

Right: Canadian Space Agency astronaut Robert Thirsk using the ARED in the Node 1 module. 

Photo Credits: NASA.

Figure 28. Body mass and composition changes (left panel, total body mass; middle panel, % lean 

body mass; right panel, % body fat) in astronauts exercising with iRED (dashed red line) or ARED 

(solid blue line). Data are from pre- and postflight DXA, and are mean ± SD. * denotes significant 

group x time interaction (P<0.01). Figure adapted from (124).

Figure 29. BMD loss in astronauts on Mir 

(n=17) and ISS missions. The ISS crews 

had access to either the iRED (n=7) or the 

ARED (n=40) exercise device. Data are 

expressed as percent change per month 

of flight. Figure updated and adapted 

from (124), with Mir data from (357, 360).

Figure 30. Whole-body BMD loss after flight 

in men (blue checked bars) and women 

(gold solid bars) who used either the iRED 

or the ARED exercise device. Data are 

expressed as percent change per month 

of flight and are mean ± SD. Figure adapted 

from (147). Total Body Mass (g)

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impact bone architecture and strength, 

which are not currently routinely evaluated 

(365). Studies to assess bone architecture 

and strength identified a variability in 

response among astronauts; however, 

yet again, exercise helped attenuate 

the declines in bone mineral and bone 

density (478).

Extensive ground-based research 

has been conducted to evaluate the 

effectiveness of different types of exercise 

as a countermeasure for musculoskeletal 

deconditioning. Assessments have 

included resistive exercise using weights 

(479), pneumatic devices (406, 480, 481), 

or a flywheel device (458, 482, 483); 

aerobic and resistance exercise (484); 

resistance exercise coupled with vibration 

(406, 410, 485-487); resistance exercise 

with pulleys or bone compression (488); 

aerobic exercise using treadmill and cycle 

(489); treadmill exercise while in a lowerbody negative pressure (LBNP) chamber 

(423, 490); treadmill exercise while in 

a LBNP chamber coupled with flywheel 

exercise (420); and treadmill exercise 

with addition cycle ergometry (491). 

LBNP is used as a means to draw 

blood from the head and torso into the 

lower extremities (492, 493), presenting 

a means to counteract the headward 

shift of fluids (494-496).

Heavy resistance exercise during bed rest 

protected BMD (479)—not by suppressing 

the bed rest-induced bone resorption, 

but rather by increasing bone formation 

(Figure 31), as was observed in actual 

spaceflight (124, 210). Heavy resistance 

exercise 6 days a week during bed rest 

led to dramatic increases in markers of 

bone formation (479). During the bed 

rest study dubbed WISE (WISE-2005, 

Women International Space Simulation 

for Exploration), resistance exercise was 

achieved using a flywheel device, but it 

was used only every other day (with a 

treadmill/LBNP protocol on alternating 

days). Subjects had roughly half the 

bone formation response (420) of subjects 

in the first study who performed heavy 

resistance exercises 6 days a week (479). 

Similar findings (i.e., increased formation, 

unchanged resorption) were seen when 

subjects performed resistance exercise 

with a flywheel device (458).

Male bed rest subjects who exercised 

on a treadmill while wearing a LBNP 

device had reduced bone resorptive 

response (423). Similar trends were 

observed in female bed rest subjects 

who performed these exercises (490), 

although these changes did not reach 

statistical significance in women. 

Treadmill exercise in real or simulated 

weightlessness is typically not thought 

to affect bone, given the difficulty in 

attaining significant ground reaction 

force; however, the ground reaction 

force (approximately 1.2 x body mass) 

attained during this novel exercise using 

the LBNP device was apparently enough 

to trigger bone loading. Earlier studies 

of LBNP alone had no effect on loss of 

bone calcium during bed rest (488).

In the subsequent WISE-2005 60-d bed 

rest study, the exercise treatment group 

performed a combination of flywheel 

resistance and LBNP/treadmill exercises 

on alternating days. These subjects had 

approximately half the bone formation 

response than did bed rest subjects who 

performed only resistance exercise every 

day during the same bed rest period (420). 

This is intriguing given that the amount 

of resistance exercise performed in the 

WISE-2005 study was essentially half that 

performed in the resistance exercise only 

study. However, treadmill/LBNP exercise 

had no effect on bone resorption in the 

WISE-2005 study. 

Although testing continues on potential 

exercise regimens (484), the exact 

advanced exercise concepts for 

exploration missions are currently 

unknown. These protocols must protect 

crew fitness while likely being required 

to fit in a much smaller footprint than 

exercise hardware on ISS.

Gravity

Because it is assumed that lack 

of gravity stimulates spaceflightinduced bone loss, gravity induced 

by centrifugation (“artificial gravity”) 

has been suggested as a countermeasure 

to protect multiple body systems (497-

504), particularly bone, during spaceflight. 

In early bed rest studies, 2-, 3-, or 4-hour 

intervals of standing or walking mitigated 

the increase in urinary calcium excretion 

associated with bed rest (497, 505, 506). 

Sitting for 8 hours followed by 16-hour 

bed rest did not mitigate the increased 

urinary calcium (506).

Some studies have used short-radius 

centrifuges to induce artificial gravity 

(507), whereas others have used rotating 

exercise devices (508, 509) intended 

to provide gravitational impact as well 

as physical exercise. Artificial gravity 

during space simulations and during 

hypergravity (above unit gravity) has been 

shown to positively affect bone in human 

and some animal studies (510-512). 

An extensive pilot study used 

centrifugation to create artificial gravity 

transients during a 21-day bed rest study 

(513). One hour per day of centrifugation 

resulting in 1 Gz exposure at the heart 

and 2.5 Gz at the feet was beneficial 

for some systems (e.g., cardiovascular, 

muscle) (513-515); however, this regimen 

did not have any effect on bone or calcium 

metabolism (424, 481). Similarly, during 

a 5-day bed rest study, 30 minutes per 

day of centrifugation resulting in 1 Gz at 

the center of mass, applied continuously 

or in 5-minute increments, did not affect 

bone metabolism (516). Although greater 

durations of centrifugation, intermittent 

application, increased g forces, or 

centrifugations combined with exercise 

protocols have all been proposed (497, 

508, 513, 516, 517), these have not yet 

been extensively tested. The optimal 

artificial gravity prescription for protecting 

bone during spaceflight (or bed rest for 

that matter), including the g level, duration, 

and frequency of centrifugation, remains 

to be clarified (501), as do the potential 

effects of this treatment on nutritional 

needs and related systems (518).

Vibration

Protocols for exposure to vibration 

of high or low frequency have also 

been proposed and tested in spaceflight 

analogs, as reviewed by Rittweger 

(487). Although low-frequency vibration 

protocols showed promise for protecting 

bone in both animal and ambulatory 

human studies (519-529), the beneficial 

findings were more limited when 

Figure 31. Bone resorption (as indicated by urinary NTX, left panel) and bone formation 

(as evaluated by serum BSAP, right panel) during 17 weeks of bed rest with (solid blue line) 

or without (dashed red line) heavy resistance exercise. Data are expressed as percentage of 

pre-bed rest values, and are mean ± SD. The vertical lines represent the beginning and end 

of the bed rest phase. Data adapted from (479).

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testing occurred during head-down 

tilt bed rest (530). 

Higher-frequency vibration coupled with 

resistive exercise, often referred to as 

resistance vibration exercise (531), has 

generally shown positive effects on bone 

and muscle during bed rest (408, 410, 

486, 487, 532), but not in all cases (399). 

Generally, resistance exercise yielded 

similar effects on bone metabolism as 

did resistance vibration exercise (406). 

Debate continues over the usefulness 

of resistance vibration exercise as a 

potential countermeasure protocol and 

the safety concerns regarding potential 

neuromuscular issues that could occur 

with repeated exposure to vibration. 

Pharmacological Agents

Pharmacological agents, the most 

common being the bisphosphonate 

class of compounds, have long been 

proposed as a potential method to 

mitigate weightlessness-induced 

bone loss. Interest in bisphosphonates 

arose when it was discovered that they 

suppress hydroxyapatite dissolution 

(i.e., bone resorption) in vitro and in vivo 

(533-535), and because they could be 

used to successfully treat patients with 

bone diseases (536) and individuals 

immobilized because of spinal cord injury 

or other reasons (537, 538). As with most 

pharmaceuticals, they work as expected. 

In this case, through cytotoxicity of the 

osteoclast (539, 540). 

In the early 1970s, etidronate 

(ethane-1-hydroxy-1,1-diphosphonate, 

aka EHDP) (541) was administered to four 

individuals during 20 weeks of bed rest; 

two individuals received a high dose 

(20 mg/kg/d) and two received a low dose 

(5 mg/kg/d). The high dose had significant 

effects on calcium balance and on 

the bone markers available at the time 

(e.g., hydroxyproline) compared to calcium 

balance and bone markers in untreated 

bed rest subjects. However, both groups 

of subjects had the same amount of bone 

loss; the lower dose of etidronate was 

determined to be ineffective (488, 542, 

543). During a 120-day bed rest study 

conducted in Moscow, etidronate 

(900 mg/d, approximately 11.25 mg/kg/d 

as determined from reported body weights 

of the test subjects) mitigated negative 

effects of bed rest on bone biochemistry 

and cellular activities as determined from 

iliac crest biopsies (491, 540). However, 

bone loss was not detected in these 

studies, attributed at the time to the 

short duration of the bed rest (404). 

During a 360-day bed rest study, 

etidronate (900 mg/d, approximately 

11.25 mg/kg/d as determined from 

reported body weights of test subjects) 

coupled with exercise (treadmill and 

bicycle) was effective at mitigating losses 

of bone and calcium (489) and changes 

to the bones as detected by bone biopsy 

(491). Parathyroid hormone concentrations 

were increased in these bisphosphonatetreated subjects (489), likely because 

their bodies were attempting to maintain 

circulating calcium concentrations when 

the bone was unable to release calcium. 

Clodronate (dichloromethylene 

diphosphonate) was the next 

bisphosphonate to be considered to 

inhibit bone resorption (536). Clodronate 

administration during a 17-wk bed rest 

study significantly affected calcium and 

bone metabolism, and phosphorus 

and fluoride balance (418, 544).

In a 90-day bed rest study, pamidronate 

(60 mg, administered intravenously 

14 days before bed rest) protected 

against bone loss (458, 483). It also 

reduced urinary calcium and reduced 

the number of renal stones identified 

by abdominal radiograph after bed 

rest, although this was not statistically 

significant given the small number of 

subjects (457). Nonetheless, this result 

was used to advocate for the use of 

bisphosphonates to mitigate renal 

stone risk during flight (456).

A 17-week bed rest study was used 

to test alendronate (10 mg/d), the 

next-generation bisphosphonate. 

Findings documented that alendronate 

protected bone: alendronate-treated 

subjects had biochemical changes 

reflecting reduced activity of osteoclasts 

and osteoblasts (545). Urine calcium 

excretion was reduced and calcium 

balance improved in the treated subjects 

as compared to levels in control subjects 

(545). Alendronate-treated subjects also 

had significantly higher circulating PTH 

concentrations, and a significant reduction 

in serum concentration of total and 

ionized calcium than did the non-treated 

subjects (545). 

Alendronate (70 mg administered once 

per week) was tested in a spaceflight 

experiment on the ISS (478, 546) when 

seven astronauts took the bisphosphonate 

throughout their mission. Three other 

astronauts had signed up for the study 

but discontinued participation—two of 

those due to gastric issues (478, 546). 

This study was complicated by the change 

in resistive exercise devices on the ISS 

(546). The control group exercised using 

the iRED, whereas the bisphosphonate 

group exercised using the ARED. 

Additional controls were recruited 

later and were included in the results 

published in 2019 (478). In general, 

the bisphosphonate treatment protected 

bone. Yet, intriguingly, at every bone region 

measured, the subjects who responded 

best to the ARED exercise protocol alone 

lost less bone than did the subjects who 

responded least to bisphosphonate plus 

ARED exercise protocol. The nature 

of this individual variability is unknown 

but warrants investigation. 

Bisphosphonates are often advocated 

not only for their bone-protective 

effects, but also for reducing urinary 

calcium and mitigating renal stone risk. 

Although bisphosphonate-treated bed 

rest subjects have documented reductions 

in urinary calcium, spaceflight studies 

have not documented a clear effect 

of bisphosphonates on urine calcium. 

Specifically, when urinary calcium 

excretion during flight was compared 

to preflight levels (i.e., expressed as 

percent change), the subjects who 

took bisphosphonate did indeed have 

lower urinary calcium excretion (546). 

However, examination of the raw data 

revealed that the subjects who took 

bisphosphonate had higher baseline 

calcium excretion (329) (Figure 32), 

which influenced the percent change 

from preflight. When comparing urine 

calcium excretion in subjects who 

exercised on the ARED with those 

who exercised on the ARED and took 

bisphosphonate, the bisphosphonatetreated subjects’ calcium excretion 

was lower at flight day (FD)15 and FD30. 

However, by FD60, both groups of 

crewmembers were excreting the 

same amount of calcium per day (329). 

Whether this is an escape from the effect 

of the drug is not known; however, data 

from animal studies suggest that the 

disuse-induced or the spaceflight-induced 

increase in bone resorption cannot fully, 

or chronically, be mitigated by 

bisphosphonates (547, 548). 

Discussion and debate have always 

surrounded the use of bisphosphonate 

in otherwise healthy individuals 

(astronauts), as opposed to the target 

population for whom the drugs were 

Figure 32. Urine calcium excretion before, 

during, and after spaceflight in astronauts 

who had access to iRED (dashed line, red 

triangles), ARED (solid line, blue squares), 

or bisphosphonate+ARED (dashed line, 

green circles). Data adapted from (329).

L-180

L-45

FD15FD30FD60

FD120FD180

R+0

R+30

0

2

4

6

8

10

12

Urine Calcium

(mmol/d)
70 71

developed (patients with bone diseases, 

such as osteoporosis). Although there 

are some concerns regarding use 

in the general clinical population 

(e.g., related to incidence of diseases 

such as osteonecrosis of the jaw), those 

concerns will not be addressed here. 

One concern of bisphosphonate 

use is hypocalcemia secondary to 

the pharmacologic blocking of the 

body’s ability to get calcium from bone. 

Data from astronauts show that, indeed, 

serum calcium concentrations were lower 

in the bisphosphonate-treated astronauts 

(Figure 33), and, in some cases, levels 

are outside of normal range (329).

Bisphosphonates have an approximate 

10-year half-life in the bone, which is 

one of the concerns of administering 

them to generally healthy 40- to 50-yearold astronauts. Given the long transient 

in bone, potential exists for long-term 

influence on bone health; i.e., after the 

return to Earth. An evaluation of BMD 

and estimates of hip strength in astronauts 

soon after landing showed a protective 

effect of bisphosphonate treatment 

in combination with ARED exercise 

protocols. However, when measured a 

year later, these individuals had significant 

losses in BMD and bone strength (478). 

Although this study involved a small 

number of subjects, and the individual 

variability was significant, these findings 

should give pause to the use of these 

potent pharmaceuticals until more 

extensive testing is conducted.

Endocrine therapies, including 

administration of exogenous calcitonin 

(415, 488), have also been tested for 

their ability to reduce bone loss, albeit 

unsuccessfully. In animal models, 

testosterone has also been suggested 

as a countermeasure for bone loss (549, 

550) on the basis of limited data showing 

a reduction in testosterone concentrations 

during flight in human, animal, and cellular 

models (551-556). However, recently it has 

been shown that reduction of testosterone 

is likely not a concern during spaceflight. 

See Chapter 7 for a more detailed 

discussion of these data.

Nutritional Countermeasures

It has been noted that “Nutrition is 

critical for maintenance of bone mass, 

yet adequate nutrition alone is unlikely 

to prevent bone loss in all crewmembers.” 

(351). This statement was validated in 

a more recent systematic review that 

came to the same conclusion (557). 

The converse is no doubt also true—that 

inadequate nutrition will likely exacerbate 

bone loss in all crewmembers. As detailed 

below, inadequate intake of energy, 

protein, vitamin D, or calcium will all lead 

to loss of bone and calcium. The key to 

successful exploration missions is to find 

the optimal diet, and to ensure it is safe, 

stable, nutritious, palatable, and resistant 

to menu fatigue.

One of the most obvious nutritional 

countermeasures—providing calcium—

does not protect against spaceflightinduced bone loss (558, 559), probably 

because of decreased calcium absorption 

that occurs during bed rest (413, 481) and 

spaceflight (112, 152, 384). This is likely 

related to reduced circulating parathyroid 

hormone and 1,25-dihydroxyvitamin D. 

Phosphate supplementation, used in 

an attempt to reduce calcium excretion, 

was also ineffective at mitigating bone 

loss and hypercalciuria (560), as was 

combination therapy with calcium and 

phosphorus (415).

Supplementing potassium bicarbonate 

to an already alkaline diet was able to 

reduce calcium excretion but failed to 

prevent immobilization-induced bone 

resorption in a 21-day bed rest study 

(561). Whether this effect could be 

obtained when applying an alkaline 

salt together with an acidic diet during 

immobilization is not known yet.

Omega-3 fatty acids have been shown 

to protect bone in the general population 

(228-230) and in animal studies (562), 

as well as in spaceflight analog studies, 

including bed rest and cell culture (231). 

Although omega-3 fatty acids have not 

been studied in a controlled fashion during 

actual spaceflight, a positive correlation 

was found between fish intake and bone 

loss in astronauts (231). See Chapter 4 

and Figure 13 for additional details. 

Other nutrients, specifically sodium, 

protein, potassium, and vitamin K, have 

been documented to have effects on 

bone, and/or have been proposed or 

tested as countermeasures to bone loss 

(341). These are discussed in detail below 

and in other sections of this book.

Although it is easier to evaluate specific 

nutrients and their effect on bone health, 

dietary patterns are also important. 

One key example is vegetarian or vegan 

diets and implications for bone health. 

The literature are somewhat mixed 

in this regard. Some studies suggest 

vegetarianism is beneficial (or, at a 

minimum, not detrimental) for acid/base 

balance and bone (563-568), and others 

suggest that vegetarians are at greater risk 

for low BMD and increased fractures (569-

571). However, vegetarian (572) 

and Mediterranean (573) diets have 

been associated with reduced incidence 

of renal stone formation. 

Nutrients Associated with Bone Health

The role of nutrition and bone health is 

complex. Many nutrients are required 

to maintain bone tissue. Whereas some 

nutrients have been evaluated and 

identified as potential countermeasures 

for spaceflight-induced bone loss, others 

can be detrimental to bone in insufficient 

quantities (e.g., energy, calcium, vitamin D) 

or when provided in excess (e.g., iron).

Energy

Adequate energy intake is required 

for bone health or, conversely, energy 

restriction leads to altered bone 

metabolism and bone loss. A critical 

element of the success of the ARED 

exercise protocol in mitigating BMD 

loss was likely due to the astronauts 

maintaining energy intake and body mass 

(124). The effect of energy restriction on 

bone has been demonstrated in humans 

(165, 574) and in animal models (166, 

575-578). Conversely, providing additional 

energy aided bone formation during 

military operations (579).

Weight loss in obese individuals is known 

to lead to bone loss and increased fracture 

risk (580-582). Although this may not be 

the best comparison group for astronauts, 

it raises the intriguing concept that 

bone loss in these two groups is actually 

similar in that the effective body mass 

and mechanical loading of bone is 

reduced, either by loss of weight through 

dieting, exercise, etc. or by reducing 

the gravitational pull of the Earth.

Calcium

Calcium metabolism is of critical 

importance for bone health, and for health 

in general (583, 584). Effects of spaceflight 

(and space analogs) on calcium balance 

and metabolism are described above. 

As mentioned in other sections of this book,

excess dietary calcium will not mitigate 

bone loss during spaceflight (391, 585).

Figure 33. Serum calcium before, during, 

and after spaceflight in astronauts who 

had access to iRED (dashed line, red 

triangles), ARED (solid line, blue squares), 

or bisphosphonate+ARED (dashed line, 

green circles). Data adapted from (329).

L-180

L-45

FD15FD30FD60

FD120FD180

R+0

R+30

1.9

2.0

2.1

2.2

2.3

2.4

2.5

Serum Calcium (mmol/L)
72 73

Intriguingly, calcium can potentially 

be used to analytically assess bone 

metabolism. Densitometry techniques 

(such as DXA and quantitative 

computerized tomography) provide 

valuable assessment of specific bones, 

although these techniques detect only 

relatively large changes in bone, which 

could take months to occur, while the 

initiation of biochemical changes likely 

commence within hours of exposure to 

spaceflight. Studying calcium metabolism 

requires either intensive balance studies 

or tracer kinetic studies because calcium 

excretion alone is confounded by too 

many factors to be useful in non-controlled 

studies. Markers of bone formation and 

resorption provide the ability to assess 

changes in bone biochemistry. However, 

assessing the relative association of these 

two factors has not been possible to date, 

and thus it is difficult (or impossible) 

to assess net changes in bone mineral 

from these markers.

A technique to rapidly detect and predict 

changes in whole-body bone mineral 

balance has been studied (586, 587) 

and has been validated in bed rest (588). 

This technique is based on biologically 

induced variations in the presence of the 

naturally occurring stable (nonradioactive) 

calcium isotopes (40Ca, 42Ca, 43Ca, 44Ca, 46Ca, and 48Ca), which react at different 

rates depending on their mass (589). 

These variations exist because bone 

formation favors the lighter isotopes, 

and thus the blood and urine (and other 

“soft tissue”) tends to have the “heavier” 

calcium isotopes. Bone resorption, 

however, releases whatever calcium is 

in bone, and that tends to be the lighter 

isotopes. Thus, when bone is being 

resorbed (as it is during bed rest), 

the urine contains greater amounts 

of the lighter calcium isotopes than 

it did before resorption levels increased.

When the isotope ratio technique was 

applied to a bed rest study, it showed 

that the calcium isotope ratio shifted 

in a direction consistent with bone loss 

after just 7 days of bed rest—long before 

changes in bone density were detected. 

Consistent with this interpretation, the 

calcium isotope variation accompanied 

changes in n-telopeptide, whereas 

BSAP—a bone-formation biomarker—

was unchanged (588).

Because the relationship between calcium 

isotopes and whole-body bone mineral 

balance is well established (586, 587, 

590), this relationship can be used to 

quantitatively translate the changes in 

the calcium isotope ratio in urine to 

changes in BMD using a simple model. 

Using this model, it was estimated that 

subjects lost 0.25 ± 0.07% (1 SD) of their 

bone mass from day 7 to day 30 of bed 

rest (588). This rate of loss extrapolates 

to a loss of 1.36 ± 0.38% of skeletal mass 

over 119 days, which is equivalent, within 

error, to bone loss rates determined 

by DXA scans in long-term (119-d) 

bed rest studies (405).

Given that calcium isotope measurements 

can detect changes in bone long before 

densitometry, and their potential for use 

in assessing bone loss, this technique 

is ideally suited for spaceflight studies 

in which changes in bone formation and 

resorption are not only being altered by 

spaceflight itself but are being manipulated 

by various countermeasures. Although 

work has been initiated, results have not 

been published as of this writing.

Vitamin D

The best-understood role of vitamin D 

is its involvement in calcium metabolism. 

One of the major functions of this vitamin 

is to maintain normal blood levels of 

calcium and phosphorus. The liver 

converts vitamin D to 25-hydroxyvitamin 

D, which to date is the gold-standard 

measurement for assessing vitamin D 

status. 25-hydroxyvitamin D is converted 

to 1,25-dihydroxyvitamin D in the kidney, 

a conversion that is regulated by 

parathyroid hormone. After release 

into the circulation, it is transported 

systemically to target organs. Classic 

target organs include bone, intestine, 

and kidney.

In 2011, the Institute of Medicine (IOM, 

now the Health and Medicine Division 

of the National Academies of Sciences, 

Engineering, and Medicine) conducted 

an extensive review of the literature and 

raised the recommended dietary allowance 

(RDA) for vitamin D to 600 IU/d (from 

400 IU/d) for healthy males and females 

9 to 70 years old, and to 800 IU/d (from 

600 IU/d) for those older than 70 years 

(584). The main factors that were taken 

into account included changes in bone 

density and fracture risk. The IOM 

Committee felt there was not a strong 

enough evidence base to make dietary 

recommendations based on the role of 

vitamin D in extraskeletal health outcomes 

(584), and the committee maintains that 

additional evidence is required (591-594). 

People who are exposed to sunlight 

make vitamin D in their skin. Ultraviolet 

B light, a component of sunlight, converts 

7-dehydrocholesterol to 25-hydroxyvitamin 

D3 in the skin (595). Although sunlight has 

a positive effect on health through its role 

in making vitamin D, caution must still be 

exercised to avoid too much sun exposure 

(596-598).

Examination of vitamin D on short (7-d) 

Space Shuttle missions found essentially 

no differences in 25(OH)vitamin D or 

1,25(OH)2-vitamin D during flight (599), 

although significant preflight variability 

existed. Rodent studies showed no effect 

of unloading on 25(OH)vitamin D, and 

reductions in 1,25(OH)2-vitamin D during 

unloading (600, 601) were likely secondary 

to transient hypercalcemia (602).

Starting with ISS Expedition 1 in 2000, 

ISS crews were provided 400 IU vitamin 

D/d, based on evidence that vitamin D 

status (i.e., serum 25-hydroxyvitamin D) 

decreased after long-duration spaceflight 

(110-112, 122, 152). The absence 

of ultraviolet light during spaceflight 

diminishes vitamin D stores in the body, 

as observed during the 84-day Skylab 

mission (122), Mir missions (112, 152), 

and early ISS expeditions (111). 

Despite the reported use of vitamin D 

supplements by some of the astronauts 

on early ISS expeditions (average 

supplement use was 3.0 ± 2.8 per 

week of a 400-IU vitamin D supplement), 

the mean serum concentration of 

25-hydroxyvitamin D for the ISS 

crewmembers was about 25% less 

after landing compared to concentration 

before launch.

In 2006, vitamin D supplement 

recommendations for ISS crews 

increased from 400 IU vitamin D/d to 

800 IU vitamin D/d. Coincidentally, that 

same year, a project (the Nutritional Status 

Assessment SMO) was initiated to collect 

blood and urine samples during flight. 

25-hydroxyvitamin D analysis of samples 

collected during flight provide evidence 

that 800 IU vitamin D/d is enough to 

maintain vitamin D status during longduration spaceflight (Figure 34) (124, 210). 

Adequate vitamin D status is believed 

to have been a contributing factor in 

the ability of the ARED exercise to 

maintain BMD in astronauts (124), 

as described above.

An ideal ground-based analog for 

individuals lacking ultraviolet light 

exposure is the Antarctic, where winter 

levels of ultraviolet B radiation are 

essentially zero. Research conducted 

at McMurdo Station in Antarctica helped 

determine the dose of supplemental 

vitamin D required to sustain serum 

levels of 25-hydroxyvitamin D, without 

increasing risks of hypercalcemia, during 

a 5- to 6-month period when there is little 

to no ultraviolet B exposure (603, 604). 

These and other ground-based studies 

(performed in Antarctica and at the 

Johnson Space Center) provide evidence 

that a vitamin D supplement dose in the 

range of 800-2000 IU/d is tolerable and 

safe, and can maintain vitamin D status 

for 3 to 6 months even in environments 

with no ultraviolet light exposure 
74 75

(603-605). This dietary recommendation 

is for at-risk populations (584).

One study conducted at McMurdo Station 

showed an interactive effect of stress 

(i.e., serum cortisol) and vitamin D status 

on immune function (604): higher serum 

cortisol and lower vitamin D status was 

associated with higher incidence of latent 

virus reactivation. This may be relevant 

to other viruses (606). Thus, vitamin D 

appears to affect other systems besides 

bone. However, further research is required 

before evidence-based recommendations 

can be made for the other systems.

Vitamin D deficiency is linked to calcium 

metabolism and can lead to osteomalacia 

and osteoporosis in adults (and rickets 

in children). Supplementation of 

vitamin D to ISS crews is intended 

to prevent deficiency and to ensure 

optimal vitamin D status. It should not 

be misinterpreted that this is intended 

as a countermeasure for spaceflightinduced bone loss. Activation of 

vitamin D from 25-hydroxyvitamin D 

to 1,25-dihydroxyvitamin D requires 

parathyroid hormone action, which 

is typically decreased during flight 

(112, 152). As described above, this 

is likely the result of the increased 

release of calcium from resorbed 

bone, and results in decreased intestinal 

absorption of calcium. Adequate stores 

of 25-hydroxyvitamin D will not affect 

this process. Any attempt to directly 

provide the 1,25-dihydroxyvitamin D—

or, as in some cases on Earth, excess 

25-hydroxyvitamin D levels—may lead 

to hypercalcemia, renal stones, softtissue calcification, and even death. 

Controlled trials in bedridden subjects 

have also proven that several months 

of supplementation fail to affect bone 

metabolism. In one trial, bedridden elderly 

people took supplemental vitamin D (400 

or 1200 IU/d, or placebo) for 6 months. 

Little effect was found on parathyroid 

hormone, and no effect on bone markers 

(607). In a similar 40-week trial, neither 

1000 IU of vitamin D2 (plant-based 

vitamin D) nor vitamin D3 (two groups), 

had an effect on bone markers (390). 

The problem of weightlessness-induced 

bone loss must be solved; however, 

vitamin D is not the answer. Nevertheless, 

even if bone loss is not stemmed, ensuring 

an adequate amount of vitamin D will 

remain important. The ISS space food 

system includes few dietary sources 

of vitamin D, and vitamin D cannot be 

synthesized endogenously due to lack 

of ultraviolet light. Therefore, decreased 

vitamin D status is a serious concern 

for exploration missions that could last 

1000 days. 

The DRI report includes a recommended 

upper limit of vitamin D intake of 4000 

IU/d (584), which was also the upper 

limit defined in Europe (608). The IOM 

also defined upper limits for circulating 

25-hydroxyvitamin D (125 nmol/L) 

and levels associated with toxicity 

(>200 nmol/L) (584). Additional studies 

have indicated that high doses of 

supplementation are detrimental (609-

611). Toxicity of vitamin D is typically less 

likely to occur than a deficiency (612-615). 

However, use of supplements, especially 

very large dose supplements, increase 

the likelihood of toxicity. Excessive 

levels of vitamin D in the blood can 

lead to hypercalcemia, nephrocalcinosis, 

arteriosclerosis, and soft tissue 

calcification. In one study conducted 

in Houston in healthy individuals, a 

50,000 IU dose of vitamin D administered 

weekly for 4 weeks and then monthly for 

3 months increased mean urinary calcium 

excretion to levels outside the normal 

range (605). In that study, a daily dose 

of 2000 IU or a single weekly dose of 

10,000 IU did not increase the incidence 

of hypercalciuria. Most studies evaluating 

the safety of high doses of vitamin D 

rarely collect 24-hour urine samples. 

If they collect urine at all, they only 

collect a spot urine sample, which does 

not provide sufficient evidence to declare 

these doses safe, especially for individuals 

in a remote spacecraft.

Vitamin K

The function of vitamin K was originally 

assumed to be limited to involvement in 

blood coagulation. However, an increasing 

amount of evidence indicates that this 

vitamin affects multiple physiological 

systems (616). Vitamin K is a cofactor 

in the posttranslational synthesis of 

gamma-carboxyglutamic acid (GLA). 

ɣ-Carboxyglutamic acid is a constituent 

of all vitamin K-dependent proteins, and 

its role is related to increasing the affinity 

of the proteins for calcium (617, 618). 

Vitamin K-dependent proteins include 

blood coagulation proteins and bone 

proteins (e.g., osteocalcin, matrix GLA 

protein) (618, 619). Given the association 

with bone proteins, the relationships 

between vitamin K and bone health 

have begun to be elucidated (618-622). 

It seems that perhaps analogous to 

vitamin D, vitamin K deficiency is 

associated with fracture risk and other 

bone issues. However, supplemental 

vitamin K above nominal requirements 

has not proven effective as a countermeasure to bone loss (618, 623).

Studies on Mir (624) determined that 

undercarboxylated osteocalcin was 

elevated (a sign of vitamin K insufficiency) 

as early as day 8 of spaceflight, and 

remained high during 21- and 180-day 

missions (625). Markers of vitamin K 

status were decreased after 12.5 weeks 

of spaceflight during the EuroMir 95 

mission. Vitamin K supplementation 

(10 mg/d for 6 wk) reversed these effects 

(626). Vitamin K supplementation elevated 

GLA and decreased undercarboxylated 

osteocalcin (625, 626). Based on these 

limited findings, vitamin K had been 

proposed as a countermeasure for 

spaceflight-induced bone loss (345).

Data from 11 U.S. astronauts who 

participated in early ISS missions 

(Expeditions 1 to 8, mission durations 

of 128 to 195 days during 2000-2004) 

revealed that on landing day, their 

serum phylloquinone (vitamin K1) was 

42% lower than it was before flight, 

whereas urinary GLA did not change (111). 

Despite the changes on landing day, 

monitoring of vitamin K status during flight 

has documented no evidence that vitamin 

K status is decreased during spaceflight. 

Fifteen astronauts on Expeditions 14 to 22 

had no major changes in phylloquinone, 

urinary GLA, or undercarboxylated 

osteocalcin during their flights (627). 

Phylloquinone data from those 15 crewmembers (627) plus an additional 10 are 

shown in Figure 35. The additional data 

confirm that vitamin K status does not 

significantly decrease during flight.

Figure 34. Pre- and postflight data from 

early ISS missions show that vitamin D 

status decreased after long-duration 

spaceflight, despite provision of 400 IU 

vitamin D3/d supplement (black dashed 

line, N=16). In-flight data (purple line) 

show that 800 IU vitamin D3/d is enough 

to maintain status during flight (N=26). 

Red dashed lines depict IOM-defined 

upper and lower acceptable limits 

(with respect to bone health) (584). 

The green dashed line at 80 nmol/L 

reflects what many perceive as an 

optimal level with respect to parathyroid 

hormone suppression and non-bone 

health outcomes. Data are mean ± SD. 

Figure adapted, and data updated, 

from (111, 327).

Preflight

FD15

FD30

FD60

FD120

FD180

R+0

R+30

0

25

50

75

100

125

25(OH)Vitamin D

(nmol/L)
76 77

Vitamin C

Vitamin C is discussed in greater detail 

in Chapter 12, but as a cofactor in 

collagen synthesis, vitamin C has been 

investigated for potential effects on bone 

health. Although, in the Framingham 

Study, higher vitamin C intake was found 

to be associated with lower bone mass 

(628), the significance of this association 

was marginal when data were adjusted 

for potassium intake. This suggests that 

vitamin C may be a secondary factor in 

bone loss, related to fruit and vegetable 

reduction (629-632), as described 

elsewhere in this text. Other studies 

have found that vitamin C intake or 

supplement use is related to improved 

bone health and bone mass. 

This relationship, however, depends 

on adequate calcium intake (633-636). 

Vitamin C has been related to cataract 

and cancer incidence (637-639), both 

of concern for space travelers.

Sodium and Chloride

Sodium is the major cation of extracellular 

fluid (279). Together with chloride, 

sodium is used by the body to maintain 

normal water distribution, osmotic 

pressure, and anion cation balance in 

the extracellular fluid compartment (640). 

Electrolytes in the body are essential 

for proper cardiovascular function, and 

concentrations are under renal and 

hormonal control (39). Increases in blood 

sodium levels can be caused by diabetes, 

renal polyuria, diarrhea, insufficient water 

intake, excessive sweating, or increased 

dietary sodium intake. Sodium levels 

decrease with edema, excessive water 

intake, vomiting, diarrhea, diuretic therapy, 

renal tubular damage, hyperaldosteronism, 

or lower dietary intake. For the normal 

adult, total body sodium averages 

about 60 mmol/kg body weight. 

Forty to 45% of total sodium resides 

in bone, and the balance is in 

extracellular and intracellular fluid. 

These sodium stores are classified 

as either exchangeable (42 mmol/kg 

body weight) or nonexchangeable, the 

exchangeable stores being composed 

of all cellular sodium and less than half 

of bone sodium (641). Exchangeable 

sodium becomes available by diffusion 

when plasma sodium levels become low. 

In states of edema, the exchangeable 

sodium stores absorb sodium.

Animal studies show that symptoms 

of sodium deficiency occur after 3 to 

4 weeks of dietary sodium restriction 

(642). During acute starvation, excretion 

of urinary sodium decreases to less than 

0.2 g within 10 days (643) and can be 

affected by the amount of sweat (644). 

Plasma sodium levels are maintained 

fairly well during acute starvation: an initial 

decrease is followed by a return toward 

normal values (645). Blood sodium is 

also maintained during semi-starvation. 

During the Minnesota Experiment, plasma 

sodium levels in samples taken after the 

6-month semi-starvation period were 

0.6% ± 7.3% higher than baseline levels 

(N = 4) (644). Six days of undernutrition 

resulted in large negative balances of 

sodium chloride (–12.8 ± 3.6 g/d), likely 

related to changes in water balance (644). 

Concentrations of sodium and chloride 

in plasma were measured in astronauts 

before, during, and after Apollo, Skylab, 

and Space Shuttle missions, and results 

have been reviewed extensively (1, 113, 

289, 291, 292, 646). Daily sodium intakes 

during Skylab and Space Shuttle flights 

averaged 4 to 5 g, which was similar 

to the astronauts’ preflight intakes (125). 

Sodium homeostasis and blood sodium 

levels are generally maintained during 

real and simulated spaceflight (647).

The ISS food system was initially very 

high in sodium content. Typical intakes 

on the ISS were in excess of 4.5 g, 

even with suboptimal food intake (111). 

Intakes as high as 7 to 10 g of sodium 

per day have occurred, corresponding 

to 17.5 to 25 g of salt (NaCl) per day. 

Serum and urine sodium in ISS crews 

did not change significantly during flight 

(Figure 36).

An effort was made to reformulate the ISS 

food system to reduce sodium content 

in response to astronaut ocular issues 

(see Chapter 10), along with other health 

concerns. This resulted in an approximate 

40% reduction in sodium content of the 

food system, which is reflected in dietary 

intake and urine excretion (Figure 37, 

Figure 38). ISS astronauts are briefed on 

nutrition prior to flight, and are reminded 

of concerns about sodium and the fact 

that despite reformulating the food system, 

care must be taken to avoid excesses 

in specific foods and/or condiments. 

Sodium is one of the nutrients that the 

ISS FIT App displays, thus allowing crews 

to monitor consumption in real time. 

Sodium intake has improved (Figure 39); 

however, like most terrestrial humans, 

needs more effort to lower sodium 

consumption to <2300 mg/d.

European studies of Mir crewmembers 

documented that positive sodium balance 

occurred in a non-osmotic fashion during 

spaceflight (i.e., without a concomitant 

increase in fluid compartments) (113, 

123, 291, 292, 299, 302). These data 

were confirmed in a series of groundbased studies that documented an 

increase in messenger RNA expression 

of some of the enzymes required for 

Figure 35. Serum phylloquinone before, 

during, and after flight in 25 male 

(blue line) and 8 female (gold line) ISS 

astronauts. The dashed lines indicate the 

normal range for phylloquinone. Data are 

mean ± SD. Data and N are expanded 

from the original publication of these 

findings (627).

Figure 36. Serum and urine sodium 

in 47 male (blue line/symbols) and 

11 female (gold line/symbols) ISS 

astronauts. Black dashed lines 

represent normal ranges.

Figure 37. Sodium intake of ISS 

crewmembers between 2006 and 2018, 

reflecting the reformulation in the early 2010s. 

NOTE: these data are not exact, as there 

was little insight into when specific items 

transitioned from high to low sodium. 

Each point represents reported sodium 

intake expressed as mg/kcal. Mean ± SD 

are shown for each grouping.

L-180

L-45

FD15FD30FD60

FD120FD180

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R+30

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Serum Phylloquinone

(nmol/L)

L-180

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Serum Sodium

(mmol/L)

L-180

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Urine Sodium

(mmol/d)

Sodium intake

(mg/kcal)

2001-02

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2017-18

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78 79

glycosaminoglycan syntheses in the 

skin, the displacement of sodium by 

hydrogen in the glycosaminoglycans, 

and a subsequent acidosis (299, 648-

653). Increased sodium and proteoglycan 

binding has been observed in animal 

studies conducted by Ivanova and 

colleagues in the 1970s (654). The skin 

functions as a reservoir that stores sodium 

in cases of overconsumption, and releases 

sodium when it is insufficiently supplied. 

Titze and colleagues (648, 649, 651) 

demonstrated that the lymph capillary 

system is involved in clearing sodium and 

chloride from the skin through a process 

that increases the density of lymph 

capillaries in the skin. When hyperplasia 

of the cutaneous lymph capillary system 

was inhibited, retention of skin sodium 

and chloride was augmented, thereby 

leading to increased blood pressure (655).

Although sodium is also stored in bone, 

this sodium store does not seem to 

be exchangeable and therefore does 

not take part in day-to-day sodium 

regulation. However, on Earth, excessive 

intake of sodium has been associated 

with increased bone turnover (656-658). 

Dietary sodium is known to affect calcium 

homeostasis (659-664). A predictable 

relationship exists between urinary sodium 

and calcium; that is, for each 100 mmol 

of sodium excreted in urine, 1 mmol of 

calcium is excreted (665)—a phenomenon 

that occurs with high intakes of sodium. 

More than 90% of dietary sodium is 

absorbed even when intake is high (666). 

Sodium is excreted mostly in the urine; 

however, about two-thirds of the sodium 

filtered by the kidney is reabsorbed by 

mechanisms thought to involve solvent 

drag, electrochemical gradients, and 

urea-dependent water conservation 

mechanisms to preserve total body water 

content (655). The sodium-dependent 

calcium transport system uses the energy 

stored in the electrochemical gradient of 

sodium to drive calcium into the lumen 

of the proximal renal tubule. Ultimately, 

the presence of calcium in this location 

leads to increased calcium loss secondary 

to increased sodium excretion. In the 

distal tubule, calcium is preferentially 

reabsorbed—an event stimulated by PTH 

and cyclic adenosine monophosphate 

(cyclic AMP) (667). Cyclic AMP also 

influences reabsorption of sodium (668).

A small amount of sodium is excreted 

in feces. When 550 mmol sodium was 

ingested each day for 7 days, an average 

of 1.8 ± 0.4% of the total dose was 

excreted in feces. When smaller amounts 

of sodium were ingested (50 mmol/d), 

an average of 6.0 ± 1.0% was excreted 

in the feces (1).

Salt loading alone increases intestinal 

calcium absorption. In hypoparathyroid 

patients, dietary salt increased intestinal 

calcium absorption in one study 

conducted by Meyer (669) but not in 

another study conducted by Breslau (670). 

In Breslau’s study, calcium absorption 

correlated with serum concentration 

of 1,25-dihydroxyvitamin D. 

Thus, conclusions about the role 

that PTH plays in increasing intestinal 

calcium absorption after a sodium 

load are speculative.

Studies in premenopausal women 

suggest that increased intestinal 

calcium absorption, rather than 

increased resorption of bone, 

compensates for sodium-induced 

hypercalciuria in subjects with intact 

adaptive processes related to bone 

metabolism (671, 672).

Ginty et al. (671) examined how 7 days 

of high or low intake of dietary sodium 

affected bone markers in young women. 

Although high intakes (180 mmol/d) of 

sodium resulted in increased levels of 

urinary calcium, low levels (80 mmol/d) 

or high levels of sodium intake had no 

effect on markers of bone resorption (671). 

Lietz et al. (672) also found that intakes 

of 170 mmol/d or 60 mmol/d of sodium 

for 8 days had no effect on bone 

resorption markers in postmenopausal 

women. However, Evans et al. (658) 

reported that postmenopausal women 

who ingested 300 mmol sodium per day 

for 7 days had greater excretion of bone 

resorption markers than those ingesting 

50 mmol sodium per day—an effect 

not observed in a premenopausal group 

(658). Similar results were obtained in 

ambulatory metabolic ward studies 

of healthy male test subjects (673). 

Bone resorption markers significantly 

increased only when sodium intake 

was increased from 2.8 mmol/kg body 

weight/day (approximately 220 mml/d) 

to 7.7 mmol/kg body weight/day 

(approximately 550 mmol/d), and 

not when sodium was increased 

from 0.7 mmol/kg body weight/day 

(approximately 50 mmol/d) to 2.8 mmol/kg 

body weight/day. This is in line with results 

of a study of pre- and postmenopausal 

Korean women (n=9526, >18 years of 

age with a sodium intake of >2000 mg/d): 

woman who had lower bone mass had a 

higher odds ratio for osteoporosis after 

adjusting for confounding variables (674). 

These results suggest that bone resorption 

is increased in situations where the 

adaptive responses of bone are limited 

or altered, as they are after menopause 

or during inactivity, and might also 

suggest that above a certain level of 

sodium intake per day, the regulatory 

processes are different.

Data from human and animal studies 

suggest that high intake of dietary 

sodium chloride leads to bone loss 

from increased bone resorption (675-681), 

thereby increasing the risk of osteoporosis 

(682). These studies even suggest that 

restriction of dietary sodium will reduce 

bone resorption (683). In a review of the 

interactions between dietary salt, calcium, 

and bone, Massey and Whiting (679) 

suggested that habitual excessive 

intake of salt contributes to bone loss. 

Other reviewers have concluded that 

increased intake of sodium chloride 

negatively affects acid-base balance, 

with subsequent loss of calcium 

(684, 685).

Massey and Whiting (679) found that 

specific subpopulations modulate the 

bone loss induced by excessive intake 

of salt. For example, people who tend 

to form renal calcium stones are more 

responsive to changes in dietary salt 

than are non-stone formers. Although 

stone formers and non-stone formers 

typically consume similar amounts of 

sodium (686, 687), the detrimental effects 

of high intakes of sodium intake on renal 

stone risk have been well documented 

(675, 681, 685). Increasing sodium intake 

Figure 38. Urine sodium to creatinine 

ratio in ISS crewmembers between 

2006 and 2018. The decrease reflects 

the reformulation of the food system 

to lower sodium content. Boxes and 

error bars reflect mean ± SD.

Figure 39. Sodium intake in 27 crewmembers 

and the ISS "standard menu.“ Each symbol 

represents a day’s intake during flight. 

Circles are male astronauts, and triangles 

are females. These represent crewmembers 

who recorded dietary intake with the ISS FIT 

App or kept a detailed food log. The black 

lines represent mean ± SD for each 

crewmember. Dashed lines represent 

the lower intake limit of 1500 mg/d and 

the ISS recommended <3500 mg/d. 

The DRI and exploration mission requirement 

is 2300 mg sodium/d (green dotted line).

Year of collection

Sodium/Creatinine

2006-072008-092010-112012-132014-152016-18

0

5

10

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Sodium Intake (mg/d)
80 81

from 50 mmol/d to 300 mmol/d increased 

renal stone risk by elevating urinary 

saturation of calcium phosphate and 

monosodium urate, and reducing inhibition 

of calcium oxalate crystallization (688).

Work by Goulding (656, 657) and Matkovic 

et al. (689) has generated interest in 

how dietary sodium affects bone mass. 

High levels of dietary sodium are not 

only major predictors of urinary calcium 

and hydroxyproline excretion, but are 

also associated with greater loss of 

bone with age, unless dietary calcium is 

supplemented (690). There is a significant 

bone resorption response to high levels 

of dietary sodium, and acid-base 

balance plays a role in this process (673). 

Dietary sodium also seems to exacerbate 

the calciuric responses to musculoskeletal 

unloading in weightlessness (Figure 40). 

Bed rest subjects consuming a lowsodium diet (100 mmol/d) had no change 

in urinary calcium, whereas those on 

a high-sodium diet (190 mmol/d) had 

hypercalciuria (417). Another bed rest 

study documented that the increased 

levels of bone resorption induced by 

a high-sodium diet exceeded the levels 

of bone resorption induced by bed 

rest, and that excess sodium induces 

bone resorption through a mechanism 

mediated by acid-base balance (673, 691) 

that could involve metabolic acidosisinduced increases in urinary corticosterone 

(692). Increased consumption of sodium 

and consequent low-grade metabolic 

acidosis increased bioactive 

glucocorticoids (650, 693, 694). 

Increased levels of glucocorticoid 

cause muscle wasting because the 

muscle must provide sufficient urea 

osmolytes to excrete surplus sodium (655). 

Even moderate increases in glucocorticoid 

concentrations, within the normal range, 

are associated with lower BMD and bone 

strength in healthy children (695) and 

can cause rapid bone loss (696-699). 

Consuming alkaline salt together with 

high levels of sodium (693) reduced 

excretion of calcium, bone resorption 

markers, and bioactive glucocorticoids 

during bed rest, thus supporting the idea 

that acid-base balance plays a role in the 

effects on bone metabolism by consuming 

excess levels of sodium (700-703). 

Consuming high levels of sodium both 

on Earth and during spaceflight can 

exacerbate bone loss and lead to an 

increased risk of developing renal stones. 

In and of itself, excess sodium can lead 

to hypernatremia, hypertension, and even 

death. Although it has not been a concern 

to date during spaceflight, too little dietary 

sodium or a deficiency of this electrolyte 

could lead to hyponatremia, hypotension, 

and even death.

Although the role of other factors 

(e.g., other dietary factors, exercise, 

cabin atmosphere) are not well 

understood in relation to the effects 

of excess sodium intake on bone, 

calcium, and pH, the hypothesis remains 

that adjustments in sodium intake may 

serve as a viable countermeasure 

to bone loss. Furthermore, the role 

of a high-sodium diet in potassium 

homeostasis is not well understood. 

It is possible that nutrition and 

cardiovascular effects of spaceflight 

may interact, and dietary countermeasures 

may mitigate these effects (See Chapter 8).

Protein 

Protein is a critical dietary element that 

provides amino acids to support protein 

synthesis as well as a source of fuel. 

Deficiency of protein leads to muscle 

loss, weakness, wasting, tissue 

breakdown, inability to perform 

the job (including getting out of the 

spacecraft), and ultimately death. 

The relationship between protein and 

bone health is complex, and often 

seemingly contradictory. In certain 

populations (such as growing children), 

protein is essential for bone growth. 

Diets low in protein can have negative 

consequences for bone (241, 674-676). 

However, in some cases, consuming 

too much protein can be detrimental 

to bone (704). This fact is confounded 

by the type of protein (and amino acids) 

consumed and by relations to other 

factors, including diet and physical 

activity (705-708). Excess protein can 

exacerbate the increased excretion of 

calcium during spaceflight, and increase 

the risk of bone fracture and renal stone 

formation (705, 709). 

In one 5-year study of 120 men, subjects 

who consumed a diet with restricted 

protein (52 g/d) and salt (50 mEq/d) 

had a 50% lower risk of developing 

a renal stone than did subjects who 

consumed a calcium-restricted diet 

(400 mg/d) (710). The reason for this 

decreased risk of developing renal stones 

while consuming a low-protein diet is 

not well understood; however, it is well 

accepted that diets with high levels of 

protein can induce hypercalciuria, and 

this can contribute to formation of calcium 

oxalate or calcium phosphate stones. 

One hypothesis that can explain proteininduced hypercalciuria could be related 

to the “acid-ash” hypothesis: excessive 

intake of animal protein provides excess 

sulfur-containing amino acids that are 

metabolized to sulfuric acid (711, 712) 

and, because bone is a large reservoir 

of base, it can be broken down to provide 

carbonate or phosphate to neutralize this 

acid load. Increased uric acid excretion 

can decrease the pH of urine and reduce 

urinary excretion of citrate, thereby 

increasing the risk of stone formation 

(451). Net acid excretion, as determined 

by the composition of acid and base 

components in the diet, has also been 

associated with calcium loss (713) and 

a subsequent increase in intestinal 

absorption of calcium (714). Animal protein 

is rich in purines that may raise uric acid 

excretion (451). Although vegetable protein 

and animal protein have the same sulfur 

content per gram of protein, a larger mass 

of vegetables than meat would have to 

be consumed to ingest the same amount 

of protein. Subjects who consumed animal 

protein diets had higher levels of urinary 

calcium excretion and lower urinary pH 

than subjects who consumed similar diets 

consisting mainly of vegetable protein 

(715). When subjects consumed diets 

containing either meat or soy protein, with 

and without additional supplementation 

of sulfur amino acids, the meat diet 

elicited higher levels of urinary calcium, 

sulfur, ammonia, and titratable acids than 

the soy diet elicited (716). When the soy 

diet was supplemented with sulfur amino 

acids, urinary calcium and acid excretion 

increased. Conversely, the addition of 

dietary potassium (in the form of fruit or 

K+ supplement) to both diets decreased 

excretion of urinary calcium and acid (716). 

Other studies have shown that consuming 

greater amounts of protein or higher ratios 

of animal protein to potassium are more 

detrimental when bone health is already 

compromised (such as during bed 

rest, and potentially during spaceflight) 

(247, 717).

Although increased dietary protein is 

associated with increased urinary calcium, 

debate continues as to whether increased 

urinary calcium is associated with negative 

effects on bone (718). Some studies show 

that high-protein diets increase intestinal 

absorption of calcium (714); however, 

this has not been widely accepted. 

Studies of the relationship between protein 

consumption and bone are complex. 

Figure 40. Proposed mechanism of the 

effects of high dietary sodium on bone loss. 

Image Credit: NASA.
82 83

The many nutrients and environmental 

factors involved in these studies should 

be considered when drawing conclusions 

(244, 567, 632, 707, 719, 720).

Excess consumption of protein, especially 

specific types of protein, and patterns 

of acid and base precursors have been 

associated with increased concentrations 

of urinary markers of bone resorption 

during bed rest (247, 341, 490). 

In one study of male identical twins, 

the relationship between acid and base 

precursors in the diet and markers 

of bone and calcium metabolism during 

bed rest were investigated (423), and 

a strong positive correlation was found 

between markers of bone resorption and 

the ratio of animal protein to potassium 

intake. A positive correlation existed 

between urinary NTX excretion and 

the ratio of animal protein to potassium 

consumed during the fourth week of bed 

rest (247). This study also documented 

that the dietary animal protein:potassium 

ratio was less related to markers of bone 

metabolism in the group of subjects 

who exercised and more related to 

bone markers at the end of bed rest, 

when calcium excretion was highest. 

These results support the hypothesis 

that calcium status could have an 

important role in determining the effect 

of protein on bone. If calcium is being 

resorbed from bone, then acid load can 

be more detrimental to bone, as has been 

observed in other studies assessing the 

effects of high-protein intake on bone 

(704, 705).

A dietary supplement containing 

essential amino acids and carbohydrate 

(45 g/d essential amino acids and 

90 g/d sucrose) has been assessed 

to determine whether it can mitigate 

muscle loss (717). The supplement 

contained 1.5 g of methionine; i.e., 

about 1.13 times the recommended 

daily intake for this amino acid. 

The sulfur in methionine is converted 

in the body to sulfuric acid, and thus 

methionine is an acid precursor. 

It was evident that more methionine 

was broken down than was used by 

the body because urine pH decreased in 

the amino acid-supplemented group (717). 

It was hypothesized that this low-grade 

metabolic acidosis (700) contributed to 

the higher urinary concentrations of bone 

resorption markers and calcium excretion 

in the supplemented group, thereby 

supporting the hypothesis that levels 

of acid and base precursors in the diet 

can affect bone and calcium metabolism.

Studies have been conducted to evaluate 

supplementing with base, typically 

potassium bicarbonate (KHCO3

), as an 

external means of counteracting dietary 

acid load. These studies have documented 

mitigation of the increased calcium 

loss and bone turnover (721-723), with 

questions remaining of long-term efficacy. 

European studies have combined KHCO3

with whey protein supplements. These are 

discussed in Chapter 7.

A recent study, dubbed Pro K, has 

evaluated (249) the relationship between 

protein:potassium ratio and bone effects 

during spaceflight. For 4 days, subjects 

consumed diets that contained either high 

or low ratios of animal protein:potassium, 

and blood and urine were collected at 

the end of the 4 days. During one inflight session, the net endogenous acid 

production (NEAP) was evaluated in 

astronauts who consumed the typical 

spaceflight diet. The controlled diet did 

not induce changes in biomarkers of bone 

turnover as hypothesized, and it was 

suspected that exercise protocols, the 

high CO2

 cabin environment, and/or some 

other factor(s), obscured an acute effect 

of the diet (249). The NEAP of the subjects 

who consumed the typical spaceflight 

diet ad libitum, however, was associated 

with regional bone loss as detected with 

postflight DXA determinations (Figure 42) 

(249). Thus, despite the complexity, this is 

another case where diet provides potential 

to mitigate bone loss associated with 

spaceflight (724).

Iron

Iron is an essential element involved 

in oxygen transport, oxidative 

phosphorylation during metabolism 

of carbohydrates and lipids, and electron 

transport by cytochromes and cytochrome 

oxidase (725-727). Intake of adequate 

levels of iron is crucial for meeting the 

needs of many organs and tissues, but 

excess iron is detrimental to cells and 

can cause oxidative damage (728), 

especially in the spaceflight environment, 

as reviewed by Yang et al. (729). The body 

achieves iron balance through hepcidincontrolled regulation of iron absorption by 

enterocytes in the intestine and export of 

iron from cells (730). Once iron is absorbed 

into the enterocyte, it can be bound to 

ferritin and stored. Serum ferritin is a 

sensitive indicator of iron stores (731, 732).

Iron deficiency is the most common 

nutritional deficiency worldwide; however, 

iron toxicity is also worthy of concern. 

Deficiency of iron leads to anemia, 

fatigue, reduced work capacity, impaired 

behavior and impaired intellectual 

performance, cognitive deficits and 

memory loss, heart palpitations, impaired 

thermoregulation, and altered immune 

function (725-727, 733). 

High iron status, as reflected by high 

serum ferritin concentrations, has 

been linked to tissue damage, disease 

incidence, and mortality (734). Excessive 

intake of iron has also been related to 

GI distress, and moderately increased 

iron stores exacerbate bone loss, oxidative 

stress, cardiovascular disease, and 

cataracts or other ophthalmic issues. 

The toxic potential of iron derives from 

its ability to exist in two oxidative states 

(ferrous and ferric forms). Iron serves as 

a catalyst in redox reactions; however, 

when these reactions are not properly 

modulated by antioxidants or iron-binding 

proteins, cellular damage can occur (735). 

Iron metabolism adapts to maintain normal 

concentrations of iron in the body despite 

disparate physiological requirements and 

dietary supply (735). Levels of iron in the 

body, about 4 g in the adult human, are 

determined by physiological demands 

for iron, dietary supply, and adaptation 

(735, 736). The amount of iron consumed 

is a function of both the content and the 

bioavailability of iron in food; bioavailability 

is lower in non-heme than in heme iron 

sources. Dietary sources that inhibit 

absorption of iron include tea, coffee, 

bran, calcium, phosphate, egg yolk, 

Figure 41. NASA astronaut T.J. Creamer shown 

here with his FD15 Pro K food container, with 

a few items floating loose. Photo Credit: NASA.

Figure 42. Relationship between NEAP 

and loss of lumbar spine BMC after flight. 

Figure adapted from Zwart et al. (249).

0 10 20 30 40 50 60 70 80 90

-10

-8

-6

-4

-2

0

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L Spine BMC

(D from preflight, g)
84 85

polyphenols, and certain forms of 

dietary fiber (735). Conversely, meat, 

fish, poultry, and ascorbic acid will 

enhance the bioavailability of 

non-heme iron.

When RBC mass decreases, such as 

during spaceflight, iron subsequently 

transfers from newly synthesized RBCs 

into storage proteins, including serum 

ferritin, an index of iron storage (111, 737, 

738). In addition to these physiologic 

changes that can increase astronauts’ iron 

stores, astronauts typically consume high 

levels of iron during spaceflight (Figure 43). 

The iron content of the ISS food system 

is very high, largely because many of the 

commercial food items in the ISS menu 

are fortified with iron (1). The mean iron 

content of the standard ISS menu is 

20 ± 6 mg/d; however, some crewmembers have consumed more 

than 47 mg/d during some weeks 

on the ISS. For reference, the defined 

iron requirement for exploration missions 

is 8 mg/d for both men and women (1, 37), 

and the current U.S. DRI for individuals 

31 to 50 years of age is 8 mg/d for men 

and 18 mg/d for women. The DRI for both 

men and women over 51 years of age is 

8 mg/d (273). The tolerable upper intake 

limit for iron as defined by the Institute of 

Medicine is 45 mg/d (273). Although the 

nominal spaceflight requirements for iron 

are the same for men and women, given 

the assumptions about changes in iron 

metabolism during flight, individual 

assessment is required with regard to 

menstrual cycle status (including possible 

pharmacological suppression during 

flight), and preflight iron status. Thus, iron 

requirements may be higher for some 

individuals, and intake recommendations 

and/or supplementation should be 

considered to prevent iron deficiency 

and anemia in these individuals. 

The recommended iron intake for 

female astronauts not suppressing 

their menstrual cycle is 18 mg/d.

Indices of iron metabolism and 

erythropoiesis return toward normal 

relatively quickly (days) after landing, 

although the replenishment of RBC 

mass may take several weeks. 

The repletion of RBCs usually occurs 

after the disproportionate return of 

plasma volume after spaceflight that often 

induces a dilutional “anemia” effect (739). 

For example, a 3% to 5% decrease in 

hematocrit between landing (R+0 d) and 

R+3 days is common after both shortand long-duration flights (739). 

Serum ferritin concentrations often 

decrease in the weeks after flight 

because iron is mobilized to replete 

RBCs and other tissues after flight. 

This repletion can also result in anemia 

if iron reserves are not adequate. 

Anemia and tissue iron depletion 

have been observed after flight (740).

Although the spaceflight-induced decrease 

in RBC mass is substantial, the efficient 

recovery after flight suggests that this 

change represents an adaptation to 

weightlessness. After the first weeks of 

flight, RBC mass and body fluid volumes 

reach new plateaus (lower than volumes 

on Earth), as shown by data obtained 

during long-duration flights (128, 741-

743). The triggering mechanism for these 

changes is unknown. One hypothesis 

is that the body senses a decreased 

requirement for blood volume and adapts 

in response to changes in fluid (circulatory) 

dynamics. That is, reduced gravitational 

strain on the circulatory system during 

flight may result in more-efficient delivery 

of oxygen to tissues, or may cause the 

decreased plasma volume and increased 

concentration of RBCs in the first few 

days of spaceflight. The decrease in 

RBC mass has no documented 

functional consequence.

Iron stores increase early during a 

mission (within 15 days) and then return 

to preflight concentrations by the end 

of a 6-month mission (10). In a recent 

study of 23 crewmembers who flew for 

50 to 247 days, serum ferritin increased 

about 220% in women and 70% in men 

by FD15 (10). In the same study, the 

transferrin index often exceeded 1 μmol 

iron/μmol transferrin, which provides 

evidence that iron overload occurred (744). 

Levels of other acute-phase proteins 

(C-reactive protein and ceruloplasmin) 

were not changed during flight, indicating 

that the ferritin response was likely not just 

an inflammatory response. The increased 

iron storage response (i.e., the area under 

the serum ferritin curve) correlated with 

the spaceflight-induced change in BMD, 

and an association was also found 

between increases in the levels of ferritin 

and other markers of iron status and 

increased levels of bone resorption 

markers. The greater the increase in ferritin 

during flight (or the longer it was elevated; 

either case would result in a greater area 

under the curve), the greater the decrease 

in BMD in the hip, trochanter, hip neck, 

and pelvis after long-duration spaceflight 

(10). The change in ferritin levels over the 

course of a 6-month mission (Figure 44) 

is nearly identical to the change in urinary 

8-hydroxy-2'-deoxyguanosine (8OHdG, 

a marker for oxidative damage) during 

spaceflight. These findings indicate 

that ferritin concentrations during flight, 

concentrations that were not outside 

the normal clinical range, were associated 

with evidence of oxidative damage 

and bone resorption, as has been 

demonstrated in other studies in healthy 

ground-based populations (745-747). 

For example, increased body iron stores 

were related to the rate of change in 

regional bone loss over a 3-year period 

in healthy individuals (748). Further 

evidence exists that radiation, oxidative 

stress, and bone health are also related 

(749), as reviewed by Yang et al. (729).

Bed rest studies have not proven to 

be consistently reliable models for the 

hematological changes induced by 

spaceflight. A decrease in RBC mass 

was recorded during early bed rest 

studies, whereas erythropoietin was 

unchanged and hematocrit increased 

in these studies (750), suggesting 

that the mechanisms that bring about 

hematological changes during bed rest 

are different from those that act during 

spaceflight. If the reduced RBC mass 

during flight is caused by the reduced 

gravitational load on the circulatory 

system, it is reasonable to assume 

Figure 43. Iron intake in 27 crewmembers 

and the ISS "standard menu." Each symbol 

represents a day’s intake during flight. 

Circles are male astronauts, and triangles 

are females. These represent crewmembers 

who recorded dietary intake with the ISS FIT 

App or kept a detailed food log. The black lines 

represent mean ± SD for each crewmember. 

Dashed lines represent the upper limit of 

45 mg/d (red line), the RDA for women of 18 

mg/d (purple line), and the RDA for men of 8 

mg/d (blue line). See text for details 

on spaceflight requirements.

Figure 44. Iron stores, reflected by serum 

ferritin (red circles, solid line) and oxidative 

damage to DNA, reflected by urinary 8OHdG 

(blue squares, dashed line) before, during, and 

after long-duration spaceflight. Data are mean 

± SD for 23 ISS astronauts. Data are expressed 

as percent change from preflight. Figure 

adapted from (10).

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8OHdG (% D from preflight)

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that bed rest alone would not alleviate 

these forces. Bed rest would only 

change the direction relative to the 

body. Small changes in iron status 

have been recorded during bed rest, 

the most consistent change being 

a drop in hematocrit and hemoglobin 

levels after re-ambulation (254, 419), 

suggesting an effect of plasma volume 

replacement and a smaller role of 

hematopoiesis. 

An intriguing study of iron metabolism 

during 5 days of dry immersion 

showed a shift in iron metabolism (751). 

Some of these findings may be related 

to fluid shifts, which resulted in an 

increased hemoglobin and hematocrit 

after only 5 days. The changes observed 

are evidence of a need for future studies 

concerning the role of iron in adaptation 

to microgravity, and in astronaut health.

Changes in altitude can induce 

hematological changes; descent from 

high to low altitude induces changes 

similar to those observed during 

spaceflight (decreased RBC mass, 

increased iron storage) (752). 

Exogenous erythropoietin prevented 

the changes (752), suggesting that 

erythropoietin is involved as a regulating 

mechanism, and may also be involved 

in regulating the initial blood volume 

changes during spaceflight.

The NASA Extreme Environment 

Mission Operations (NEEMO) undersea 

habitat provides an excellent analog 

for spaceflight-induced changes in iron 

status (753), as detailed in Chapter 14. 

Because of the increased air pressure 

in the habitat, NEEMO crewmembers 

are exposed to higher oxygen pressures, 

which increase their risk for oxidative 

damage to DNA, proteins, and lipids 

(754-757). Probably because of the 

increased pressure and greater oxygen 

availability, body iron stores are elevated 

during the saturation dive (111, 737). 

Levels of ferritin in the serum increase 

during the NEEMO saturation dives 

(10-14 d), and evidence of oxidative 

damage and stress is also observed 

during these dives (753). On a recent 

NEEMO mission, levels of RBC folate 

decreased during the dive, and plasma 

concentration of folate was inversely 

correlated with serum concentration 

of ferritin (758). Decreased activity of 

superoxide dismutase and peripheral 

blood mononuclear cell poly(adenosine 

diphosphate [ADP]-ribose) were also 

evident during the dive, indicating a 

DNA repair response was activated (758).

Iron overload is also associated with 

retinal degeneration and cataract risk 

(759). Increased oxidative damage 

occurred in the retina and the liver of 

irradiated rats that consumed excess 

levels of iron (760). Furthermore, the 

formation of free radicals subsequent 

to elevation of iron stores has been 

linked on Earth to increased risk of 

cardiovascular disease and cancer. 

Although some studies provide 

contradictory evidence (761, 762), 

a correlation between coronary heart 

disease and iron status has been 

described in a number of recent studies 

(763-765), and an association between 

increased incidence of myocardial 

infarction and increased iron stores has 

been observed (765, 766). In a prospective 

Finnish study, increased risk of all cancer 

types combined, and colorectal cancer 

in particular, was associated with high 

iron stores (767). The relationship 

between iron and lipid levels and cancer 

incidents has also been documented in 

the Framingham study (768). Excessive 

iron stores have also been linked to 

deficiency of ascorbic acid; when 

reductions in ascorbic acid occur, vitamin 

A and selenium tend to exacerbate ironinduced peroxidation processes (769). 

These data suggest that the alterations 

in erythropoiesis and iron metabolism 

that occur in microgravity could cause 

significant changes to crew health.

Better characterization of iron metabolism 

during spaceflight with respect to other 

systems is warranted because of the high 

levels of dietary iron in space food, 

the increase in iron stores early during 

flight, and the potential for iron to act 

as an oxidizing agent during spaceflight, 

which could be exacerbated by increased 

radiation exposure during exploration 

missions. Specific bacteria under some 

growth conditions can be more virulent 

in microgravity (770). Ground studies 

show that elevated iron status can 

increase risk for infection (771). 

Investigating the increase in iron status 

during flight with respect to changes in 

immune function will be an important 

next step in understanding the implications 

of elevated iron status during spaceflight. 

Furthermore, iron absorption, and any 

effect on iron status, has yet to be 

determined during flight.

Phosphorus

Phosphorus is an important component 

of cell membranes and bone mineral, 

and it also contributes to cellular energy 

(772, 773). Phosphate accounts for 

about 60% of bone mineral (772), and 

most (85%) of the body’s extracellular 

phosphorus is in bone (772). Phosphorus 

homeostasis is somewhat analogous 

to calcium, with controlled circulating 

concentrations, renal excretion balancing 

intestinal absorption, and regulatory 

factors that include PTH and other 

compounds (772, 774). High levels of 

phosphorus intake, relative to calcium 

intake in particular, can have detrimental 

effects on many systems, including 

skeletal, renal, and cardiovascular 

systems (772, 775-780). 

The recommended dietary intake of 

phosphorus for men and women is 

700 mg P/d (772, 781). Ideally, the 

calcium:phosphorus ratio in the diet 

should be around 1.0 or higher (780), 

based on evidence that consumption 

of high levels phosphorus relative to 

levels of calcium can decrease calcium 

absorption, increase bone turnover, and 

ultimately can affect skeletal integrity (780). 

Phosphorus is found in multiple forms 

in the diet; a large source being salts 

added in processed foods (772).

The ISS and exploration mission 

requirements match the RDA for 

phosphorus, with a notation that the 

phosphorus intake should not exceed 

1.5 times the calcium intake (1, 36-38). 

To date, phosphorus intakes have been 

higher than desired (Figure 45). The ISS 

“standard menu” has a Ca:P ratio of 

0.48 (1) (Figure 43); actual intakes have 

been slightly lower than that (Figure 46). 

During bed rest studies, subjects have 

tended to consume Ca:P ratios closer 

to 1.0 (782).

After ISS missions, urinary excretion of 

phosphorus was about 45% lower than 

levels before flight (111). Excretion of 

Figure 45. Phosphorus intake in 27 ISS 

astronauts and in the "standard menu.” 

The dashed line represents the requirement 

of 700 mg/d.

Figure 46. Dietary calcium (Ca):phosphorus (P) 

ratio in 27 ISS crewmembers and the “standard 

menu.” Ideally, the Ca:P ratio would be no less 

than 0.67 (i.e., P:Ca <1.5), as shown by the 

black dashed line.

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phosphorus during bed rest was not 

changed (419) from ambulatory conditions. 

An earlier study of three bed rest subjects 

revealed increased urinary phosphorus 

and negative phosphorus balance (412). 

Investigators have attempted to use a 

combination of calcium and phosphorus 

to mitigate bone loss and hypercalciuria 

during bed rest, which have induced 

trends in the right direction but no 

significant changes (415).

Magnesium

Magnesium is the fourth most abundant 

cation in the body, and more than half 

of the body’s magnesium is in bone 

(783). Good-quality diets that are rich 

in magnesium and potassium have been 

associated with improved bone health 

(784, 785). Magnesium is also critical 

for neuromuscular function, serving 

as a cofactor in a multitude of cellular 

functions, and is a keystone of 

cardiovascular health (786, 787). 

Excessive magnesium intake from 

supplements can impair calcium 

absorption (788), whereas magnesium 

deficiency leads to bone loss and 

other health implications (789).

Magnesium status is not easily assessed. 

Although serum and urinary magnesium 

are relatively easy to determine, serum 

contains only 1% of the body pool 

of magnesium, and changes (or lack 

of changes) do not necessarily reflect 

magnesium status (783, 790, 791). 

The concentration of magnesium 

in tissue provides a more direct, if 

not the best, assessment of magnesium 

status, and can be estimated through 

analysis of sublingual cells (791, 792). 

However, these analytical tests are 

challenging and expensive.

The recommended intake of magnesium 

for adults (age 31-70 y), is 420 mg/d for 

men, and 320 mg/d for women (781). 

These recommendations were proposed 

for exploration missions (38), whereas the 

recommendation for ISS crewmembers 

is only 350 mg/d (36). Additionally, the 

recommended upper limit for magnesium 

supplements on exploration missions 

is defined as 350 mg/d (38).

On Earth, a clear relationship exists 

between energy intake and magnesium 

intake, and the same holds in flight 

(Figure 48). As a result, astronauts 

may not consume enough magnesium 

due to the overarching concern of 

adequate dietary energy intake (1, 111). 

Athletes who restrict energy intake (e.g., 

dancers, wrestlers, gymnasts) can also 

be deficient in magnesium (793).

Magnesium assessments before and 

after Apollo (794) and 4- to 6-month 

ISS missions (111) have documented a 

consistent decrease in urinary magnesium. 

Small decreases in the concentration 

of magnesium in serum or plasma 

were detected after Apollo and Skylab 

missions (122), and slight increases in 

the concentration of magnesium were 

detected after early ISS missions (1). 

In addition to the limitations of determining 

magnesium status from assessments of 

magnesium in serum and urine, postflight 

assessments need to be interpreted 

cautiously given the fluid shifts that 

occur during flight and the fluid loading 

and recovery that occurs after flight. 

In-flight analyses during some shortduration (≤ 30 d) space missions and 

some missions of up to 3 months 

(1, 795) have shown that the concentration 

of magnesium in serum is slightly lower 

than preflight values. The decrease was 

likely not statistically significant (statistics 

were not performed due to the small n 

[2-6]), and the magnitude of change was 

also small (an average of 2.3-8.3% below 

preflight values) (1, 795). During Skylab 

missions, the concentration of urinary 

magnesium increased during the first 

2 months of flight, did not change 

during the third month, and decreased 

after flight (122). 

Autopsy results after the tragic 

end of the 24-day Salyut-1 mission 

documented that, relative to control 

subjects, the Salyut-1 cosmonauts had 

12% to 32% lower concentrations of 

magnesium in the compact layer of the 

femoral epiphysis and diaphysis, vertebral 

body, and sternum (796). These changes 

were reported “with a high degree of 

certainty.” Magnesium balance was 

slightly negative during extended-duration 

bed rest studies conducted in Russia 

(489), and exercise or bisphosphonate 

supplements had little effect on this 

change. Magnesium excretion was lower 

during both short- and long-duration bed 

rest (254, 419). 

A comprehensive evaluation of magnesium 

and spaceflight was published in 2015 

(797). This publication includes data from 

short- and long-duration space missions 

and long-duration bed rest studies, 

and included not only serum and urine 

data, but a unique assessment of tissue 

magnesium status using a sublingual 

scraping and cellular magnesium analysis 

(797) (Figure 49).

Figure 47. Magnesium intake in 27 ISS 

astronauts and in the “standard menu.” 

Each symbol represents one 24-hour intake. 

Female crewmembers are represented as 

triangles, males as circles. The blue dashed 

line represents the requirement for men 

(420 mg/d), and the purple dashed line 

represents the RDA for women (320 mg/d).

Figure 48. The relationship between magnesium 

intake and energy intake in astronauts during 

flight. Each point represents a day’s record; 

however, even partial days were included 

when available. Data are from 27 astronauts 

who kept detailed dietary records, and 

represent 3458 days of collection.

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Magnesium Intake

(mg/d)

Figure 49. Tissue magnesium concentration, assessed through analysis of sublingual cells, before 

and after flight (left panel) and bed rest (right panel). In the flight data, solid blue line/squares 

denotes crewmembers who had access to ARED, dashed red triangles iRED, and dashed green/

circles ARED+ bisphosphonate. In the bed rest data, blue dashed represents 60-day bed rest 

subjects, and red solid line the 90-day bed rest subjects. Figure adapted from (797).

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Magnesium is a critical nutrient 

that has many important functions. 

Although magnesium homeostasis 

can be altered on Earth by disease 

states and medication use, the available 

data document that despite consistent 

and significant alterations in the 

concentration of urinary magnesium 

after spaceflight, tissue stores of the 

mineral are maintained. In addition, 

in-flight data reveal increased 

concentrations of magnesium in serum 

and urine. Thus, there is no general 

cause for concern that astronauts have 

magnesium deficiency. Additional studies 

are warranted to better understand the 

role of magnesium in astronaut health 

and to better define astronauts’ 

requirements for magnesium (797). 

Copper

Copper is an essential cofactor for 

enzymes involved in energy production 

and neuroendocrine signaling, in 

metabolism of oxygen and iron, and 

in maturation of extracellular matrix 

and neuropeptides (798, 799). 

Deficiencies in copper have implications 

for bone, nervous system, and 

cardiovascular health, and for immune 

function and lipid metabolism (800). 

Copper is one of many nutrients that 

can be toxic at high levels (801-805). 

When divalent copper is consumed in 

high amounts, it can accumulate in the 

brain and enhance the aggregation of 

amyloid-β into amyloid plaques that 

become neurotoxic and release oxygen 

free radicals (806). High concentrations 

of copper have been implicated in 

cardiovascular disease (807, 808), and 

in neurodegenerative conditions such as 

Alzheimer’s disease (801). Divalent copper 

is found in supplements and in drinking 

water that is transported in copper pipes.

The involvement of copper in bone health 

is specifically related to lysyl oxidase 

function and collagen synthesis (800, 809). 

Copper is not usually stored in tissues 

per se; however, liver, brain, and kidney 

typically contain the largest amounts per 

unit tissue mass (800). Total amount of 

copper in the human body ranges from 

about 50 to 120 mg (0.79-1.9 mmol) 

(810). Transport and regulation of 

copper involves the blood protein 

ceruloplasmin (811). 

Copper deficiency leads to normocytic, 

hypochromic anemia; decreased 

production of leukocytes and neutrophils; 

and defects in connective tissue 

(specifically in collagen synthesis) 

that can lead to vascular and skeletal 

problems and central nervous system 

dysfunction, or even death (812). 

Heartbeat irregularities have also been 

reported in cases of copper deficiency 

(813). Deficiency symptoms, including 

macrocytic anemia, bone abnormalities, 

and decreased neutrophil production, 

have been reported in subjects with serum 

copper concentrations ranging from 0.9 to 

7.2 μmol/L (814). Toxic concentrations of 

copper can lead to oxidative damage, GI 

distress, liver damage, or even death (800).

One Russian report (796) documented 

“non-uniform changes” in copper content 

of bone from different regions after 

spaceflight relative to levels in non-flight 

controls. Copper content of the femoral 

epiphysis was 81% to 159% greater 

after flight than before flight, whereas 

the amounts of copper in the vertebral 

body and sternum were 36% and 58% 

less, respectively, after flight. (This study 

reported autopsy results after the tragic 

end of the 24-day Salyut-1 mission, 

relative to controls.)

Serum concentrations of copper and 

ceruloplasmin (the major copper-carrying 

protein in blood) were measured before 

and after early (2000-2005) ISS missions 

as part of the medical requirement to 

assess nutritional status in crewmembers, 

and no significant changes were observed 

after flight (111). Additional testing was 

implemented with the Nutrition SMO 

and Biochemical Profile projects. 

Results indicated that serum 

concentration of copper and urinary 

copper excretion were unchanged 

during flight (815) (Figure 50).

During a 17-week bed rest study, copper 

balance was unchanged; however, it 

increased after re-ambulation (816). 

During and after 3 weeks of bed 

rest, concentrations of copper and 

ceruloplasmin in serum were unchanged 

(254). After 90 days of bed rest, the 

concentration of serum copper was 

only slightly elevated, but the increase 

was statistically significant (419). 

During 60 and 90 days of bed rest, 

ceruloplasmin concentrations were 

unchanged (419). Copper balance was 

lower during 21-day bed rest, and seemed 

to be even lower in subjects who were 

exposed to 1 hour per day of artificial 

gravity to counter the effects of bed 

rest (815). The causes and implications 

of this are unknown and warrant 

further investigation.

Zinc (and Lead)

Zinc is an important mineral with a broad 

range of functions, including a role as a 

structural and functional enzyme cofactor 

in a myriad of reactions, and has effects 

on many systems, including brain function 

and cognition, immune system function, 

and bone health (817-820). Studies 

have identified preliminary associations 

between zinc deficiency and incidence 

of diseases such as diabetes and cancer 

(819). However, as with many nutrition 

components of disease, the relationships 

are not always clear (821).

Assessment of zinc status has been 

a topic of debate. Some claim that zinc 

content of plasma, urine, and even hair 

are reliable indicators of zinc status 

in healthy individuals (822); however, 

the general consensus remains that 

circulating zinc levels are an imperfect 

tool to evaluate zinc status because 

other physiological factors may affect 

levels of zinc in the blood (817). 

Leukocyte metallothionine content 

has been advocated as a biomarker 

of zinc exposure, but additional work 

remains to confirm these findings (823). 

The recommended dietary intakes of zinc 

for adult men and women are 11mg/d and 

8 mg/d, respectively (273), matching the 

recommendations for space travelers (38). 

Because zinc is stored in bone along 

with other minerals, the release of zinc 

and other heavy metals from bones 

(as a result of demineralization) during 

spaceflight (or bed rest) raises concerns 

about potential toxicity. Release of zinc 

from bone has been noted in bed rest 

studies (816, 824), and a similar increase 

in excretion of zinc was noted in Wistar 

rats flown during COSMOS 1129 

(a 20-day spaceflight) (442). 

As was seen with copper, zinc levels 

were lower during 21 days of bed rest than 

levels before bed rest, and levels seemed 

to be even lower in subjects who were 

exposed to 1 hour of artificial gravity per 

day (815). The mechanism or significance 

of these finding are unknown but could 

be related to transient artificial gravityinduced fluid shifts and/or gravitational 

forces affecting mineral transport and 

metabolism, or even that the artificial 

gravity could have decreased GI transit 

time and thus affected mineral absorption. 

Figure 50. Serum copper in ISS 

crewmembers before, during, and after 

flight. Males are represented by blue line, 

and females the gold. Adapted from (815).

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On early ISS missions, concentrations 

of zinc in serum and urine excretion did 

not change after flight (111). The Nutrition 

SMO and Biochemical Profile projects 

allowed for the determination of zinc in 

serum and urine before, during, and after 

flight. Serum zinc concentration was 

unchanged for preflight values during 

flight, but was significantly lower when 

tested soon after landing, and again 

30 days later (815) (Figure 51). 

Concentrations of urinary zinc were 

higher in the first weeks of spaceflight; 

however, at other time points during 

the mission, no statistically significant 

change from preflight was detected (815). 

Although these changes likely reflect 

the release of zinc during bone 

mobilization early inflight, and recovery 

of musculoskeletal tissue after flight, 

they require further evaluation. 

Concern exists that other metals, including 

lead, could also be released secondary to 

weightlessness-induced bone resorption 

(825, 826). A computational model 

developed by Garcia et al. predicted 

that lead levels in the blood would actually 

decrease during microgravity exposure. 

The model predicted that for the majority 

of astronauts, any increase in circulating 

lead would be more than offset by 

decreases in ingested or inhaled lead 

during the mission (827). Postflight data 

supported this model (827).

Figure 51. Serum (left) and urine (right) zinc in ISS crewmembers before, during, and after flight. 

Males (n=48) are represented by the blue line, and females (n=12) the gold. Black dashed lines 

represent normal ranges. Adapted from (815).

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Protein Biochemistry 

Negative nitrogen balance, a gross 

indicator of muscle loss, was detected 

during Space Shuttle flights (852, 853). 

Potassium and nitrogen balances became 

increasingly negative throughout the 

duration of Skylab flights; however, levels 

of urinary creatinine (a measure of muscle 

mass) did not change (122, 366) despite 

volume losses in the leg (121, 840). 

Serum concentrations of total protein 

and albumin were elevated at landing 

after Skylab missions. After Space Shuttle 

missions, synthesis of plasma proteins 

increased at landing but decreased in 

the week after flight, potentially secondary 

to competition for amino acid substrates 

required to replete muscle, RBC, and 

other proteins after flight (250, 853).

The concentration of urinary albumin 

is reduced during spaceflight and 

bed rest (314-316). Levels of urinary 

albumin excretion are typically low 

in healthy individuals, reflecting renal 

protein function.

Levels of amino acid in the urine 

and plasma do not provide an accurate 

indication of muscle metabolism, or even 

protein metabolism; however, in some 

cases, these are the only available data 

for this assessment. A general increase 

in levels of plasma amino acids was 

noted in cosmonauts after they returned 

from short- (2-day and 21-day) (854, 855) 

or long-duration (63-day) flights (856, 857). 

However, these levels had declined a week 

after flight (858). The limited data available 

from Space Shuttle crewmembers indicate 

a tendency for plasma levels of branchedchain amino acids to increase during flight, 

relative to preflight levels (859). Crewmembers of short-duration Space Shuttle 

flights had little or no change in their 

urinary amino acid profiles during flight 

(118), whereas Apollo and Skylab crewmembers had increased urinary excretion 

of the amino acid metabolites creatinine, 

sarcosine, and 3-methylhistidine during 

flight (376), suggesting that contractile 

proteins of skeletal muscle are degraded 

in weightlessness.

7 Muscle

Exposure to microgravity induces loss of muscle volume and performance capabilities 

such as decrements in maximal force and power production. These effects occur, 

especially in the legs, during both short- (121, 828-834) and long-duration flights 

(121, 828, 835-841). As with bone, regional changes in muscle loss appear to be 

dependent on the muscle’s role in counteracting gravity; and thus although the lower 

extremity and core muscles are significantly affected, upper body muscles are not (842).

This topic has been extensively reviewed (164, 464, 828, 829, 831, 839, 843-851). 

Interpreting findings reported in the literature can be difficult (833, 843, 846). That is 

because, as with most physiological systems, a variety of techniques are used to assess 

multiple aspects of muscle, including exercise tests of functional muscle performance 

that evaluate multiple muscle groups, single joint evaluations that focus on a single 

muscle group, muscle biopsies to evaluate cellular changes, and magnetic resonance 

imaging (MRI) of muscle size. From a nutrition perspective, muscle and protein are 

almost synonymous; therefore, amino acids and protein biochemistry are studied, 

along with tracer kinetic studies to evaluate changes in protein metabolism. 
116 117

The balance of protein synthesis and 

protein catabolism affects the amount of 

protein in the body or in individual tissues. 

Studies aimed at understanding changes 

in body protein include measures of both 

of these factors, in addition to turnover. 

Directly measuring protein metabolism 

is not easy, and the results are variable 

(839, 860). For example, although both 

decreased protein synthesis and increased 

protein catabolism will yield a net loss of 

muscle, the mechanisms involved in these 

two processes are quite different, and 

therefore different measures would 

be required to counter each process.

Studies that used stable isotopes to 

measure protein turnover indicate that 

turnover of whole-body protein increases 

during short-duration spaceflight: 

although levels of protein synthesis 

increase, a greater percentage increase 

occurs in protein breakdown (852, 853). 

Stein et al. (847, 861) hypothesized that 

this increase in protein synthesis is related 

to physiological stress, as indicated by 

generally (but not consistently) increased 

levels of urinary cortisol during flight 

(7, 105, 208). Serum and urine cortisol 

in ISS crewmembers are shown 

in Figure 52. Studies of Apollo 17 

crewmembers found that excretion 

of urinary cortisol was higher on 

days with more physically and mentally 

demanding mission tasks (862).

Decreased prostaglandin secretion has 

also been implicated in the loss of muscle 

tissue during spaceflight, secondary to 

decreased mechanical stress on muscle 

(208). Conversely, on long-duration Mir 

flights, investigators noted decreased 

rates of protein synthesis (102), secondary 

to reduced dietary energy intake (158).

The processes that induce muscle loss 

during spaceflight or bed rest are similar 

to the processes that induce metabolic 

breakdown in catabolic patients. This is 

a critical and confounding issue because 

inadequate energy intake will lead to 

these same effects. Therefore, because 

most astronauts do not meet energy 

intake requirements and they lose body 

mass, and it is unknown whether (or the 

extent of) loss of muscle mass results 

from the effects of spaceflight alone, 

or to what degree inadequate dietary 

intake confounds this loss. 

Ground Analog Studies

Bed rest is the most common model 

used for studying changes in muscle 

and protein during disuse. Many studies 

have shown decrements in muscle mass, 

strength, and performance in this analog 

(829, 832, 864-875). A recent bed rest 

study assessed whether feeding patterns 

affected muscle loss and metabolism; 

no difference in muscle loss or glucose 

metabolism was detected when food 

was delivered using nasogastric tube 

feeding, either continuously or in four 

bolus administrations per day (876).

Dry immersion is another method 

of invoking muscle disuse. Muscle 

changes may be induced faster during 

dry immersion than during bed rest; 

however, long-duration dry immersion 

studies are more difficult to implement 

than long-duration bed rest studies 

(429-431, 877-884). Unilateral limb 

suspension (ULLS) can also be used 

to induce muscle changes as a result 

of disuse. These studies incur significantly 

less expense than bed rest studies and 

the subjects have more freedom (885-889). 

Loss of muscle mass and strength in the 

suspended limb is the same as losses 

induced in the same muscle during bed 

rest, although changes are restricted 

to the immobilized muscle whereas 

bed rest induces muscle loss through 

the body (890-892). These models all 

provide a means to collect data that 

would be difficult if not impossible to 

collect from large groups of subjects 

during actual spaceflight. However, 

it is important to remember that model 

systems are just that, and that they 

likely do not provide an exact replica 

of the physiological changes that occur 

during spaceflight (893). 

Spaceflight-induced loss of muscle 

mass and muscle strength may be 

related to changes in whole body 

protein turnover. Many studies have 

documented a decrease in protein 

synthesis during bed rest (515, 894-901). 

Evidence of increased rates of protein 

catabolism during bed rest is more limited, 

as reviewed by Bodine (846). The loss of 

muscle loss with disuse is associated with 

increased oxidative stress, as reviewed 

by Powers et al. (902).

Muscle Loss Countermeasures

Mechanical

Exercise is perhaps the most obvious 

measure to maintain muscle, bone, 

and cardiovascular health (464, 467, 

469, 829, 845, 848, 884, 903-910). 

On Mir flights, crewmembers differed 

significantly with respect to frequency 

and intensity of their in-flight exercise 

(related to such factors as mission 

requirements and personal habits). 

However, all subjects lost almost 

20% of the volume of their leg muscles, 

as detected immediately after flight 

using MRI (841). 

The ISS has the size and volume 

to accommodate a suite of exercise 

equipment that includes a treadmill, 

a cycle ergometer (Figure 57), and 

resistive exercise devices (476, 911, 

912). On early ISS missions, the exercise 

regimens generally did not help to maintain 

muscle or bone mass (475) or muscle 

mass or strength (906). When a secondgeneration treadmill and an advanced 

resistance exercise device were launched 

in 2008 (Figure 53), ISS crewmembers 

were able to maintain bone and increase 

their lean body mass (124, 147); however, 

these countermeasures did not fully 

protect muscle strength.

Many types of exercise devices and 

protocols have been proposed to aid 

in maintaining musculoskeletal and 

cardiovascular health during flight, 

including resistance exercise using 

traditional resistance (479, 886, 898), 

rowing (913), flywheel devices (871, 

914-918), jumping systems (919), 

and treadmill exercise within a LBNP 

system (920), or combinations of the 

above (921, 922). 

Given that ISS crews use multiple 

exercise devices, it will be important to 

assess the effects of exercise protocols 

that involve combined use of these 

devices. Combined resistance and 

aerobic exercise protocols have 

shown promise for protecting muscle 

Figure 52. Serum and urine cortisol in 13 astronauts before, during, and after ISS missions. 

Adapted from (863).

0

5

10

15

20

25

30

35

40

Serum Cortisol (μg/dL)

L-180

L-60

FD15FD60

FD160

R+5

L-180

L-60

FD15

FD60

FD160

R+5

0

20

40

60

80

Urine Cortisol (μg/d)
118 119

(and the cardiovascular system) during 

bed rest (923, 924). A shorter, moreintense combined exercise regimen 

has been proposed as a way to save 

time while protecting muscle, bone, 

and cardiovascular health. Although 

ground results were promising (484), 

initial spaceflight results suggest these 

regimens did not provide additional 

physiological benefit, but did save 

crew time (925, 926).

Whole-body vibration alone or while 

performing resistive exercise may provide 

a viable musculoskeletal countermeasure 

(485, 526, 531, 532, 927-931), particularly 

when strenuous exercise is not advised 

due to increased risk for injury—for 

instance, in older people. As mentioned 

earlier, mechanical stimulation is a 

prerequisite to avoid degradation 

of muscle and bone. According to 

Frost’s mechanostat theory (387, 932), 

a certain individual level of mechanical 

stimulation has to be achieved to 

maintain muscle and bone mass and 

muscle strength, and that lowering 

or increasing that level of mechanical 

stimulation will affect the response. 

The vibration magnitude during wholebody vibration training seems to be one 

of the key factors. Vibration magnitude 

is defined as the vibration frequency 

(Hz) times the amplitude or displacement 

(mm) (929). This is most likely the reason 

why whole-body vibration training with 

a frequency of 20 Hz has not always been 

effective for protecting muscle and bone 

(399), whereas whole-body vibration while 

performing resistive exercise seemed to 

be more effective. When young, healthy 

male subjects performed this combined 

protocol during bed rest studies of 

56 or 60 days (485, 931), they were 

able to attenuate atrophy of their muscle 

and bone and deconditioning of their 

lumbar spine, and prevent accumulation 

of fat in their vertebral marrow (408, 410, 

411, 485, 531, 933-935). Although the 

efficacy, vibration dose, frequency, and 

duration of whole-body vibration exercise 

have not been thoroughly researched, this 

does not seem a viable countermeasure 

for use inflight given the associated risks.

Electrical stimulation is another way to 

invoke muscle activity in cases of disuse 

(936, 937), as reviewed by Dirks et al. 

(938). However, electrical stimulation 

maintains muscle mass but not strength 

(939), and electrical stimulation is likely 

a much-less-effective countermeasure 

than exercise, which provides many 

additional benefits.

Blood flow restriction in combination with 

either resistance or vibration exercise has 

been advocated as a countermeasure for 

muscle loss (940-942); however, results 

have been varied (886, 943). As reviewed 

by Behringer and Willberg, blood flow 

restriction may provide a potential way 

to augment exercise, but concerns 

about safety and utility in microgravity 

require further study (941). Whether the 

recent findings of thrombosis (944, 945) 

during flight dampen enthusiasm for this 

technique is not yet known.

Pharmacological

Exogenous testosterone is commonly 

suggested as a pharmacological method 

to mitigate spaceflight-included muscle 

(and/or bone) loss, because testosterone 

concentration can decrease in humans 

(551-556, 946, 947) and animals (549, 

550) during flight, and in cellular models 

of spaceflight. Among the potential 

confounding factors for the reduced 

levels of testosterone is inadequate 

energy intake. Decreases in testosterone 

have been observed in exercising bed rest 

subjects, whereas sedentary controls had 

no change in testosterone (948). A recent 

study in rats showed that suppression 

of testosterone (via orchiectomy) did 

not exacerbate disuse-induced muscle 

loss (949).

The initial in-flight testosterone data 

from human spaceflight were from three 

astronauts on Skylab 4, an 84-day mission 

(950), followed by one in-flight data point 

from four astronauts on Space Shuttle 

mission STS-55, which flew in 1993. 

On the Space Shuttle mission, circulating 

testosterone levels were decreased after 

4 or 5 days of flight relative to preflight 

levels, when measured in serum, saliva, 

and urine. Serum cortisol, cortisol 

biorhythms, and dehydroepiandrosteronesulfate concentrations in these four 

astronauts were unchanged during 

flight (947, 951).

A significant confounding issue is that 

these crewmembers were consuming 

only about 60% to 85% of their basal 

metabolic energy requirements during 

the flight (113). Estimates of spaceflight 

energy requirements calculated with the 

WHO equation typically use an activity 

factor of 1.7 (i.e., 1.7 x basal metabolic 

rate) (1, 40). This factor is based on 

data documenting that total energy 

requirements are unchanged during flight 

(101) or, in some cases, are even increased 

with heavy exercise (102), relative to 

before flight. Even if lower estimates of 

activity were used, the result would reveal 

significant energy deficit in crewmembers 

on the STS-55 mission, especially during 

the days of sample collections (113). 

Indeed, energy intake, which was very 

carefully documented on these missions, 

was below even basal requirements. 

Energy deficits, both short- and longterm, are associated with lower circulating 

testosterone (free and total) (952-954). 

Thus, the discrepancy between the 

long-duration data presented here 

(Figure 54) and the earlier reports 

of effects observed during the first 

week of flight could be explained 

simply by inadequate energy intake.

Data from ISS show that testosterone 

and related hormones are unchanged 

by real or simulated weightlessness, 

apart from transient effects on landing 

day (209). Furthermore, Skylab missions 

reported urinary testosterone from three 

crewmembers at two in-flight data points, 

and found that testosterone excretion 

was increased relative to the preflight 

period (209, 950).

Figure 53. NASA astronaut Shannon Walker, 

equipped with a bungee harness, exercises 

on the Combined Operational Load Bearing 

External Resistance Treadmill (COLBERT) 

in Node 3 of the ISS. Photo Credit: NASA.

Figure 54. Serum total testosterone 

concentrations before, during, and after 

flight on the ISS. Although circulating 

concentrations decreased significantly after 

flight (at R+0), no other time point differed 

significantly from the preflight mean. Data are 

mean ± SD. Data are from Smith et al. (209).

L-180

L-45

FD15

FD30FD60

FD120FD180

R+0

R+30

0

10

20

30

40

Serum Total Testosterone

(nmol/L)
120 121

Plasma data from the three Skylab 

missions (N=9) are reported to have 

shown “a trend toward lower values 

after the mission” (950). Although we 

do not have urinary testosterone data 

on all crewmembers, these reports 

from the 1970s confirm the findings 

from the ISS (209).

Several ground-analog studies 

demonstrate that bed rest has no 

effect on circulating testosterone 

concentrations in sedentary subjects 

(209, 897, 948, 955-957). In one such 

study, consistent decreases in serum 

testosterone were observed after 

subjects had been in the bed rest facility 

for 7 days (while they were still ambulatory) 

and then another decrease occurred when 

testosterone was measured 5 days after 

re-ambulation. The pre-bed rest change 

is likely related to stress and decreased 

ambulation while subjects were in the 

bed rest facility, and the post-bed rest 

change was probably related to body 

fluid shifts during and after bed rest. 

No changes in testosterone occurred 

during bed rest (209).

Bed rest subjects are typically required 

to consume energy at a level to maintain 

body mass. If energy deficits are 

indeed part of the observed decrease 

in testosterone during the Space Shuttle 

flights previously reported, this may 

also explain the difference between 

those flight data and bed rest study 

data, reported herein and elsewhere. 

Although we showed an intermittent 

decrease in total and free testosterone 

in bed rest subjects with or without 

an artificial gravity (i.e., centrifugation) 

protocol (254), this study had combined 

the two pre-bed rest collection sessions. 

When these sessions were analyzed 

separately because of our results in 

the later bed rest study, it turned out 

that testosterone concentrations were 

indeed higher only at the first data 

collection point (BR-10) than during 

or after bed rest (209) (Figure 55).

One criticism of sedentary bed rest 

studies as an analog for spaceflight 

is that astronauts are not sedentary, 

especially on long-duration missions, 

when they exercise extensively. 

Wade et al. reported that in a 4-week 

study, bed rest subjects with intensive 

exercise protocols had lower nonfasting circulating plasma testosterone 

concentrations than non-exercising 

bed rested controls (948). They reported 

a small loss of (non-fasting) post-breakfast 

body mass (948, 958), and reported that 

caloric and liquid intakes were designed 

to maintain body mass. Despite the 

exercise, which was described as 

including an expenditure of 214 or 

446 kcal/d (5 times a week), actual 

intakes in the exercise groups were only 

155 or 212 kcal/d greater than those 

of the no-exercise group (958). A bed 

rest study of exercise with and without 

testosterone administration showed some 

beneficial effects on metabolism and an 

enhanced muscle response (957, 959), 

with the steroid adding some protections 

beyond exercise itself. In another bed 

rest study, exogenous testosterone 

administration maintained muscle mass 

and protein balance, but with no effect 

on muscle strength (956).

In a 30-day study, Zorbas et al. showed 

that serum testosterone decreased during 

bed rest only in trained subjects, whereas 

it did not change in untrained subjects 

during bed rest (960). Interestingly, 

when conditioned subjects were 

“hyperhydrated” by saline ingestion 

during bed rest, testosterone did not 

change relative to the pre-bed rest period. 

In a shorter, 3-day bed rest, no differences 

in plasma testosterone were observed 

before or after exercise in typically 

untrained or trained individuals, 

either cyclists or weight trainers (961). 

Astronauts on ISS missions are typically 

relatively fit before flight and exercise 

heavily during flight, using treadmill, 

cycle, and resistive exercise devices. 

As reviewed by Tou (962), in studies 

of rats with sample collections after 

spaceflight, serum (963) and urinary 

(964) testosterone were generally 

decreased relative to the preflight 

period (965). Unfortunately, in-flight 

biological samples are typically not 

available, given the difficulties with 

collection procedures in the microgravity 

environment. These postflight conclusions 

are consistent with data reported on 

landing day after a short-duration 

spaceflight (209). 

In ground-based rodent models, 

short-duration (7-12 d) unloading 

generally results in reduced circulating 

testosterone concentrations and an 

associated loss of bone and muscle 

mass (549, 550, 966). One study of 

unilateral limb immobilized rats found that 

androgen deficiency did not exacerbate 

muscle loss of immobilization (i.e., that 

these two factors are not additive) (949). 

Unloading of longer-duration (6 weeks) 

in rats resulted in impaired spermatogenesis, but had no effect on circulating 

testosterone concentrations (967). 

Similarly, the production of testosterone 

by rat testes after actual spaceflight is 

diminished, as is response to stimulation 

by luteinizing hormone (968). Contradicting 

these findings, another study showed 

no change in circulating testosterone 

in suspended rats after suspension for 

1 or 3 weeks, but it did show an increase 

in testosterone of suspended animals after 

8 weeks, despite reduced testicular weight 

(969). One critical confounding factor in 

the hind-limb suspended rat model is that 

not all studies take (surgical) precautions 

to prevent ascension of the testicles 

into the abdominal cavity, which can 

significantly affect testosterone production 

and the interpretation of the study. 

Some, but not all, studies have accounted 

for this, and this limitation contributes to 

inconsistencies in the literature.

Rotating cell culture vessels have also 

been used as an analog of weightlessness, 

with some limitations, as with all analogs. 

Cultured testicular fragments exposed to 

this environment, compared with static 

1g cultures, have maintained cellular 

architecture and have increased both 

proliferation and testosterone secretion 

(970), but with altered testicular physiology 

(971), including impaired Leydig cell 

responsiveness to luteinizing hormone 

stimulation. Whether the lack of change 

in circulating testosterone observed in 

the studies reported herein obscured 

alterations in testicular physiology is 

unclear, but it seems imprudent to 

make that leap without additional data.

Administration of testosterone to 

suspended rats mitigates muscle and 

bone losses (549). The bone data in rats 

are confounded by differential effects on 

growing and adult rats (447); however, 

Figure 55. Serum total serum testosterone 

concentrations in subjects in multiple bed rest 

studies: data from a 21-day bed rest testing 

an artificial gravity countermeasure are shown 

with blue triangles, filled symbols and solid 

line = control, n=7, open symbols and dashed 

line = AG, n=8 (254). Note: pre-bed rest data 

assigned to BR-10; control subjects in 60- to 

90-day bed rest studies are shown with red 

circles and solid line, n=15 (209); control 

subjects in a 70-day bed rest study are shown 

with purple diamonds and solid line (957); 

control subjects in a 30-day bed rest study are 

shown with black squares and solid line, n=8 

(209); subjects treated with vibration for 60- to 

90-day bed rest are shown with open black 

circles and dashed line, n=7 (209). Vertical 

lines represent the beginning and end of 

bed rest. All data are mean ± SD.

BR-10

BR-3/1

BR 7/8

BR 14/15

BR 21 BR 28 BR 35 BR 42 BR 49 BR 56

BR 60/63

BR 70 BR+0

BR+5-8

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15

20

25

30

Total Testosterone

(nmol/L)
122 123

these results are of interest nonetheless. 

Testosterone administration to elderly 

individuals has shown that the bone 

response to testosterone depended 

on the initial circulating testosterone 

concentrations (972). That is, subjects 

who had normal blood concentrations 

of testosterone had less or no response 

to testosterone administration. 

Given these data, there is little 

rationale for providing testosterone 

during flight to mitigate bone loss.

Hypergravity, induced by centrifugation, 

has been shown to result in increased 

urinary testosterone excretion in monkeys 

(946), as well as in rats (964, 966). 

Hypergravity has also been found to affect 

tissues of rats and some other endocrine 

variables, but increased gravitational force 

had no effect on circulating testosterone 

(963). On the basis of these data, authors 

have suggested that the response to 

gravity is roughly linear, from hypergravity 

(increased), to unit gravity, to microgravity 

(decreased) (946, 963). Intriguing as this 

concept may be, the data presented 

herein do not support it.

As is understandable, the proposed 

use of exogenous steroids is somewhat 

controversial. Muscle physiologists 

argue that despite the lack of change 

in endogenous steroids, exogenous 

androgens may prove a viable 

countermeasure nonetheless. 

Treatments with such androgens 

have been reported to improve physical 

performance, muscle mass, and muscle 

strength in both young athletes and older 

sedentary men (973). The interaction of 

endocrine factors, aging (including middle 

age), the spaceflight environment, and the 

use of exercise to replace loading is not 

well understood.

In summary, circulating testosterone 

and related hormones are unchanged 

by real or simulated weightlessness, 

apart from transient effects after flight. 

The interrelationships of energy balance, 

exercise, stress response, and endocrine 

function are complicated, and evaluation 

of available literature must be done so 

carefully to assess study design, dietary 

intake, controls and countermeasure 

treatments, and fitness of subjects. 

As we contemplate space exploration 

beyond low-Earth orbit, endocrine data 

will be critical for understanding human 

adaptation in this unique environment, 

and potentially for helping to counteract 

the negative effects of spaceflight on 

the human body.

Nutritional

Use of protein and amino acid 

supplementation has long been studied 

as a potential means to mitigate muscle 

loss associated with spaceflight (865, 

974, 975); however, results have been 

inconclusive at best (976). Noteworthy, 

feeding Skylab crewmembers energy 

and protein equivalent to those given 

to a comparison bed rest group did not 

prevent negative nitrogen balance and 

loss of leg muscle strength observed 

during flight (366, 836, 840). 

In a 2011 review, Stein and Blanc 

evaluated the literature from bed rest 

studies (977), and found that the effect 

(or lack thereof) of amino acids on muscle 

depended greatly on protein intake and 

energy provision. Specifically, if nominal 

protein intake (i.e., in both treatment and 

control groups) was at levels greater than 

1.1 to 1.2 g protein/kg body mass/d, 

then supplemental amino acids had no 

effect. If control subjects were provided 

with ≤0.8 g protein/kg body mass/d while 

the supplemented group consumed 

>1.0 g protein/kg body mass/d, then the 

supplement appeared to have a beneficial 

effect. We review many of these studies in 

this report, and attempt to highlight details 

and differences that potentially contribute 

to the varied effects.

Two recent studies were conducted 

using unilateral leg immobilization. 

One fed subjects eucaloric diets with 

high (1.6 g protein/kg body weight), 

low (0.5 g protein/kg body weight), 

or no/very low (0.15 g protein/kg body 

weight) for 3 days, and found no difference 

in protein intake on loss of muscle mass 

or strength (978). The other fed high-dose 

leucine (15 gm/d) and found no protection 

of muscle strength (979). The latter 

paper was accompanied by an editorial 

concluding that these protein and amino 

acid supplementation studies had run 

their course (976). 

Feeding a bed rest group adequate 

energy with higher protein reversed 

nitrogen losses (899). These subjects 

consumed isocaloric diets, with either 

0.6 or 1.0 g protein/kg body weight (899). 

Given the lower protein intakes are below 

the RDA of 0.8 g/kg body weight, these 

findings aren’t surprising. Typical intakes 

of protein during flight exceed the 

RDA (as with most Western diets). 

Recent updates to the spaceflight 

nutritional requirements have used 

protein recommendations set for 

“high intensity athletes,” and target 

1.2-1.8 g/kg body weight.

A series of studies evaluated amino 

acid supplementation in bed rest 

and other ground models (980). 

Supplementation of essential amino 

acids (16.5 g) and carbohydrate 

(30 g sucrose) three times per day 

maintained muscle mass and strength 

via maintenance of protein synthetic 

pathways during 28-day bed rest 

(981, 982), compared to those not 

receiving the supplements. The sucrose 

was added “to improve palatability” 

of the supplement; in turn, the 

supplement provided 558 kcals/d 

to the treatment group. Including 

exogenous hypercortisolemia as a 

treatment group improved the relative 

effect of essential AA/carbohydrate 

supplementation when compared to the 

bed rest with hypercortisolemia (982-984).

A 10-day bed rest study of older 

individuals (group average age: 

68 years and 71 years) receiving 

placebo or essential amino acid 

supplementation (45 g/d) had minimal 

effect on muscle parameters when 

pre-bed rest differences among subjects 

were taken into account (985). A 7-day 

bed rest of older (60- to 80-year-old) 

individuals supplemented with either 

leucine (14.6 g/d on average) or alanine 

(13.2 g/d on average) found positive 

effects of leucine on maintenance of 

muscle mass, but not of strength or 

function (986) when compared to alanine. 

The difference in dose amounts was 

related to differences in body mass 

of the subjects between groups, and 

the doses were per kg body mass. 

Similarly, provision of a whey protein 

isolate supplement in a eucaloric diet 

had some effect on muscle mass, but 

not on function (973). In this study and 

others, individual response variability 

highlights concern of the nature 

of the effect and potential for 

confounding factors.

A 28-day bed rest study evaluating 

the timing of amino acid administration 

provided subjects with 15 g of essential 

amino acids with carbohydrate 

(35 g sucrose) before or 3 hours after 

exercise, with findings suggesting that 

exercise plus the supplement is better 

than the supplement alone (987-989). 

Although this essential amino acid 

supplement was similar to the regimen 

described above, it was given only once 

per day, and 6 days per week (to align 

with exercise sessions). The supplement 

was also given to all treatment groups. 

The supplement plus exercise ameliorated, 

but did not eliminate, loss of muscle 

mass and strength (987, 989) as well 

as metabolic changes (e.g., altered lipid 

profiles) (988).

Protein/amino acid supplementation 

was one countermeasure that was tested 

in the Women in Space Exploration study 

(WISE-2005) (990), a 60-day bed rest study 

with female subjects. The control group 

consumed 1 g protein/kg body mass, 
124 125

and the treatment group consumed 

1.45 g protein/kg body mass with an 

additional 0.72 gm branched chain amino 

acids (leucine, isoleucine, and valine) daily. 

By design, the diet during bed rest was 

hypocaloric, and subjects in this study 

were not required to eat all of their food, 

resulting in body mass loss and increased 

subject variability (248). Nonetheless, 

this approach did not mitigate losses 

of muscle mass or strength (923, 991, 

992). As reviewed in Chapter 6, excess 

protein is a concern for bone health, 

as documented in this study as well 

(248, 409), in part related to effects 

of amino acid oxidation on acid/base 

balance, specifically driving pH lower.

To address this acidogenic effect, some 

studies have employed providing a source 

of base to counteract the acid. In a pair 

of bed rest studies, 19 and 21 days, 

Bosutti et al. evaluated effects of bed rest 

on muscle fatigue and metabolism, and 

the ability of a whey protein (0.6 g/kg/d 

in addition to the baseline 1.2 g/kg body 

weight protein, provided isocalorically 

in place of carbohydrate and fat) plus 

potassium bicarbonate supplement to 

counteract any decrements (993, 994). 

Although muscle volume was reduced, 

resistance to fatigue was not affected by 

bed rest alone, or by the countermeasure 

(993). Oxidative capacity was reduced with 

bed rest. A similar 21-day bed rest study 

evaluated whey protein and potassium 

bicarbonate supplementation, with no 

mitigation of muscle atrophy or on the 

effects of bed rest on cartilage (995, 996).

Using a single leg immobilization model 

in healthy older men (average age 

69 years), Dirks et al. tested a nutritional 

supplement that provided 300 kcal/d, 

and specifically included protein 

(41.4 g total protein per day, including 

21.2 g essential amino acids), 

carbohydrate (18.8 g/d), and fat (6 g/), 

along with vitamins and minerals (997). 

The supplement (and inherent additional 

caloric intake) did not mitigate loss of 

muscle mass and strength.

Although many continue to argue for 

the importance and benefit of protein 

as a spaceflight countermeasure, 

or for different sources of protein, 

or specific amino acid mixtures, or 

the timing of protein intake relative 

to exercise (as described in the review 

of a subset of this literature provided here), 

clear evidence supporting this is simply 

not available. The existing studies are 

often too short to allow an understanding 

of long-term effects and adaptation, and 

are often not completely controlled with 

respect to treatment groups. This presents 

a confounding factor that is often ignored, 

given that protein (or amino acids) provide 

not only a nitrogen source, but moreover, 

an energy source. Studies often compare 

protein supplementation to controls 

getting no supplement, and the caloric 

intake difference could explain (i.e., 

confound) effects. Few if any studies 

evaluate the simple effect of providing 

more food (i.e., a balanced diet) would 

offer similar benefit. Providing protein 

supplements to subjects that are losing 

weight because of hypocaloric provisions 

seems an ill-fated approach to the 

maintenance of muscle. Well-controlled, 

balanced, long-term studies are required 

to conclusively define the effect of protein 

intake on musculoskeletal health. 

From the data to date, if crewmembers 

consume enough energy and protein, 

with adequate exercise, then supplemental 

amino acids (or other variants of protein 

supplementation) provide no benefit 

and, at worst case, they may actually be 

detrimental, as described in Chapter 6.

Nutrients Associated with 

Muscle Health

Energy and protein are key nutritional 

components when it comes to muscle 

health. Energy was described in detail 

in Chapter 4, and protein was also 

discussed in Chapter 7, as well as 

being discussed above in relation 

to counteracting muscle loss. 

Potassium

As the most plentiful intracellular cation, 

potassium has a significant role in several 

physiological processes (39, 998, 999). 

It is crucial to regulation of acid-base 

balance, energy metabolism, blood 

pressure, membrane transport, and 

distribution of fluid within the body. 

It is also involved in the transmission 

of nerve impulses and cardiac function 

(1000). Potassium metabolism that is 

disordered because of excessive or 

deficient circulating levels has negative 

consequences for cardiac, muscle, 

and neurological function.

Deficiency of potassium leads 

to hypokalemia, muscle weakness, 

constipation, and fatigue, or even 

death. No evidence of adverse effects 

is associated with toxicity of potassium 

from naturally occurring sources. 

However, supplemental intake may 

cause hyperkalemia (and associated 

weakness, cardiac arrest, and paralysis), 

metabolic acidosis (700), decreased 

neuromuscular function, or even death.

Serum and urinary levels of potassium 

were both decreased after spaceflight in 

Apollo crewmembers (1001), and evidence 

exists that a similar decrease occurred in 

Skylab crewmembers (122). Loss of both 

total body potassium and exchangeable 

potassium was observed in Apollo 

crewmembers (1001). Increased levels 

of urinary potassium during spaceflight 

may be related to muscle disuse atrophy 

and inadequate intake (647). 

In the initial days of bed rest, excess 

dietary sodium was shown to be 

potassium-depleting (Heer, et al., 

unpublished observations). Loss of lean 

body mass, along with high sodium intake, 

may also result in potassium depletion.

Figure 56. Front to back: Expedition 34 crew astronaut Tom Marshburn and cosmonauts 

Roman Romanenko and Evgeny Tarelkin with floating fruit and vegetables in ISS Node 1. 

Photo Credit: NASA.
126 127

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136 137 8 Cardiovascular 

Cardiovascular health is a concern for space travelers, and is one of the most studied 

aspects of human physiology during actual and simulated flight. Although a brief 

overview is presented here, along with a focus on nutritional aspects of cardiovascular 

health, the overarching topic of cardiovascular health in space has been reviewed 

in the scientific literature (1002-1009), and in evidence books analogous to this 

one (1010-1012). 

Studies on the ISS have shown mixed results, with some, but not all, investigations 

finding evidence of vascular changes (1013, 1014). Recent studies identified few 

changes in arterial structure and function, but noted accompanying metabolic changes 

(e.g., insulin resistance) and oxidative stress and inflammation (863, 1015, 1016). 

Whether these differences represent individual variability in responses among astronaut 

cohorts in different experiments, or differences in techniques, timing, or other factors 

remains unknown.

As discussed in Chapter 12, exposure to ionizing radiation during spaceflight can 

produce reactive oxygen species (ROS) and reactive nitrogen species (RNS), which 

can induce oxidative stress and damage. Oxygen participates in high-energy electron 

transfers during biological reduction/oxidation (aka redox) reactions such as the 

synthesis of adenosine-5-triphosphate (1017). Because of their biochemistry, proteins, 

lipids, and DNA are all susceptible to oxidative damage from ROS and RNS. 

ROS and RNS are produced by endogenous and exogenous sources and the 

body has antioxidant systems to remove them. As reviewed by Tahimic and Globus, 

ROS and RNS play a role in regulating tissue function and structural integrity, including 

specifically vascular and bone health (1018). These reactive species are known to 

contribute to atherogenic processes (1019). Oxidative stress and inflammation in 

general are known risk factors for the development of cardiovascular disease and has 

been extensively reviewed (1020). Several studies conducted during spaceflight provide 

evidence that oxidative damage markers are elevated during flight (10, 863, 1021). 

Plasma inflammatory cytokines are also elevated in most crewmembers during flight 

(1022). ROS generation during spaceflight seems to be from radiation exposure and 

through upregulation of oxidative enzymes and downregulation of antioxidant enzymes, 

all of which are associated with concerns for cardiovascular health (1023). Whether the 

oxidative damage and inflammation observed in crewmembers contributes greatly to 

cardiovascular changes is still not well understood. One study with 13 crewmembers 

on long-duration missions to the ISS did observe increased oxidative damage and 

inflammation; however, no changes occurred in common carotid artery and brachial 

artery structure and function (863). Long-term follow-up continues to assess residual 

effects of spaceflight on cardiovascular health. 

The findings from these studies may have significant implications for future missions 

(1024). As described later in this book, oxidative stress is a multifaceted issue that 

affects many systems; given the radiation concerns of exploration-class missions 

(1011, 1025), and space radiation concerns related to cardiovascular health in 

particular (1026-1029), this issue will draw greater attention in the future.

European Space Agency astronaut Tim Peake 

uses hardware for the Vascular Echo experiment. 

Photo Credit: NASA. 
138 139

Nutrients Associated with 

Cardiovascular Health

Energy

As discussed in Chapter 4, cardio

vascular deconditioning is associated 

with restricted energy consumption 

during bed rest (161, 162). Insufficient 

energy intake is associated with 

greater plasma volume loss (Figure 58). 

The spaceflight data came from the 

work of Dr. William Carpentier, who 

evaluated crewmember medical 

records from the Mercury, Gemini, 

and Apollo programs (88). 

Dr. Carpentier’s data from astronauts 

in the early U.S. space programs 

have been integrated and modeled 

to predict postflight heart rate 

response to LBNP, standing, and 

tilt from factors including flight 

duration, plasma volume loss or 

energy intake, and preflight resting 

heart rate. Project Mercury data 

documented effects of weight loss 

corresponding to changes in heart rate 

and, moreover, that these effects were 

more related to time in the pressure suit 

than time in microgravity (88). These data 

clearly link energy intake and plasma 

volume loss with cardiovascular health 

during and after spaceflight, as reviewed 

in more detail in (154).

One piece of the spaceflight puzzle 

that is still missing is the effect of 

longer flight durations. That is, the 

data presented in Figure 58 were 

generated from short-term flights, and 

this relationship may change on longer 

ISS missions. Given the inference that 

energy intake should be greater than 

33 kcal/kg body mass to avoid plasma 

volume loss, we evaluated ISS intake 

data (Figure 59) and found that few 

crewmembers are meeting this threshold.

Similar findings relating energy intake and 

cardiovascular deficits were obtained from 

bed rest studies to evaluate the effects of 

hypocaloric diets on many physiological 

systems (159, 1034). The cardiovascular 

data showed that caloric restriction 

during bed rest led to decrements in 

cardiovascular physiology (specifically, 

performance on a stand test or during 

lower body negative pressure), thus 

exceeding the decrements that occurred 

during bed rest when subjects received 

adequate calories (161, 162). Interestingly, 

caloric restriction (and low-fat diet) were 

associated with mitigating bed rest effects 

on endothelial function and circulating 

lipids (1035).

Although bed rest, specifically using -6° head-down tilt, is a common model for 

cardiovascular adaptation to spaceflight (1030), the resulting fluid shift does not 

appear to be the same (303, 396), as reviewed in Chapter 5. Comparisons of bed 

rest and dry immersion had found generally similar effects, albeit with some 

differences in magnitude, over a much shorter duration of dry immersion 

(3 days) compared to bed rest (21 days) (430, 1031). 

Exercise is a common countermeasure for many systems, but especially 

for cardiovascular health. A recent 21-day bed rest study of resistive vibration 

exercise, with or without a protein supplement (whey protein, 1.8 g/kg body weight), 

with controls, revealed that it had no effect on cardiovascular deconditioning (1032). 

An earlier study of rowing and resistance exercise training revealed that it did protect 

against cardiovascular degradation 

and, when coupled with an oral 

fluid/salt load before reambulation, 

protected against orthostatic 

intolerance (1033).

The role of nutrition in cardiovascular adaptation to spaceflight 

has not been well characterized. 

Diet and nutrition obviously play 

a huge role in cardiovascular 

disease development on Earth. 

The space food system, as 

described in Chapter 3, provides 

excess cholesterol and saturated 

fat, with insufficient quantities of 

fruits and vegetables, omega-3 

fatty acids, and specific vitamins 

(e.g., choline) and minerals 

(e.g., copper, selenium) and 

other phytochemicals with known 

cardiovascular benefits. The Food 

Physiology study–both flight 

and ground-based aspects–will 

help define the role of enhanced 

nutrition on immune function 

and biochemistry. Although 

cardiovascular health was not 

a primary end point, the dietary 

modifications implemented here 

are also expected to provide 

benefits for many systems, 

cardiovascular included.

Figure 57. NASA astronaut Catherine (Cady) 

Coleman exercises on the Cycle Ergometer with 

Vibration Isolation System (CEVIS) in the U.S. 

Laboratory module on the ISS. Photo Credit: NASA.

Figure 58. Relationship between energy 

intake (kcal/kg body mass/d) and change 

in plasma volume loss (mL/d) during Apollo 

missions. N = 21. Data are courtesy of 

William Carpentier.

Figure 59. Energy intake during ISS 

missions (N=60). Each point represents 

an individual crewmember and is his or 

her reported average daily energy intake 

over the course of the mission, expressed 

per kg body mass. The dashed line 

represents 33 kcal/kg body mass.

15 20 25 30 35 40

-20

0

20

40

60

80

kcal/kg/d

D plasma volume

(mL/day)

y = -3.9x + 127.2

r = 0.75 (p<0.001)

10

15

20

25

30

35

40

45

Energy Intake

(kcal/kg/d)
140 141

Magnesium

As detailed in Chapter 6, magnesium 

has benefits for metabolism of bone 

and calcium and for reduction of renal 

stone risk. In addition, magnesium has 

been shown to have effects on the 

cardiovascular system (783, 1036-1038). 

Specifically, lower plasma magnesium 

concentrations are associated with 

atherosclerosis, and magnesium 

supplementation can lower serum 

lipids (1039-1042). Although consistently 

decreased magnesium excretion after 

flight is a concern for many reasons, and 

ensuring adequate intake during and after 

flight is important, the available evidence 

does not bear out concerns about 

magnesium during flight (797). 

Antioxidants and Oxidative Stress

Reducing inflammation and oxidative 

stress through diet during spaceflight 

may be a viable countermeasure to 

help minimize cardiovascular risk factors 

during spaceflight. Although dietary 

antioxidants have yet to be tested during 

flight, their beneficial effects on oxidative 

stress and damage associated with 

space radiation have been shown in 

many ground-based studies (1043-1045). 

Beyond individual nutrients, overall dietary 

patterns that are rich in antioxidants, 

such as the Mediterranean diet in 

the general population, have been 

reviewed and are associated with 

lower inflammation and protective 

against cardiovascular events (1046).

Omega-3 Fatty Acids

Omega-3 fatty acids have beneficial 

impact on cardiovascular health 

on Earth (1047); however, such 

effects have not been evaluated during 

spaceflight. Nonetheless, the initial efforts 

being made to increase fish and omega-3 

fatty acid intake in astronauts for the 

benefit of other systems (bone, muscle) 

will likely have positive effects here as 

well. As reviewed in Chapters 4 and 6, 

although dietary intake of omega-3 fatty 

acids is beneficial (1048, 1049), there is 

little-to-no evidence in support of omega-3 

supplements for cardiovascular health for 

the general population (1050-1054). 

Overall Diet Effects on 

Cardiovascular Health

Although individual nutrients are easier to 

study in a controlled, experimental fashion, 

the effect of overall dietary quality is one 

topic that is continuing to gain ground, 

particularly as studies of individual 

supplements fail to produce the 

“magic” supplement. Overall dietary 

quality, including the intake of fruits and 

vegetables, fish (omega-3 and vitamin D), 

and foods rich in phytochemicals and 

lower in sodium, has broad health—

specifically, cardiovascular—effects 

(1055-1061). Shivappa et al. (1062) have 

described a dietary inflammatory index 

that consists of pro-inflammatory and 

anti-inflammatory dietary components 

that predicts six inflammatory cytokines 

and C-reactive protein. Many studies have 

documented how dietary inflammatory 

index is associated with cardiovascular 

risk factors (1063-1071).

Dr. Douglas’ Food Physiology experiment 

is designed to evaluate the effects of 

an enhanced diet on immune function, 

microbiome, and nutritional biochemistry. 

The ground-based portion of this study 

was completed in 45-d HERA missions 

(data are currently being analyzed, 

publications should begin to appear 

in 2021). The flight portion of this 

experiment started in 2020.

Figure 60. A Salmo-rita (salmon and hot 

sauce on a tortilla) floats near the Galley 

Table in the Unity Node 1 on the ISS.

Photo Credit: NASA.

Figure 61. NASA astronaut Jessica Meir harvests Mizuna mustard plant leaves from plants in 

the Vegetable Production System (Veggie) for Veg-04B experiment plant harvesting operations. 

Photo Credit: NASA.
142 143

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146 147 9 Brain

Nutrition has significant importance for brain function, and is even more critical 

during space travel where factors such as microgravity and radiation can affect 

both brain structure and function. Understanding how nutrition supports brain 

function in astronauts, and how nutrition can counteract these effects, may be 

critical for enabling exploration missions beyond low-Earth orbit.

Radiation and Central Nervous 

System, Behavior/Performance, 

and Sensorimotor Function

Radiation exposure during deep space 

missions is unavoidable and it could 

affect many physiological systems 

including the central nervous system 

(CNS), behavior, and sensorimotor 

function (14). Radiation can affect the 

brain and induce neuroinflammation by 

activating microglia, producing oxidative 

stress, inducing mitochondrial dysfunction 

that leads to altered energy production 

in the brain, and directly effecting the 

permeability of the blood-brain barrier. 

Increased neuroinflammation is associated 

with progressive neuronal loss and 

with increased risk of decrements in 

behavior and cognitive performance. 

Evidence indicates that specific nutrients 

and/or dietary intake patterns can mitigate 

neuroinflammation; thus, nutrition could 

protect against neuroinflammatory 

processes caused by the hazards 

of spaceflight. 

The brain requires micro- and 

macronutrients to build and maintain 

structure and function, not only during 

development but also throughout 

adulthood. The human brain accounts 

for about 2% of the weight of an average 

human; however, it consumes 20% to 

25% of the body’s total energy (1072). 

The half-lives of proteins in the brain 

vary from a few hours to more than 

20 days, depending on their location. 

This turnover is necessary to ensure that 

synapses (structures that allow chemical 

or electrical impulses to travel from one 

nerve cell to another) remain flexible 

(1073). Maintaining synaptic plasticity 

is essential for memory and learning 

(1074). Nutritional deficits can affect 

the pathophysiology of mood disorders, 

including depression, which could in turn 

affect an astronaut’s performance during 

an exploration mission. B vitamins such 

as thiamin, riboflavin, niacin, and folate 

are associated with abstract thought 

processes, whereas vitamin C status 

can affect visuo-spatial performance 

(1075). Vitamins A, E, B12, and B

6

 are 

associated with both visuo-spatial memory 

and abstract thought processes (1075). 

These vitamins also play a role in cognition 

and degenerative diseases (1076-1081). 

Although each of these vitamins has 

an individual role in cerebral function, 

nutrients are generally consumed in a 

food matrix and they interact with other 

nutrients and compounds. Historical 

events remind us of the importance 

of individual nutrients—for example, the 

associations between vitamin C deficiency 

and scurvy, thiamin and beriberi, vitamin D 

and rickets, and iodine and goiter (1074). 

Research studies that focus on single 

nutrients often do not reach the same 

conclusions as studies focusing on diets 

as a whole (1082). Although delivery of 

individual nutrients will continue to serve 

Expedition 61 Flight Engineer Christina 

Koch is shown with a New Year's Eve 

meal in the Zvezda Service Module. 

Photo Credit: NASA. 
148 149

medical needs in certain instances, 

high-quality diets rich in nutrients 

known to be involved in cerebral 

health is the preferred long-term 

approach for sustaining a healthy 

brain over a lifetime. Chapter 11 

includes more detail on microbiome 

and brain, mood, and behavior.

The fact that high-LET radiation affects 

cognition and behavior is becoming 

increasingly evident. Rodents irradiated 

with acute doses of accelerated particles 

have changes in cognition and behavior 

that involve altered learning and memory, 

anxiety, social behavior, and fear/startle 

responses (13). After young animals 

were exposed to high-LET radiation, 

they develop changes in neuronal signal 

transduction and accompanying changes 

in motor performance that are similar 

to effects seen in aging animals (1083). 

Mice exposed to either protons alone, 

or a combination of protons and heavy 

ions, had acute and chronic cognitive 

impairment as assessed by a novel 

object recognition task (1084), and this 

response was believed to be mediated 

by changes in or by the hippocampus. 

Exposure to high-LET radiation can 

also alter patterns of gene expression 

and change networks in the hippocampus 

that affect spatial memory (1084, 1085). 

Kiffer and colleagues recently completed 

a comprehensive review of behavioral 

and cognitive changes in animals that 

were irradiated with either a single type 

of charged particle (56Fe, 48Ti, 28Si, 16O, 

12C, or protons) or a mixed radiation field 

(14). By far, 56Fe is the most well studied 

type of charged particle radiation for 

assessing behavior outcomes. This type 

of radiation exposure clearly has behavioral

and cognitive consequences in mice and 

rats. Doses of 56Fe ranging from 0.05 to 

5 Gy affected behavior or cognition at 

many time points after irradiation (14).

Nutrition Countermeasures

A single antioxidant may not be effective 

for countering the effects of oxidative 

stress or neuroinflammation because 

these processes are complex and 

simultaneously involve many biological 

cascades. Differences in effectiveness 

of dietary components may be due 

to the differences in their bioactive 

compounds. All berries contain phenolics, 

anthocyanins, and flavonols; however, 

blueberries contain more proanthocyanins, 

whereas strawberries contain more 

ellagitannins (1086). These variations 

can affect antioxidant properties and 

their capacity to cross the blood-brain 

barrier (1086-1088). Numerous largescale epidemiological studies show 

improvements in disease state by diet 

but not with individual supplements 

(1050, 1089-1093), which underscores 

the importance of phytochemicals 

in whole foods. Similarly, although 

an abundance of data show that 

individual nutrients are radioprotective 

(1094-1099), whole foods with an 

equivalent dose of the specific nutrient 

may confer more radioprotection than 

a supplement because the myriad 

phytochemicals in foods also have 

radioprotective effects (1100). 

Detailed reviews have been published 

on the many radioprotective effects 

of phytochemicals (1101-1103). 

Flavonoids are a subclass of phenolics 

that have a structure with two aromatic 

rings attached by three carbons, usually 

in a heterocyclic ring (57). Flavonoids 

have strong antioxidant properties 

because they can bind to heavy metals 

and scavenge free radicals (1104). 

Berries are especially rich in phytochemicals and have beneficial 

effects on cognitive and motor 

behaviors (1105, 1106). Luteolin, a 

flavonoid found in citrus fruit, and 

diosmin, a citrus flavone derivative 

that is structurally similar to luteolin, 

reduced formation of amyloid plaque 

peptides in a mouse model of Alzheimer’s 

disease (1107). The suggested mechanism 

of diosmin action is through glycogen 

synthase kinase 3 inhibition, which affects 

formation of presenilin-1 phosphorylation 

and amyloid plaques (1107). Other specific 

polyphenols such as naringenin, which is 

also found in citrus fruits, inhibit activation 

of amyloid β-induced microglia (1108). 

A recent systematic review discusses 

how plant flavonoids and other phenolics 

affect human health (1109). Some of the 

beneficial effects of flavonoids include 

their antioxidant, anti-inflammatory, 

and antibacterial actions, and their 

actions in protecting against cancer, 

cardio and immune dysfunction, and 

ultraviolet radiation damage. Flavonoidrich diets are associated with enhanced 

cognitive capabilities and are believed to 

slow the progression of neurodegenerative 

disease such as Alzheimer’s disease 

(1110-1112). It is thought that flavonoids 

relay their neuroprotective effects by 

maintaining the quality and number 

of neurons through inhibition of 

neuroinflammation and oxidative stress, 

thus averting the trigger or advancement 

of the disease that causes the decline 

in cognitive function (1104). Cheki and 

colleagues (1113) provide a convenient 

list of the radioprotective effects of 

phytochemicals that have been tested 

at various doses of ionizing radiation. 

They determined that phytochemicals 

can protect against the effects of ionizing 

radiation at doses of 1-5 Gy, which is 

within the realm of possibility of a total 

mission dose during a Mars mission.

Figure 62. NASA astronaut Kjell Lindgren is photographed with a bag of assorted fruit (oranges, 

lemons, grapefruits) floating in the Node 2 module after being unpacked from the Kounotori H-II 

Transfer Vehicle 5. Photo Credit: NASA.
150 151

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152 153

Ocular

Nutrition is known to be an important factor for ophthalmic health in general. This chapter 

will review the available literature on this topic and general nutrition in ophthalmic health, 

along with ongoing research to understand and counteract the effects of spaceflight. 

The harsh environment of spaceflight affects vision and ocular health. Some of the 

environmental aspects that can contribute to changes in ocular health are radiation 

exposure, cephalad shifts of body fluid, spacecraft cabin and spacesuit gas mixtures, 

and the spaceflight food system. Astronauts have an increased risk to develop cataracts, 

one of the ocular pathologies, as has been documented. 

Cataracts are opacities of the lens and have a multifactorial etiology. Diet, genetics, 

and environmental stressors can all play a role in initiating oxidative damage that can 

lead to cataract formation. Several studies have confirmed that astronauts and 

cosmonauts have an increased risk of cataract formation after spaceflight (1114-1117). 

Cucinotta et al. (1115) identified an increased risk of all types of cataracts (including 

posterior subcapsular, cortical, and nuclear) among astronauts with higher exposure 

to radiation. Longitudinal follow-up studies have been conducted and it was determined 

that progression of cortical cataracts, but not posterior subcapsular or nuclear cataracts, 

is related to space radiation exposure (1116, 1118). Although radiation exposure is a 

large driving force for the oxidative damage that leads to some types of cataracts, the 

longitudinal study provided evidence that intake of specific nutrients may provide some 

protective effects (1116). In the first report of the NASA Study of Cataract in Astronauts, 

nutritional intake estimates were obtained from a questionnaire, and the data provided 

evidence that beta-carotene and lycopene intake had a protective effect for some types 

of cataracts in astronauts (1116). As reviewed by Agte and Tarwadi, numerous groundbased studies have provided evidence for associations between micronutrients and 

antioxidants (either blood levels or estimated intakes) and cataracts (1119). 

Although epidemiological data support the idea that lower nutritional status—particularly 

vitamin A, riboflavin, vitamin E, beta-carotene, zinc, and vitamin C status—is associated 

with cataract risk (1120-1123), it is not known whether altered micronutrient and antioxidant

intake during spaceflight could minimize cataract incidence related to space radiation. 

Further interventional study and better estimates of in-flight nutrient intake along with 

nutrient status assessments will help to answer these important questions in the future.

10

In the International Space Station's Harmony node, European Space Agency 

astronaut Alexander Gerst, Expedition 40 flight engineer, performs an eye exam 

for the Ocular Health experiment. Photo Credit: NASA.

Spaceflight Associated 

Neuro-ocular Syndrome

In addition to a general increase in 

cataract risk (1115, 1116, 1118), some 

crewmembers have experienced ocular 

changes after long-duration spaceflight. 

Spaceflight Associated Neuro-ocular 

Syndrome (SANS) is characterized as 

the occurrence of optic disc edema, 

flattening of the posterior region of 

the sclera, hyperopic refractive error 

shifts, and choroidal and retinal folds 

(1124, 1125).

Although the precise mechanism is not yet 

fully understood, out of several published 

theories, some suggest an involvement 

of a cephalad fluid shift (1, 289, 1124). 

Other possible contributing factors include 

elevated cabin CO2

 exposure or local 
154 155

Spaceflight Associated Neuro-ocular 

Syndrome, Vitamins, and One Carbon 

Biochemistry

SANS only affects a subset of astronauts 

(31). Although no single cause has 

been documented, the fact that not 

all astronauts develop SANS increases 

the likelihood that this is multifactorial. 

Physiological (e.g., headward fluid shift, 

intracranial hypertension), environmental 

(e.g., CO2, radiation), dietary (e.g., sodium, 

fluid), and genetic influences have all been 

posited to have a role or influence on this 

syndrome (31, 1132). 

In astronauts, vitamin B12-dependent 

one-carbon metabolic pathway 

intermediates, including homocysteine, 

were significantly higher in affected 

astronauts before, during, and after 

flight (Figure 64). Although the four 

one-carbon metabolites we measured 

were significantly higher, serum folate 

was significantly lower in affected 

astronauts during flight (19, 1128).

In addition to biochemical intermediates 

in the one-carbon metabolic pathway, 

one-carbon pathway genetic variations

 in astronauts are linked to SANS 

outcomes (1129, 1133). Specifically, 

the G and C alleles for MTRR A66G 

and SHMT1 C1420T polymorphisms, 

respectively, both contributed to the 

odds of SANS pathologies (e.g., choroidal 

folds, cotton wool spots, optic disc 

edema) after flight (1129) (Figure 65). 

In a ground-analog study, one-carbon 

pathway genetics are associated with 

acute response to head-down tilt and 

CO2

 exposure (1134). In a pilot study with 

eight subjects, a multiple regression model 

significantly predicted end-tidal CO2 from 

the number of G alleles for MTRR 66 with 

vitamin B12 status as a covariate (1134) 

(Figure 66).

Figure 63. NASA astronaut Karen Nyberg performs fundoscopy in the Destiny laboratory 

of the ISS. Photo Credit: NASA.

intraorbital (choridal and optic nerve 

sheath) changes. Elevated intracranial 

pressure has also been postulated to be 

a contributing factor; however, so far there 

are no supporting data for this proposed 

mechanism, and astronauts typically do 

not report any other symptoms associated 

with elevated intracranial pressure (1126, 

1127). It is important to note that not all 

crewmembers who have flown on longduration missions develop SANS (1126), 

thus it is likely that the cause is 

multifactorial. The impact of a cephalad 

fluid shift on one crewmember may be 

different than for another crewmember. 

One hypothesis to explain different 

responses to a fluid shift is genetic 

differences. Biochemical and genetic 

evidence confirms that the folateand vitamin B12-dependent pathway 

are involved (1128, 1129), as described 

in detail below.

Mader and colleagues first described 

seven cases among long-duration 

crewmembers on the ISS who had 

evidence of ophthalmic changes after 

flight, including optic disc edema, globe 

flattening, choroidal folds, and hyperopic 

shifts (1125). The definition of SANS 

has changed over the years, related 

to additional data and expanded 

assessment technology, and is still 

under some debate. With additional 

cases having been identified, the 

incidence of optic disc edema based 

upon fundoscopy is approximately 

15% (1126), and some maintain a 

much higher incidence rate based on 

ocular coherence tomography imagery 

(1126, 1130).

Myasnikov and Stepanova reported 

evidence of postflight optic disc edema 

among Russian cosmonauts and one 

case (out of 10) with signs of intracranial 

hypertension, although they note the 

measurements were made before and 

after (not during) flight (1131). 

Figure 64. Homocysteine is significantly 

higher (P<0.001) in astronauts with 

ophthalmic findings (blue squares) than 

in those without ophthalmic findings 

(red circles) (1128). The “1C” sample (open 

symbols) was collected 2 to 6 years after 

flight as part of the experiment evaluating 

one-carbon pathway SNPs (1129).

Figure 66. Relationship between MTRR A66G 

genotype and end tidal CO2

. The individual with 

AG genotype denoted by the open circle was 

vitamin B12 deficient. Adapted from (1134).

Figure 65. The presence of more risk alleles 

(i.e., G and C alleles for MTRR A66G and 

SHMT1 C1420T) was significantly related to 

incidence of optic disc edema in astronauts 

after 4 – to 6-month space missions.

Homocysteine, mmol/L

-180 -45 -10 15 30 60 120 180 R+0 R+30 1-C

0

2

4

6

8

10

12

14

Preflight In-fight Postflight

30

35

40

45

50

AA AG GG

MTRR 66 genotype

PETCO2 (mm Hg)

during HDT+CO2

- Disc edema

0

1

2

3

4

# Risk Alleles

(MTRR 66 G + SHMT1 1420 C)

P=0.02
156 157

In a ground-analog study conducted in 

Germany (the “VaPER” study), optic disc 

edema was observed in 5 of 11 subjects 

during and after a 30-day head-down 

tilt bed rest with 0.5% CO2 exposure 

(1135); the degree of optic disc edema 

was correlated with the total number of 

G and C alleles for MTRR 66 and SHMT1 

1420 SNPs, respectively. Although work 

is ongoing to determine whether the strict 

head-down tilt and/or 0.5% CO2 were 

causative, the fact that only 45% of the 

bed rest subjects developed optic disc 

edema further supports a role for 

genetics contributing to divergent 

responses among subjects–in this 

case, during well-controlled studies. 

The change in total retinal thickness, 

a quantitative measure of optic disc 

edema, was greater in subjects with 

3 to 4 risk alleles than those with 1 to 

2 risk alleles during and after bed rest 

(1136) and (Figure 67).

It is also worth noting that folate status 

in the VaPER bed rest subjects was 

much lower than those of subjects in 

head-down tilt bed rest studies conducted 

at the University of Texas Medical Branch 

(UTMB) in Galveston (Figure 68). This is 

likely due to lack of folate fortification 

of the food supply in Europe, a process 

initiated in the United States more than 

20 years ago. None of the UTMB 

subjects in bed rest studies up to 70 days 

experienced optic disc edema (1137-1139). 

Another difference was noted between 

these studies: UTMB subjects were 

allowed use of a small head pillow and 

were allowed to prop themselves up on 

one elbow during meals. This change was 

implemented in the VaPER study based on 

concerns that the pillow, or leaning on an 

elbow to eat, might reduce the fluid shift 

pressures at the level of the eye (1127).

How could one-carbon pathway 

function contribute to optic disc 

edema and SANS? 

Based on biochemical and genetic 

data, there is an undeniable association 

between altered one-carbon pathway 

function and SANS incidence (1128, 

1129). The mechanism for how onecarbon metabolism might induce SANS 

is unknown, as is the mechanism for 

SANS. One hypothesized mechanism 

has been published (1136, 1140, 1141) 

and is detailed in Figure 64. Briefly, we 

hypothesize that because one-carbon 

metabolic pathway genetic variants 

can impair efficiency of the pathway, a 

resulting decrease in cofactor availability 

(including folate) occurs, which ultimately 

affects endothelial nitric oxide synthase 

(eNOS) coupling, nitric oxide synthesis, 

and peroxynitrite formation. This is 

explained in further detail below. 

One Carbon Metabolism

Before detailing the hypothesis, it is 

necessary to understand the importance 

of the one-carbon metabolic pathway 

and its role in nitric oxide production. 

One-carbon metabolism is a universal 

metabolic pathway that serves to activate 

and transfer single carbon units for 

biosynthetic processes including purine 

and thymidylate biosynthesis, and for 

remethylation of homocysteine to 

methionine. A subsection of the pathway 

is shown in Figure 69.

Several B vitamins act as cofactors 

in the one-carbon metabolic pathway, 

including folate, vitamin B12, vitamin B6, 

and riboflavin. No cell can survive without 

these B vitamins, given the pathway’s 

key role in DNA and RNA synthesis. 

These processes are therefore sensitive 

to vitamin status. For one example related 

to folate: all cellular forms of folate are 

Figure 67. Change in peripapillary total retina thickness in subjects with 3 to 4 (n=4) or 0 to 

2 (n=7) risk alleles, after 1, 15, and 30 days of head-down tilt bed rest and 6 and 13 days of 

recovery (left). Peripapillary retinal nerve fiber layer means showing a difference between the two 

genetic categories at all time points (BR-6, 6 days before head-down tilt bed rest began) (right). 

Data are means ± 95% CI. Adapted from (1136).

Figure 68. Red blood cell folate in VaPER 

subjects (red symbols/lines) and UTMB 

30-day bed rest subjects (gray symbols/lines) 

before and after bed rest. Data adapted and 

expanded from (262).

Figure 69. Overview of one-carbon metabolism. AA = amino acids; CBS = cystathionine ß-synthase;

CYS = cystathionine; FA = fatty acids; HCY = homocysteine; αKBT = α-ketobutyrate; 

MCA = methylcitric acid; MM-CoA = methylmalonyl coenzyme A (CoA); 

MMA = methylmalonic acid; MS = methionine synthase; 5-MTHF = 5-methyltetrahydrofolate; 

5,10-MTHF = 5,10-methylenetetrahydrofolate; MTHFR = methylenetetrahydrofolate reductase; 

MTRR = 5-methyltetrahydrofolate homocysteine methyltransferase reductase; 

PRP-CoA = propionyl CoA; SAH = S-adenosylhomocysteine; SAM = S-adenosylmethionine; 

SUC-CoA = succinyl CoA; THF = tetrahydrofolate. Image Credit: NASA.

Pre-bed rest

Post bed rest

0

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600

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expected to be protein bound, given 

binding constants (i.e., Kd values) in 

the nanomolar range. Folate-dependent 

anabolic pathways must compete for 

a rate-limiting pool of folate (1142) 

and are thus sensitive to primary folate 

deficiency. Furthermore, genetic variation 

that alters B-vitamin cofactors through 

any folate-dependent pathway influences 

the entire one-carbon metabolic pathway 

(1143). Clinical deficiencies of these 

B vitamins lead to hematologic and 

neurologic symptoms in adults, and folate 

insufficiency during development involves 

failure of neural tube closure early in 

pregnancy (1144-1146). Folate, vitamin 

B12, and vitamin B6 insufficiency due 

to either diet or genetic variants that alter 

pathway function and efficiency can lead 

to increased circulating homocysteine 

(1147). Animal studies show that folate 

deficiency or homocysteine exposure 

during development contributes to 

not only neural tube defects, but 

also negatively impacts normal eye 

development and can cause optic cup 

modifications (1148, 1149). Elevated 

homocysteine has been reported 

in numerous ocular conditions, 

including macular degeneration, 

diabetic retinopathy, macular edema, 

pseudoexfoliation glaucoma, and retinal 

venous and arterial occlusions (1150, 

1151). Impaired nitric oxide metabolism 

is found to be one of the main effects 

of homocysteine toxicity (1152). 

Role of One-Carbon Metabolism and 

Nitric Oxide in Endothelial Function

The vascular endothelium is a monolayer 

of cells that control vascular tone. Vascular 

tone is modulated by the synthesis and 

release of endothelium-derived relaxing 

factors (e.g., nitric oxide) and endotheliumderived contracting factors (1153). 

In healthy endothelium, nitric oxide is 

synthesized by a constitutively expressed 

enzyme: eNOS. Nitric oxide is an 

important vasodilator that maintains 

vascular health and function through 

its anti-thrombotic, anti-inflammatory, 

anti-angiogenic properties. It also plays 

an important role in inhibiting platelet 

adhesion and aggregation, leukocyte 

adhesion, and smooth muscle cell 

proliferation, which are events that 

contribute to atherosclerosis (1154). 

Endothelial dysfunction is mainly caused 

by reduced production or action of 

endothelium-derived relaxing factors and 

can be an early indicator of cardiovascular 

disease (1153). A hallmark of cardiovascular disease is the reduced ability 

of the endothelium to produce nitric 

oxide, resulting in increased vascular 

stiffness (1155, 1156). 

The eNOS enzyme is a dimer that relies 

on tetrahydrobiopterin (BH4

) as a cofactor 

to couple the oxidation of L-arginine 

to the reduction of molecular oxygen to 

produce nitric oxide. The eNOS dimer 

can be decoupled when there is too 

little substrate or cofactor available. 

When eNOS is decoupled, superoxide 

radicals are produced instead of nitric 

oxide, and peroxynitrite forms (1157). 

Oxidative stress itself can directly 

oxidize BH4 to dihydrobiopterin (BH2) 

to deplete the supply of BH4 or it can 

decrease de novo synthesis of BH4 (1158). 

During spaceflight, astronauts are exposed 

to several sources of oxidative stress, 

including a low, chronic exposure to 

ionizing radiation. As reviewed by Pathak 

et al. (1159), in vitro studies show that 

ionizing radiation-induced oxidation can 

lead to decreased BH4

. Oxidation of BH4

to BH2 leads to decoupling of eNOS 

because BH2 can compete for eNOS 

binding with BH4 (1159). The formation 

of peroxynitrite can directly oxidize BH4

to BH2 (1160), thus creating a cycle that 

produces even more superoxide radicals. 

A deficiency of nitric oxide and excess 

peroxynitrite are both markers of 

endothelial dysfunction (1159).

Folate status can affect endothelial 

function through several direct actions. 

First, 5-methyltetrahydrofolate (5-MTHF), 

the primary circulating form of folate, 

can decrease superoxide generation 

in the vascular wall (1161). Both in 

vitro and in vivo studies show that 

5-MTHF can reduce superoxide 

production and increase nitric oxide 

synthesis (1161-1163). The mechanism 

of action for increasing nitric oxide 

synthesis includes 5-MTHF acting to 

preserve the coupling of eNOS with 

consumption of nicotinamide adenine 

dinucleotide phosphate (NADPH) (1164). 

Second, 5-MTHF preserves eNOS 

coupling by increasing availability 

of BH4

 through its role in stabilizing 

BH4 and facilitating its binding to eNOS 

(1161, 1165). Third, 5-MTHF plays a role 

in upregulating dihydrofolate reductase 

(DHFR), an enzyme that recycles BH2

to BH4 (as illustrated in Figure 64) (1166). 

This preservation of eNOS coupling is 

associated with improved endothelial 

function (1164). Finally, 5-MTHF can 

directly scavenge peroxynitrite radicals 

that otherwise oxidize BH4 (1161). 

There is debate over the role of 

homocysteine in cardiovascular health 

(1167), and it appears that some of the 

reasons behind the disparate results 

in the field could be due to populationspecific genetic and dietary intake 

differences. One example is a link 

found between the MTHFR C677T 

polymorphism and increased risk of 

venous thromboembolism; however, 

the association is not found in North 

America where dietary intakes of 

folate is higher due to fortification 

practices (1168).

Several studies have documented 

that high doses of folic acid can mitigate 

endothelial dysfunction as assessed by 

flow-mediated dilation in patients with 

cardiovascular disease, amenorrheic 

runners, or known endothelial dysfunction 

(1169-1173). In a thorough review by 

Stanhewicz and Kenney (1174), they 

present evidence from several folic acid 

supplementation trials, and summarized 

that daily doses of ≥5 mg folic acid are 

efficacious in improving flow mediated 

dilation. In comparison, the current RDA 

for folate is 0.4 mg/d (266). They report 

that doses lower than 5 mg/d may lower 

plasma homocysteine, but they are not 

effective in improving flow-mediated 

dilation (1174). In many studies showing 

improved vascular endothelial function 

with folate or folic acid supplementation, 

no relationship exists between 

homocysteine concentration and 

endothelial function, suggesting that 

the protective effects of folate on 

endothelial function are likely not mediated 

through homocysteine (1163, 1169, 1175). 

Supportive of these studies showing 

improvement in flow-mediated dilation, 

local 5-MTHF administration as well as 

folic acid treatment improved vasodilator 

function in healthy older adults’ 

skin through nitric oxide-dependent 

mechanisms (1176). Furthermore, folic 

acid supplementation (5 mg/d for 6 weeks) 

increased nitric oxide-dependent 

vasodilation of non-cutaneous vascular 

beds (1177). In older adults, folic acid 

supplementation improved skeletal muscle 

blood flow (1177). These studies support 

endothelial dysfunction as a systemic 

condition, and an improvement in 

endothelial function includes an 

improvement in microvascular function.

Endothelial Dysfunction: 

Nitric Oxide, Peroxynitrite, and 

sclera/lamina cribrosa integrity 

Endothelial dysfunction from decoupled 

eNOS and increased peroxynitrite 

formation could be exacerbated, during 

spaceflight, by other factor(s) known to 

affect endothelial dysfunction (e.g., fluid 

shifts, CO2, radiation exposure, insulin 

sensitivity) (1140). There are multiple 

potential downstream implications 

of decoupled eNOS. 

Peroxynitrite formation from an inefficient 

one-carbon metabolism pathway may 

influence risk for optic disc edema through 

an effect on elasticity of the extracellular 

matrix near the optic disc (lamina cribrosa) 

or sclera, possibly affecting the optic cup 

shape and/or rendering some individuals 

more vulnerable to pressure from a 
160 161

headward fluid shift during head-down 

tilt bed rest or spaceflight. The sclera 

is a dense layer of connective tissue that 

defines the shape and size of the eye. 

It is a strong framework that supports 

the retina so that it can withstand forces 

of intraocular pressure (sclera and 

lamina cribrosa) and intracranial pressure 

(lamina cribrosa), while providing a 

pathway for aqueous drainage and 

protecting the eye from trauma (1178). 

Scleral tissue contains about 50% 

collagen by weight (1179), embedded 

in a matrix of proteoglycans and 

non-collagenous glycoproteins. 

Scleral tissue remodeling is an ongoing 

dynamic process involving both synthesis 

and degradation of component elements. 

Matrix metalloproteinases (MMPs) are 

zinc-dependent proteolytic enzymes that 

degrade extracellular matrix components, 

including structural components such 

as collagen and elastin. There are several 

types of MMPs, and the ones found in 

scleral tissue include MMP-1, MMP-2, 

MMP-3, and MMP-9 (1178). Most vascular 

and scleral MMPs are constitutively latent 

because of the presence of inhibitors 

(e.g., NO) (1180). When activators are 

present, including peroxynitrite or even 

increased mechanical strain (1181), 

MMPs are activated and degradation 

is instigated. One study found high levels 

of active MMP-2 and MMP-9 (as opposed 

to latent forms of MMPs) in the optic nerve 

and optic rim area. The authors suggest 

that the high turnover of collagen within 

the optic nerve area may be an important 

mechanism for maintaining elasticity of the 

lamina cribrosa (1182). Additionally, cells 

in the optic nerve head and sclera have 

mechanosensory capabilities and respond 

to hydrostatic pressure by upregulating 

MMP-2 activity (1181, 1183). Osteocalcin 

can increase expression of matrix 

metalloproteinase proteins (1184) 

that contribute to soft tissue turnover. 

Inefficient one-carbon pathway function, 

and specifically reduced MTRR activity 

(due to the presence of the MTRR 66 G 

allele), is associated with higher circulating 

osteocalcin concentrations (1185). 

Interestingly, the MTRR 66 G variant that 

has been described above as a risk allele 

for optic disc edema in spaceflight and 

bed rest, has 4-fold lower activity than 

the wild type variant (1186). In addition 

to peroxynitrite affecting MMP activation, 

low folate status and higher homocysteine 

can directly activate MMP-9, thus affecting 

NO bioavailability, resulting in constrictive 

vascular remodeling, and reduced arterial 

compliance (1187-1189), and folic acid 

supplementation can attenuate an 

increase in MMP-9 activation due to 

a genetically-induced slower one-carbon 

pathway (1190). Activation of MMPs in 

the sclera could decrease firmness and 

elasticity and affect response to headward 

fluid shifts during HDT bed rest and 

spaceflight. As an aside, neural tube 

defects are a common result in offspring 

where there is maternal folate deficiency 

(1191), and maintaining closure of the 

neural tube during mammalian formation 

requires MMPs to be inactive (1192). 

In other words, an optimal folate status 

is necessary to maintain MMPs in their 

latent state to maintain closure of neural 

tubes during development, providing 

evidence that folate can directly 

impact extracellular matrix structure. 

Further evidence for the role of folate 

in collagen metabolism: folic acid 

supplementation increases collagen fiber 

density resulting in skin firmness (1193).

One more factor that can contribute 

to endothelial dysfunction and/or sclera 

structural differences is insulin resistance. 

Insulin resistance is documented in 

astronauts (192) and bed rest subjects 

(187, 206). There is also evidence to 

suggest altered insulin responsiveness 

and carbohydrate metabolism in 

astronauts who experienced optic disc 

edema, with a lower myo-inositol:chiroinositol ratio (1129). Advanced glycation 

end products (AGEs) are another factor 

that can affect extracellular matrix 

stiffness. AGEs are generated through 

non-enzymatic reactions between sugars 

and proteins, lipids, or DNA. AGEs also 

result from diets rich in animal protein 

and fat, particularly where the meat has 

been cooked at high temperatures (1194). 

AGEs can affect sclera structure because 

they promote collagen crosslinking (1195, 

1196), making it stiffer. Cell culture studies 

of interstitial tissue demonstrate that 

impaired glucose metabolism may affect 

crosslink formation through manipulation 

of MMP activation, in particular MMP-2 

(1197). Serum MMP-2 has been measured 

in astronauts (192), but caution must be 

used in interpreting those results because 

it is known that serum (but not plasma) 

MMP measurements primarily reflect 

release of proteases by leukocytes during 

the clotting process in the blood collection 

tube (the use of anticoagulant can prevent 

this in vitro serum artifact) (1198-1201). 

Taken together, a potential impact of the 

contributing factors that lead to endothelial dysfunction could result in SANS 

pathologies through multiple mechanisms. 

One potential impact is that endothelial 

dysfunction could lead to leakier 

vasculature and edema, which could 

block cerebrospinal fluid drainage and 

increase subarachnoid space pressure, 

impinging on the optic nerve and eye 

(1140, 1141). Additionally, there is the 

potential for structural alterations 

in sclera and lamina cribrosa as the 

result of oxidative stress and matrix 

Figure 70. Depiction of hypothesized multi-hit mechanism relating one-carbon pathway genetics 

with ocular pathologies. Genetics and B-vitamin status lead to endothelial dysfunction and leaking 

microvasculature; the resulting edema could block cerebrospinal fluid (CSF) drainage, increasing 

subarachnoid space CSF pressure impinging on the optic nerve and eye (1140, 1141). Similarly, 

uncoupled eNOS yields increased oxidative stressors, including peroxynitrite. Peroxynitrite may 

affect the elasticity of the lamina cribrosa or sclera, affecting the optic cup shape and rendering 

some individuals vulnerable to pressure from a headward fluid shift during head-down tilt bed 

rest or spaceflight. MMPs are zinc-dependent proteolytic enzymes that degrade extracellular 

matrix components, including structural components such as collagen and elastin. Most vascular 

and scleral MMPs are constitutively latent because of the presence of inhibitors, including nitric 

oxide (1180). Cells in the optic nerve head and sclera have mechanosensory capabilities and 

respond to hydrostatic pressure by activating MMPs (1181). Additionally, low folate status and 

higher homocysteine can directly activate MMPs, affect nitric oxide bioavailability and production, 

cause constrictive vascular remodeling, and reduce arterial compliance (1188). Connective tissue 

remodeling could lead to changes in elasticity, fluid leakage, and ultimately ophthalmic changes. 

Adapted from (1136).
162 163

metalloproteinase (MMP) activation, 

altering scleral elasticity and thus making 

it more susceptible to develop ocular 

pathologies when exposed to spaceflightinduced fluid shifts and/or intracranial 

hypertension. These hypotheses are 

characterized in Figure 70, adapted 

from (1136). 

Nutrients Associated with 

Ocular Health

Folate

Folate is the general term used to 

describe the vitamin folate and compounds

that have activity similar to that of folate, 

(1202, 1203). Folic acid is the synthetic 

form of the vitamin used in vitamin 

supplements and fortified food products; 

however, it is not found to occur naturally 

in food. The reduction of folic acid and 

dihydrofolate by a cytosolic enzyme 

dihydrofolate reductase produces the 

active form of folate, tetrahydrofolate 

(THF). Tetrahydrofolate accepts singlecarbon groups from reactions in amino 

acid metabolism to form active derivatives 

of THF (1202). This pathway is called 

one-carbon metabolism, and it not only 

requires folate, but also vitamin B12, and 

vitamin B6. The pathway is required for 

purine and pyrimidine synthesis, amino 

acid metabolism, and synthesis of the 

methylating agent S-adenosylmethionine 

(SAM) (Figure 63). Alterations in the 

efficiency of this pathway due to various 

single nucleotide polymorphism variants 

or low B-vitamin availability can lead to 

a buildup of certain intermediates, 

including homocysteine. Factors such as 

genetic polymorphisms, pharmacological 

agents, and dietary intake and status of 

folate, vitamin B6

, and vitamin B12 can 

influence plasma homocysteine 

concentration (1204, 1205).

Much of the homocysteine literature has 

focused on its association with coronary 

artery disease, stroke, and migraines 

(1204, 1206, 1207); however, some studies 

show associations of homocysteine with 

ophthalmic health issues. Issues such as 

age-related macular degeneration result 

from lipid deposits under the retinal 

pigment epithelium (1208) and decreased 

retinal vessel functionality (1209), and 

some theorize that age-related macular 

degeneration is similar to the development 

of cardiovascular disease (1210). 

Because homocysteine is a risk factor 

for cardiovascular disease, many 

have looked at relationships between 

homocysteine, or other metabolites and 

vitamins in the one-carbon metabolism 

pathway, and ophthalmic health issues 

such as age-related macular degeneration, 

dry eye, glaucoma, retinopathy, 

pseudoexfoliative glaucoma maculopathy, 

cataract, retinal vessel atherosclerosis, 

and optic neuropathy (1211-1216). 

For instance, a meta-analysis showed 

that elevated plasma homocysteine 

was associated with an increased risk 

of primary open-angle glaucoma (1217). 

Other meta-analyses have shown that 

increased serum homocysteine and low 

vitamin B12 status were independently 

associated with increased risk for agerelated macular degeneration (1214, 1218). 

Daily supplementation with folate, vitamin 

B6, and vitamin B12 is associated with 

a 30% to 40% decreased risk for agerelated macular degeneration (1219). 

Deficiency of folate leads to megaloblastic 

anemia. Low folate intake will cause RBC 

folate concentrations to diminish within 

4 months. Bone marrow cells become 

megaloblastic (that is, they take on a 

nucleated, embryonic form), and anemia 

occurs after 4 to 5 months of low folate 

intake (1220). Folate deficiency in humans 

has been described as a 4-stage process 

(1221, 1222), including changes in serum 

folate (Stage 1), changes in RBC folate 

(Stage 2), defective DNA synthesis 

and elevated homocysteine (Stage 3), 

and clinical folate deficiency (Stage 4), 

manifested by macroovalocytosis (many 

large, oval cells in the blood), elevated 

mean corpuscular (RBC) volume, and 

large, nucleated embryonic cells.

Early spaceflight data showed a reduction 

in RBC folate after long-duration missions 

(110, 111). Serum folate is variable 

among crewmembers, but generally 

does not change during flight (Figure 71). 

Interestingly, serum folate was lower 

during spaceflight in crewmembers 

with SANS compared to those that 

did not have SANS (1128).

Vitamin B12

Vitamin B12 functions in many enzymatic 

reactions, and deficiencies result in 

anemia, as well as neurological disorders. 

Vitamin B12 works as a cofactor for 

three different enzymatic reactions: 

1) the conversion of homocysteine 

to methionine; 2) the conversion of 

L-methylmalonyl-coenzyme A (CoA) 

to succinyl-CoA; and 3) the isomerization 

of L-leucine and ß-leucine. Vitamin B12

deficiency may cause the accumulation 

of folate in the serum because 

of a reduction in B12-dependent 

methyltransferase, also known 

as the methyl-folate trap (1223). 

Vitamin B12 also functions in the 

synthesis of choline, which can be 

converted to the neurotransmitter 

acetylcholine.

Unlike other water-soluble vitamins, 

vitamin B12 can be stored in the body 

for years. It is stored predominantly in 

the liver; however, smaller amounts 

can be found in the muscles, kidneys, 

bones, heart, brain, and spleen. 

About 2 to 5 mg of vitamin B12 is 

stored in the body (266). The size 

of B12 stores remains relatively stable, 

partly because urinary and fecal 

excretion decrease in direct relationship 

to decreases in the body pools. 

The half-life of vitamin B12 in humans 

is 350 to 400 days (266).

No evidence of toxicity has been found 

with vitamin B12 supplementation in 

amounts greater than the RDA (266), 

and no adverse effects have been 

reported to be caused by an excess 

of vitamin B12 (1224). If a person went for 

many years without adequate intake and/

or supplementation, body stores could 

be depleted. Other factors that could 

contribute to a vitamin B12 deficiency 

include a decrease in gastric acidity, 

the presence of atrophic gastritis, 

and uncontrolled growth of bacteria 

accompanied by malabsorption of 

food- bound B12 (1225). Deficiency of 

vitamin B12 leads to pernicious anemia 

and demyelination of the central nervous 

system, effects on cognition and 

neurodegenerative diseases (1226-1228), 

and can lead to death (1229).

Methylmalonic acid is generally unchanged 

during spaceflight, suggesting that vitamin 

B12 deficiency is not a significant issue 

during flight. However, blood concentrations

of methylmalonic acid were shown to be 

Figure 71. RBC (left) and serum folate (right) before, during, and after long-duration spaceflight 

(data are mean ± SD). Note: RBC folate data are not available during flight because of sample 

processing requirements.

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higher in crewmembers who experienced 

vision-related issues after flight than in 

those who did not have such issues 

(1128). This difference was evident before, 

during, and after spaceflight. Several 

studies support the notion that perturbations

in the vitamin B12 metabolic pathway can 

cause ophthalmic health issues such as 

optic neuropathy and age-related macular 

degeneration (1211-1214).

Riboflavin

Riboflavin has been discussed in the 

Energy section, but it is also relevant to 

ocular health, mainly due to its antioxidant 

properties. Riboflavin status influences 

antioxidant enzymes such as superoxide 

dismutase, catalase, and glutathione 

peroxidase. Glutathione reductase 

requires riboflavin in the form of FAD 

to convert oxidized glutathione to the 

reduced form (1230).

Among other B vitamins, riboflavin has 

been used in dietary supplements for 

protecting against or treating cataracts 

(1230, 1231). Cataract formation among 

elderly is associated with riboflavin 

deficiency, but this does not appear 

to be the case for the general population 

(1232). Riboflavin status can affect 

glutathione concentration in the lens 

of the eye, and glutathione is protective 

against oxidative damage (1233). 

Riboflavin status is low among Russian 

cosmonauts during intensive preflight 

training (1234). An initial look at riboflavin 

status from astronauts before and after 

4- to 6-month missions to the ISS, as 

assessed by RBC glutathione reductase, 

showed no evidence of reduced riboflavin 

status after flight (111). We documented 

that a lower B-vitamin status (folate, B6

, 

and riboflavin, in particular) combined with 

the presence of specific genetic variants 

in the one-carbon metabolic pathway 

was associated with greater risk of 

ocular changes after flight (1129). 

Riboflavin status can affect the efficiency 

of enzymes in that pathway and can 

affect metabolite concentrations including 

homocysteine (1235).

Vitamin A

Another important vitamin involved in 

vision health is vitamin A. Vitamin A is 

a general term that refers to a family of 

fat-soluble compounds that are structurally 

similar to retinol and share its biological 

activity. Among these are retinol, 

α-carotene, ß-carotene, and retinyl 

palmitate. Vitamin A or carotenoids can 

be found in dark green leafy vegetables 

and in vegetables and fruits that are 

yellow, orange, or red. Vitamin A plays 

a fundamental role in the retinal response 

to light. Inadequate vitamin A can result 

in night blindness, delayed light and dark 

adaptation, and dry eye (1236).

Beyond its essential role in the visual 

process, vitamin A is directly involved in 

gene expression, reproduction, embryonic 

development, and immunity. Vitamin A and 

ß-carotene serve as biological antioxidants 

and have been shown, in multiple studies, 

to reduce the risk of cancer and coronary 

heart disease (1237, 1238). Vitamin A also 

plays a role, albeit sometimes indirectly, 

in the function of almost all of the body’s 

organs (1239). Oxidative stress is 

increased during spaceflight, and this 

could affect cardiovascular health and 

cancer risk, as described in other sections 

of this book. Vitamin A status may play 

a critical role in maintaining antioxidant 

health during spaceflight; however, as 

with many antioxidants, the desire to 

supplement with high doses in the hope 

of staving off one disease is high, 

but is unwarranted and potentially 

counterproductive. Excess vitamin A, 

in levels on the order of twice the 

recommended daily intake, has been 

shown to increase bone resorption 

and fracture risk (809, 1240-1242). 

Furthermore, supplementation with 

ß-carotene should be done with caution 

(either alone or with vitamin A or in 

combination with vitamin E), because 

of unanticipated outcomes of an 

increased risk of lung cancer in smokers 

(1243, 1244). This increased risk among 

smokers might be related to pro-oxidant 

actions of ß-carotene in the lung.

When considering pre- and postspaceflight data, there is a significant 

interaction between the effects of landing 

site and spaceflight on serum levels of 

both retinol and retinol-binding protein 

(111). Russian landings are different from 

U.S. landings in that blood samples are 

usually collected later (8 to 24 hours after 

landing) than on Space Shuttle missions 

(2 to 4 hours after landing) because of the 

logistics of the landing site and crew return 

to data collection facilities. This time delay 

is important, as crewmembers begin 

to eat and drink soon after landing, 

and the spaceflight fluid shift (described 

in Chapter 5) begins to readapt to gravity 

immediately. Serum retinol decreased from 

0.73 ± 0.17 μg/mL to 0.59 ± 0.13 μg/mL 

when landings were in Russia, and 

increased from 0.52 ± 0.09 μg/mL to 

0.63 ± 0.12 μg/mL when landings were in 

the United States. Similarly, retinol-binding 

protein decreased from 61.4 ± 5.6 to 

50.9 ± 8.4 mg/L when landings were 

in Russia, and increased from 49.2 ± 9.2 to 

53.0 ± 8.7 mg/L when landings were in the 

United States. These differences in landing 

sites could be related to the time delay in 

sample collection, the fact that crewmembers might have consumed food 

during the time delay, or even variations 

in the stress response at different sites. 

These data, however, do not provide 

evidence that there is a deficiency of 

any sort for vitamin A.

In-flight vitamin A data have been 

collected as part of Nutrition experiments 

on the ISS. Figure 72 shows that no 

significant changes in retinol or ß-carotene 

occur during spaceflight.

Figure 72. Serum retinol (left) and ß-carotene (right) before, during, and after long-duration 

spaceflight. Dashed lines represent normal range. Data are mean ± SD.

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(mg/mL)

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(mg/mL)

References for Chapter 10

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Yue Z. Vitamin B12 modulates Parkinson's disease LRRK2 kinase activity through allosteric regulation and 

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Ueland PM, Meyer K, Murphy MM. Riboflavin status modifies the effects of methylenetetrahydrofolate 

reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms on homocysteine. 

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172 173

Diet, Gastrointestinal Microbiota, 

and Immune Response 

The composition and dynamic of the 

gut microbiota is tightly linked to dietary 

habits, the ability to respond to dietary 

intervention, and the potential to modulate 

immune dysregulation (1255-1262). 

Dietary shifts have the ability to rapidly 

alter the composition of the gastrointestinal microbiome, resulting microbial 

metabolites, and the effect on the immune 

system (1259, 1263, 1264). Microbiota, 

their components, or their metabolites 

interact with receptors on intestinal 

epithelial cells or immune cells 

in the lamina propria, inducing straindependent responses that may impact 

both the innate and adaptive immune 

system. Mechanisms have been 

demonstrated that link some strains 

with immune benefits such as immune 

tolerance, anti-inflammatory effects, 

and integrity of the epithelial barrier 

(1265-1267).

The metabolites available in diets rich 

in diverse plant-based foods can promote 

a varied microbiome, both enriching 

beneficial species and metabolic 

capabilities, and reducing inflammationassociated species (1268, 1269). 

Plant foods provide a diverse variety 

of fibers and prebiotics (defined as 

“dietary substrates that are selectively 

utilized by host microorganisms conferring 

a health benefit”) that are nondigestible 

to humans, and require a wide variety 

of microbial enzymes for hydrolysis 

(1268, 1270). Key products include short 

chain fatty acids—predominantly butyrate, 

acetate, and propionate—that may 

regulate inflammatory response (1261). 

Butyrate supplies the majority of the 

energy needs of colonocytes, and has 

been associated with normal colonocyte 

growth, anti-inflammatory effects, multiple 

mechanisms that may protect against 

infection, and tumor suppression (1266, 

1271). Increasing intake of fruits and 

vegetables has been associated with 

significantly higher butyrate production. 

African children consuming a plant-based 

high-fiber diet had a gut microbiota 

significantly enriched in Bacteroides 

and lower in Firmicutes, with reduced 

numbers of pathogenic bacteria and twice 

the production of butyrate, acetate, and 

propionate compared to European children 

consuming a low-fiber, high-protein 

Western diet (1272). Healthy adults 

11Immune Expedition 62 special delivery of a 

limited shelf life Space Charcuterie 

includes brie cheese, dry salami 

nuggets, cube of cheese, dried 

figs and nuts. Photo Credit: NASA.

Adequate nutrition is required for nominal immune system function and for provision 

of all components needed to generate an effective immune response (1245, 1246). 

Nutrients act as antioxidants and as cofactors (1247). Historically, crews generally 

have lower dietary intake during spaceflight than they do under normal conditions 

on the ground (1). It is well known from ground research that a lack of macronutrients 

or selected micronutrients, such as zinc, selenium, and the antioxidant vitamins, can 

have profound effects on immune function (1248-1251). Such a lack of nutrients also 

leads to deregulation of the balanced host response (1252). Disruption of nutritional 

balance and dietary intake of astronauts during spaceflight, which is often accompanied by a stress response, might influence their immune response (1253, 1254). 

However, detailed information on the effects of many micronutrients during spaceflight 

are mandatory before specific nutritional recommendations can be made, especially 

with respect to their relationship with immune system function.
174 175

consuming a plant-based diet for 

4 days produced nearly twice as much 

butyrate as the same adults on an animalbased diet for the same time (1273). 

These results indicate that differences 

in short chain fatty acid production may 

be induced by diet after only a few days. 

Similarly, plant-derived polyphenols, 

including flavonoids, require microbial 

enzymes for the production of many 

beneficial substrates, some of which 

are associated with anti-inflammatory 

effects (59, 1274, 1275). One example, 

3,4-dihydroxybenzoic (protocatechuic) 

acid (PCA) is a microbial metabolite 

that can be produced from several 

polyphenols, with benefits that 

may include anti-inflammatory and 

anticarcinogenic effects (1275, 1276).

Despite links between diet, microbiota, 

the immune system, and disease state, 

defining a healthy microbiome is complex, 

as composition and responses vary by 

individual (1277, 1278). However, dysbiosis 

of the microbiota, which can include loss 

of beneficial bacteria or overgrowth of 

detrimental bacteria, has been associated 

with inflammation, loss of epithelial barrier 

integrity, and disease (1265, 1279). 

Dietary components such as fat, sugar, 

and high animal protein have been 

associated with alterations to the 

composition of the gut microbiome that 

may be linked to disease and inflammatory 

conditions (1264). For instance, low 

gastrointestinal microflora diversity 

has been linked to diets enriched in 

fat and sugars (1280), and also to 

metabolic disorders such as obesity and 

inflammatory bowel disease (1281, 1282). 

Few spaceflight studies have evaluated 

the microbiome to date (1283). However, 

alterations in the microbiome of astronauts 

have been reported, and associations with 

the inflammatory immune response in 

spaceflight have been suggested (1284). 

These results were not evaluated in 

relation to diet. Therefore, the effect 

of diet, as well as its ability to provide 

a countermeasure to microbiome 

changes may be an important 

consideration in spaceflight (1283). 

However, even if the dietary substrates 

are present, beneficial end products 

cannot be produced in the absence 

of the necessary bacteria (1268, 1269). 

Probiotic supplements may provide 

a benefit in cases where bacteria are 

depleted, such as through antibiotic 

use. It has previously been suggested 

that probiotics may benefit some of 

the conditions that have manifested in 

spaceflight (1283, 1285); however, they 

have not been systematically evaluated 

in spaceflight to date.

In addition to immune interactions, 

the microbiota and associated metabolites 

have been increasingly linked with 

stress and psychological health (1286). 

The gastrointestinal microbiome may 

also influence the brain, mood, and 

behavior through interaction with the 

gut-brain axis (66), the immune system 

(1286-1288), or through production of 

odorants that act as social cues (1289). 

Although human studies in these areas 

are limited, a preliminary investigation 

in a confined 105-day human analog study 

indicated a potential relationship between 

gastrointestinal microbial composition 

and mood (1290). Microorganisms with 

probiotic psychiatric effects, meaning 

they can produce a mental health benefit 

if consumed in adequate amounts, have 

been described as “psychobiotics” (1291). 

Evidence from both animal studies and 

human clinical trials supports that 

ingestion of psychobiotics, many 

of which are associated with foods 

and supplements, can reduce symptoms 

of stress, anxiety, and depression (1285, 

1292, 1293). Considering the substantial 

impact that the microbiome may have 

on cognitive function, neuro-inflammation, 

and behavior, the impacts that the 

spaceflight diet and individual crew food 

selection may have on the gastrointestinal 

composition warrants further investigation. 

Although current data indicate a strong 

link between the interaction of the diet, 

the microbiome, and immune response, 

the diet may directly impact innate 

immunity completely independent 

of the microbiome (1265). This was 

effectively demonstrated in a recent study, 

where a Western diet was associated with 

increased sepsis severity and mortality in 

both colonized and germ-free mice (1294).

Skin

The skin is an active immune organ 

that provides a physical barrier between 

internal organs and toxins and microbes 

in the environment. When the epidermal 

layer of skin is disrupted, there is a local 

release of cytokines in the epidermal layer 

with subsequent systemic absorption 

through the upper dermis (1295). This is 

an early signal to the host immune system 

that the skin barrier has been disrupted. 

Skin is a target organ involved in food 

or medication hypersensitivity responses 

including rash or atopic dermatitis. 

In addition to hypersensitivity reactions, 

dermatologic conditions can result 

from nutritional deficiencies, metabolic 

disorders, or even nutrient excess, and 

can help provide diagnostic clues (1296). 

Deficiencies of zinc, vitamin A, vitamin B6

, 

vitamin C, riboflavin, and niacin are all 

associated with dermatological symptoms 

(1297). Although these are usually rare, 

they can happen in individuals with 

restricted diets (e.g., vegetarian) or 

in individuals who have issues with 

absorption of nutrients for various reasons. 

Beyond deficiencies or toxicities, specific 

nutrients can be used in the treatment of 

some dermatologic conditions including 

psoriasis, which is an inflammatory 

condition that can be aggravated by 

an inflammatory diet (1296). 

The most common reported medical 

events during spaceflight are 

dermatological in nature (1298). 

These manifestations include contact 

dermatitis, eczematous patches, 

viral reactivation, and skin infections. 

There is evidence that skin microbiome 

changes during long-duration missions 

to the ISS (1284), which may be a 

contributing factor. Nutritional deficiencies or insufficiencies could also be a 

contributing factor and should be 

considered in future analyses. 

Unfortunately, biomarkers of nutritional 

status are not routinely collected during 

flight unless there is a scientific study 

specifically looking at those markers.

Nutrients Associated with Immune 

and Dermatologic Health

Energy

As discussed earlier, some crewmembers 

have an insufficient energy intake, which 

can lead to more extensive free radical 

propagation because of diminished 

protein-based antioxidant defense 

mechanisms (1, 1021). On the other hand, 

caloric restriction with otherwise optimal 

nutrition in healthy, non-obese subjects 

has been shown to reduce oxidative 

stress (1299). On the Mir and the Life 

and Microgravity Science Space Shuttle 

mission, space travelers who consumed 

inadequate energy intake had significant 

increases in urinary excretion of 8-isoprostaglandin-F2α and 8OHdG, which 

are markers for oxidative damage (1300). 

In the NASA Twins study, where one twin 

stayed on the ISS for 1 year and the other 

one being the control on Earth, these 

biomarkers were not consistently 

Figure 73. NASA astronaut Chris Cassidy 

processes a fecal sample as part of the Food 

Physiology experiment. Photo Credit: NASA.
176 177

increased although the twin who stayed 

in space lost about 8% of the preflight 

body mass, thus suggesting insufficient 

energy intake inflight (19). In spaceflight, 

other factors inducing oxidative stress 

such as changes in metabolism, 

inflammation status, and radiation need 

to be considered when interpreting effects 

on the antioxidant defense mechanisms.

Protein and Amino Acids

Stein et al. suggest that spaceflight 

triggers a stress response similar to 

the one triggered by stress induced 

by injury (1301). Protein and amino acid 

deficiencies can have profound effects 

on a variety of immune system functions 

(1302, 1303). Increasing protein intake 

and/or supplementing certain amino acids 

may have a positive impact on the immune 

system function. Whey protein containing 

high levels of leucine, for instance, could 

enhance natural killer (NK) cell function 

and IL-12 concentration (1304) and 

improve immune function in sarcopenic 

older adults (1305) and cancer patients 

(1306). Lactoferrin, an essential 

glycoprotein extracted from milk or whey, 

demonstrated improvement of the innate 

immune system and functioning as a 

bactericide (1307). Improved antiviral 

responses have also been obtained 

in studies involving the elderly (1308). 

Although further studies are needed, 

provision of protein- and/or peptide-rich 

foods and/or supplements might be a 

means to maintain immune system 

function on exploration missions.

With respect to specific amino acids, 

arginine is necessary for normal T-cell 

function and may become essential in 

catabolic states. Supplementary dietary 

arginine has been shown to have useful 

effects on cellular immunity in animal 

studies, showing increased size of 

the thymus, enhanced lymphocyte 

proliferation in response to mitogen 

and alloantigen, augmented macrophage 

and killer cell lysis, and increased 

lymphocyte interleukin 2 production 

and receptor activity (1309). 

Supplementation of arginine led to 

improved wound healing and immune 

responses in elderly subjects (1310). 

Patients following an arthroplasty had 

lower C-reactive protein levels and could 

leave the hospital earlier when arginine 

was part of an immune supplement (1311). 

Judging by these observations it might 

seem promising to supplement arginine 

during long-term missions; however, 

up to now, no studies have been carried 

out to test arginine as a measure to 

improve immune response during 

space missions. 

Another amino acid beneficial for the 

immune system is glutamine. Glutamine 

is the most abundant free amino acid in 

the body. It can inhibit NF-κB activation 

and cytokine expression after sepsis 

(1312). Some of the beneficial effects of 

glutamine are its antioxidant effects and 

its actions as a precursor to glutathione, 

an energy substrate for lymphocytes 

and neutrophils, and as a stimulator 

of nucleotide synthesis (1313, 1314). 

Glutathione is the most abundant 

endogenous antioxidant and plays 

a central role in antioxidant defense. 

Glutamine seems to have a significant 

beneficial effect on mortality, length of 

hospital stay, and infectious morbidity 

in critical illness (1314). Positive results 

of glutamine supplementation have been 

shown in critically ill patients in whom 

supplemental glutamine reduced 

complications and mortality rates in 

addition to having a stimulating action 

on the immune system (1315, 1316). 

However, up to now, supplementation 

of glutamine as a pharmaconutrient 

has not been tested in spaceflight 

or spaceflight analogs (e.g., bed rest). 

However, as was reviewed in Chapter 7, 

studies often compare protein 

supplementation to controls getting 

no supplement, and the caloric intake 

difference could explain (i.e., confound) 

effects. Few, if any, studies evaluate 

whether the simple effect of providing 

more food (i.e., a balanced diet) would 

offer similar benefit.

Vitamin D

As described in Chapter 6, the classical 

function of vitamin D is to regulate calcium 

homeostasis and thus bone formation 

and resorption. However, recent 

publications show that vitamin D also 

exerts non-skeletal biological activities 

including immunomodulation (1317, 1318). 

The latter seems to be mediated by 

the (nuclear) vitamin D receptor (VDR) 

expressed in antigen-presenting cells 

and activated T cells (1319). Vitamin D 

and the VDR are required for the blood to 

have normal numbers of regulatory T cells.

The discovery that VDR is inducible 

in lymphocytes suggests a role for 

1,25(OH)2

D3 in the immune system (1320). 

Even the enzyme 25(OH)D3-1-α-hydroxylase

is expressed by active macrophages, 

making them able to synthesize and 

secrete 1,25(OH)2D3 (1321). However, 

in macrophages, the enzyme is mainly 

activated by immune signals such as 

interferon-γ rather than by parathyroid 

hormone, which is the activator in the 

kidney (695). Moreover, the active 

vitamin D metabolite 1,25(OH)2D3

can also be modulated by alternative 

mechanisms to increase the ability 

of peripheral blood mononuclear cells 

from sensitized human donors to resist 

microbes (here mycobacteria). Martineau 

et al. found that 1,25(OH)2D3 suppressed 

both bacillus Calmette-Guérin, a live 

attenuated strain of Mycobacterium bovis

used in vaccines, and Mycobacterium 

tuberculosis in infected cell cultures, 

likely through “nonclassical” mechanisms 

including the induction of antimicrobial 

peptides (1322, 1323). Kondo et al. found 

that vitamin D supplementation improved 

the sensitivity of the treatment response 

to pegylated interferon α/ribavirin therapy 

in chronic hepatitis C patients (1324). 

Im et al. (1325) observed in patients with 

Coronavirus disease 2019 (COVID-19) 

a vitamin D and selenium deficiency 

suggesting that this may decrease 

immune defense against the virus and 

may cause progression to a severe 

disease. People might therefore benefit 

from higher Vitamin D levels—for instance 

by supplementing vitamin D—and have a 

reduced risk to get infected (1326-1328). 

This is in line with the conclusions drawn 

from spaceflight analog studies (606) 

(Figure 74). 

Figure 74. Vitamin D actions on the Renin-Angiotensin Aldosterone System, and how vitamin D 

might promote tissue protection from SARS-CoV-2 infection. Adapted from (606).
178 179

Vitamin D might also be linked to the 

regulation of glutathione synthesis, 

as shown in in vitro studies, resulting 

in reduced oxidative stress and TGF-β

levels (1329). When human monocytes 

were supplemented with calcitriol, 

they increased glutathione syntheses 

(1329), demonstrating an immuneenhancing effect.

Studies during or after spaceflight have 

shown numerous changes in astronauts’ 

immune status, including altered 

distribution of circulating leukocytes, 

altered production of cytokines, decreased 

activity of NK cells, decreased function 

of granulocytes, decreased activation of 

T cells, altered levels of immunoglobulins, 

reactivation of latent viruses, altered 

virus-specific immunity, expression of 

Epstein-Barr virus immediate early and 

late genes, and altered neuroendocrine 

responses (19, 1330-1334). Cell culture 

studies in microgravity demonstrated 

a temporary immunosuppression, which 

could promote infections by respective 

pathogens (1335). When including the 

molecular drivers for the immunosuppressive

state, it turned out that the molecular 

architecture links energy metabolism 

and immunodeficiency in microgravity. 

Based on that, a hypocaloric nutrition 

in space could lead to a dysregulation 

of protein metabolism and impairment 

of host immunity (1336). 

Furthermore, evidence exists that among 

individuals wintering over in the Antarctic 

for 6 months, who have high serum 

cortisol, a higher vitamin D status is related 

to a lower probability of viral shedding in 

saliva (604). In that study, an interactive 

effect occurred between cortisol and 

vitamin D. Subjects with lower serum 

25-hydroxyvitamin D and with the highest 

quartile of serum cortisol (22.5 μg/dL or 

higher) had more evidence of shedding 

Epstein-Barr virus (EBV) in saliva than 

did individuals in the lowest quartile of 

cortisol (13.1 μg/dL or below, Figure 75). 

Thus, a low vitamin D status of astronauts 

during space missions might have 

an impact on their immune status. 

Although improvements of immunity and 

the reactivation of latent herpesviruses 

have been demonstrated lately onboard 

the ISS based on dietary, operational, 

and stress-relieving countermeasures (49), 

studies are still mandatory to distinguish 

between the effects of vitamin D deficiency 

and of microgravity.

Vitamin B12

Vitamin B12 was described in detail in 

Chapter 10. With regard to the immune 

system, vitamin B12 deficiency may lead 

to alterations of immunological indicators, 

such as a reduction of lymphocytes and 

suppression of NK cell activity, both of 

which can be reversed by supplementation 

with vitamin B12 (1337). In one study, for 

4 months elderly subjects (aged 70 years) 

received—in addition to the regular diet—

a special nutritional formula that provided, 

among other nutrients, 120 IU vitamin E, 

3.8 mg vitamin B12, and 400 mg folic acid. 

NK-cell cytotoxic activity increased in 

supplemented subjects, indicating 

increased innate immunity in elderly 

people (1338). Vitamin B12 deficiency 

can also manifest as skin hyperpigmentation or skin lesions. 

Restoration of vitamin B12 status 

can resolve these symptoms (1339).

Riboflavin

People with diets low in dairy and 

meat products are at risk for a riboflavin 

deficiency. Symptoms include angular 

stomatitis, glossitis, cheilosis, and 

dermatitis (1297). Skin dyscrasias similar 

to those associated with deficiencies in 

essential fatty acids are also found with 

marginal riboflavin deficiencies (263).

Vitamin B6

Cutaneous manifestation of a vitamin B6

deficiency include seborrheic dermatitis 

and eczema. These changes are likely 

due to impaired synthesis of proline from 

ornithine and the resulting suppression 

of collagen neogenesis in the skin (1340).

Biotin

Biotin is a required cofactor for pyruvate 

carboxylase, acetyl-CoA carboxylase 

isoforms 1 and 2, propionyl-CoA 

carboxylase, and ß-methylcrotonyl-CoA 

carboxylase (1341, 1342). The five biotindependent enzymes are involved in 

carbohydrate, fatty acid, and amino acid 

metabolism (1341, 1342). The primary role 

of biotin is to transfer CO2 units from one 

compound to another. Biotin exists in a 

free state or bound to proteins. About 81% 

of biotin in the human body is free biotin in 

serum, and 10% is free in tissues (1343).

Despite the observation that frank signs 

of deficiency are rare, there is growing 

appreciation of genetic, physiologic, 

and pharmacologic conditions that 

marginally impair biotin status (1344-

1346). This suggests that the lack of 

physiologic manifestations of biotin 

deficiency may not be a reliable measure 

to gauge biotin status. Marginal changes 

in biotin status have been shown to 

affect a range of metabolic factors, 

from carboxylase activity to the 

expression of non-biotin-dependent 

enzymes such as glucokinase, 

ornithine transcarbamylase, and 

phosphoenolpyruvate carboxykinase 

(1347-1349).

Biotin status has never been measured 

during or after long-duration spaceflight; 

however, it is unlikely there are any frank 

biotin deficiencies, which would present 

as neurological and dermatological 

manifestations.

Sodium

High sodium intake is correlated with 

the development of hypertension in 

sodium-sensitive people. We have shown 

in spaceflight, as well as in ambulatory 

conditions on Earth, that at an intake level 

of about 4000 mg/d, sodium is retained 

without being accompanied by fluid 

retention (123, 299, 1350). A hypothesis 

that might explain how sodium can be 

bound in an osmotically inactive way has 

been brought forward by Titze et al. (653, 

1351) and proposes that sodium can be 

stored on proteoglycans in interstitial sites. 

This uniquely bound sodium can induce 

a state of local hypertonicity in the skin 

interstitium. In a further study, they 

suggest that the local hypertonicity is 

sensed by macrophages, which then 

activate a transcription factor (tonicity 

enhanced binding protein), which in 

turn induces vascular endothelial growth 

factor C signaling (648, 649, 1352). 

High cutaneous sodium content may 

also facilitate T helper 2 cell mediated 

atopic dermatitis (1353). Therefore, high 

dietary sodium intake can be considered 

proinflammatory. Additionally, high sodium 

intake has shown systemic immunosuppressive effects, which lead to an 

impaired antibacterial immune defense 

(1354). Further studies in microgravity 

should distinguish between the effects 

of microgravity and high sodium intake 

on the immune system.

Figure 75. An interaction between serum 

cortisol, vitamin D status, and the probability 

of EBV shedding. Data from all 41 participants 

in the Antarctic study are included in the 

graph. The data were statistically analyzed 

using the continuous data set of cortisol data. 

The data are split into the two subgroups for 

presentation purposes. The graph is from 

Zwart et al. (604).

20 30 40 50 60 70 80 90 100 110

0.0001

0.01

1

Serum 25-hydroxyvitamin D

(nmol/L)

Probability of EBV shedding
180 181

Vitamin A

Vitamin A plays a well-known role in 

immune function and protection against 

infections (1355-1358). A vitamin A 

deficiency impairs mucosal barriers 

and diminishes the function of neutrophils, 

macrophages, and NK cells (1359); it may 

affect host defenses directly (1360) or 

indirectly through its role in epithelial 

cell differentiation and host barrier function 

(1357). The considerable immunity benefits 

of vitamin A, which would contribute to 

reducing the risk of various pathogenmediated diseases, warrant a recommendation to supplement individuals 

with minimal or poor vitamin A status. 

Supplementing vitamin A after training 

in rats led to increased total serum 

antioxidant capacity; however, 

concurrently, expression of superoxide 

dismutase-1 was down regulated and 

upregulation of superoxide dismutase-2 

induced by exercise was blunted by 

vitamin A (1361). Additionally, IL-10 and 

heat shock protein 70 expression, which 

are both positive for tissue damage 

protection after exercise, were 

decreased (1361, 1362). In obese 

mice, supplementing vitamin A following 

vaccination with inactivated influenza virus 

improved antibody responses and reduced 

blood concentration of inflammatory 

cytokines (1363). When supplementing 

young children (6 to 23 months) together 

with the measles vaccine, significant sex 

differences were found (1364). Additionally, 

previous supplementation with vitamin A 

affected the immunological responses 

(1364). In a study in healthy-aged subjects, 

vitamin A supplementation did not affect 

lymphocyte proliferation (1365). However, 

whether immunity benefits accrue from 

providing additional vitamin A to those 

with sufficient status is not known (1366). 

Whether vitamin A supplementation would 

be a desired measure to improve immune 

response in spaceflight has not been 

investigated up to now and needs to 

be thoroughly thought through.

Vitamin C

Ascorbic acid (vitamin C) is an essential 

component of every living cell. Although 

discussed in more detail in the Oxidative 

Stress section of the book, the role of 

vitamin C in maintaining a healthy 

immune system is discussed briefly here. 

The concentration of vitamin C is very 

high in leukocytes. The vitamin is used 

rapidly during infection to prevent 

oxidative damage. Vitamin C is a regulator 

of redox and metabolic checkpoints that 

control activation and survival of immune 

cells (1252). A deficiency in vitamin C 

status is associated with reduced immune 

function (1367) and, due to its role in 

the formation of collagen, clinical 

manifestations of scurvy are cutaneous 

findings including follicular hyperkeratosis 

with fragmented corkscrew hair and 

perifollicular hemorrhages (1368). 

Vitamin C has been shown to stimulate 

the immune system by enhancing 

T-lymphocyte proliferation in response 

to infection, and increasing cytokine 

production and synthesis of immunoglobulins (1369). Vitamin C stimulates 

neutrophil migration to the site of infection, 

enhances phagocytosis and oxidant 

generation, and microbial killing (1370). 

The antiviral effects of vitamin C are 

carried out by promoting lymphocyte 

activity, modulating cytokines, and 

reducing inflammation (reviewed in (1371).

Supplementation of very high doses of 

vitamin C in patients with shingles led to 

a lower incidence of postherpetic neuralgia 

(reviewed in (1371). In analog studies such 

as (short- or long-duration) bed rest, no 

significant change in vitamin C could be 

shown (262, 419); however, a trend for 

an increase was apparent. This might be 

related to dietary vitamin C intake during 

the study relative to the intake before the 

study (419). Up to now, however, the 

antioxidant role of vitamin C has not 

been tested in spaceflight.

Vitamin E

Vitamin E is a lipid-soluble, chain-breaking 

antioxidant found in body tissues, and is 

also the first line of defense against lipid 

peroxidation reactions. Eight naturally 

occurring compounds have vitamin E 

activity: four tocopherol derivatives (α-, γ-, 

δ-, and ß-tocopherol) and four tocotrienol 

derivatives (α-, γ-, δ-, and ß-tocotrienol) 

(1372, 1373). The tocopherols that are 

most abundant in biological systems are 

α- and γ-tocopherol; however, small 

amounts of δ-tocopherol and γ-tocopheryl 

quinine are also present. About 90% of 

the tocopherol found in human plasma 

is in the form of α-tocopherol (1374). 

Vitamin E can support monocyte/

macrophage-mediated responses (1375). 

Vitamin E and selenium have synergistic 

functions in tissues to reduce damage to 

lipid membranes by the formation of ROS 

during infections. The ability of vitamin E 

to scavenge lipid-soluble free radicals 

depends to some extent on the status of 

two other antioxidant compounds, vitamin 

C and glutathione, which are involved in 

reducing oxidized vitamin E back to a 

reusable (i.e., able to be oxidized) form. 

Additionally, vitamin E may improve 

T-cell function by decreasing production 

of prostaglandin E2 by macrophages 

by modulating the amino acid cascade 

initiated by lipoxygenase and/or 

cyclooxygenase (213). Furthermore, 

vitamin E influences lymphocyte 

maturation, possibly by stabilizing 

membranes and allowing enhanced 

binding of antigen-presenting cells 

to immature T cells through increased 

expression of intercellular adhesion 

molecule-1.

After ISS crewmembers spent 4 to 

6 months in space, their plasma 

γ-tocopherol was 50% less than 

preflight levels (111). No change in 

α-tocopherol occurred in these subjects. 

Vitamin E data have not yet been 

investigated in light of immune 

function changes during spaceflight. 

Copper

Copper has wide-ranging functions in 

the body, including a catalytic cofactor 

for oxidation-reduction reactions for 

copper enzymes. Copper enzymes are 

involved in several metabolic pathways 

such as energy production and iron 

metabolism. Copper deficiency may lead 

to anemia and neurological alterations 

(798). Many functions of copper are 

considered vital for spaceflight (179, 

1376-1379). This might have direct or 

indirect (when alterations are induced 

by psychological stress or radiation stress) 

implications for nutrition and nutritional 

status being possible causes (or effects) 

of alterations in immune system function 

(1). In a 3-week bed rest study where 

artificial gravity was applied for 1 hour 

per day as a countermeasure, no change 

in urinary copper excretion was observed 

(815). Urinary excretion during 180 days 

of spaceflight did not change either, 

whether different mechanical loading 

during exercise or bisphosphonate was 

applied (815). Nonetheless, to date, no 

further information is available about 

copper metabolism during spaceflight.

Zinc

In addition to its many essential functions 

in growth and development, zinc is 

essential for the function of cells of the 

immune system (1380). It has an important 

role in promotion of wound healing and in 

maintenance of intestinal integrity. Zinc is 

also involved in the synthesis of ROSturning enzymes and thereby takes part in 

antioxidant reactions (1381) On the other 

hand, the synthesis of the proinflammatory 

markers Il-6 and TNF-α in zinc-deficient 

monocytes were lower, thus suggesting a 

strengthening of the innate defense (1382). 

A zinc deficiency can manifest with 

cutaneous changes such as periorificial 

lesions and angular cheilitis (1297). 

Eczematous annular plaques develop in 

areas with substantial amounts of friction 

(1297). A deficiency of zinc is also 
182 183

associated with reduced concentrations 

of insulin-like growth factor 1 and reduced 

rates of protein synthesis. Therefore, zinc 

deficiency could be especially detrimental 

during immobility. However, zinc status of 

astronauts, as assessed by mean serum 

zinc and urinary zinc excretion (admittedly, 

not the best markers of zinc status), did 

not change after long-duration spaceflight 

(1, 815). Practicing different exercise 

regimes leading to different mechanical 

loads or supplementing bisphosphonates 

did not change urinary zinc excretion 

either (815). In a 3-week bed rest study, 

however, urinary and fecal zinc excretion 

increased with and without application 

of artificial gravity (1 hour per day) as a 

countermeasure leading to zinc losses 

during bed rest (815). Notably, zinc losses 

tended to be higher in the artificial gravity 

group (815). No data are available on 

the use of zinc supplementation as 

a countermeasure during spaceflight.

Selenium

Comparable to zinc, the physiological 

role of selenium is a cofactor of enzymes 

exerting their effects as antioxidants. 

Selenocysteine and selenomethionine 

are incorporated into selenoproteins, 

which function alongside others as 

antioxidants. Selenium deficiency may 

lead to increased oxidative stress, reduced 

immune function, and chronic low level of 

inflammation (1381). Selenium should only 

be supplemented after thorough analysis 

of the selenium status because selenium 

supplementation seems to be associated 

with increased mortality (1383). 

Supplementing supraphysiological 

amounts of selenium does not seem 

to lead to further optimization of the 

immune status (reviewed in (1382)). 

Polyphenols

The polyphenol family—according to their 

chemical structure—can be subclassed 

into flavonoids, phenolic acids, tannins, 

and stilbenes. Naturally occurring 

polyphenols such as resveratrol, 

quercetin, curcumin, and catechins have 

shown antioxidant and anti-inflammatory 

effects (1384). These effects seem to 

be modulated through different pathways 

such as protein kinase-dependent 

pathways activated by NF-κB or 

mitogens, as well as through preventing 

the generation of ROS by iron binding 

(1385). Curcumin, quercetin, and 

epigallocatechingallate may induce 

epigenetic changes within cells (1386, 

1387). Additionally, polyphenols seem to 

activate sirtuin 1 directly or indirectly and 

thereby are beneficial—besides having 

other functions—for regulation of oxidative 

stress, inflammation, and autoimmunity. 

Accumulating evidence has shown that 

polyphenols such as resveratrol, curcumin, 

catechins, and quercetins have a 

regulatory role in immune function in vitro 

and in vivo (1388-1394). Regarding the 

effect of polyphenols on their capability 

to prevent allergies, these are the most 

studied natural compounds. They seem to 

dampen the onset of allergic inflammation 

by affecting the interference with T-helper 

cell activation (1395, 1396). Based on 

these results, polyphenol supplementation 

might be a promising countermeasure to 

counteract oxidative stress and changes 

in immune function in spaceflight; 

however, oxidative stress is not merely 

negative. During exercise, for instance, 

mitochondria produce ROS as one 

product of oxidative phosphorylation. 

The increased ROS production is one 

signal to induce adaptation processes. 

This adaptation is one of the positive 

functions of ROS because it induces 

mitochondrial, cell- and system-wide 

adaptations (1397). In this context, 

the ROS increase reduces the 

incidents of diseases and extends 

life expectancy (1397). 

Polyphenols might also have beneficial 

effects in prevention of immune 

dysfunction during long-term space 

missions, particularly because body 

iron stores are higher during spaceflight. 

However, the role of polyphenols in 

sirtuin-1-mediated or iron-related 

regulation in immune function remains 

to be studied. To prove any effects of 

antioxidants, the ESA sponsored a 60-day 

bed rest study, which has been finished 

recently. The antioxidant cocktail evaluated 

consisted of an antioxidant and antiinflammatory food supplement (i.e., a 

mixture of natural polyphenolic extracts 

from edible plants) that was supplied in 

the form of capsules. The respective 

experiments will address effects of the 

cocktail on metabolism, the cardiovascular 

system, muscles, bones, immunology, the 

neurosensory system, and sleep. At this 

juncture, no results have been obtained 

during spaceflight; however, a recently 

initiated flight study will examine the role 

of increasing polyphenol intake, along 

with other dietary modifications, on 

immune health and nutritional status.

Iron

As mentioned previously, the maintenance 

of iron homeostasis is extremely important 

for human health. Iron is known to be 

involved in immune system function—

specifically, adaptive and innate immune 

response—and both iron overload and 

iron deficiency affect immune function. 

As reviewed by Dao and Meydani, 

iron overload can affect susceptibility 

to infection (1398). Conversely, iron 

deficiency affects the function of 

certain immune cells, including 

neutrophils and NK cells, and 

production of cytokines (1398).

As with any nutrient, supplementation 

must be used with caution because 

in areas of the world where infection 

rates are high, such as malaria-endemic 

regions, iron supplementation can actually 

increase risk of infection, suggesting 

that the supplemented iron provides an 

environment for pathogens to thrive (1399). 

Others have shown that iron deficiency 

can help protect against some types of 

infections (1400). Evidence from short- 

(weeks) and long-duration (months) space 

missions shows that RBC mass decreases 

during flight because of neocytolysis 

(9, 1401). An early hypothesis for the 

cause of decreased RBC mass was 

that RBC synthesis in space was 

understimulated relative to synthesis 

on the ground (1402). Decreased release 

of mature RBCs into the circulation is 

associated with a decrease in circulating 

erythropoietin concentrations. Serum 

erythropoietin concentrations decrease 

in the first few days of spaceflight; 

however, return to preflight levels later 

in the flight and iron turnover is 

unchanged during flight (9, 1403), 

indicating that synthesis of RBCs 

and hemoglobin is unchanged.

The decreased RBC mass, increased 

serum ferritin, decreased transferrin 

receptors, and increased serum iron 

all provide evidence for increased iron 

storage during spaceflight. Furthermore, 

the space food system provides almost 

three times the recommended intake (1). 

Iron plays an ambiguous role in human 

health: not only do humans require it for 

survival, but microorganisms (including 

pathogens) also require iron acquisition 

from the environment for their survival. 

Cells of the innate immune system have 

genes that regulate proteins that can 

modulate iron homeostasis at the cellular 

and systemic level to restrict iron 

availability to invading microorganisms. 

One such protein is hepcidin, a key 

regulator of iron homeostasis and a 

critical factor in the anemia of inflammation 

(1404, 1405). Hepcidin has been shown 

to be endogenously expressed by innate 

immune cells—macrophages and 

neutrophils. It plays a role in making iron 

less available by increasing intracellular 

iron sequestration and decreasing 

circulating iron concentrations, and it 

is influenced by cytokines IL-6 and IL-1 

(1406, 1407). Iron, on the other hand, 

catalyzes the formation of ROS and 

thereby may contribute to bone loss in 

microgravity (reviewed in (729)). It is also 

associated with certain optic neuropathies 

and retinal degeneration (1408, 1409). 

Studies suggest that some types of 

radiation exposure and oxidative stress 

can release ferrous iron (Fe2+) from ferritin 

(1410), further adding to the load of free 

iron in the body. Independently, both 
184 185

radiation exposure and high dietary iron 

load promote a state of oxidative stress 

with increased risk of pathophysiological 

outcomes (1411, 1412). In a recent study 

in rats, the effect of high dietary iron intake 

and whole-body radiation exposure was 

analyzed (1409). They found evidence of 

increased DNA damage (i.e., increased 

8-OH-dG) in the high iron intake group, 

the radiation group, and in the combined 

treatment group. An attenuation of 

radiation-induced DNA oxidation in the 

retina of animals under the high-iron 

diet was observed (1409). Studies need 

to be done to determine the role of 

increased iron stores on immune 

function and reactivation of latent 

viruses during spaceflight.

Polyunsaturated Fatty Acids

Polyunsaturated fatty acids, such as 

omega-3 and omega-6 fatty acids may 

exert different effects on the immune 

system. Omega-3 fatty acids may protect 

from oxidative damage and radiationrelated risks (212, 1413), both of which 

are concerns for space travelers. 

Omega-6 fatty acids are rather 

proinflammatory whereas omega-3 

fatty acids have anti-inflammatory 

properties (reviewed in (1414)). 

The mode of action of polyunsaturated 

fatty acids seem to be through multiple 

pathways. The main ones (reviewed 

in (1414)) seem to be: 1) Providing 

substrates for biosynthesis of 

inflammatory eicosanoid mediators, 

providing precursors for the production 

of specific leukotrienes, anti-inflammatory 

lipids or the production of proinflammatory mediators, other kinds 

of leukotrienes. 2) Interactions with 

cell surface receptors with immune cells 

such as peroxisome proliferation activating 

receptor (PPAR) and Toll-like receptors 

and thereby affecting the transcription 

of respective pro- and anti-inflammatory 

cytokines. PPAR-γ seems to affect the 

inflammatory response through NF-κB. 

This transcription factor affects 

transcription of genes involved in 

cell cycle regulation and inflammatory 

processes. NF-κB is activated by 

arachidonic acid, an omega-6 fatty acid, 

and specifically by prostaglandin E2. 

The suppression of NF-κB induced 

pro-inflammatory responses by 

eicosapentaenoic acid (omega-3 fatty 

acid), however, seems to be independent 

of PPAR-γ (1415). 3) Affecting lymphocyte 

proliferation and cytokine profiles. 

Omega-3 fatty acids, for instance, 

promote an acute immune response 

by reducing TNFα syntheses and/or 

can stimulate IL-4 production (reviewed 

in (1414)). We have reported elevated 

NF-κB after short-duration spaceflight 

(231). The effects of omega-3 fatty acids 

on inflammatory cytokines, and specifically 

TNFα, are well documented on the ground 

(231, 1416-1418), but warrant further 

studies during spaceflight.

In summary, astronauts in space 

are generally not optimally nourished, 

particularly with regard to nutrients 

supporting the immune system. 

Dietary intake tailored to the astronauts’ 

needs may be beneficial for their immune 

system function. Furthermore, the 

environmental stress of spaceflight 

can lead to changes in immune response 

as well as in the nutritional needs of the 

individual astronaut. Nutrition for optimal 

immune response and other functions 

is required to support optimal astronaut 

health during long-duration missions. 

However, it is important to be aware that 

‘‘one size does not fit all.’’ An immune 

nutrient intake profile that is appropriate 

for one astronaut or one condition may 

be of minimal benefit for another individual 

or condition, and could be harmful in 

other settings. This implies that genetics 

and other impact factors need to be 

considered to develop a personalized 

optimal immunonutrition. Although further 

research both on the ground and in 

spaceflight may continue to advance 

the science of personalized nutrition, the 

constraints of spaceflight resources and 

prepositioned food systems make it even 

more important to understand the benefits 

of standardized whole food diets to the 

health and performance of the astronauts. 

The use of basic clinical pharmacology, 

genetics, molecular biology, and clinical 

research principles in the study of 

nutritional therapy during spaceflight 

and analog studies will lead to answers 

on how to administer the right nutrients, 

in the right amounts, at the right time 

during space travelers’ missions.

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1405. Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 2011;117:4425-33.

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and interleukin-6. Proc Natl Acad Sci USA. 2005;102:1906-10.

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inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271-6.

1408. Theriot CA, Zanello SB. Molecular effects of spaceflight in the mouse eye after space shuttle mission STS-135. 

Gravit Space Res. 2014;2:3-24.

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and radiosensitivity in the rat retina and vasculature after exposure to fractionated gamma radiation. 

NPJ Microgravity. 2016;2:16014.

1410. Aubailly M, Santus R, Salmon S. Ferrous ion release from ferritin by ultraviolet-A radiations. Photochem 

Photobiol. 1991;54:769-73.

1411. Sannita WG, Acquaviva M, Ball SL, Belli F, Bisti S, Bidoli V, Carozzo S, Casolino M, Cucinotta F, De Pascale MP, 

Di Fino L, Di Marco S, Maccarone R, Martello C, Miller J, Narici L, Peachey NS, Picozza P, Rinaldi A, Ruggieri D, 

Saturno M, Schardt D, Vazquez M. Effects of heavy ions on visual function and electrophysiology of rodents: 

the ALTEA-MICE project. Adv Space Res. 2004;33:1347-51.

1412. Stevens RG, Morris JE, Anderson LE. Hemochromatosis heterozygotes may constitute a radiation-sensitive 

subpopulation. Radiat Res. 2000;153:844-7.

1413. Vanamala J, Glagolenko A, Yang P, Carroll RJ, Murphy ME, Newman RA, Ford JR, Braby LA, Chapkin RS, 

Turner ND, Lupton JR. Dietary fish oil and pectin enhance colonocyte apoptosis in part through suppression 

of PPARdelta/PGE2 and elevation of PGE3. Carcinogenesis. 2008;29:790-6.

1414. Kumar NG, Contaifer D, Madurantakam P, Carbone S, Price ET, Van Tassell B, Brophy DF, Wijesinghe DS. 

Dietary Bioactive Fatty Acids as Modulators of Immune Function: Implications on Human Health. Nutrients. 

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Nuclear factor kB is activated by arachidonic acid but not by eicosapentaenoic acid. Biochem Biophys Res 

Commun. 1996;229:643-7.

1416. Kang JX, Weylandt KH. Modulation of inflammatory cytokines by omega-3 fatty acids. Subcell Biochem. 

2008;49:133-43.

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2008;368:343-9.

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194 195

Radiation Exposure

Long-duration exploration missions 

beyond low-Earth orbit will be accompanied

by high-LET galactic cosmic rays consisting

of high-energy protons and high-charge 

and high-energy nuclei (11). High-LET 

radiation deposits part of its energy in 

ion tracks known as cores and the 

remaining energy is dispersed randomly 

outside of the core by energetic electrons, 

whereas low-LET ionizing radiation, 

including x-rays or gamma rays, deposit 

energy uniformly in tissue (13). In addition 

to galactic cosmic rays, solar particle 

events comprised mainly of low- to 

medium-energy protons periodically 

bombard the solar system. The timing 

of these events depends on the phase 

of the 11-year solar cycle (14). 

Galactic cosmic radiation exposures 

during exploration missions to Mars will 

be about 10 times higher than exposures 

on the ISS (15). These higher radiation 

doses will increase the astronauts’ risk 

of both short- and long-term health 

effects. The maximum annual radiation 

exposure from galactic cosmic radiation 

during a Mars mission is predicted to 

be of the order of 300 to 450 mGy for 

the 365- to 900-day planetary mission 

with less than 50% of the dose from high 

atomic number (Z) and energy radiation 

(HZE) particles (1011). 

Reactive Oxygen Species and Exercise

Exercise-induced fatigue and muscle 

atrophy are mediated in part by ROS. 

Electron spin resonance spectroscopy 

technology confirmed earlier findings 

from the 1950s suggesting that shortlived reactive intermediate molecules like 

ROS are present in skeletal muscle after 

exercise (1423). Since then, numerous 

studies have supported a role of ROS 

in skeletal muscle fatigue (1423-1425). 

Mitochondria are the major source of 

ROS in muscle cells, where a fine balance 

of ROS exists between maximizing force 

and minimizing fatigue (1420). Antioxidantmediated depletion of ROS from unfatigued

muscle yields decreased production of 

skeletal muscle force (1426). On the other 

hand, excess ROS can be detrimental in 

terms of fatigue. ROS can denature 

proteins directly associated with the 

sarcoplasmic reticulum Ca2+ release 

mechanism (1427), thus compromising 

tension development. Also, rat studies 

show that xanthine oxidase-induced ROS 

yields increased diaphragm fatigue, and 

that the elevated ROS during intense 

exercise is implicated in the onset of 

muscle fatigue (1428). Furthermore, 

decreased antioxidant status lowers 

exercise capacity and increases the 

onset of fatigue in human and animal 

studies (1423, 1425).

12 Oxidative Stress

Expedition 54 crewmember 

Mark Vande Hei rides the 

Canadarm2 Space Station 

Remote Manipulator System to 

a worksite during Extravehicular 

Activity 48. Photo Credit: NASA.

Many natural processes produce ROS, including breathing, metabolism, and converting 

fats into fuels. Low levels of ROS are important for intracellular destruction of bacteria 

by phagocytes and redox signaling, and they are beneficial for maintaining homeostasis, 

in general (1419). The body has natural antioxidant defense systems that minimize 

damage from free radicals, if they are present in excessive amounts, then damage 

to proteins, lipids, and DNA can occur. Some sources of ROS and reactive nitrogen 

species during spaceflight include ionizing radiation exposure, EVA and EVA prebreathe 

protocols, exercise, and even diet (10, 746, 1420-1422)
196 197

Astronauts perform prolonged upper-body 

exercise during EVA activity. One of the 

limiting factors in completing EVA tasks 

is forearm and hand muscle fatigue due 

to extensive tool operation. The fatigue 

often requires crewmembers to stop 

and rest, thereby prolonging the duration 

of EVA, and limits the number of tasks 

performed during each EVA. To date, 

there is little evidence showing that 

antioxidant supplementation has a 

benefit for improving muscle performance 

and inhibiting fatigue. Given the nature 

of the requirement for homeostasis of 

redox systems, there is a potential for 

antioxidant overload to decrease muscle 

force potential instead of having 

a protective effect.

Oxidative Damage Markers during 

Spaceflight and in Ground Analogs

Evidence for oxidative stress resulting 

from spaceflight exposure exists in 

multiple tissues, including ocular tissue 

(1117, 1429), urinary and blood biomarkers 

of damage to DNA, lipids, and protein (10, 

111, 1300, 1430), and in gene expression 

(1431, 1432). Plasma malondialdehyde 

(MDA), 8-iso-prostaglandin F2α(PGF2α), 

and urinary 8OHdG have been measured 

during and after flight as indicators of lipid 

peroxidation (MDA and PGF2α

) and DNA 

damage (8OHdG) (110, 1300). A significant 

elevation of urinary 8OHdG has been 

noted after long-duration missions 

(Mir and ISS) (111). These data are 

supported by results from the groundbased analog NEEMO, in which 

crewmembers underwent 10- to 14-day 

saturation dives (753, 1433). In one study, 

urinary PGF2α was significantly decreased 

during flight but elevated about 2.5-fold 

after flight (1300). Plasma MDA was 

increased both during and after flight 

(1300). In another ISS study with 

13 astronauts, PGF2α was approximately 

65% higher during flight compared to 

preflight (863). In a Russian 120-day 

bed rest study, increased concentrations 

of markers of lipid peroxidation were 

found in subjects. This increase was 

mitigated with vitamin E (1434). In a 

study of mice launched to the ISS, 

oxidative stress impacted blood-brain 

barrier function (1435).

The apparent increases in oxidative 

damage observed during and after flight 

could be caused by a number of factors, 

including altered DNA repair mechanisms, 

decreased antioxidant defense systems, 

or simply increased oxidative stress. 

Microgravity does not affect the repair 

of double-strand chromosome breaks 

(1436, 1437); however, evidence exists 

that downregulation of antioxidant defense 

systems occurs during spaceflight (1438). 

Along with increases in markers of 

oxidative damage and decreases in 

antioxidant defense systems, a decrease 

in total antioxidant capacity also occurs.

Nutrients Associated with Antioxidant 

Protection and Oxidative Stress

Selenium 

Selenium has been shown to play a 

role in the maintenance or induction of 

cytochrome P450, pancreatic function, 

DNA repair, enzyme activation, immune 

system function, and detoxification of 

heavy metals (1439). Selenium is also 

a cofactor for glutathione peroxidase, 

which plays a role in the reduction of 

organic peroxides and hydrogen peroxide. 

We previously reviewed the basics of 

selenium function (1). Postflight reductions 

in serum selenium of more than 10% have 

been observed after ISS flights (111). 

Whether this is related to intake or 

metabolism is not known.

Deficiency of selenium can lead to 

oxidation of biomolecules and cell injury. 

Excess selenium can lead to problems 

affecting gastrointestinal, neurological, 

cardiopulmonary, and renal systems 

(1439). Toxicity is not likely to occur 

except when selenium is consumed 

in large amounts in dietary supplements; 

however, care must be taken to avoid 

toxicity despite the relationship of 

selenium to cancer risk and 

antioxidant status. 

Vitamin E

Oxidative stress can increase in 

microgravity and high-radiation 

environments (1021, 1300, 1440). 

The antioxidant properties of vitamin E 

may help to counteract the free-radical 

damage caused by high-LET radiation 

in space. Pretreatment with antioxidants 

may help decrease radiation damage 

during missions (1441), and it may be 

necessary to provide enough vitamin E 

for astronauts’ blood levels of the vitamin 

to be higher during spaceflight than on 

Earth. However, knowledge gaps weaken 

the evidence for use of vitamin E as 

a countermeasure. Clinical trials have 

documented negative side effects of 

pharmacologic vitamin E supplementation 

alone or with other antioxidants; it can 

increase risks of cancer in humans and 

animals (1442-1445).

After ISS crewmembers had spent 

4 to 6 months in space, their plasma 

γ-tocopherol was 50% less than preflight 

levels (111). No change in α-tocopherol 

occurred in these subjects.

Vitamin C

The term “vitamin C” actually refers to two 

different compounds—ascorbic acid and 

dehydroascorbic acid—both of which 

have activity against scurvy (1446, 1447). 

Vitamin C functions as an antioxidant 

because it acts as a reducing agent for 

most physiologically relevant ROS, 

reactive nitrogen species, singlet oxygen, 

and hypochlorite. It serves as a cofactor 

for enzymes involved in the biosynthesis 

of collagen, carnitine, and neurotransmitters

(1446, 1447). Vitamin C also provides 

antioxidant protection by returning 

α-tocopherol to its biologically active state 

during lipid oxidation. The reducing agents 

glutathione and either reduced NADH or 

reduced NADPH regenerate the oxidation 

products of ascorbate (1446, 1447).

It has been suggested that vitamin C 

requirements should be greater for 

Figure 76. NASA astronaut Anne McClain works on the International Space Station's 

Port-4 truss structure during a six-hour, 39-minute spacewalk to upgrade the orbital 

complex's power storage capacity. Photo Credit: NASA.
198 199

persons who are under excessive physical 

or emotional stress, given the role of 

ascorbate in the biosynthesis of steroid 

hormones and neurotransmitters. 

However, no substantial data show 

that vitamin C metabolism is altered 

in healthy subjects under mental or 

emotional stress (1374). As a cofactor 

in collagen synthesis, vitamin C has been 

investigated for potential effects on bone 

health (as described in Chapter 6). 

Deficiency of vitamin C leads to fatigue, 

depressed immune function, scurvy 

(fatigue, muscle cramps, bruised and/or 

bleeding gums), and eventually even 

death. As noted in the introduction, scurvy 

resulted in more sailor deaths during the 

age of sail than all other causes of death 

combined (2). Toxicity of vitamin C leads 

to gastrointestinal distress, and has been 

reported in subjects consuming more 

than 1000 mg/d (637).

Vitamin C assessments of ISS crewmembers have been conducted, with 

generally no changes after landing relative 

to before launch (Smith and Zwart, 

unpublished data). Recent long- and shortduration bed rest studies documented no 

statistically significant change in vitamin C; 

however, results showed a trend for an 

increase, which might be related to dietary 

intake during the study relative to the 

subjects’ nominal intake (254, 262).

The stability of vitamin C in food supplies 

has been studied, and it is generally 

unstable at a neutral or alkaline pH and 

in high-oxygen environments (1448). 

Vitamin C is also unstable when exposed 

to light or heat (1448), and in irradiated 

foods (1449, 1450). Salem (1450) found 

that gamma irradiation of fresh onion 

bulbs significantly reduced their vitamin C 

content. This group also found that vitamin 

C content of onion bulbs had decreased 

about 50% after 6 months of storage. 

The destructive effects of gamma irradiation

(10 kGy) on vitamin C were also evident in 

commercial spices such as basil, black 

pepper, cinnamon, nutmeg, oregano, 

parsley, rosemary, and sage (1451). 

Exposure of these spices to gamma rays 

for >3 months resulted in a marked 

increase in the concentration of quinone 

radicals. Radiation levels and sources 

used in these ground studies are generally 

higher and different than those that will be 

encountered in deep space. Limited data 

available from the ISS indicate that storage 

time impacts vitamin C concentration 

more than the level of radiation that the 

foods received (87); however, the stability 

of foods and vitamins should be validated 

in deep space, or using deep space 

relevant radiation sources (97), with 

a greater variety of foods.

Free-radical formation is increased 

in space because greater amounts 

of radiation are present than on Earth. 

Because of this and increases in other 

oxidative stressors, antioxidants such 

as vitamin C are in greater demand by 

the body to act as buffers and minimize 

the oxidative damage. Studies have shown 

that supplementation with vitamin C and 

other antioxidants can modify human 

tissue radiosensitivity and protect DNA 

against damage (1452, 1453). Just as 

important to consider, however, is the 

possibility that vitamin C could induce 

DNA damage. Cai and colleagues (1453) 

found that vitamin C can act as an 

antioxidant to prevent DNA damage 

caused by ionizing radiation. However, in 

the presence of copper, it can also act as 

a reducing agent to induce DNA damage. 

Because vitamin C can reduce redoxactive metals such as iron and copper, 

this “antioxidant” can increase the prooxidant chemistry of these metals (1454). 

Thus, vitamin C can serve as both a prooxidant and an antioxidant, and the 

amount of it required by exploration crewmembers needs to be carefully addressed 

(as does the amount of almost all nutrients).

Vitamin C has been shown to degrade 

over time with storage in the space food 

supply (84), as discussed in Chapter 3. 

Methods to improve stability are being 

investigated. Evaluation of the impact 

of vitamin C supplementation during 

exposure to oxygen or high-LET 

radiation should be investigated before 

recommendations can be made for 

supplement use during flight. This should 

be evaluated in a coordinated effort to find 

an antioxidant profile for space travelers. 

An evaluation of intake requirements 

needs to be made after data have been 

gathered about vitamin C status during 

and after flight, and preferably after data 

are available pertaining to the influence of 

spaceflight-induced stress on vitamin C.

Folate 

Antioxidant properties of folate have been 

studied, and folate was found to have the 

ability to efficiently scavenge a diverse 

array of ROS (1455). Animal studies 

show that low folate status increases 

chromosome damage resulting from 

radiation exposure (1456-1459); however, 

it should be noted that excessive folate 

supplementation provided no additional 

benefit (1456). Similarly, cell models have 

shown that folate deficiency increases 

sensitivity to chromosome breakage from 

ionizing radiation (1458). Evidence exists 

that folate status decreases in subjects 

living in saturation diving conditions with 

increased partial pressure of oxygen for 

10 to 14 days, which may be related to 

its antioxidant properties (758). In that 

environment, tissue iron stores increase, 

similar to how they are increased during 

spaceflight (753, 758, 1433). Folate status 

may be even more important during 

exploration missions than on the ISS 

because of known increases in iron 

storage during long-duration spaceflight 

(111) and exposure to ionizing radiation. 

Cell models show the ability of folate to 

reduce iron toxicity in cases of iron 

overload by oxidizing free or chelated 

iron (1455).

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1449. Fan X, Thayer DW. gamma-Radiation influences browning, antioxidant activity, and malondialdehyde level 

of apple juice. J Agric Food Chem. 2002;50:710-5.

1450. Salem SA. Effect of gamma radiation on the storage of onions used in the dehydration industry. 

J Sci Food Agric. 1974;25:257-62.

1451. Calucci L, Pinzino C, Zandomeneghi M, Capocchi A, Ghiringhelli S, Saviozzi F, Tozzi S, Galleschi L. 

Effects of gamma-irradiation on the free radical and antioxidant contents in nine aromatic herbs 

and spices. J Agric Food Chem. 2003;51:927-34.

1452. Jagetia GC, Rajanikant GK, Baliga MS, Rao KV, Kumar P. Augmentation of wound healing by ascorbic 

acid treatment in mice exposed to gamma-radiation. Int J Radiat Biol. 2004;80:347-54.

1453. Cai L, Koropatnick J, Cherian MG. Roles of vitamin C in radiation-induced DNA damage in presence 

and absence of copper. Chem Biol Interact. 2001;137:75-88.

1454. Buettner GR, Jurkiewicz BA. Catalytic metals, ascorbate and free radicals: combinations to avoid. 

Radiat Res. 1996;145:532-41.

1455. Joshi R, Adhikari S, Patro BS, Chattopadhyay S, Mukherjee T. Free radical scavenging behavior of folic acid: 

evidence for possible antioxidant activity. Free Radic Biol Med. 2001;30:1390-9.

1456. Endoh K, Murakami M, Araki R, Maruyama C, Umegaki K. Low folate status increases chromosomal damage 

by X-ray irradiation. Int J Radiat Biol. 2006;82:223-30.

1457. Endoh K, Murakami M, Umegaki K. Vulnerability of folate in plasma and bone marrow to total body irradiation 

in mice. Int J Radiat Biol. 2007;83:65-71.

1458. Beetstra S, Thomas P, Salisbury C, Turner J, Fenech M. Folic acid deficiency increases chromosomal instability, 

chromosome 21 aneuploidy and sensitivity to radiation-induced micronuclei. Mutat Res. 2005;578:317-26.

1459. Courtemanche C, Huang AC, Elson-Schwab I, Kerry N, Ng BY, Ames BN. Folate deficiency and ionizing 

radiation cause DNA breaks in primary human lymphocytes: a comparison. FASEB J. 2004;18:209-11.
202 203

13

The BioNutrients investigation, shown during Expedition 61, demonstrates a technology 

that enables on-demand production of human nutrients during long-duration space 

missions. The process uses engineered microbes, like yeast, to generate carotenoids 

from an edible media to supplement potential vitamin losses from food that is stored 

for very long periods. Photo Credit: NASA.

Supplements, Foods, and 

Pharmaceuticals

The benefits of supplements are such that individual nutrients can be obtained when 

the diet cannot meet needs. Drawbacks to supplements include the potential for side 

effects, interactions with medications, and the fact that isolated nutrients may not 

provide the same protective effect as they would in the matrix of the whole food. 

For example, more than 100 phytochemicals in tomatoes likely contribute to the 

chemoprotective effect of tomato puree in addition to the lycopene known to protect 

against certain types of cancers. Tomato puree has much stronger dose-dependent, 

antimutagenic effects and lowers biomarkers of oxidative stress more than pure 

lycopene alone (1460, 1461). Similarly, omega-3 fatty acids have different effects 

on vasodilation, depending on whether they are supplied as a supplement or in 

a whole food (1462, 1463).

Besides the fact that supplements lack the synergistic effects of nutrients in 

whole foods, there are numerous examples of negative side effects associated 

with supplement use. Symptoms can range from gastrointestinal effects, dizziness, 

or decreased white blood cell count (from ipriflavone, which is synthesized from 

the soy isoflavone daidzein) to increased cancer risk (ß-carotene in the CARET study) 

or increased risk of stroke (1243, 1464-1466).

Provision of nutrients through supplements also ignores the fact that in some cases—

for example, the omega 3:omega 6 ratio—the negative effects of other foods cannot 

be overcome simply by provision of supplements. Although this phenomenon is more 

difficult to document, it is likely the reason that epidemiological data continue to show 

benefits of dietary patterns over supplements.

The issue of supplement use often arises with discussion of nutrient requirements for 

space travelers and the use of nutrients as countermeasures to the negative effects 

of spaceflight, especially oxidative damage and radiation-induced cancer risk. It is 

generally agreed that nutrients should be provided to astronauts in standard foods 

instead of supplements (35-37, 128, 1467). The need for more detailed information 

about the “psychophysiology of hunger and eating” was noted decades ago during 

the early space programs (98), but this topic has yet to be studied in detail. It is clear 

from astronauts’ experiences that when humans are in an isolated environment far 

from home, food becomes a psychological factor that can be a source of support 

or a source of frustration.

NASA currently does not recommend that astronauts take general nutritional 

supplements (beyond vitamin D) during flight for several reasons. Experience to date 

indicates that crewmembers do not consume the recommended amount of energy 

intake; accordingly, intake of many individual nutrients is therefore also inadequate. 

Unfortunately, the concept of a vitamin and mineral supplement to remedy this is 

unwarranted, as the primary problem—inadequate intake of food/energy—will not be 

resolved by a supplement. This situation may even be worsened if crewmembers believe 

that taking the supplement reduces the need for adequate food consumption, and thus 

eat even less. Furthermore, when many nutrients are provided as oral supplements, 
204 205

they are not metabolized by the body as they are when in foods (53). Changes in 

bioavailability and metabolism of nutrients can increase the risk of malnutrition.

Vitamin or mineral supplements should be used only when the nutrient content of the 

nominal food system does not meet the requirements for a given nutrient, or when data 

show that the efficacy of single (or multiple) nutrient supplementation is advantageous. 

To date, one supplement has met this standard: vitamin D. Vitamin D supplements have 

been provided to all U.S. crewmembers on the ISS. Early crews received 400 IU vitamin 

D3 per day (111). However, this was initially raised to 800 IU per day (37). This level 

allows maintenance of serum 25-hydroxyvitamin D around 75 nmol/L (124). More 

recently, 1000 IU vitamin D3 supplements have been provided for crews to take daily. 

The difference between 800 and 1000 is likely negligible, based on Antarctic dosing 

studies (603). A clear deficit of that nutrient in the space food system must be identified 

before a supplement is recommended, as was the case with vitamin D. Stability of 

nutrients in the form of supplements would also need to be addressed; shelf lives for 

exploration travel must be particularly long. Supplements, if they are recommended, 

would need to be tested in ground models for their efficacy in maintaining nutrient 

status, their stability over a long duration (3 to 5 y), and their potential interaction 

with pharmaceuticals.

Most importantly, supplements will need rigorous testing to demonstrate that the level 

used is not toxic to other body systems, and will need close monitoring during flight to 

ensure that their interactions with the spaceflight environment do not prevent them from 

being effective or safe. For example, ground-based studies have shown that high doses 

of antioxidants, when provided in situations where oxidant stressors are present (such 

as cigarette smoking), can actually have a detrimental effect (1468). Recent studies have 

also found that supplementation with certain antioxidants such as vitamin E and vitamin 

A can increase risks of cancer and all-cause mortality (1444, 1445). 

An understanding of interactions between nutrients and drugs used in medical care 

is necessary to implement safe and effective medical care and clinical intervention 

operations for astronauts on long-duration missions. Long-term use of over-the-counter 

pharmaceuticals can induce subclinical and clinically relevant micronutrient deficiencies, 

thus it will be important to assess any chronic medications that are potentially taken 

on an exploration-class mission lasting several years. The most common studies of 

nutrient-drug interactions concern their effects on influencing food intake, nutrient’s 

or drug’s absorption, distribution, biotransformation, function, catabolism, and 

excretion (1469). 

Generally, astronauts are healthy individuals. Those selected to be astronauts do 

not have chronic diseases. However, over the course of their career, they may develop 

hypertension as do 29% of adults (1470), or hypercholesterolemia as do 27% of adults 

in the general population (1471), as reported from the National Health Interview Survey. 

As a result, astronauts may need to take chronic medications, which can affect nutrient 

status (1469). Similarly, the aging process itself can lead to changes that require chronic 

medications, such as proton pump inhibitors for reducing gastric acid production. 

Normally, drugs must undergo biotransformation to allow their activation or excretion. 

For the activity of a drug to be terminated by excretion, the compound must be made 

water-soluble by biotransformation. For most drugs, this process yields a water-soluble 

compound that is less active than the original compound. Biotransformation occurs 

in two phases. Phase I is an oxidation or hydrolysis reaction to expose, add, or cleave 

a functional group. Cytochrome P450 enzymes are involved in this process.

Humans have 12 families of cytochrome P450 enzymes; however, CYP1, CYP2, and 

CYP3 are the forms most commonly used in drug metabolism (1472). Cytochrome 

P450 enzymes are unique in their ability to use a wide range of substrates (1473). 

Phase II biotransformation involves the conjugation of the parent compound to a polar 

group (i.e., acetate, glucuronides, sulfates, amino acids, glutathione), which inactivates 

most drugs. Biotransformation of drugs is influenced by several factors that could 

be affected by spaceflight and the space food system. These factors include: dietary 

factors, nutrient metabolism, monoamine oxidase inhibitors, and antacids and proton 

pump inhibitors.

Dietary Factors

Dietary factors (either excess or deficiency) 

can influence both phases of drug biotransformation. In phase I, three factors 

are required: a sufficient energy source 

(because of the high energy demands of 

this system); a protein source for enzyme 

synthesis; and iron for cytochrome 

formation (1474). Phase II requires 

glucose, sulfur-containing amino 

acids, and glutathione (1474).

The effects of nutrients on drug 

metabolism have been well studied 

in animal models; however, relatively 

few dietary factors have been studied 

in humans (1474, 1475). Results from 

animal studies must be carefully weighed 

because of some differences between 

the cytochrome P450 enzymes of animals 

and humans. One of the most well 

documented food-drug interactions is 

between grapefruit juice and a number 

of medications (1476, 1477). Flavonoid 

compounds such as naringin, naringenin, 

limonin, and obacunone, which are present 

in grapefruit juice, act as substrates for 

particular intestinal cytochrome P450 

enzymes (CYP3A4 and CYP1A2). 

Within hours of ingestion, grapefruit juice 

decreases CYP3A4 protein expression for 

up to 24 hours (1478, 1479). The decrease 

in CYP3A4 is associated with a decreased 

capability for drug metabolism and, 

therefore, increased drug bioavailability 

and exposure to a higher dose of the 

particular medication than intended.

Other foods, nutrients, or supplements 

known to affect phase I and II 

biotransformations and cytochrome 

P450 enzymes include protein, 

carbohydrates, lipids, certain vitamins, 

minerals, charbroiled foods, red wine, 

monosodium glutamate and aspartate, 

and herbs such as St. John’s wort (1474, 

1475, 1480-1483). Generally, high-protein 

diets increase drug metabolism, and 

low-protein diets decrease drug 

metabolism. For instance, antipyrine and 

theophylline are metabolized more rapidly 

when subjects are on a high-protein diet 

(1475). Other macronutrients, including 

carbohydrates, can affect phase I and 

phase II biotransformation reactions when 

intakes are very high or low. Theophylline 

(for asthma) is particularly sensitive to 

dietary protein:carbohydrate ratios; 

increasing the ratio can decrease 

effectiveness of the drug, and decreasing 

the ratio may lead to toxicity of the drug 

(1484). Fatty acids in the diet can also 

affect cytochrome P450 enzymes because 

they can be metabolized by these enzymes.

Specifically, CYP2E1 is responsible for 

lipid peroxidation; activity of this enzyme 

is enhanced in the presence of highly 

polyunsaturated fatty acids such as 

fish oils.

Metabolism of Nutrients

Some nutrients are metabolized by 

cytochrome P450 enzymes; therefore, 

drugs or other nutrients that alter the 
206 207

activity of these enzymes can alter 

nutrient metabolism. Vitamin D and 

vitamin A are two examples of nutrients 

whose metabolism involves cytochrome 

P450 enzymes. Exposure of 7-dehydrocholesterol to sunlight converts this 

substrate to previtamin D3. Previtamin 

D3

 undergoes an isomerization to form 

vitamin D3, a biologically inactive 

compound. CYP27A is a mitochondrial 

mixed-function oxidase that is responsible 

for hydroxylating vitamin D3

 to form 

25-hydroxyvitamin D3

 (1485). CYP3A4 

has been found to be a 25-hydroxylase 

as well (1486). CYP27B converts 

25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3

. CYP24 is a 24-hydroxylase 

that hydroxylates the vitamin D side chain 

and ultimately terminates hormonal activity 

of the vitamin. Inhibition of CYP24 has 

recently been targeted in the development 

of novel anti-cancer drugs. Because 

1,25-dihydroxyvitamin D3

 exerts 

antiproliferative and differentiating 

effects on many cell types including 

cancer, preventing its inactivation by 

inhibiting CYP24 activity may prove to 

be beneficial in treating cancer (1487). 

Certain drugs are known to activate 

CYP24 activity, including rifampin, 

isoniazid, and phenobarbital (1488, 

1489). Several studies show a relationship 

between the use of these drugs and 

osteomalacia (1490, 1491), which is 

caused by a deficiency of vitamin D. 

The discovery of the involvement of 

CYP3A4 in the metabolism of vitamin D 

may explain the effects on the vitamin 

D metabolism of numerous drugs, 

including inducers or inhibitors of 

this enzyme (e.g., grapefruit juice, 

erythromycin, omeprazole, carbamazepine, 

and dexamethasone), or implicate them 

in unexplained effects on vitamin D 

metabolism. Vitamin A metabolism 

involves the actions of CYP1A2 and 

CYP4A4 in the conversion of retinol 

to retinoic acid (1492, 1493). Inducers 

of CYP1A2 (e.g., cigarette smoke, 

cruciferous vegetables, broiled beef, 

rifampin) may affect vitamin A metabolism.

Monoamine Oxidase Inhibitors

First-generation monoamine 

oxidase inhibitors include agents 

such as antidepressants (phenelzine, 

tranylcypromine, pargyline, and selegiline), 

chemotherapeutic drugs (procarbazine), 

antiprotozoal drugs (furazolidone), and 

analgesics (meperidine). Monoamine 

oxidase is responsible for metabolizing 

dietary phenylethylamines, including 

tyramine, in the gastrointestinal tract 

and in the liver. Inhibitors of monoamine 

oxidase prevent the breakdown of these 

compounds; therefore, the compounds 

are taken up in the brain. Tyramine 

displaces norepinephrine from storage 

vesicles in the brain, which results in 

release of a flood of norepinephrine at 

synapses. Acute hypertension and the 

potential for stroke or myocardial infarction 

could result from this process (1474). 

Fermented foods and protein-rich 

foods that have begun to spoil are 

rich in phenylethylamines (1474).

Antacids and Proton Pump Inhibitors

By altering the pH of the stomach, chronic 

antacid or proton pump medications can 

negatively affect the bioavailability of 

several nutrients including phosphate, 

thiamin, folate, vitamin B12, vitamin C, 

iron, and vitamin A that depend on low 

pH for the uptake into intestinal cells 

(1474, 1494, 1495). Antacids can 

precipitate folic acid at a pH greater 

than 4.0, thus rendering it insoluble 

and not available for absorption (1496). 

A high pH also affects thiamin bioavailability because the vitamin is not 

stable at high pH (1474). Similarly, at 

a neutral pH, the antioxidant action of 

vitamin C on dietary nitrites is hindered. 

Normally, dietary nitrite is quickly reduced 

to nitric oxide by ascorbic acid in the 

acidic gastric juice and it is then absorbed 

by the mucosa. However, at neutral pH, 

the nitrite does not react with ascorbic 

acid and instead accumulates in the 

stomach, which can increase the likelihood 

that potentially carcinogenic N-nitroso 

compounds will be formed (1495). 

These changes are observed mostly in 

subjects who are infected by Helicobacter 

pylori and are taking proton-pump 

inhibitors (1495).

Vitamin B12 and vitamin A are also 

malabsorbed at higher pH because an 

acidic environment is essential for their 

release from dietary proteins. Because 

large stores of vitamin B12 exist in the 

body, malabsorption of this vitamin is 

unlikely to lead to deficiency unless a 

subject has been taking proton pump 

inhibitors chronically for at least 2 years 

(1494). Results from population studies, 

however, are inconsistent (1494). Age is 

a contributing factor, as well as genetic 

polymorphisms that inhibit CYP450 (1469). 

This would be particularly harmful if 

vitamin B12 stores were low before 

initiation of therapy.

Anti-Hypertensives: AngiotensinConverting Enzyme Inhibitors 

There is some evidence that long-term 

treatment with Angiotensin-Converting 

Enzyme (ACE) inhibitors may increase 

the risk for zinc deficiency (1497). 

The mechanism may be due to 

chelation of zinc and may enhance 

its excretion (1498).

Oral Contraceptives 

It is common for astronauts to continually 

suppress their menstrual cycles during ISS 

missions (1499). Women who take oral 

contraceptives may be at a higher risk for 

nutrient deficiencies (1469). One example 

is folate. Oral contraceptives may play a 

role in increasing metabolism and urinary 

excretion of folate (1500), as the use of 

these medications is associated with 

folate status (1501). Regarding vitamin B6

, 

results are not conclusive as to whether 

oral contraceptives affect status, and the 

answer seems to rely on the biomarker 

of vitamin B6 status that is analyzed. 

When erythrocyte transaminase is used 

as a functional biomarker of vitamin B6

status, half of women taking oral 

contraceptives were vitamin B6 deficient 

compared to 18% of women not taking 

the medication (1502). In a dietarycontrolled depletion-repletion study, 

vitamin B6

 requirements were not higher 

in women taking oral contraceptives 

based on numerous markers of vitamin 

B6

 status (1503, 1504). There is evidence 

that tryptophan metabolism may be 

altered with contraceptive use by some 

other means than through a vitamin B6

deficiency (1505). Other nutrients that 

may be affected by oral contraceptive use 

include vitamin B12, calcium, magnesium, 

and vitamins C and E (1469). It will be 

prudent to monitor crewmembers’ status 

of these nutrients—in particular, leading 

up to their flights—among women who 

choose to take oral contraceptives during 

long-duration missions.

Pharmacology and Drug-Nutrient 

Interactions

Currently no data are available that 

pertain to specific drug-nutrient 

interactions during spaceflight. 

The main concerns for a long-duration 

mission lasting several years involve 

the use of pharmacological agents 

that are taken chronically. Side effects 

will be especially harmful if the status 

of all nutrients is not adequate at the 

beginning of a long-duration mission. 

Addressing these concerns of drugnutrient interactions before a mission 

will be especially crucial for crewmembers 

who embark on exploration-class missions 

lasting several years.
208 209

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and angiotensin-converting enzyme inhibitors affect zinc status in hypertensive patients on monotherapy: 

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micronutrients: A story rarely told. Nutrition. 2013;29:605-10.

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Gynecol. 1971;111:782-91.

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metabolites, vitamin B6, and pyridoxic acid levels in urine. Am J Clin Nutr. 1979;32:1024-32.

1505. Leklem JE, Brown RR, Rose DP, Linkswiler HM. Vitamin B6 requirements of women using oral contraceptives. 

Am J Clin Nutr. 1975;28:535-41.

Although ground-based research offers the opportunity to study a greater number 

of subjects in a more-controlled environment, often using more-invasive protocols, 

nothing is quite as exciting and informative than the research conducted during actual 

spaceflight. These studies are constrained and challenged by many factors, including 

crew time, launch and return mass, sample storage, fluid handling in microgravity, 

and more. In this section, we describe some of these challenges, and how the ISS 

has allowed research to happen. We also provide an overview of some ground-based 

analogs that allow for research in a space-like environment.

Flight Research

Blood Collection

Blood collections have been occurring 

in space since the 1970s, and phlebotomy 

techniques are the same with or without 

gravity. The turning point for nutrition 

(and biochemistry) research on the ISS 

came in 2006, when the capability for 

collection, processing, and frozen storage 

of blood and urine samples was brought 

to orbit. Crewmembers are trained in 

procedures and the use of required 

equipment. Depending on the planned 

crew complement and schedules, many 

crewmembers are trained for autophlebotomy—i.e., drawing their own blood. 

In October 2006, early in the Expedition 14 

mission, Michael Lopez-Alegria collected 

the first blood samples to be drawn on 

the ISS (Figure 77). After the samples 

are collected, they are allowed to clot, 

and are then centrifuged (Figure 78).

14 Conducting Space Research

Figure 77. NASA astronaut Michael Lopez-Alegria collects the first blood sample on the ISS 

on October 5, 2006, having inserted the needle himself. The collection tubes can be seen 

(one in hand, the others in elastic bands on his belt assembly), along with a sharps container 

and detailed procedures (both Velcroed to the wall). Photo Credit: NASA.
212 213

Urine Collection

The nominal toilet on the ISS (aka, the 

Waste Collection System) does not allow 

for the collection of samples to be returned 

to Earth. Thus, another technique is 

required for experimental purposes. 

Most often, urine is collected by using 

urine collection devices (UCDs) (Figure 79). 

A UCD is essentially a bag with a one-way 

valve on one end, allowing urine entry 

while voiding, and a port at the other end 

to withdraw syringe samples. Each void, 

typically over a 24-hour period, is collected 

in this manner. Two or three syringes are 

used per void to withdraw about 6 to 7 mL 

of urine. Before flight, a small amount of 

lithium chloride solution is added to the 

bags. After the void is complete, the UCD 

is kneaded to facilitate mixing of the lithium 

chloride with the void. 

After the syringe(s) are collected, they are 

placed in the freezer (described below), 

and the UCD is placed in a ziplock bag 

to provide another layer of containment 

(Figure 80). The ziplock is then placed in 

a urine containment bag (UCB) (Figure 81). 

Typically, after the day’s collections are 

complete, the UCBs are stowed for 

eventual disposal with other ISS trash. 

Most trash is discarded in departing cargo 

vehicles that are not designed for reentry 

(i.e., they burn up coming back through the 

atmosphere). Before the Space Shuttle was 

retired in 2011, some trash was brought 

home on Space Shuttle vehicles. 

After the samples are returned to Earth, 

the lithium concentration in the urine of 

each syringe is determined to allow backcalculation of the urine void volume so 

that 24-hour pools may be created from 

the individual voids.

Frozen Storage 

The other key piece of hardware launched 

to the ISS in 2006 was the freezer, the 

minus eighty (degrees) laboratory freezer 

(MELFI) for the ISS (Figure 82). The three 

MELFIs located on the ISS allow increased 

stowage volume for intervals between 

returns to Earth. Each MELFI has four 

dewars (double-walled containers). 

On the outside of the MELFI, the dewars 

are covered. Each dewar has four trays, 

which are pulled out to store samples 

(Figure 83). The MELFIs are primarily 

designed for ultracold storage 

(temperatures below -80°C), and 

typically maintain temperatures close 

to -96°C. They are capable of refrigerated 

storage as well; typically, one of the four 

dewars will be at refrigerator temperature, 

while the others will be at -96°C.

Figure 78. ESA crewmember Samantha 

Cristoforetti centrifuging blood samples 

on the ISS. Photo Credit: NASA.

Figure 80. NASA astronaut Sunita Williams 

shown here with a UCD, placed in a ziplock 

bag to provide another layer of containment.

Photo Credit: NASA.

Figure 81. UCB, used for holding 

discarded UCDs until they can be 

disposed of along with other trash 

from the ISS. Photo Credit: NASA.

Figure 82. NASA astronaut Mike Barratt puts 

samples in the MELFI, which is typically 

maintained at -96°C. Photo Credit: NASA.

Figure 83. NASA astronaut Nicole Stott stores 

samples from her first day of the Nutrition 

experiment in MELFI, located in the JAXA 

Experiment Module. Photo Credit: NASA.

Figure 79. Left: UCD, shown here with a female adapter. Right: a UCD with a male adapter 

shown floating on the ISS. Photo Credits: NASA.
214 215

Sample Return

Samples are returned to Earth whenever 

possible. The Space Shuttle was the only 

ride home for frozen blood and urine 

samples before its retirement in 2011. 

Since then, the SpaceX Dragon is the 

only space cargo vehicle that is able to 

return payloads from the ISS (Figure 85). 

Other cargo vehicles exist but are 

designed to bring supplies and equipment 

to the ISS—not to return them to Earth. 

Thus, these other vehicles will burn up 

in the atmosphere on return, by design. 

The SpaceX capsules splash down in the 

ocean, typically off the coast of California.

Frozen samples are transferred from the 

MELFI to either passive or active devices 

to maintain them in a frozen state until 

reaching ground personnel. “Double 

Cold Bags” (Figure 84 ) contain specially 

designed ice packs to maintain samples 

at a temperature lower than -30°C for up 

to 125 hours. A powered -96°C freezer 

is also flown on many flights to increase 

the volume of returning samples.

Dietary Intake Recording 

During Spaceflight

Methods of recording food intake 

have evolved over the course of human 

spaceflight. On Mercury, Gemini, and Apollo 

missions, meals were planned and provided 

for each crewmember. The crewmembers 

reported any foods they did not eat or 

completely consume (116, 117, 862). 

Skylab missions in the mid-1970s included 

metabolic diets. Crews provided daily 

reports to the ground support team of 

any foods not eaten. Dietitians would 

then calculate any missing nutrient intake. 

The crew were directed to take protein and 

mineral supplements to maintain consistent 

intake of key nutrients: kcals, protein, 

calcium, nitrogen, and potassium 

(368, 369, 1506).

When required for specific research 

protocols, detailed dietary intake data 

has been obtained through written food 

intake logs or even with barcode scanning. 

Barcode scanning often seems an attractive 

alternative; however, it comes with its own 

set of issues when used during spaceflight. 

Not all space foods have barcode labels. 

Or, for many commercially packaged items, 

the label is not in the database on the 

reader, thus the item information will not be 

displayed on the screen. Additionally, many 

of the space foods do not have flat surfaces 

on their packaging; wrinkles in the label can 

be difficult for the barcode reader to detect.

On Space Shuttle missions, crews were 

provided with foods from menus they 

had selected before the flight (with the 

assistance of a dietitian), and they ate 

ad libitum while on orbit. Only a handful 

of missions that included life sciences 

experiments required detailed monitoring 

of dietary intake. In most of those cases, 

monitoring was done either using a basic 

food log, or using barcode technology 

where the crew could scan the food 

package label to record intake. Because 

the Space Shuttle was a closed system, 

the remaining food inventory and even the 

trash were inspected to validate the intake 

data (101). This barcode technique was 

implemented on Mir missions for crews 

participating in experiments requiring 

data on dietary intake.

With the implementation of the nutritional 

assessment protocol on the ISS (initial 

testing was performed in ground-based 

studies and during flight with the last two 

U.S. astronauts on Mir), a food frequency 

questionnaire was developed and deployed 

on laptop computers (110, 111, 1507). 

The questionnaire provided a list of 

foods categorized by nutrient content. 

Crewmembers would report the number 

of items they consumed for each category 

in the past week. The data were analyzed, 

and six key nutrients—energy, fluid, 

calcium, protein, sodium, and iron—

were reported weekly to flight surgeons: 

Later, potassium was also added to this list. 

The food frequency questionnaire was 

intended as a clinical tool to easily, and 

relatively quickly, estimate dietary intake 

as opposed to more-detailed, exact, and 

time-consuming diet records. Nonetheless, 

concerns were often raised about the 

astronauts’ ability to recall dietary intake 

for this reporting. This was shown not to 

be a major concern, largely because the 

food choices were limited and repeated 

approximately every 8 days, the portion 

sizes were fixed, and the nutrient content 

of the foods was well defined. 

Some astronauts on the ISS chose to 

keep detailed dietary records, typically 

with a simple spreadsheet. This approach 

was also adopted for episodic use in 

some experiments on the space station. 

When crews were asked whether this 

required much time, the response was 

that this took essentially no time. 

That, while eating, they could grab a 

laptop, type in what they were eating, 

and they were done. Subsequently, 

an iPad App was developed to record 

detailed dietary intake.

The ISS food intake tracker, or ISS FIT 

(Figure 86 and Figure 87), was developed 

using NASA’s open innovation processes. 

TopCoder helped crowdsource the detailed 

development of the ISS FIT, from initial 

concept to final prototype. The development 

process included working with the 

Astronaut Office to ensure ease of use, 

and to develop an intuitive interface that 

can display real-time information to the 

user. Ground testing was conducted during 

chamber study missions (i.e., the Human 

Exploration Research Analog [HERA]) 

at the Johnson Space Center where 

subjects consumed space food. 

This testing yielded valuable updates 

to the software and user interface. 

Although we will not belabor the details 

here, most of the difficulty in deploying 

the iPad software application on the ISS 

involved interfacing the iPads with the 

server on the ISS to store and transfer 

the data to Earth. The initial application 

was uplinked in June 2016. Astronaut 

Kate Rubins deployed the application 

to iPads on the ISS on August 11, 2016. 

Figure 85. Picture from the Pacific Ocean 

showing the SpaceX Dragon capsule following 

its splashdown west of Baja California, Mexico, 

returning from a 5-day, 16-hour and 5-minute 

mission to the ISS. Photo Credit: NASA.

Figure 84. NASA astronauts Jeff Williams and 

Kate Rubins prepare to transfer samples from 

the MELFI to the Double Cold Bags for sample 

return to Earth. Photo Credit: NASA.
216 217

In 2019, and again in 2020, updates to the 

software were deployed to the ISS, mostly 

to help the server interface and to fix a few 

bugs in the original application (e.g., the 

user could capture an image of a food item 

for data entry; however, the image files 

were corrupted somewhere between the 

application and the ground support team). 

Through Expedition 63 in 2020, after more 

than 3500 days of use by 22 astronauts, 

we have detailed dietary data from more 

than 89% of those days.

The ISS FIT provides accurate data for the 

continuing weekly reports to flight surgeons, 

and provides invaluable data on dietary 

intake that can be evaluated in relation 

to other systems (e.g., musculoskeletal, 

cardiovascular health, immune). Throughout 

this book, we provide data on dietary intake 

that was collected from ISS FIT, along with 

the data from crewmembers who logged 

detailed intake using a spreadsheet.

Body Mass Measurement

Determining body mass is one of the most 

basic overall measures of health, as noted 

every time one visits a physician’s office on 

Earth. Determination of “weight” in weightlessness, however, presents some unique 

challenges, as described (113, 153). 

There are two devices on the ISS: a Body 

Mass Measurement Device, which uses 

spring oscillation, and a Space Linear 

Acceleration Mass Measurement Device, 

which uses the physics of the equation: 

force = mass x acceleration. Figure 89 

shows images of the two devices available 

on the ISS.

Ground-based Analogs 

As described throughout this text, groundbased analogs of spaceflight are required 

to allow testing that either cannot feasibly 

be conducted during flight or needs to be 

conducted/validated before advancing to 

flight testing. Although bed rest and other 

models have been described in the text, 

we focus here on habitats that recreate 

elements of spacecraft or space missions.

Despite the central importance of 

food, the nutrition it provides, and the 

psychosocial roles it fills, there have 

been limited evaluations of the integrated 

interaction of food and nutrition with 

other human health risks in spaceflight. 

For example, although ground-based 

data indicate the importance of food and 

nutrition in cognitive performance (61), 

few reports may indicate the impact of 

food intake and nutritional status on 

cognitive performance over extended 

Figure 86. ISS FIT, seen floating on the ISS. 

Photo Credit: NASA.

Figure 88. Screenshots from ISS FIT. Image Credits: NASA.

Figure 87. NASA astronaut Peggy Whitson 

uses the ISS FIT. Photo Credit: NASA.

Figure 89. Left: NASA astronaut Joe Acaba works with the Space Linear Acceleration 

Mass Measurement Device in the Columbus laboratory of the ISS. Right: JAXA astronaut 

Aki Hoshide uses the Body Mass Measurement Device in the Zvezda Service Module of 

the ISS. Photo Credits: NASA.
218 219

isolation and confinement, with hightempo mission-realistic workload and 

sleep deprivation. Crew time on the ISS 

to evaluate extensive integrated factors 

is limited, and, as described in Chapter 3, 

future exploration food systems may be 

much more restricted than the ISS food 

system. Although data obtained from the 

ISS contribute important health and 

performance data that include spaceflightassociated risk profiles (i.e., stress, 

microgravity, radiation), they do not 

accurately define the risks in relation 

to future exploration mission risk profiles 

(i.e., isolation and confinement for multiple 

years, extreme distance from Earth with 

no immediate return capability, greater 

radiation risk, no resupply, more-limited 

food system, and performance of regular 

high-energy tasks such as EVAs).

Ground-based spaceflight analog missions 

that include mission-realistic crew selection, 

procedures, protocols, and stressors 

provide an opportunity to begin 

establishing integrated health and 

performance outcomes in relation to 

realistic exploration food system design 

and nutritional intake. Although food 

studies in ground-based spaceflight 

analogs to date have been limited, 

the need for these studies is evident. 

For example, the food system was 

not evaluated in the Russian Mars 500 

Program; however, the analog reports 

identified food as one of the greatest 

problems in isolation (82). 

Changes in nutritional status were 

measured in several short-duration 

analogs, including the EXEMSI (80), 

thereby indicating the importance of 

understanding food intake within limited 

choice, closed food systems, and changes 

in nutritional requirements that may occur 

in extreme environments. Reduced caloric 

intake and behavioral impacts were 

associated with meal replacement 

in 30 days in the HERA (Figure 90), 

despite acceptable pre-mission sensory 

evaluations, further supporting the 

importance of understanding food system 

design impacts in closed systems (74).

Changes in nutritional status were 

measured in NEEMO V (753), an 

undersea habitat that provides a 

normoxic yet hyperbaric environment 

(1508). This has been used to simulate 

the effects of spaceflight on iron and folate 

metabolism, along with effects on oxidative 

stress (753, 758, 1433) and immune system 

function (1509).

Many analogs do not have spaceflightrealistic food systems (e.g., many have 

included full kitchens, cold storage, fresh 

foods, and cooking capabilities), thus 

limiting their use to single-nutrient studies. 

However, the data that have been obtained 

indicate their potential as a resource to 

fill data gaps. For example, the results 

of the evaluation of vitamin D status and 

supplementation and its impact on viral 

reactivation at McMurdo Station in 

Antarctica contributed to establishing 

adequate supplementation for spaceflight 

crews (603, 604). The Antarctic provides 

a valuable analog for many elements of 

spaceflight, most notably isolation and 

stress. However, during the Antarctic 

winter (March – October), when there 

is no sunlight, the lack of ultraviolet light 

exposure means the only source of vitamin 

D is through diet or supplement.

Some analogs evaluated the inclusion 

of bioregenerative foods. A crew of eight 

lived in Biosphere 2, a closed-system 

environment with finite natural resources 

and no resupply for 2 years. Subjects 

depended on food entirely produced within 

the mission. Average body mass losses of 

17% were attributed to food production 

challenges, effectively demonstrating the 

risk of food scarcity with a productiondependent system, and the significant 

amount of crew time that had to be 

devoted to food production tasks (1510). 

Additionally, the food system in this study 

was deficient in vitamins B12 and D, 

as defined by government RDA 

standards, and therefore the crew 

had to be supplemented (1511, 1512). 

These deficiencies were largely due to the 

limited animal foods in the diet. Vitamin D 

status was not measured; however, 

methylmalonic acid was measured to 

assess vitamin B12 status, and one 

crewmember became vitamin B12 deficient 

(1513). One other issue that arose during 

Biosphere 2 was from high concentrations 

of atmospheric nitrous oxide in the habitat 

(1513). Nitrous oxide can irreversibly 

inactivate methionine synthase, a vitamin 

B12-dependent enzyme, and essentially a 

vitamin B12 deficiency can develop (1514).

The 1990’s Lunar Mars Life Support Test 

Project (LMLSTP) in a 20-foot chamber 

at the Johnson Space Center supported 

testing of space foods, crop growth, waste 

recycling, and more (110, 1515). LMLSTP 

crew also evaluated a fresh food menu 

and found crew time requirements to be 

excessive with the available technologies 

(1515). These types of missions identified 

important knowledge and technology 

gaps to advancing bioregenerative systems 

for exploration.

Analog opportunities with mission-realistic 

food system scenarios are needed that 

can evaluate the interaction between 

food system design, nutritional intake, 

and health and performance outcomes. 

This information will be critical to establish 

accurate risk profiles, and to inform risk/

resources trades for different mission 

scenarios. However, these risk profiles and 

resource trades ultimately need to be 

validated with the full stress, altered gravity, 

and radiation impacts of spaceflight to 

ensure successful food and nutrition 

support for exploration missions. 

Figure 90. HERA at the Johnson Space Center. Photo Credit: NASA.
220 221

References for Chapter 14

61. Lieberman HR. Nutrition, brain function and cognitive performance. Appetite. 2003;40:245-54.

74. Sirmons TA, Roma PG, Whitmire AM, Smith SM, Zwart SR, Young M, Douglas GL. Meal replacement in isolated 

and confined mission environments: Consumption, acceptability, and implications for physical and behavioral 

health. Physiol Behav. 2020;219:112829.

80. Milon H, Decarli B, Adine AM, Kihm E. Food intake and nutritional status during EXEMSI. Experimental 

Campaign for the European Manned Space Infrastructure. Adv Space Biol Med. 1996;5:79-91.

82. Poláčková Šolcová I, Šolcová I, Stuchlíková I, Mazehóová Y. The story of 520 days on a simulated flight 

to Mars. Acta Astronaut. 2016;126:178-89.

101. Lane HW, Gretebeck RJ, Schoeller DA, Davis-Street J, Socki RA, Gibson EK. Comparison of ground-based and 

space flight energy expenditure and water turnover in middle-aged healthy male US astronauts. Am J Clin Nutr. 

1997;65:4-12.

110. Smith SM, Davis-Street JE, Rice BL, Nillen JL, Gillman PL, Block G. Nutritional status assessment in semiclosed 

environments: ground-based and space flight studies in humans. J Nutr. 2001;131:2053-61.

111. Smith SM, Zwart SR, Block G, Rice BL, Davis-Street JE. The nutritional status of astronauts is altered after 

long-term space flight aboard the International Space Station. J Nutr. 2005;135:437-43.

113. Heer M, Boerger A, Kamps N, Mika C, Korr C, Drummer C. Nutrient supply during recent European missions. 

Pflugers Arch. 2000;441:R8-14.

116. Rambaut PC, Smith MC, Jr, Wheeler HO. Nutritional studies. In: Johnston RS, Dietlein LF, Berry CA, editors. 

Biomedical results of Apollo (NASA SP-368). Washington, DC: National Aeronautics and Space Administration; 

1975. p. 277-302.

117. Rambaut PC, Leach CS, Johnson PC. Calcium and phosphorus change of the Apollo 17 crew members. 

Nutr Metab. 1975;18:62-9.

153. Zwart SR, Launius RD, Coen GK, Morgan JLL, Charles JB, Smith SM. Body mass changes during long-duration 

spaceflight. Aviat Space Environ Med. 2014;85:897-904.

368. Whedon GD, Lutwak L, Reid J, Rambaut PC, Whittle MW, Smith MC, Leach CS. Mineral and nitrogen metabolic 

studies on Skylab orbital space flights. Trans Assoc Am Physicians. 1974;87:95-110.

369. Whedon GD, Lutwak L, Rambaut PC, Whittle MW, Reid J, Smith MC, Leach C, Stadler CR, Sanford DD. 

Mineral and nitrogen balance study observations: the second manned Skylab mission. Aviat Space Environ 

Med. 1976;47:391-6.

603. Smith SM, Gardner KK, Locke J, Zwart SR. Vitamin D supplementation during Antarctic winter. Am J Clin Nutr. 

2009;89:1092-8.

604. Zwart SR, Mehta SK, Ploutz-Snyder R, Bourbeau Y, Locke JP, Pierson DL, Smith SM. Response to vitamin D 

supplementation during Antarctic winter is related to BMI, and supplementation can mitigate Epstein-Barr 

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753. Smith SM, Davis-Street JE, Fesperman JV, Smith MD, Rice BL, Zwart SR. Nutritional assessment during a 

14-d saturation dive: the NASA Extreme Environment Mission Operations V Project. J Nutr. 2004;134:1765-71.

758. Zwart SR, Jessup JM, Ji J, Smith SM. Saturation diving alters folate status and biomarkers of DNA damage 

and repair. PLoS One. 2012;7:e31058.

862. Leach CS, Rambaut PC, Johnson PC. Adrenocortical responses of the Apollo 17 crew members. Aerosp Med. 

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1433. Zwart SR, Kala G, Smith SM. Body iron stores and oxidative damage in humans increased during and after 

a 10- to 12-day undersea dive. J Nutr. 2009;139:90-5.

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results of metabolic observations on Skylab II 28-day orbital mission. Acta Astronaut. 1975;2:297-309.

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1509. Strewe C, Crucian BE, Sams CF, Feuerecker B, Stowe RP, Choukér A, Feuerecker M. Hyperbaric hyperoxia 

alters innate immune functional properties during NASA Extreme Environment Mission Operation (NEEMO). 

Brain Behav Immun. 2015;50:52-7.

1510. Walford RL, Mock D, Verdery R, MacCallum T. Calorie restriction in biosphere 2: alterations in physiologic, 

hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. J Gerontol 

A Biol Sci Med Sci. 2002;57:B211-24.

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Life Support Biosph Sci. 1997;4:167-78.

1512. Silverstone SE, Nelson M. Food production and nutrition in Biosphere 2: results from the first mission 

September 1991 to September 1993. Adv Space Res. 1996;18:49-61.

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2: Structure, composition and function. Ecol Eng. 1999;13:199-234.

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222 223

As we write this section of the book in the fall of 2020, the Space Shuttle has been 

retired for almost a decade, the ISS is celebrating 20 years of continuous crewed 

operations, and commercial vehicles just started bringing crews to the ISS from 

American soil. The second 1-year stay on the ISS was recently completed. 

Much effort and planning are underway for missions to return humans to the Moon. 

As vehicles are designed for these missions, the challenges for the food system will 

be similar to those met by all previous space food systems: mass and volume of the 

food system and its associated packaging will need to be limited; refrigerators and 

freezers will not be available. Additional challenges are being raised to water and calorie 

requirements, and consideration is even being given to increasing the fat content of the 

diet to reduce mass and volume; questions remain as to whether hot and cold water will 

be available to the crews on early lunar missions. As we look beyond the Moon to future 

Mars missions, acceptability of the food items will become even more important on 

these multi-year missions. New challenges will include a need for even longer shelf 

life stability (i.e., 5 years) potentially with reduced resource allocation and infrastructure 

compared to the ISS.

Long-term plans for exploration will include the establishment of settlements, which 

will need to be more Earth-independent and self-sustainable. This may require the 

growing of plants to aid in the recycling of air and water within the habitat (825). 

These crops could then also be available for use in the food system. The food system 

may further evolve as crew time becomes less of a resource constraint (with increased 

robotic capability, or transition from exploration to settlements). The presence of partial 

gravity will allow crops to be processed into ingredients (e.g., milling wheat into flour) 

and then used to prepare menu items for crew consumption (1516). The research to 

support these endeavors, especially the growing of crops (or possibly even other novel 

systems not discussed here) that will sustain a crew and not just supplement the meals 

made on Earth, still has some distance to go (96). These long-term missions will require 

careful planning of nutrition. Understanding nutrient requirements and utilizing the food 

system to fulfill them will allow mitigation of some of the negative effects of microgravity 

on human physiology. Even a marginal nutrient deficiency over a long enough period 

could be devastating. After the requirements are defined and we have a detailed 

understanding of absorption, metabolism, and excretion of each nutrient, provision 

of these nutrients and an understanding of their stability in the space environment 

(for the months to years before they are consumed) will be critical.

Nutrition is essential for health—on Earth and in space. Determining the nutritional 

requirements for travelers on short-, medium-, and long-duration exploration missions 

will be crucial for ensuring crewmembers’ health and safety, during the mission and 

after their return. At this point, most of the requirements match terrestrial nutrient 

recommendations. This will help stave off nutrient deficiency but will not mitigate 

disease risk. Food and nutrition offer a multisystem countermeasure that requires no 

additional crew time than that already allotted for meals. We need research to define 

and develop an optimized food system to mitigate disease risks during spaceflight. 

15 Summary

Artist's rendering of the proposed Gateway lunar orbital outpost. Built with commercial 

and international partners, the Gateway is critical to sustainable lunar exploration and 

will serve as a model for future missions to Mars. Image Credit: NASA.
224 225

Some of this is underway. Care needs to be taken to avoid excess amounts of any 

nutrient; however, the risks of using food and nutritional countermeasures relative 

to those of using pharmacological countermeasures are negligible in comparison.

This document summarizes evidence demonstrating why inadequate food and 

nutrition is a risk during long-term space travel, and the implications of this risk. 

Just as for the sailors who left Europe in ships, it is not enough to have food; 

one must have the right food.

References for Chapter 15

96. Anderson MS, Barta D, Douglas G, Fritsche R, Massa GD, Wheeler R, Quincy C, Romeyn M, Motil B, 

Hanford A, editors. Key gaps for enabling plant growth in future missions. AIAA Space and Astronautics 

Forum and Exposition; 2017; Orlando, FL: AIAA.

1516. Lane HW, Kloeris V, Perchonok M, Zwart S, Smith SM. Food and nutrition for the moon base: 

what have we learned in 45 years of spaceflight. Nutr Today. 2007;42:102-10.

16 Appendices

Authors 

Scott M. Smith is Nutritionist and Manager for Nutritional Biochemistry at the NASA 

Johnson Space Center in Houston, Texas. This group is charged with keeping crews 

healthy with respect to nutrition, including using nutrition as a means to optimize 

astronaut health and safety. To this end, they conduct ground-based and flight 

research to understand how nutrition can mitigate the negative effects of spaceflight 

on the human. He has conducted research on the Space Shuttle, the Russian space 

station Mir, and ongoing research on the International Space Station. He has led several 

ground-based research projects, including studies vitamin D in of crews wintering over 

in Antarctica, studies of crews living on the bottom of the ocean, and test subjects 

spending weeks-to-months in bed. Smith participated in the definition of the current 

nutritional requirements for extended-duration spaceflight. He is the Co-Chair of the 

Multilateral Medical Operations Panel - Nutrition Working Group. 

Sara R. Zwart is a Senior Scientist and Deputy Manager of the Nutritional Biochemistry 

Laboratory at the NASA Johnson Space Center in Houston, Texas. She has been 

involved with research investigating relationships between nutrition and side effects 

of spaceflight, including bone loss, changes in iron metabolism, and oxidative damage. 

She has also worked with ground-based analogs of spaceflight, including cell culture 

models, NASA Extreme Environment Mission Operations (NEEMO) projects, extravehicular activity analogs at the Neutral Buoyancy Laboratory at the Johnson Space 

Center, and bed rest models.

Grace L. Douglas is the Lead Scientist for NASA’s Advanced Food Technology research 

effort and the Manager of the Space Food Systems Laboratory at the NASA Johnson 

Space Center in Houston, Texas. Her research focuses on determining methods, 

technologies, and requirements for developing a safe, nutritious, and palatable 

food system that will promote astronaut health during long-duration space missions. 

She works with both ground-based analogs and spaceflight experiments to determine 

risk-resource trades that may factor into vehicle designs and mission concepts.

Martina Heer is Senior Nutritionist, Professor and Program Director of Nutritional 

Sciences at the IU International University of Applied Sciences, Erfurt, Germany, and 

Adjunct Professor at the University of Bonn, Institute of Food and Nutrition Sciences, 

Bonn, Germany. She also represents the European Space Agency (ESA) in the 

Multilateral Medical Operations Panel’s Nutrition Working Group for the International 

Space Station (ISS) and is a member of the ESA Nutrition Expert Committee. Previously, 

she headed the Space Physiology Division, Institute of Aerospace Medicine, at the 

German Aerospace Center (DLR) for 6 years. Her main research interest is to understand 

the interaction of nutrition and nutrients with metabolism and other physiological 

systems such as the musculoskeletal and cardiovascular systems. Her spaceflight 

studies started with Space Shuttle missions and missions to the Russian space station 

Mir, and they continue with experiments on the ISS. The space studies are combined 

with extensive research in the form of space analog studies on the ground.
226 227

Acknowledgments

This book represents a review of many areas of research as seen from the 

perspective of a few space nutritionists and a food scientist; however, many 

people have contributed to this research and we would like to recognize as 

many as we can. 

At the heart of all space life sciences research are the astronauts who bravely 

soar into space. Beyond their required duty of flying and maintaining the 

spacecraft that is their home and workplace and refuge from the space 

environment and all that that entails, they also volunteer to be operator and/

or subject (aka guinea pig) for science experiments. Without their efforts and 

dedication to this process, none of the research on space physiology and 

medicine would be possible, and we are greatly in their debt.

Our Laboratory Teams have played a central role in much of the work reviewed 

herein. Although few original data are reported, the primary publications 

represent the efforts of many individuals. We recognize the NASA Nutritional 

Biochemistry Laboratory (NBL) team, a continually evolving group of dedicated 

individuals who work tirelessly to ensure that all samples, from flight- or groundbased studies, are collected, processed, and analyzed according to detailed 

plans and procedures. Sample and data management represent a somewhat 

tedious, but absolutely critical, element of this research, and the NBL team 

members handle this with unparalleled grace and tenacity.

We also recognize the NASA Space Food Systems Laboratory team for their 

efforts to produce and provision safe, acceptable, and nutritious foods that 

meet the challenging requirements of spaceflight, as well as theirs, and others, 

continued research and development efforts to improve upon this system in 

accordance with research findings.

Spaceflight research is literally unlike anything on Earth. The teams of review 

and support staff, from the engineers who develop flight hardware to trainers 

who work with the crews to accomplish on-orbit data and sample collection, 

to experiment support personnel who watch over every aspect of a study, all 

ensure that nothing escapes completion. Again, these teams represent evolving 

and ever-changing groups of names, but without their dedication, these studies 

would simply not be possible. Similarly, NASA management personnel across 

organizations and over the years have supported efforts to allow these research 

projects to happen. The NASA Human Research Program (HRP), established in 

2006, set the stage for conduct of most of the studies from which we obtained 

the International Space Station data reported herein. The HRP includes the 

Human Health and Countermeasures Element, where the Nutrition Risk part 

of the human spaceflight research plan resides. Although many considered 

nutrition an afterthought on the list of potential countermeasures—or worse, 

thought nutrition to be simply what the food system provided—others continue 

to help fight the good fight.

We are indebted to many of the scientists at NASA who took time to review 

sections of the text. Specifically, Dr. Brian Crucian for Immune, Dr. Meghan 

Downs for the Energy and Muscle, Dr. Steve Laurie and Dr. Brandon Macias 

for Ocular Health, Dr. Stuart Lee for Cardiovascular, Sara Mason for Renal Stone, 

and Dr. Jean Sibonga for Bone. Their input was extremely helpful and valuable, 

and the authors take blame for any mistakes or oversights remaining. 

If any of this is readable, you can thank the two outstanding technical editors—

Kerry George and Susan Breeden. Kerry worked with us as we were writing, 

which one imagines is a bit like painting a car while it speeds down the highway. 

She did her best, but all flaws remain the fault of the authors.

We are grateful to Cynthia Bush, Senior Graphic Design Specialist/Illustrator 

at the Johnson Space Center in Houston. The products of her efforts to create 

the cover and several of the specialized figures herein are outstanding. She was 

subsequently also responsible for the content layout work. If what you hold in 

your hands (or see on a screen) looks good, it is thanks to Cindy.

As evidenced by the affiliations of Dr. Martina Heer, the collaboration between 

U.S. and German investigators over the past 20-plus years has promoted 

growth and expansion of knowledge, as any good collaboration does. European 

Space Agency (ESA) and German Aerospace Center (DLR) support of nutrition 

research has contributed greatly to this field of science as reviewed herein. 

Similar to those described above for NASA, a management structure and 

dedicated laboratory support team have enabled outstanding research.

We are indebted to many for the opportunities we have had to conduct research, 

to publish research, and to review research herein. We hope you find this volume 

useful for your own knowledge base.

SMS, SRZ, GLD, MH.
228 229

List of Figures

Figure 1. ......................................................................................................................... 10

The ISS as seen from the last Space Shuttle mission. Photo Credit: NASA.

Figure 2. ......................................................................................................................... 14

The ISS Galley in the USOS includes a conduction food warmer and a Potable Water 

Dispenser with metered hot or ambient temperature water. NASA astronaut Christina 

Koch is heating pizzas, part of the limited shelf life foods that may be included in some 

resupply provisions to the ISS. Inset: Example of a food package during rehydration. 

Photo Credits: NASA

Figure 3. ......................................................................................................................... 16

Space food system requirements. Adapted from (6).

Figure 4. ......................................................................................................................... 18

The Expedition 50 crewmembers share a meal during the Christmas holidays. 

Back row (left to right): Cosmonauts Sergei Ryzhikov, Andrei Borisenko, Oleg Novitskiy. 

Front row (left to right): ESA astronaut Thomas Pesquet (wearing Santa cap), NASA 

astronauts Shane Kimbrough, Peggy Whitson. Food, and gatherings around the table, 

are important to celebrations and holidays in spaceflight, just as they are on Earth. 

Photo Credit: NASA.

Figure 5. ......................................................................................................................... 19

NASA astronaut Sandra Magnus, Expedition 18 flight engineer, prepares to eat a 

Christmas meal at the Galley in the Zvezda Service Module. Photo Credit: NASA.

Figure 6. ......................................................................................................................... 20

Nutrient stability over 3 years of study. Data are presented based on the content 

(after processing) of each nutrient as included in the standard menu. Although there 

is an expectation that crews will consume at least 10% (and often 20% to 25%) of their 

food from CSM containers, the content of vitamin D, vitamin K, calcium, and potassium 

start below nominal recommendations. Thiamin and vitamin C degrade to inadequate 

amounts over the 3-year study period. Other nutrients (vitamins A, B6, and B12) degrade, 

but remain above required minimums. Adapted from Cooper et al. (84).

Figure 7. ......................................................................................................................... 21

Depiction of Orion, Gateway, and Artemis mission profile. Image Credit: NASA

Figure 8. ......................................................................................................................... 29

In-flight energy intake of crewmembers in different space programs. Data are expressed 

as percentage of energy requirements predicted by the World Health Organization 

equation (40) and are mean ± SD. Apollo and Skylab data are from Bourland et al. 

(125). Figure is adapted from earlier publications (1, 126), with additional published data 

included (111, 124, 127).

Figure 9. ......................................................................................................................... 30

Body mass during flight. The left panel shows body mass in 49 male (blue line, open 

symbols) and 12 female (gold line, solid symbols) ISS astronauts during and after flight 

as a percent of preflight. In the right panel, each point represents the lowest point for 

each crewmember as compared to preflight. Three percent of astronauts (2 of 79) lost 

>10% body mass, whereas 57% (45 of 79) lost 5% to 10% of preflight mass.

Figure 10. ....................................................................................................................... 31

Relationship between energy intake (kcal/kg body mass/d) and weight loss (change in 

body mass/d, kg) during Apollo missions. N=33. Data are courtesy of William Carpentier, 

as previously published. (154).

Figure 11. ....................................................................................................................... 34

Dietary fiber intake in 27 astronauts and the ISS "standard menu." Green shaded area 

represents intakes meeting the daily requirement. Each symbol represents a day’s intake 

during flight. Circles are male astronauts, and triangles are females. These represent 

crewmembers who recorded dietary intake with the ISS FIT App or kept a detailed 

food log. The black lines represent mean ± SD for each crewmember.

Figure 12. ....................................................................................................................... 35

Dietary cholesterol (left panel) and saturated fat (right panel) intake in 27 astronauts 

and the ISS "standard menu." Green shaded area represents intakes meeting the 

recommended intakes. Each symbol represents a day’s intake during flight. 

Circles are male astronauts, and triangles are females. These represent crewmembers who recorded dietary intake with the ISS FIT App or kept a detailed 

food log. The black lines represent mean ± SD for each crewmember.

Figure 13. ....................................................................................................................... 36

Relationship between fish intake during long-duration flight and loss of whole-body 

BMD after flights on the ISS. Figure adapted from (231).

Figure 14. ....................................................................................................................... 37

Protein intake during spaceflight on ISS missions. Each point represents the reported 

average intake for an individual crewmember over the course of their mission. 

Green dashed line represents the US Recommended Dietary Allowance (41), and 

the range of protein intakes (1.2.-1.7 g/kg) recommended by the American Dietetic 

Association, Dietitians of Canada, and American College of Sports Medicine for 

high-intensity athletes (245).

Figure 15. ....................................................................................................................... 37

Protein intake for 27 ISS astronauts and the "standard menu." Each symbol represents 

a day’s intake during flight. Circles are male astronauts, and triangles are females. 

These represent crewmembers who recorded dietary intake with the ISS FIT App 

or kept a detailed food log. Standard menu data are calculated for an 83 kg individual—

i.e., the average male astronaut’s body mass. The black lines represent mean ± SD for 

each crewmember. Dashed lines are as described in Figure 14.

Figure 16. ....................................................................................................................... 39

Erythrocyte transketolase activation before and after flight in ISS astronauts. 

Data are mean ± SD of 49 male astronauts (blue line) and 12 female astronauts 

(gold line). The black dashed line represents the normal range (i.e., <15% is 

considered adequate thiamine status).

Figure 17. ....................................................................................................................... 40

Erythrocyte glutathione reductase activation before and after flight in ISS astronauts. 

Data are mean ± SD of 49 male astronauts (blue line) and 12 female astronauts 

(gold line). The black dashed line represents the normal range (i.e., <40% is consider 

adequate riboflavin status).

Figure 18. ....................................................................................................................... 40

NAD:NADP in 23 ISS astronauts before and after flight. An NAD:NADP ratio >1.0 is 

considered to reflect adequate niacin status.

Figure 19. ....................................................................................................................... 40

Niacin intake in 27 astronauts and the ISS "standard menu." Each symbol represents 

a day’s intake during flight. Circles are male astronauts, and triangles are females. 

These represent crewmembers who recorded dietary intake with the ISS FIT App or 

kept a detailed food log. The black lines represent mean ± SD for each crewmember. 
230 231

Dashed lines represent required intakes for men (blue line) and women (purple line), red 

line represents the upper limit for niacin intake from supplements or fortification (266).

Figure 20. ....................................................................................................................... 41

Urine iodine excretion in male (blue line) and female (gold line) ISS astronauts. Black 

dashed line represents normal limits.

Figure 21. ....................................................................................................................... 53

Hydration status of astronauts by two measures: urine osmolality (left panel) and 

serum sodium concentration (right panel). Forty percent of ISS astronauts met the 

sports medicine definition of dehydration with urine osmolality above 700 mOsm/kg 

(above the red dashed line, left panel). 8.7% of astronauts met the clinical definition 

of dehydration (serum Na >145 mmol/L, above the red dashed line, right panel).

Figure 22. ....................................................................................................................... 59

Calcium intake in 27 crewmembers and the ISS "standard menu.“ Each symbol 

represents a day’s intake during flight. Circles are male astronauts, and triangles 

are females. These represent crewmembers who recorded dietary intake with the 

ISS FIT App or kept a detailed food log. The black lines represent mean ± SD for 

each crewmember. Dashed lines represent the DRI and exploration mission 

requirement of 1000 mg calcium/d.

Figure 23. ....................................................................................................................... 61

Calcium oxalate relative supersaturation risk before (left panel) and during (right panel) 

flight. Each symbol represents a 24-hour urine pool. The box/error bars reflect the 

group mean and SD. Data are shown over the course of Nutrition SMO and Biochemical 

Profile projects on ISS (2006-2018), n=61. The red dashed line is the point above which 

the risk is greater than in the non-stone-forming population. Data adapted 

and expanded from (210).

Figure 24. ....................................................................................................................... 62

Liquid salt and pepper dispensers float on the Space Shuttle Columbia’s middeck 

during STS-94. Photo Credit: NASA.

Figure 25. ....................................................................................................................... 62

Fluid intake in relation to the concentration of calcium in the urine. The green dashed line 

represents the concentration above which precipitation would be expected. The vertical 

line at 32 ml/kg represents the level of fluid intake recommended to mitigate this risk.

Figure 26. ....................................................................................................................... 63

NASA astronauts Michael Finke and Chris Ferguson hold beverages with notes written 

on them: TODAY'S COFFEE and YESTERDAY'S COFFEE. Eric Boe and Donald Pettit 

are in the background. Photo Credit: NASA.

Figure 27. ....................................................................................................................... 64

Left: NASA astronaut Sunita Williams uses the iRED. The iRED was launched in 

2000 with the first ISS crew. The Advanced Resistive Exercise Device (ARED) 

replaced it in late 2008. Right: Canadian Space Agency astronaut Robert Thirsk 

using the ARED in the Node 1 module. Photo Credits: NASA.

Figure 28. ....................................................................................................................... 65

Body mass and composition changes (left panel, total body mass; middle panel, % lean 

body mass; right panel, % body fat) in astronauts exercising with iRED (dashed red line) 

or ARED (solid blue line). Data are from pre- and postflight DXA, and are mean ± SD. * 

denotes significant group x time interaction (P<0.01). Figure adapted from (124).

Figure 29. ....................................................................................................................... 65

BMD loss in astronauts on Mir (n=17) and ISS missions. The ISS crews had access 

to either the iRED (n=7) or the ARED (n=40) exercise device. Data are expressed 

as percent change per month of flight. Figure updated and adapted from (124), with 

Mir data from (357, 360).

Figure 30. ....................................................................................................................... 65

Whole-body BMD loss after flight in men (blue checked bars) and women (gold solid 

bars) who used either the iRED or the ARED exercise device. Data are expressed as 

percent change per month of flight and are mean ± SD. Figure adapted from (147).

Figure 31. ....................................................................................................................... 66

Bone resorption (as indicated by urinary NTX, left panel) and bone formation 

(as evaluated by serum BSAP, right panel) during 17 weeks of bed rest with 

(solid blue line) or without (dashed red line) heavy resistance exercise. Data are 

expressed as percentage of pre-bed rest values, and are mean ± SD. The vertical 

lines represent the beginning and end of the bed rest phase. Data adapted from (479).

Figure 32. ....................................................................................................................... 69

Urine calcium excretion before, during, and after spaceflight in astronauts who 

had access to iRED (dashed line, red triangles), ARED (solid line, blue squares), 

or bisphosphonate+ARED (dashed line, green circles). Data adapted from (329).

Figure 33. ....................................................................................................................... 70

Serum calcium before, during, and after spaceflight in astronauts who had 

access to iRED (dashed line, red triangles), ARED (solid line, blue squares), 

or bisphosphonate+ARED (dashed line, green circles). Data adapted from (329).

Figure 34. ....................................................................................................................... 74

Pre- and postflight data from early ISS missions show that vitamin D status decreased 

after long-duration spaceflight, despite provision of 400 IU vitamin D3/d supplement 

(black dashed line, N=16). In-flight data (purple line) show that 800 IU vitamin D3/d is 

enough to maintain status during flight (N=26). Red dashed lines depict IOM-defined 

upper and lower acceptable limits (with respect to bone health) (584). The green dashed 

line at 80 nmol/L reflects what many perceive as an optimal level with respect to 

parathyroid hormone suppression and non-bone health outcomes. Data are mean ± SD. 

Figure adapted, and data updated, from (111, 327). 

Figure 35. ....................................................................................................................... 76

Serum phylloquinone before, during, and after flight in 25 male (blue line) and 8 female 

(gold line) ISS astronauts. The dashed lines indicate the normal range for phylloquinone. 

Data are mean ± SD. Data and N are expanded from the original publication of these 

findings (627).

Figure 36. ....................................................................................................................... 77

Serum and urine sodium in 47 male (blue line/symbols) and 11 female (gold line/

symbols) ISS astronauts. Black dashed lines represent normal ranges.

Figure 37. ....................................................................................................................... 77

Sodium intake of ISS crewmembers between 2006 and 2018, reflecting the reformulation 

in the early 2010s. NOTE: these data are not exact, as there was little insight into when 

specific items transitioned from high to low sodium. Each point represents reported 

sodium intake expressed as mg/kcal. Mean ± SD are shown for each grouping.
232 233

Figure 38. ....................................................................................................................... 78

Urine sodium to creatinine ratio in ISS crewmembers between 2006 and 2018. 

The decrease reflects the reformulation of the food system to lower sodium content. 

Boxes and error bars reflect mean ± SD.

Figure 39. ....................................................................................................................... 78

Sodium intake in 27 crewmembers and the ISS "standard menu.“ Each symbol 

represents a day’s intake during flight. Circles are male astronauts, and triangles are 

females. These represent crewmembers who recorded dietary intake with the ISS 

FIT App or kept a detailed food log. The black lines represent mean ± SD for each 

crewmember. Dashed lines represent the lower intake limit of 1500 mg/d and the ISS 

recommended <3500 mg/d. The DRI and exploration mission requirement is 2300 mg 

sodium/d (green dotted line).

Figure 40. ....................................................................................................................... 80

Proposed mechanism of the effects of high dietary sodium on bone loss. 

Image Credit: NASA.

Figure 41. ....................................................................................................................... 82

NASA astronaut T.J. Creamer shown here with his FD15 Pro K food container, 

with a few items floating loose.

Figure 42. ....................................................................................................................... 83

Relationship between NEAP and loss of lumbar spine BMC after flight. 

Figure adapted from Zwart et al. (249). Photo Credit: NASA.

Figure 43. ....................................................................................................................... 84

Iron intake in 27 crewmembers and the ISS "standard menu." Each symbol represents 

a day’s intake during flight. Circles are male astronauts, and triangles are females. 

These represent crewmembers who recorded dietary intake with the ISS FIT App or 

kept a detailed food log. The black lines represent mean ± SD for each crewmember. 

Dashed lines represent the upper limit of 45 mg/d (red line), the RDA for women of 

18 mg/d (purple line), and the RDA for men of 8 mg/d (blue line). See text for details 

on spaceflight requirements.

Figure 44. ....................................................................................................................... 85

Iron stores, reflected by serum ferritin (red circles, solid line) and oxidative damage 

to DNA, reflected by urinary 8OHdG (blue squares, dashed line) before, during, and 

after long-duration spaceflight. Data are mean ± SD for 23 ISS astronauts. Data are 

expressed as percent change from preflight. Figure adapted from (10).

Figure 45. ....................................................................................................................... 87

Phosphorus intake in ISS astronauts and in the "standard menu.” The dashed line 

represents the requirement of 700 mg/d.

Figure 46. ....................................................................................................................... 87

Dietary calcium (Ca):phosphorus (P) ratio in 27 ISS crewmembers and the “standard 

menu.” Ideally, the Ca:P ratio would be no less than 0.67 (i.e., P:Ca <1.5), as shown 

by the black dashed line.

Figure 47. ....................................................................................................................... 88

Magnesium intake in 27 ISS astronauts and in the “standard menu.” Each symbol 

represents one 24-hour intake. Female crewmembers are represented as triangles, 

males as circles. The blue dashed line represents the requirement for men (420 mg/d), 

and the purple dashed line represents the RDA for women (320 mg/d).

Figure 48. ....................................................................................................................... 88

The relationship between magnesium intake and energy intake in astronauts during 

flight. Each point represents a day’s record; however, even partial days were included 

when available. Data are from 27 astronauts who kept detailed dietary records, and 

represent 3458 days of collection.

Figure 49. ....................................................................................................................... 89

Tissue magnesium concentration, assessed through analysis of sublingual cells, before 

and after flight (left panel) and bed rest (right panel). In the flight data, solid blue line/

squares denotes crewmembers who had access to ARED, dashed red triangles iRED, 

and dashed green/circles ARED+ bisphosphonate. In the bed rest data, blue dashed 

represents 60-day bed rest subjects, and red solid line the 90-day bed rest subjects. 

Figure adapted from (797).

Figure 50. ....................................................................................................................... 91

Serum copper in ISS crewmembers before, during, and after flight. 

Males are represented by blue line, and females the gold.

Figure 51. ....................................................................................................................... 92

Serum (left) and urine (right) zinc in ISS crewmembers before, during, and 

after flight. Males (n=48) are represented by the blue line, and females (n=12) 

the gold. Black dashed lines represent normal ranges. Adapted from (815).

Figure 52. ..................................................................................................................... 116

Serum and urine cortisol in 13 astronauts before, during, and after ISS missions. 

Adapted from (863).

Figure 53. ..................................................................................................................... 118

NASA astronaut Shannon Walker, equipped with a bungee harness, exercises 

on the Combined Operational Load Bearing External Resistance Treadmill (COLBERT) 

in Node 3 of the ISS. Photo Credit: NASA.

Figure 54. ..................................................................................................................... 119

Serum total testosterone concentrations before, during, and after flight on the ISS. 

Although circulating concentrations decreased significantly after flight (at R+0), 

no other time point differed significantly from the preflight mean. Data are mean ± SD. 

Data are from Smith et al. (209).

Figure 55. ..................................................................................................................... 120

Serum total serum testosterone concentrations in subjects in multiple bed rest studies: 

data from a 21-day bed rest testing an artificial gravity countermeasure are shown with 

blue triangles, filled symbols and solid line = control, n=7, open symbols and dashed line 

= AG, n=8 (254). Note: pre-bed rest data assigned to BR-10; control subjects in 60- to 

90-day bed rest studies are shown with red circles and solid line, n=15 (209); control 

subjects in a 70-day bed rest study are shown with purple diamonds and solid line (957); 

control subjects in a 30-day bed rest study are shown with black squares and solid line, 

n=8 (209); subjects treated with vibration for 60- to 90-day bed rest are shown with open 

black circles and dashed line, n=7 (209).

Figure 56. ..................................................................................................................... 125

Front to back: Expedition 34 crew astronaut Tom Marshburn and cosmonauts Roman 

Romanenko and Evgeny Tarelkin with floating fruit and vegetables in ISS Node 1. 

Photo Credit: NASA.

Figure 57. ..................................................................................................................... 138

NASA astronaut Catherine (Cady) Coleman exercises on the Cycle Ergometer 

with Vibration Isolation System (CEVIS) in the U.S. Laboratory module on the ISS. 

Photo Credit: NASA.
234 235

Figure 58. ..................................................................................................................... 139

Relationship between energy intake (kcal/kg body mass/d) and change in plasma volume 

loss (mL/d) during Apollo missions. N = 21. Data are courtesy of William Carpentier.

Figure 59. ..................................................................................................................... 139

Energy intake during ISS missions (N=60). Each point represents an individual crewmember and is his or her reported average daily energy intake over the course of the 

mission, expressed per kg body mass. The dashed line represents 33 kcal/kg body mass.

Figure 60. ..................................................................................................................... 140

A Salmo-rita (salmon and hot sauce on a tortilla) floats near the Galley Table in the Unity 

Node 1 on the ISS. Photo Credit: NASA.

Figure 61. ..................................................................................................................... 141

NASA astronaut Jessica Meir harvests Mizuna mustard plant leaves from plants in 

the Vegetable Production System (Veggie) for Veg-04B experiment plant harvesting 

operations. Photo Credit: NASA.

Figure 62. ..................................................................................................................... 148

NASA astronaut Kjell Lindgren is photographed with a bag of assorted fruit (oranges, 

lemons, grapefruits) floating in the Node 2 module after being unpacked from the 

Kounotori H-II Transfer Vehicle 5. Photo Credit: NASA.

Figure 63. ..................................................................................................................... 154

NASA astronaut Karen Nyberg performs fundoscopy in the Destiny laboratory of the ISS. 

Photo Credit: NASA.

Figure 64. ..................................................................................................................... 155

Homocysteine is significantly higher (P<0.001) in astronauts with ophthalmic findings 

(blue squares) than in those without ophthalmic findings (red circles) (1128). The “1C” 

sample (open symbols) was collected 2 to 6 years after flight as part of the experiment 

evaluating one-carbon pathway SNPs (1129).

Figure 65. ..................................................................................................................... 155

The presence of more risk alleles (i.e., G and C alleles for MTRR A66G and SHMT1 

C1420T) was significantly related to incidence of optic disc edema in astronauts after 

4 – to 6-month space missions.

Figure 66. ..................................................................................................................... 155

Relationship between MTRR A66G genotype and end tidal CO2. The individual with AG 

genotype denoted by the open circle was vitamin B12 deficient. Adapted from (1134).

Figure 67. ..................................................................................................................... 156

Figure 67. Change in peripapillary total retina thickness in subjects with 3 to 4 (n=4) 

or 0 to 2 (n=7) risk alleles, after 1, 15, and 30 days of head-down tilt bed rest and 

6 and 13 days of recovery (left). Peripapillary retinal nerve fiber layer means showing 

a difference between the two genetic categories at all time points (BR-6, 6 days before 

head-down tilt bed rest began) (right). Data are means ± 95% CI. Adapted from (1136).

Figure 68. ..................................................................................................................... 156

Red blood cell folate in VaPER subjects (red symbols/lines) and UTMB 30-day bed rest 

subjects (gray symbols/lines) before and after bed rest. Data adapted and expanded 

from (262).

Figure 69. ..................................................................................................................... 157

Overview of one-carbon metabolism. AA = amino acids; CBS = cystathionine 

ß-synthase; CYS = cystathionine; FA = fatty acids; HCY = homocysteine; 

αKBT = α-ketobutyrate; MCA = methylcitric acid; MM-CoA = methylmalonyl 

coenzyme A (CoA); MMA = methylmalonic acid; MS = methionine synthase; 

5-MTHF = 5-methyltetrahydrofolate; 5,10-MTHF = 5,10-methylenetetrahydrofolate; 

MTHFR = methylenetetrahydrofolate reductase; MTRR = 5-methyltetrahydrofolate 

homocysteine methyltransferase reductase; PRP-CoA = propionyl CoA; 

SAH = S-adenosylhomocysteine; SAM = S-adenosylmethionine; 

SUC-CoA = succinyl CoA; THF = tetrahydrofolate. Image Credit: NASA.

Figure 70. ..................................................................................................................... 161

Depiction of hypothesized multi-hit mechanism relating one-carbon pathway genetics 

with ocular pathologies. Genetics and B-vitamin status lead to endothelial dysfunction 

and leaking microvasculature; the resulting edema could block cerebrospinal fluid (CSF) 

drainage, increasing subarachnoid space CSF pressure impinging on the optic nerve 

and eye (1140, 1141). Similarly, uncoupled eNOS yields increased oxidative stressors, 

including peroxynitrite. Peroxynitrite may affect the elasticity of the lamina cribrosa or 

sclera, affecting the optic cup shape and rendering some individuals vulnerable 

to pressure from a headward fluid shift during head-down tilt bed rest or spaceflight. 

MMPs are zinc-dependent proteolytic enzymes that degrade extracellular matrix 

components, including structural components such as collagen and elastin. 

Most vascular and scleral MMPs are constitutively latent because of the presence 

of inhibitors, including nitric oxide (1180). Cells in the optic nerve head and sclera 

have mechanosensory capabilities and respond to hydrostatic pressure by activating 

MMPs (1181). Additionally, low folate status and higher homocysteine can directly 

activate MMPs, affect nitric oxide bioavailability and production, cause constrictive 

vascular remodeling, and reduce arterial compliance (1188). Connective tissue 

remodeling could lead to changes in elasticity, fluid leakage, and ultimately 

ophthalmic changes. Adapted from (1136).

Figure 71. ..................................................................................................................... 163

RBC (left) and serum folate (right) before, during, and after long-duration spaceflight 

(data are mean ± SD). Note: RBC folate data are not available during flight because 

of sample processing requirements.

Figure 72. ..................................................................................................................... 165

Serum retinol (left) and ß-carotene (right) before, during, and after long-duration 

spaceflight. Dashed lines represent normal range. Data are mean ± SD.

Figure 73. ..................................................................................................................... 175

NASA astronaut Chris Cassidy processes a fecal sample as part of the 

Food Physiology experiment. Photo Credit: NASA.

Figure 74. ..................................................................................................................... 177

Vitamin D actions on the Renin-Angiotensin Aldosterone System, and how vitamin D 

might promote tissue protection from SARS-CoV-2 infection. Adapted from (606).

Figure 75. ..................................................................................................................... 178

An interaction between serum cortisol, vitamin D status, and the probability of EBV 

shedding. Data from all 41 participants in the Antarctic study are included in the graph. 

The data were statistically analyzed using the continuous data set of cortisol data. 

The data are split into the two subgroups for presentation purposes. The graph is from 

Zwart et al. (604).

Figure 76. ..................................................................................................................... 196

NASA astronaut Anne McClain works on the International Space Station's Port-4 truss 

structure during a six-hour, 39-minute spacewalk to upgrade the orbital complex's 

power storage capacity. Photo Credit: NASA.
236 237

Abbreviations

8OHdG 8-hydroxy-2'-deoxyguanosine 

ACE Angiotensin-Converting Enzyme

ADP adenosine diphosphate 

AMP adenosine monophosphate

ARED Advanced Resistance Exercise Device

ATP adenosine triphosphate

BH

2 dihydrobiopterin

BH

4 tetrahydrobiopterin

BMD bone mineral density 

BR bed rest (day)

BSAP bone-specific alkaline phosphatase 

Ca calcium

cal calorie

CEVIS Cycle Ergometer with Vibration Isolation System

CNS central nervous system

CoA coenzyme A

CO

2 carbon dioxide

COLBERT Combined Operational Load Bearing External Resistance Treadmill

CSA Canadian Space Agency

CSF cerebrospinal fluid

CSM Crew Specific Menu

d day

DLR German Aerospace Center

DNA deoxyribonucleic acid

DRI dietary reference intake

DXA dual-energy x-ray absorptiometry

EBV Epstein-Barr virus

EE energy expenditure

eNOS endothelial nitric oxide synthase

Eq equivalent

ESA European Space Agency

EVA extravehicular activity (space walk)

FAD flavin adenine dinucleotide

FADH2 flavin adenine dinucleotide (reduced)

FD flight day

5-MTHF 5-methyltetrahydrofolate g gram g acceleration due to gravity (1g = Earth gravity) 

GI gastrointestinal

GLA gamma-carboxyglutamic acid

Gy Gray

Gz gravitational force applied to the vertical axis of the 

body (i.e., from head to foot)

HERA Human Exploration Research Analog

h, hr hour

Figure 77. ..................................................................................................................... 211

NASA astronaut Michael Lopez-Alegria collects the first blood sample on the ISS on 

October 5, 2006, having inserted the needle himself. The collection tubes can be seen 

(one in hand, the others in elastic bands on his belt assembly), along with a sharps 

container and detailed procedures (both Velcroed to the wall). Photo Credit: NASA.

Figure 78. ..................................................................................................................... 212

ESA crewmember Samantha Cristoforetti centrifuging blood samples on the ISS. 

Photo Credit: NASA.

Figure 79. ..................................................................................................................... 212

Left: UCD, shown here with a female adapter. Right: a UCD with a male adapter shown 

floating on the ISS. Photo Credits: NASA.

Figure 80. ..................................................................................................................... 212

NASA astronaut Sunita Williams shown here with a UCD, placed in a ziplock bag 

to provide another layer of containment. Photo Credit: NASA.

Figure 81. ..................................................................................................................... 213

UCB, used for holding discarded UCDs until they can be disposed of along with 

other trash from the ISS. Photo Credit: NASA.

Figure 82. ..................................................................................................................... 213

NASA astronaut Mike Barratt puts samples in the MELFI, which is typically maintained 

at -96°C. Photo Credit: NASA.

Figure 83. ..................................................................................................................... 213

NASA astronaut Nicole Stott stores samples from her first day of the Nutrition 

experiment in MELFI, located in the JAXA Experiment Module. Photo Credit: NASA.

Figure 84. ..................................................................................................................... 214

NASA astronauts Jeff Williams and Kate Rubins prepare to transfer samples from 

the MELFI to the Double Cold Bags for sample return to Earth. Photo Credit: NASA.

Figure 85. ..................................................................................................................... 214

Picture from the Pacific Ocean showing the SpaceX Dragon capsule following 

its splashdown west of Baja California, Mexico, returning from a 5-day, 16-hour 

and 5-minute mission to the ISS. Photo Credit: NASA.

Figure 86. ..................................................................................................................... 216

ISS FIT, seen floating on the ISS. Photo Credit: NASA.

Figure 87. ..................................................................................................................... 216

NASA astronaut Peggy Whitson uses the ISS FIT. Photo Credit: NASA.

Figure 88. ..................................................................................................................... 216

Screenshots from ISS FIT. Image Credits: NASA.

Figure 89. ..................................................................................................................... 217

Left: NASA astronaut Joe Acaba works with the Space Linear Acceleration Mass 

Measurement Device in the Columbus laboratory of the ISS. Right: JAXA astronaut 

Aki Hoshide uses the Body Mass Measurement Device in the Zvezda Service Module 

of the ISS. Photo Credit: NASA.

Figure 90. ..................................................................................................................... 218

HERA at the Johnson Space Center. Photo Credit: NASA.
238 239

HRP Human Research Program

Hz hertz

HZE High atomic number (Z) and energy radiation

IOM Institute of Medicine (since renamed the National Academy of Medicine)

iRED interim resistance exercise device

ISS International Space Station

IU international unit

J joule

JAXA Japan Aerospace Exploration Agency

JSC Johnson Space Center

k kilo

kcal kilocalorie

KCit potassium citrate

kg kilogram

KHCO3 potassium bicarbonate

KMgCit potassium magnesium citrate

L-x x days before launch

L liter

LBNP lower-body negative pressure

LET linear energy transfer

LMLSTP Lunar Mars Life Support Test Project

μ micro

m meter, milli

M molar

MDA malondialdehyde

MELFI minus eighty (-80°C) laboratory freezer for ISS

mg milligram

ml milliliter

mmol millimole

MMP matrix metalloproteinase

Mol mole

mOsm milliosmole

MRI magnetic resonance imaging 

MTRR methionine synthase reductase

n nano

n number of subjects in a subsample

N number of subjects in a sample of a population 

NAD nicotinamide adenine dinucleotide

NADH reduced form of nicotinamide adenine dinucleotide 

NADH2 nicotinamide-adenine dinucleotide

NADP nicotinamide adenine dinucleotide phosphate

NADPH reduced form of nicotinamide adenine dinucleotide phosphate 

NASA National Aeronautics and Space Administration

NBL Nutritional Biochemistry Laboratory

NEAP net endogenous acid production

NEEMO NASA Extreme Environment Mission Operations 

NF-κB NF-kappa B

NK natural killer

nmol nanomole

NTX n-telopeptide

O2 oxygen

P probability, phosphate

PGF2α 8-iso-prostaglandin F2α

PL pyridoxal

PLP pyridoxal 5'-phosphate

PM pyridoxamine

PMP pyridoxamine 5'-phosphate

PN pyridoxine

PNP pyridoxine 5'-phosphate

Post after flight or bed rest

PPAR peroxisome proliferation activating receptor

Pre before flight or bed rest

psi pound(s) per square inch

psia pound(s) per square inch absolute

PTH parathyroid hormon

r bivariate correlation coefficient

QCT quantitative computerized tomography

R+x x days after landing (recovery) or end of bed rest

RBC red blood cell

RDA recommended dietary allowance

RNA ribonucleic acid

RNS reactive nitrogen species

ROS reactive oxygen species

SANS Spaceflight Associated Neuro-ocular Syndrome

SD standard deviation

SMO Supplemental Medical Objective

STS Space Transportation System

TEE total energy expenditure

THF tetrahydrofolate

U unit

UCB urine containment bag

UCD urine collection device

ULLS unilateral limb suspension

UPA Urine Processor Assembly

U.S. United States

USOS United States Operating Segment (of ISS)

UTMB University of Texas Medical Branch

VDR vitamin D receptor

WHO World Health Organization

WISE Women International Space Simulation for Exploration

y year
240 241

A

abstract thought processes, nutritional 

support for, 147

Acaba, Joe, 217

acceptability and variety of food, 15, 

16–17, 23, 29

acid-base balance

bone metabolism, 80, 81, 82

protein/amino acid supplementation, 124

advanced glycation end products (AGEs), 

160–161

Advanced Resistance Exercise Device 

(ARED), 64, 65

age-related macular degeneration, 162

albumin, urinary, 53, 115

alendronate, 68–69

allergies, 19, 182

altitude, hematological effects of, 86

amino acids

essential, 37

immune system, 176

manganese, 42

muscle loss, 82, 115, 122–124

androgens, muscle loss countermeasure, 122

and testosterone levels, 119, 120

anemia, 84, 90, 162, 163, 183

Angiotensin-Converting Enzyme (ACE) 

inhibitors, 207

animal models

bone loss, 60

cognitive and behavioral effects 

of radiation, 148

immune system support, 176

nutrient effects on drug metabolism, 205

ocular impacts from folate deficiency 

or homocysteine exposure, 158

oxidative stress effects, 196–197

phytochemical effects on brain, 149

ROS balance effects for muscles, 195

testosterone, 121, 122

animal proteins, 81, 82

antacids and proton pump inhibitors, 

206–207

anti-hypertensives, 207

antioxidants, 196–199

cardiovascular health, 140

folate, 199

loss of defense effects during 

spaceflight, 197

muscle support for EVAs, 196

and neuroinflammation, 149

polyphenols, 182–183

riboflavin, 39, 164

selenium, 197

vitamin A, 164

vitamin C, 180, 197–199

vitamin E, 196, 197

Apollo program

cardiovascular health, 139

energy intake, 139, 214

exercise during flight, 63

fluid intake, 52

magnesium losses, 89

muscle loss indications, 115

potassium losses, 125

arginine, 176

artificial gravity, 67, 122

ascorbic acid, deficiency due to iron 

stores, 86. See also vitamin C

atherosclerosis, 140, 158

B

balanced host response, 173

barcode scanning of food intake, 214–215

Barratt, Michael, 12, 213

bed rest studies. See also head-down-tilt 

bed rest

bone loss, 59–60, 65, 66, 67, 68, 72

caloric restriction and cardiovascular 

health, 139

copper level changes, 91

energy expenditure, 28, 30, 33

glucose tolerance, 34

insulin resistance, 36

magnesium balance, 89

muscle loss, 116–117, 122–124

polyphenol antioxidant effects, 183

RBC mass, lack of change in, 85–86

sodium and calcium interactive 

effects, 80

testosterone loss, 119, 120–121

vitamin C, 198

whole-body vibration effects, 118

zinc release, 91

berries as phytochemical powerhouses, 149

beta-carotene intake, 153. See also

vitamin A

BioNutrients investigation, 202

bioregenerative foods, 219

Biosphere 2, 219

biotin, 8, 179

biotransformation of drugs, factors in, 

204–207

bisphosphonates, 65, 68–70

blood. See cardiovascular health; red 

blood cells (RBCs)

blood collection, flight research, 211–212

blood flow restriction, muscle loss 

countermeasure, 118–119

blood volume, shifts due to microgravity, 2

body mass

health impact of mission-related loss, 

21–22

loss during spaceflight, 29, 30–31

measurement of, 3, 217

water as percentage of, 52

Body Mass Measurement Device, 217

Boe, Eric, 63

bone health and bone loss, 57–92

biochemistry of bone, 58–59

bone loss countermeasures, 63–71

ground analogs and animal models, 

59–60

inadequate energy intake effects, 31

nutrients associated with bone health 

and loss, 36, 71–92, 183

partial gravity issue, 2

renal stone risk, 60–63

bone mineral density (BMD)

calcium as indicator, 72

energy intake, 33, 38

exercise countermeasures to loss, 64–65

and iron, 85

ISS astronaut losses in, 57

bone resorption

bisphosphonates as countermeasure, 

68, 69

and calcium, 72, 79, 80

exercise effects on, 65–66, 67

identifying and measuring, 58–59, 60

nutritional countermeasures, 71

and protein consumption levels, 82

and release of metals, 92

and sodium, 79, 80

bone-specific alkaline phosphatase 

(BSAP), 58, 59–60

Borisenko, Andrei, 18

brain and nervous system, 147–149

and copper, 90

food impacts on cognition, 22, 147

isolation and confinement effects, 2–3

neuro-ocular syndrome, 4, 153–162, 163

neuropathy from vitamin B6

 excess, 38

nutrition countermeasures, 149

Index

Note: All terms are listed only at spelled-out version. 

See Appendix for list of acronyms and abbreviations.
242 243

radiation impact on, 147–148

butyrate, 173–174

B vitamins. See also specific vitamins by 

name

brain/nervous system health, 147

ocular health, 162

C

calcium

bone health and bone loss, 2, 57–59, 69, 

70, 71–72

phosphorus’s relationship to, 87

and protein, 81, 82

sodium effects on, 78, 79, 80

and vitamin C, 76

calcium oxalate risk, 61, 80

calcium sulfate precipitate, 62

calcium tracer kinetic studies, 58

cancer risk

drug-nutrient interactions, 206–207

and iron stores, 86

omega-3-fatty acids, 36

from radiation, 36, 203

selenium, 197

and supplements, 204

vitamin A, 164

vitamin C, 76

vitamin E, 197

carbohydrate

with amino acids as muscle loss 

countermeasures, 82, 123

and drug metabolism, 205

as fuel source for energy, 33–34

manganese role in metabolism of, 42

nutritional requirements by mission 

type, 8

carbon dioxide (CO2), 3, 153, 155

cardiovascular health, 137–141

dietary effect on, 138, 140–141

endothelial dysfunction, 158

exercise to support, 117

fluid intake’s importance for, 51

homocysteine, 159, 162

nutrients associated with, 36, 86, 90, 

139–140, 164

undernutrition’s effect on, 31

Cargo Transfer Bag, 4

Cassidy, Chris, 175

cataracts, 76, 153, 164

centrifugation, 67, 122

cephalad fluid shift, 51–52, 153, 154, 160

chloride, 9, 76–80

cholesterol, 8, 35

choline, 9

choroidal and retinal folds, SANS, 153

chromium, 9, 42

clodronate, 68

coenzyme A, 41

cognitive impacts

of foods, 22, 147

of isolation and confinement, 2–3

cold storage solutions, 22

Coleman, Catherine (Cady), 138

collagen crosslinks, 58, 59, 161

Combined Operational Load Bearing 

External Resistance Treadmill 

(COLBERT), 118

copper, 9, 90–91, 181, 198

core body temperature, energy 

expenditure during flight, 28

coronavirus, vitamin D’s immune system 

role and, 177

cortisol, 116, 178

Creamer, T. J., 82

creatinine, and muscle mass, 115

Crew Specific Menu (CSM) containers, 15

Cristoforetti, Samantha, 212

Cycle Ergometer with Vibration Isolation 

System (CEVIS), 138

cytochrome P450 enzymes, 204–206

D

dehydration, 51, 52–53

demographic factors, in bone loss, 60

densitometry techniques, 57, 72

depression, 2, 38, 174

dermatologic issues in spaceflight, 

175, 179

De Winne, Frank, 12

diet. See also energy intake

cardiovascular health, 138, 140–141

drug biotransformation, 205

high-protein diet effects, 38

immune system effects of shifts in diet, 

173–175

vs. individual nutrient effects, 147–149

intake deficits during flight, 29, 32

ketogenic, 34

low-protein diet effects, 37

recording intake during spaceflight, 

214–217

whole foods vs. supplements, 7, 16, 

203–204

dietary inflammatory index, 140–141

Dietary Reference Intake (DRI), 28

diosmin, 149

disease prevention vs. nutrient deficiency 

mitigation, 9, 13

diuresis, 52–53

divalent copper, 90

Double Cold Bags, 214

doubly labeled water technique for 

determining oxygen consumption, 27

dry immersion studies, 60, 86, 117, 138

dual-energy x-ray absorptiometry (DXA), 

57, 72

duration of mission, 3–4, 7, 139. See also

exploration missions

E

eicosanoids, 35

eicosapentaenoic acid, 36

electrical stimulation, muscle loss 

countermeasure, 118

electrolyte homeostasis, 51, 76

endocrine therapies for bone loss, 70, 122

endothelial dysfunction, 158–162

energy intake and metabolism, 27–42. 

See also diet

bone mineral density (BMD), 33, 38

caloric restriction in bed rest 

studies, 139

carbohydrate, 8, 33–34, 42, 82, 123, 205

cardiovascular health, 139

chromium, 42

fat (and fatty acids) (See fat (and fatty 

acids))

fiber, 8, 34, 173

implications of inadequate, 30–33

iodine, 41

manganese, 41–42

niacin, 40–41

pantothenic acid, 41

protein (See protein)

research methods and tools, 214

riboflavin, 39

thiamin, 38–39

tracking systems, 214–217

underconsumption by astronauts, 13–14

vitamin B6

, 38

eNOS enzyme, 158, 159

erythrocytes glutathione reductase 

activation, 39–40

erythrocyte transketolase activation, 39

erythropoietin, blood regulation role of, 86

ESA Experimental Campaign for the 

European Manned Space Infrastructure 

(EXEMSI) study, 19, 218

essential amino acids, 37

essential fatty acids, 35

etidronate, 68

exchangeable vs. nonexchangeable 

sodium stores, 76
244 245

exercise

bone loss, 63–67, 68

cardiovascular health support, 138

energy intake, 31, 120–121

muscle mass, 117–118, 120–121, 123

reactive oxygen species, 195–196

exogenous calcitonin, 70

exogenous testosterone, 119

Expedition 1 (ISS), 10

Expedition 16 (ISS), 10

Expedition 20 (ISS), 12

Expedition 34 (ISS), 125

Expedition 40 (ISS), 152

Expedition 50 (ISS), 18

Expedition 54 (ISS), 194

Expedition 61 (ISS), 146, 202

Expedition 62 (ISS), 172

Expedition 64 (ISS), 50

exploration missions

bone loss challenge, 57

drug-nutrient interaction issues, 207

folate and iron, 199

maintaining health with food for, 15, 19

nutritional requirement definitions, 8–9

nutrition development for, 7

phytochemicals as radiation 

countermeasure, 149

radiation challenge for, 2, 195

spacecraft atmosphere research, 3

space food systems, 21–23

summary, 223–224

water reclamation, 62

extracellular fluid volume, 52, 76

extravascular space, fluid shift to, 51–52

extravehicular activities (EVAs), 3, 22, 

194, 196

eye health. See ocular (ophthalmic) health

F

fat (and fatty acids)

coenzyme A, 41

and drug metabolism, 205

energy density, 22, 35

fuel sources for energy, 35–37

immune system support, 184–185

nutritional requirements by mission 

type, 8

omega-3 fatty acids, 8, 36, 71, 140, 184

omega-6 fatty acids, 8, 184

riboflavin’s relationship to, 39

short chain fatty acid production, 

173, 174

Ferguson, Chris, 63

ferritin level changes during flight, 85

fiber, 8, 34, 173

Finke, Michael, 63

fish intake, bone maintenance effect, 36

5-methyltetrahydrofolate (5-MTHF), 

158–159

flattening of the posterior region of the 

sclera, SANS, 153

flavonoids, 149, 174, 205

flavoproteins, 39

fluid, 51–53

cephalad fluid shift, 51–52, 153, 

154, 160

diuresis and dehydration, 52–53

extracellular fluid volume, 52, 76

fluid homeostasis, 51–52, 53

fluid intake, 51, 62–63

nutritional requirements by mission 

type, 8

sources of loss, 51

fluid osmolality, 51

fluoride, 9

folate

antioxidant protection, 199

drug-nutrient interactions, 207

and iron, 199

nutritional requirements by mission 

type, 8

ocular health, 155, 156, 158–159, 

160, 163

folic acid, 159, 162, 206

foodborne illness, threat of, 20

food-drug interactions, 205

food frequency questionnaire, 215

food preferences. See acceptability 

and variety of food

food preparation, challenges for 

exploration missions, 23

food production in space, 22, 23, 219, 223

food security, 22–23

food storage, 14–15, 22, 213

food systems. See space food system

freeze-dried foods, 14

freezer for research sample collection, 213

fresh produce, 15

fuel homeostasis, 35

fuel oxidation and availability, 36

fuel sources, 33–38

carbohydrate, 8, 33–34, 42, 82, 123, 205

fat (and fatty acids) (See fat (and fatty 

acids))

fiber, 8, 34, 173

protein (See protein)

fundoscopy, 154

G

galactic cosmic radiation, 2, 195

gastrointestinal (GI) function, 29–30, 

173–175

Gateway lunar orbital outpost, 2, 3–4, 7, 

21–22, 222, 223

Gemini program, 63, 139, 214

genetic variations, and SANS incidence, 

155–156, 157–162

Gerst, Alexander, 152

Glover, Victor, 50

glucocorticoids, 80

glucose metabolism, 33–34, 36, 42, 

160–161

glutamine, 176

glutathione, 176, 178, 181

glycogen, 33, 52

gravity. See microgravity; partial gravity

ground-based analog studies. See also

animal models; bed rest studies

Antarctic vitamin D study, 72, 178, 219

Biosphere 2, 219

bone loss, 59–60, 85

dry immersion, 60, 86, 117, 138

energy usage testing, 27–28

exercise effects on bone loss, 66

HERA, 215, 218–219

iron status changes, 86

MARS-500 project, 2–3

muscle, 116–117, 123

partial gravity experiments, 2

research methods and tools, 217–219

semi-closed food systems and 

inadequate nutrition, 19

testosterone levels, 120–121

gut microbiota, 173–175

H

The Hazard Analysis Critical Control Point 

for spaceflight food system, 20

head-down-tilt bed rest

for bone loss, 59

ground-based analogs vs. spaceflight, 138

ocular impact of, 155

taste and olfactory changes, 29

vibration effects on bone loss, 67–68

headward fluid shift, 51–52, 153, 154, 160

heart health. See cardiovascular health

heating food, 13, 14

hepcidin, 183
246 247

high atomic number (Z) and energy 

radiation (HZE) particles, 195

high-linear energy transfer (HIGH-LET) 

radiation, 2, 148, 195

high-protein diet, effects of, 34, 38

histomorphometry, 60

homocysteine, 155, 159, 160, 162

hormonal changes, preflight vs. during 

flight, 35

Hoshide, Aki, 217

hot water, astronaut rating of 

importance, 13

Human Exploration Research Analog 

(HERA), 215, 218–219

human-system standards, 13

hydration. See fluid

hydroxyproline excretion, 58

hypercalciuria, 61, 71, 79, 80, 81

hypercortisolemia, 123

hypergravity, 67, 122

hyperopic refractive error shifts, 

SANS, 153

hypertension, and sodium, 179

hypocalcemia, 70

hypocaloric nutrition testing, 31

hypohydration, 53

hypoxia. See oxidative stress I

immune system, 173–185

biotin, 179

copper, 181

diet and gastrointestinal microbiota, 

173–175

energy, 175–176

from enhanced diet, 141

iron, 183–184

polyphenols, 182–183

polyunsaturated fatty acids, 184–185

protein and amino acids, 176

riboflavin, 179

selenium, 182

skin, 175

sodium, 179

spaceflight impact on, 178

vitamin A, 180

vitamin B

6

, 179

vitamin B12, 178–179

vitamin C, 180

vitamin D, 177–178

vitamin E, 181

zinc, 181–182

indirect calorimetry, 28

inflammation. See also immune system

neuroinflammation, 147, 149

from radiation exposure, 137

reducing to support cardiovascular 

health, 140–141

inflammatory cytokines, 137

insulin, 33, 42

insulin resistance, 33–34, 36, 160–161

intake of vs. magnesium, 88–89

interim resistance exercise device (iRED), 

64, 65

International Space Station (ISS)

bisphosphonate study, 69

body mass data, 30

bone loss during missions, 57, 60

cardiovascular health, 137, 139

copper status, 90–91

energy intake, 28–29, 33, 139, 215

energy requirement estimation, 28

EVAs, 194, 196

insulin resistance study, 34

iodine study, 41

iRED exercise device, 64

iron consumption, 84

isolation and confinement effects, 2

ISS food system, 14–15

magnesium intake, 88, 89

muscle loss countermeasures, 117

niacin intake, 40

nutritional requirement definitions, 8–9

phosphorus excretion, 87–88

photo of station, 10

protein intake, 37

restrictions on nutritional research, 218

riboflavin status, 164

SANS among crew, 154

selenium losses after flight, 197

skin changes from long-term flights, 175

sodium in food system, 77

testosterone levels, 119–120, 121

thiamin intake, 39

vitamin A status, 165

vitamin C status, 198

vitamin D supplementation, 73

vitamin E status, 181, 197

vitamin K status, 75–76

water reclamation from urine experiment, 

62–63

zinc status, 91

interstitial fluid volume, 51

intracranial pressure, and SANS, 154

iodine, 9, 41

ionizing radiation. See radiation

iron, 9, 83–87, 183–184, 199

isolation, stressor of spaceflight, 2–3

isotope ratio technique (for calcium), 72

ISS FIT (food tracker app for iPad), 

215–217 J

Journals experiment, 18 K

ketoacidosis, 32

ketogenic diet, effects of, 34

ketones, 34

ketosis, 32, 34

kidney stones. See renal stone risk

Kimbrough, Shane, 18

Koch, Christina, 14, 146

Kopra, Tim, 56 L

lactoferrin, 176

lead levels and microgravity, 92

lean body mass loss, 31

Lindgren, Kjell, 148

linoleic acid, 35

linolenic acid, 35

lipids, 35, 39

lipoprotein response to weight loss, 35

liver, glycogen storage role, 33

local intraorbital (choridal and optic nerve 

sheath) changes, and SANS, 153–154

Lopez-Alegria, Michael, 211

lower-body negative pressure (LBNP) 

chamber, 66–67

low-linear energy transfer (LOW-LET) 

radiation, 2, 195

low-protein diets, effects of, 37

Lunar Mars Life Support Test Project 

(LMLSTP), 219

luteolin, 149

lycopene intake, ocular protection 

from, 153 M

magnesium, 9, 88–90, 140

Malenchenko, Yuri, 56

manganese, 9, 41–42

Mars 500 mission (Russian), 2–3, 19, 218

Marshburn, Tom, 125

Mars missions, 2–3, 4, 22–23, 195, 218

matrix metalloproteinases (MMPs), 160, 

161–162

McClain, Anne, 196

meal replacement bars, 21
248 249

mealtime factors in underconsumption of 

food, 14

meal timelines, using fat to maximize 

intake during short, 22

mechanical muscle loss countermeasures, 

117–119

mechanostat theory, 118

megaloblastic anemia, 162

Meir, Jessica, 141

menu fatigue, 14, 16–17

Mercury program, 139, 214

metabolic acidosis, 38

metabolic flexibility, 36

metabolism

acid-base balance in bone metabolism, 

80, 81, 82

drug/nutrient relationships, 205–206

glucose metabolism, 33–34, 36, 42, 

160–161

manganese role in carbohydrate 

metabolism, 42

nutrients associated with energy 

metabolism, 38–42

one carbon pathway and ocular health, 

157–159

protein and amino acids in muscle 

metabolism, 115–116, 117

metabolites, 16

methionine, 82

methyl-folate trap, 163

methylmalonic acid, 163–164

microbiome, spaceflight study of, 174

microbiota, gastrointestinal, 173–175

microgravity

bone loss, 57, 58–59, 67

carbohydrate metabolism, 33–34

cardiovascular effects, 51–52, 139

cephalad fluid shift, 51–52, 153, 

154, 160

energy use in, 27–28

fluid homeostasis, 51, 52, 53

immune system effects of, 178

and iron metabolism, 86

lead levels, 92

muscle loss, 38, 115, 118–119

niacin viability, 40

oxidative stress, 197

RBC mass effects, 85

sodium, 80

stressors of spaceflight, 2

testosterone levels, 120, 122

zinc, 91, 182

Microwave Assisted Thermal 

Sterilization, 20

minus eighty (degrees) laboratory freezer 

(MELFI), 213

Mir programs

appetite test, 29

body mass losses, 30

bone loss, 57, 58

dehydration testing, 52

energy intake and immune and 

dermatological health, 175–176

exercise, 63

fluid homeostasis, 52

food intake tracking, 215

isolation and confinement effects, 2

muscle loss, 116, 117

nutritional requirements development, 7

sodium studies, 77–78

vitamin D supplementation, 73

vitamin K status, 75

molybdenum, 9

monoamine oxidase inhibitors, 206

mood disorders, 2, 147, 174

Moon missions, 2, 3–4, 7, 21–22, 223

muscle and muscle loss, 115–125

amino acids, 82, 115, 122–124

antioxidants as muscle support for 

EVAs, 196

exercise countermeasure, 117–118, 

120–121, 123

glucocorticoids, 80

glycogen, use of, 33

ground-based analog studies, 

116–117, 123

mechanical countermeasures, 117–119

nutrients associated with muscle health, 

124–125

nutritional countermeasures, 122–124

omega-3 fatty acid support for, 36

pharmacological countermeasures, 

119–122

protein biochemistry, 115–116, 117

N

NASA Extreme Environment Mission 

Operations (NEEMO), 86, 196, 219

NASA Twins Study, 41, 57, 82, 175–176

negative calcium balance, 57–58

negative nitrogen balance, 115

net endogenous acid production (NEAP), 

and bone loss, 83

neuroinflammation, 147, 149

neuro-ocular syndrome, 153–162

neuropathy, from vitamin B6

 excess, 38

neuroprotective effects of flavonoids, 149

niacin, 8, 40–41, 175

nicotinamide adenine dinucleotide 

phosphate (NADPH), 159

nitric oxide in endothelial function, 

158–161

nitrous oxide in closed system habitat, 219

nonexchangeable vs. exchangeable 

sodium stores, 76

Novitskiy, Oleg, 18

nutrients

antioxidant protection, 196–199

bone health, 71–92

brain and nervous system, 149

cardiovascular health, 139–140

deficiency mitigation vs. disease 

prevention and performance 

enhancement, 9, 13

dermatologic health, 175, 179

drug effects on nutrient metabolism, 

205–207

energy metabolism, 38–42

immune health, 175–185

muscle health, 124–125

ocular health, 153, 162–165

pharmaceutical-caused deficiencies, 204

stability over time, 20

nutrition

impact of foods on, 16

as key player in mitigating effects of 

spaceflight, 4

requirements for, 7–11, 15–16

Nyberg, Karen, 154

O

ocular (ophthalmic) health, 153–165

endothelial dysfunction, 159–162

folate, 162–163

nitric oxide in endothelial function, 

158–159

one carbon biochemistry, 155–162

optic disc edema, 153, 156, 157–162

riboflavin, 164

spaceflight-associated neuro-ocular 

syndrome, 153–162

vitamin A, 164–165

vitamin B12, 155, 162, 163–164

olfaction, in-flight changes in, 29

omega-3 fatty acids, 8, 36, 71, 140, 184

omega-6 fatty acids, 8, 184

one-carbon pathway genetics, 

ocular health

endothelial dysfunction, 159–162

metabolism, 157–158

nitric oxide in endothelial function, 

158–159

and nutrients associated with ocular 

health, 162

optic disc edema and SANS, 157–162
250 251

optic disc edema, 38, 153, 156, 157–162

oral contraceptives, 207

orbital debris, food as, 20

Orion, Gateway and Artemis mission 

profile, 21

osteocalcin, 160

oxidative stress and damage, 195–199. 

See also antioxidants

caloric restriction effects on, 175

endothelial dysfunction, 158

energy intake impact of, 30

folate, 199

iron, 83, 86, 87, 183

nutrients associated with, 196–199

to ocular systems, 153

oxidative damage markers, 196–197

radiation exposure, 137, 195

selenium, 182, 197

supplements as double-edged 

sword, 204

vitamin C, 180, 197–199

vitamin E, 196, 197

P

packaging and resource minimization 

imperative, 21

pamidronate, 68

pantothenic acid, 8, 41

partial gravity, impact on human body, 

2, 27

Payette, Julie, 12

Peake, Tim, 56, 136

performance enhancement vs. nutrient 

deficiency mitigation, 9, 13

peroxynitrite, 158, 159–160

Pesquet, Thomas, 18

Pettit, Donald, 63

pharmaceuticals, 203–207

bone loss countermeasures, 68–70

interactions with nutrients, 204–207

muscle loss countermeasures, 119–122

phenolics, 149

phenylethylamines, 206

phosphate supplementation, 71

phospholipids, 35

phosphorus, 9, 87–88

physical activity. See exercise

physiological factors, in energy intake, 

14, 16–17

phytochemicals, in countering 

radiation, 149

plant foods, importance in gut microbiota, 

173–174

plant harvesting operations, 141

plasma volume, response to microgravity, 

51–52, 139

polyphenols, 149, 174, 182–183

polyunsaturated fatty acids, 184–185

Potable Water Dispenser, 14

potassium

animal protein relationship, 81, 82

bone health, 71, 82–83

muscle health, 115, 125

nutritional requirements by mission 

type, 9

and sodium, 80

potassium bicarbonate (KHCO3), 82, 124

preference and behavior, space food 

system requirements, 17–19

“preference containers” in food 

provisions, 10

Pro K study, 82–83

prostaglandin secretion, and muscle 

loss, 116

protein. See also amino acids

bone health, 81–83

brain functions of, 147

drug metabolism, 205

energy fuel source, 34, 37–38

flavoproteins, 39

fluid shift in microgravity, 51–52

immune system support, 176

muscle metabolism, 115–116, 117

nutritional requirements by mission 

type, 8

protein catabolism, 116, 117

protein synthesis, 116, 117

proton pump inhibitors and antacids, 

206–207

psychobiotics, 174

psychological health

food’s benefits for, 19, 203

gastrointestinal biome’s role in, 174

mood disorders, nutrient role in, 2, 

147, 174

social role of food, 15, 17–19

Q

quality of stored food, 16–17, 20

quantitative computerized tomography 

(QCT), 57, 72

R

radiation

cancer risk, 36, 203

cardiovascular health, 137

career-limiting factor for astronauts, 3, 4

cataracts, 153

central nervous system performance, 

147–148

folate, 199

food storage issue, 23

iron, 184

niacin viability, 40

omega-3 fatty acids, 36

oxidative stress, 137, 195

phytochemicals as countermeasure, 149

stressor of spaceflight, 2

vitamin C, 198

reactive nitrogen species (RNS), 137

reactive oxygen species (ROS), 137, 182, 

195–196

red blood cells (RBCs), 2, 84–85, 183

rehydrating food, potential taste 

perception changes, 29

renal stone risk

bone demineralization, 60–63

hydration’s importance, 52, 53

pharmaceutical effects, 68, 69

protein’s role in, 81

sodium intake, 79–80

research issues and processes, 211–219. 

See also ground-based analog studies

blood collection, 211–212

body mass measurement, 217

bone loss, 57

dietary intake recording, 214–217

energy intake, 28

frozen storage, 213

ground-based analogs vs. spaceflight, 138

inadequate dietary intake’s impact 

on, 32

muscle loss, 115

sample return, 214

urine collection, 212–213

resistance exercise, 63–64, 68

resource minimization, space food system 

requirements, 21

retinol, 165

riboflavin, 8, 39, 164, 175, 179

Romanenko, Roman, 125

rotating cell culture vessels, 121

Rubins, Kate, 214

Russian cosmonauts

optic disc edema, 154

riboflavin status, 164

Russian Space Agency. See also Mir 

programs; Salyut-Soyuz spacecraft 

complex

as food provider, 9–10, 15

ground-based chamber study, 19

Ryzhikov, Sergei, 18
252 253 S

safety, food, 19–20, 23

Salyut-Soyuz spacecraft complex, 33, 89

sample return, flight research, 214

saturated fat, 8

scleral/lamina cribrosa (optic disc) 

integrity, 159–162

sclerostin, 60

scurvy, 1

selenium, 9, 181, 182, 197

self-selection or avoidance of food, 

physiological consequences, 18–19

semi-starvation, multiple impacts on 

performance, 32

sex differences, exercise as bone loss 

countermeasure, 66–67

shelf-stable foods, managing, 15, 17, 20

short chain fatty acid production, 173, 174

site-specific vs. systemic indices of bone 

formation, 60

skin, 78, 175, 179

Skylab program

bone loss, 57, 58

dehydration testing, 52

energy intake, 29, 30, 214

exercise, 63

hydration changes, 52

magnesium losses, 89

muscle loss, 115, 119, 122

potassium losses, 125

sodium and chloride in plasma, 77

vitamin D supplementation, 73

social role of food, meeting need for, 15, 

17–19

sodium

bone health, 76–80

factor in fluid loading failure, 52

high sodium content in shelf-stable 

foods, 17

immune system support, 179

and loss of potassium, 125

nutritional requirements by mission 

type, 9

reduction in food system, 77

reformulation of, 17

sodium store in bone, 78

solar particle events, 2, 195

spacecraft environment, as stressor 

of spaceflight, 3

Spaceflight-Associated Neuro-ocular 

Syndrome (SANS), 4, 154–162, 163

space food system, 13–23

acceptability and variety, 16–17

diet impact on cardiovascular 

health, 138

food provisioning and standard menu, 

9–11

future exploration mission 

considerations, 21–23

ISS food system, 14–15

nutrition, 15–16

preference and behavior, 17–19

requirements, 15–21

resource minimization, 21

safety, 19–20

stability, 20

Space Linear Acceleration Mass 

Measurement Device, 217

space motion sickness, 30

space research. See research issues and 

processes

Space Shuttle Program

body mass losses, 30

bone loss, 58

energy expenditure preflight vs. during 

flight, 27

food intake tracking, 215

glucose testing, 33

hydration changes, 52

ISS food system as based on, 10

muscle loss, 115

protein deficiency, 38

sodium and chloride in plasma, 77

testosterone loss, 119

Space Station Freedom, 7

spacewalks, 3, 22, 194, 196

SpaceX Dragon, 214

stability, food, 15, 17, 20

“standard menu,” workings of, 10

starvation

multiple impacts on performance, 32

protein’s importance to survival, 37

sodium levels, 76–77

steroids, muscle loss countermeasure, 122

Stott, Nicole, 213

stressors of spaceflight, 2–4

supplements

amino acids, 82, 122–124, 176

bone loss countermeasures, 70–71

degradation over time, 20

fish oil vs. fish food consumption, 36–37

folic acid, 159, 162

iron, 183

lack of impact on nervous system 

challenges from radiation, 149

niacin, 40–41

phosphate, 71

potassium, 62, 82, 125

probiotic, 174

riboflavin, 164

selenium, 182

vitamin A, 164, 180

vitamin B12, 163, 179

vitamin C, 198

vitamin D, 73, 177, 203, 204

vs. whole foods, 7, 16, 203–204

synaptic plasticity, 147

systemic vs. site-specific indices 

of bone formation, 60

T

Tarelkin, Evgeny, 125

taste changes during flight, 29

temperature, core body, 28

testosterone, 70, 119–122

tetrahydrobiopterin (BH4), 158, 159

tetrahydrofolate (THF), 162

thiamin, 8, 20, 38–39, 206

Thirsk, Robert, 64

thrombosis, 119

thyroid hormones, 41

tocopherols, 181

total energy expenditure (TEE), 27–28

trabecular bone, post-flight recovery rate 

of, 57

trans fatty acids, 8

treadmill exercise, 66–67

tryptophan, 207 U

unilateral limb suspension (ULLS), 117, 

121, 122–123, 124

United States Operating Segment 

(USOS), 14

uric acid excretion, and protein levels, 81

urine collection, 58, 62–63, 212–213

urine collection bags (UCBs), 212–213

urine collection devices (UCDs), 212

Urine Processor Assembly (UPA), 62–63

urine volume, changes during flight, 52 V

Vande Hei, Mark, 194

VaPER study, 156

Vascular Echo experiment, 136

vascular endothelium, 158

vegetarianism and veganism, 71

vibration exercise, 67–68, 118

vision. See ocular (ophthalmic) health
254 255

visuo-spatial memory, 147, 148

vitamin A

brain support, 147

detrimental effects, 204

drug-nutrient interactions, 206, 207

immune system support, 180

nutritional requirements by mission 

type, 8

ocular health, 164–165

skin health, 175

vitamin B

2

. See riboflavin

vitamin B

6

brain support, 147

drug-nutrient interactions, 207

energy metabolism, 38

immune system support, 179

nutritional requirements by mission 

type, 8

ocular health, 162

skin health, 175

vitamin B12

brain support, 147

deficiencies in low-animal food diet, 219

drug-nutrient interactions, 207

immune system support, 178–179

nutritional requirements by mission 

type, 8

ocular health, 155, 162, 163–164

vitamin C

antioxidant protection, 180, 197–199

bone health, 76

drug-nutrient interactions, 206–207

immune system support, 180

nutritional requirements by mission 

type, 8

and scurvy, 1

skin health, 175

visuo-spatial performance, 147

and vitamin E, 181, 197

vitamin D

bone health, 58, 60, 70, 72–75

deficiencies in low-animal food diet, 219

drug-nutrient interactions, 206

immune system support, 177–178

nutritional requirements by mission 

type, 8

supplementation advantage, 73, 177, 

203, 204

vitamin D receptor (VDR), 177

vitamin E

antioxidant protection, 196, 197

brain support, 147

detrimental effects, 204

immune system support, 181

nutritional requirements by mission 

type, 8

and vitamin C, 181, 197

vitamin K, 8, 75–76

vitamins, need for storage stability analysis 

in space, 198–199 W

Wakata, Koichi, 12

Walker, Shannon, 118

water. See also fluid

hot water, astronaut rating of 

importance, 13

loss as percentage of body mass, 31

reclamation of, 62–63

water intoxication, 53

weight and weight loss. See body mass

weight-bearing bones, loss of mass, 57

whey protein, 123, 176

Whitson, Peggy, 18, 216

whole-body vibration training, 118

whole foods vs. supplements, 7, 16, 

203–204

Williams, Jeff, 214

Williams, Sunita, 64, 212

Women International Space Simulation for 

Exploration (WISE-2005), 66–67, 123–124

World Health Organization (WHO), 28 Z

zinc

bone health, 91–92

drug-nutrient interactions, 207

immune system support, 181–182

nutritional requirements by mission 

type, 9

skin health, 175
National Aeronautics and Space Administration

Lyndon B. Johnson Space Center

2101 NASA Parkway

Houston, Texas 77058

www.nasa.gov

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