SPACE SCIENCE, EXPLORATION AND POLICIES SERIES

NUTRITIONAL BIOCHEMISTRY OF 

SPACE FLIGHT

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Nutritional Biochemistry of Space Flight 

Scott M. Smith, Sara R. Zwart, Vickie Kloeris and Martina Heer 

2009. ISBN 978-1-60741-641-8 
SPACE SCIENCE, EXPLORATION AND POLICIES SERIES

NUTRITIONAL BIOCHEMISTRY OF 

SPACE FLIGHT

SCOTT M. SMITH

SARA R. ZWART

VICKIE KLOERIS

AND 

MARTINA HEER

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Nutritional biochemistry of space flight / Scott M. Smith ... [et al.]. 

 p. ; cm. 

 Includes bibliographical references and index. 

 ISBN 978-1-60741-641-8 (hardcover) 

 1. Astronauts--Nutrition. I. Smith, Scott M., 1963- 

 [DNLM: 1. Nutritional Requirements. 2. Space Flight. QU 145 N9764 2009] 

 TX361.S63N88 2009 

 613.202'462945--dc22 2009017392 

Published by Nova Science Publishers, Inc.   New York
CONTENTS

Author Affiliations vii

Preface ix

Acknowledgments xi

I. Introduction 1

II. Space Programs and Space Food Systems 3

III. Nutritional Requirements 13

IV. Sources of Nutrition Data and Gaps in Nutrition Knowledge 17

V. Food, Energy, and Macronutrients 19

VI. Fat-Soluble Vitamins 57

VII. Water-Soluble Vitamins 71

VIII. Minerals 87

IX. Nutritional Issues for Extravehicular Activity 117

X. Antioxidants 119

XI. Supplements 123

XII. Nutrient-Drug Interactions 125

XIII. Looking Forward 129

XIV. Conclusion 131

XV. References 133

XVI. Authors 175

XVII. Editor 177

XVIII. List of Figures 179

XIX. List of Tables 187
vi Contents 

XX. Abbreviations 189 

Index 191 
AUTHOR AFFILIATIONS

Scott M. Smith* 

Nutritionist; Manager for Nutritional Biochemistry 

Nutritional Biochemistry Laboratory 

Human Adaptation and Countermeasures Division, NASA Johnson Space Center 

Houston, Texas USA 

Sara R. Zwart 

Senior Scientist; Deputy Manager for Nutritional Biochemistry 

Nutritional Biochemistry Laboratory 

Human Adaptation and Countermeasures Division, NASA Johnson Space Center 

Vickie Kloeris 

Food Scientist; Manager of the Space Food Systems Laboratory 

Habitability and Environmental Factors Division, NASA Johnson Space Center 

Martina Heer 

Nutritionist; Director, Nutritional Health 

Profil Institute for Metabolic Research; Neuss, Germany 

Formerly of DLR–Institute of Aerospace Medicine, Cologne, Germany

 *

 Email: scott.m.smith@nasa.gov; sara.zwart-1@nasa.gov; vickie.l.kloeris@nasa.gov; Martina.Heer@profilresearch.de 

PREFACE

This book is the result of a confluence of many activities that have occurred in the last 

several years. In late 2005, the National Aeronautics and Space Administration created the 

Human Research Program (HRP), based at the Johnson Space Center in Houston. The HRP 

held a series of workshops in 2006 to review the state of knowledge of each of the life science 

disciplines, of which Nutrition was one. In late 2007 and early 2008, HRP sought to 

document this evidence base, in a unpublished report to the Institute of Medicine. This 

“Evidence Book” was the largest contributor to this text, but many other efforts, large and 

small, made some contribution. The HRP Program Reviews in 2006 were preceded by 

workshops to define nutritional requirements for space flight (in 1991, 1995, and 1999), “tiger 

teams” to evaluate specific nutritional issues (extravehicular activity, supplement 

requirements; both in 2000), and extramural reviews of clinical assessment protocols (in 

2003) and to define requirements and “operating bands” (in 2005), all of which contributed 

significantly. Beyond the management reviews and workshops, the authors’ efforts to extend 

the medical and scientific knowledge base of food and nutrition issues for space travelers over 

the years has also contributed extensively. 

It is our hope that this volume reflects a comprehensive review of what has been done in 

the initial decades of human space flight with regard to human nutrition, and a look at what 

needs to be known before we take the next steps of exploration. 

ACKNOWLEDGMENTS

We gratefully acknowledge the expert work by Dr. Jane M. Krauhs in technical editing of 

this volume. 

I. INTRODUCTION

The importance of nutrition in exploration has been documented repeatedly throughout 

history. For example, during the roughly 400 years between Christopher Columbus’ voyage 

in 1492 and the invention of the steam engine, scurvy (vitamin C deficiency) resulted in the 

deaths of more sailors (> 2 million) than all other causes of death combined [66]. Since 

nutrients are required for the structure and function of every cell and every body system, 

defining the nutrient requirements for space flight and ensuring provision and intake of those 

nutrients are primary issues for crew health and mission success. 

Unique aspects of nutrition during space travel include its role in and how it is affected 

by physiological adaptation to weightlessness and psychological adaptation to extreme and 

remote environments, and the ability of nutrition and nutrients to serve as countermeasures to 

ameliorate the negative effects of space flight on the human body. Key areas of clinical 

concern for long-duration space flight include loss of body mass (and associated inadequate 

food intake), bone and muscle loss, increased radiation exposure, nutrient supply during 

extravehicular activity, and general depletion of body nutrient stores because of inadequate 

food supply, inadequate food intake, increased metabolism, and/or irreversible loss of 

nutrients. Other body systems (such as the cardiovascular and neurovestibular systems) are 

also affected by space flight and may affect nutrition of space travelers, or may be a target in 

developing nutritional means to mitigate the effects of space flight on those systems. 

The authors’ aims with this book are to review the existing knowledge about human 

nutrition for space flight, and to point out gaps in this knowledge that need to be filled before 

we can have confidence that the risk of an inadequate food system or inadequate nutrition to 

support humans on expeditions to the Moon and Mars is as low as possible. Much of the 

existing knowledge is extrapolated from results of studies, known as ground-based analog 

studies, conducted in laboratories on Earth by exposing human subjects to one or more 

environmental conditions similar to those produced by space flight. Since the 1940s [138], the 

physiological responses of humans to bed rest have been studied [502], albeit, at first, with 

the goal of improving the health of patients and not space travelers. Bed rest studies have 

provided much of the data available from ground-based analogs of space flight. The other 

main source of knowledge is data from space flights: short-duration Space Shuttle missions, 

and longer missions on the Russian space station Mir and the International Space Station. 

Historical data from the Apollo missions, which had durations of 5 to almost 13 days, and the 

Skylab 28-, 59-, and 84-day flights are also reviewed. 

II. SPACE PROGRAMS AND SPACE FOOD SYSTEMS

Before food was first consumed in the space environment, it was assumed by some that 

the greatest challenge of providing food in space might well be that a human would be unable 

to swallow and thus would be unable to eat in weightlessness. This was quickly disproved by 

Soviet cosmonaut Gherman Titov, who in August 1961 became the first human to consume 

food in space. U.S. astronaut John Glenn followed closely when, as the first American to 

consume food in space, he ate applesauce on the third manned Mercury mission in February 

1962 [455, 504]. This began what to this day is an ongoing odyssey of space food 

development. 

A. MERCURY (1961 TO 1963), GEMINI (1965 TO 1966),

AND APOLLO (1968 TO 1972) 

Early U.S. space food was highly engineered to minimize mass and volume and to 

prevent any possibility of food contaminating the small cabins of the earliest National 

Aeronautics and Space Administration (NASA) spacecraft. It consisted primarily of puréed 

foods in squeeze tubes, small cubed food items coated with an edible film to prevent crumbs 

from escaping, and freeze-dried, powdered food items. It was agreed by most that this early 

space food was unappetizing (Figure 1) [504]. 

As the NASA manned space program progressed in the 1960s toward the first Moon 

landing in 1969, so did the food system. The food system for the Gemini program included 

formulations and packaging that were designed specifically for the program [340]. 

Restrictions in weight and volume led to an emphasis on concentrated foods. Safety of the 

food system was strongly emphasized, and the testing procedures developed for Gemini 

signaled the beginning of the Hazard Analysis Critical Control Point (HACCP) program, 

which is now common practice for food safety around the world [250]. 

Apollo food systems introduced utensils to space food dining with the addition of the 

spoonbowl package. This allowed rehydrated food items to be consumed from the package 

with a spoon. During the Apollo program, U.S. space food systems began using 

thermostabilized (heat-treated) canned and pouched products. Irradiated food products also 

appeared for the first time during Apollo [62, 596]. Even this early in human space flight, the 

real challenge for space food became apparent: how to provide sufficient variety and 

sufficient quality to get the crewmembers to actually eat the food. Regardless of the 

nutritional content of the food, if it was not consumed, the crewmembers’ health was at risk. 
4 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

Crewmembers were returning from space flights with decreased body weight, indicating that 

their food consumption was inadequate [597]. 

Figure 1. Food kit used by Mercury astronauts. Some packets contained dehydrated food that needed 

water; other foods were ready to eat. A 12-inch ruler is shown for scale. Included are packets of 

mushroom soup, orange-grapefruit juice, cocoa beverage, pineapple juice, chicken with gravy, pears, 

strawberries, beef and vegetables, and other assorted foods. Photo credit: NASA. 

B. SKYLAB (1973 TO 1974) 

The Skylab space station (Figure 2) of the mid-1970s featured the most sophisticated 

food system that NASA has ever flown in space [252]. Frozen and refrigerated food items 

were included as part of the standard menu for the first, and to date the only, time in U.S. 

space food history [296]. The Skylab astronauts also had a dining table for meal consumption. 

Because of these advances or because of their participation in metabolic studies, or a 

combination of the two, the Skylab crews achieved the highest percentage of their planned 

energy consumption (based on World Health Organization requirements) of any U.S. crews to 

date. 
Space Programs and Space Food Systems 5

Figure 2. An overhead view of the Skylab space station cluster in Earth orbit as photographed from the 

Skylab 4 Command and Service Modules (CSM) during the final fly-around by the CSM before it 

returned home. The space station is seen against a cloud-covered Earth. Photo credit: NASA. 

C. APOLLO-SOYUZ TEST PROJECT (JULY 15 TO JULY 24, 1975) 

The Apollo-Soyuz Test Project (ASTP) was the first space flight to be conducted jointly 

by the 2 leading nations in space exploration, the United States and Russia. The primary 

purpose of the mission was to test systems for rendezvous and docking of spacecraft, as might 

occur in international space rescue missions (Figure 3). 

The U.S. vehicle was the Apollo spacecraft, so Apollo-type food and packaging was 

used. 

Previous food systems had been produced by outside contractors, but the ASTP food was 

produced by NASA at the Johnson Space Center. The facilities and processes used for the 

production of the ASTP food became the foundation of the facilities currently used to produce 

the Space Shuttle and International Space Station food systems. 
6 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

Figure 3. An artist’s concept illustrating an Apollo-type spacecraft (on left) about to dock with a Soviet 

Soyuz-type spacecraft. An agreement between the United States and the Union of Soviet Socialist 

Republics provided for the docking in space of the Soyuz and Apollo spacecraft in Earth orbit in 1975. 

The joint venture was known as the Apollo-Soyuz Test Project, or in Russia as the Soyuz-Apollo Test 

Project. Photo credit: NASA. 

Figure 4. A close-up view of cheddar cheese spread, one of the items of food selected for the ApolloSoyuz Test Project mission flown in the summer of 1975. This food item was also carried on the Apollo 

missions. Photo credit: NASA. 
Space Programs and Space Food Systems 7

D. SPACE SHUTTLE (1981 TO THE PRESENT) 

Next for NASA was the Shuttle program. As a work vehicle that was designed for shortduration missions, the Shuttle had no space and no power to support refrigerators or freezers 

for food, and thus NASA reverted to an all-shelf-stable food system [63]. A meal tray was 

developed as a replacement for a dining table, which had exceeded space limitations. The 

Shuttle food system originally had rigid plastic packages for rehydratable foods and for 

beverage items. As the program evolved and crew size and mission duration increased, these 

rigid packages had to be replaced with more flexible versions that could be compressed to 

take up less space in the trash. 

Figure 5. On April 12, 1981, just seconds after 7 a.m., the launch of the first Space Shuttle, Columbia, 

carried astronauts John Young and Robert Crippen into an Earth-orbital mission lasting 54 hours. Photo 

credit: NASA. 

In the Shuttle food program, commercially available food items constitute a very large 

percentage of the menu items. Some items are used exactly as they are marketed 

commercially (cookies, crackers, nuts, powdered beverages), while others, such as frozen 

vegetables, are further processed into freeze-dried items for space. The use of commercial 

items provides significant cost savings over developing unique foods for space flight. It also 

provides more familiar food items to the crewmembers. However, the use of commercial food 

items has the significant disadvantage that a company can change the content of a product or 

discontinue it altogether. Another disadvantage is that many commercial products have more 

fat and sodium than desired to meet nutritional recommendations. 
8 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

The use of fuel cells by the Shuttle to create electricity produces a significant quantity of 

water as a by-product of this process. Thus, freeze-dried foods and powdered beverages 

constitute a high percentage of the Shuttle menu. This is not the case, however, on the 

International Space Station, where solar arrays provide power and water has to be transported 

to orbit. 

The Shuttle menu has provided more food choices to the crewmembers than any previous 

U.S. space food system. After a food preference survey of the astronaut corps was conducted, 

the first Shuttle menus were designed by a dietitian from the list of available foods and 

standardized for each crew. Crewmembers quickly expressed their displeasure with this 

process, and early in the program, the standardized menu was replaced with a personal 

preference menu, developed for individual crewmembers using their inputs and analyzed by 

the dietitian for nutritional compliance. Experience has shown that very few adjustments to 

the menus selected by the crew are required to meet most of the nutritional requirements. The 

medical requirements for astronauts are such that they must eat healthy, nutritious diets on 

Earth to maintain their health status for space flight. Thus, when crewmembers select menus, 

they are generally within the nutritional guidelines. 

The Shuttle menus do tend to have more sodium and iron than required. This can be 

partially attributed to the use of many high-sodium commercial products and to the use of 

commercial bread and cereal products, which are enriched with iron. The requirement for an 

all-shelf-stable food system also increases sodium content, since sodium is often used in 

shelf-stable products to improve flavor and help with preservation. 

Although the Shuttle food system presents many improvements to the crew, including 

personal preference menus, hot and cold water for rehydration, and a more reliable oven for 

heating food, the average actual intake of food on Shuttle missions is often inadequate. 

Inadequate intake on Shuttle missions cannot be attributed to the food system alone, however. 

The short duration of Shuttle missions and the heavy work load often give crewmembers 

insufficient time to eat meals. In addition, space adaptation syndrome reduces food 

consumption in the first few days of Shuttle flights. 

Figure 6. View of the Space Shuttle Orbiter Atlantis on approach to the International Space Station 

(ISS) during the STS-122 mission. Visible in the payload bay are the European Laboratory / Columbus 

module, the Integrated Cargo Carrier-Lite, the Orbiter Boom Sensor System, and the Shuttle Remote 

Manipulator System. Photo credit: NASA. 
Space Programs and Space Food Systems 9

E. SHUTTLE-MIR PROGRAM (1995 TO 1998) 

In Phase 1 of the International Space Station (ISS) program, U.S. astronauts lived for 

long durations on the Russian space station Mir with cosmonauts. Under an agreement with 

the Russian Space Agency (RSA), both Shuttle foods and Russian space foods were used by 

both astronauts and cosmonauts. This early agreement with the RSA was the basis for the 

current ISS menu, which is designed to be 50% U.S. and 50% Russian space food. As 

astronauts began to stay for long periods aboard Mir, it quickly became obvious that on longduration missions, the importance of food to crewmembers was magnified many times over 

its importance on the short-duration Shuttle missions. The psychological contributions of 

food to the crew’s mental attitude became readily apparent. Crew debriefs from Mir missions 

began to reveal that the thermostabilized items had far better long-term acceptability than 

their freeze-dried counterparts. These debriefs also revealed that increasing the variety of 

foods available to the crewmembers was important for long stays, to prevent menu fatigue. 

F. INTERNATIONAL SPACE STATION

(NOVEMBER 2000 TO THE PRESENT) 

In the initial phases of design for the International Space Station (ISS) (Figure 7, Figure 

8), refrigerators and freezers for food were expected to be part of the U.S. habitation module. 

Preliminary work was done to design a packaging system for the frozen and refrigerated 

foods, as well as to develop a preliminary food list. However, because of cost and power 

constraints, the habitation module was deleted from the final ISS configuration. The ISS 

program had already set aside funding for the development of frozen and refrigerated food 

items, and NASA food specialists convinced the ISS program to redirect this funding to the 

development of new shelf-stable food items to add to the Shuttle food list. The duration of the 

ISS missions was planned to be 4 months, and to support missions of this length, more variety 

was needed than was available in the food system at that time. 

Thus, in 1998 NASA food scientists began the first real product development of custom 

space food items that had occurred since the Skylab program, 25 years earlier. The product 

development was focused mainly on thermostabilized food items, because the lack of water 

generation aboard the ISS reduced the weight advantage of freeze-dried food items and 

thermostabilized foods had greater long-term acceptability [64]. The products could be 

formulated to contain a more moderate amount of sodium and fat than commercially available 

thermostabilized products. Since 1998, about 55 new food items, most of them 

thermostabilized, have been formulated by food scientists in the Space Food Systems 

Laboratory at Johnson Space Center and added to the ISS food list. 

Although the product development resulted from ISS needs, Shuttle crews are also able to 

take advantage of the longer list of available foods. The additional variety available in the ISS 

menu as a result of this product development proved to be even more important when the 

Columbia accident in February 2003 forced the ISS program to extend mission durations 

aboard the ISS from 4 months to 6 months. 
10 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

Figure 7. The International Space Station is seen from Space Shuttle Discovery on March 25, 2009. 

Photo credit: NASA. 

The U.S. food list currently consists of about 185 foods and beverages from which the 

Shuttle and ISS crewmembers can build their menus. As mentioned previously, the crews on 

the ISS select foods from a menu that is composed equally of U.S. space food and Russian 

space food. The Russian food list adds about 100 items to the total ISS food selection. The 

ISS crewmembers sample and score each of the U.S. and Russian food items available to 

them. Their menus are prepared using the food items to which they gave the highest scores. 

Figure 8. Astronaut Peggy A. Whitson, Expedition 16 commander, prepares a meal at the galley in the 

Zvezda Service Module of the International Space Station. Cosmonaut Yuri I. Malenchenko, flight 

engineer representing Russia’s Federal Space Agency, is visible in the background. Photo credit: 

NASA. 
Space Programs and Space Food Systems 11

Crewmembers’ flight menus are supplemented with a small quantity of “bonus food” 

each month. The bonus foods are chosen by the crew and can be additional menu food items, 

but often are commercially available items, such as candies, cookies, and crackers, that are 

not part of the standard ISS menu. Bonus food items must have certain levels of 

microbiological quality and shelf life. 

Food is transported to the ISS via Shuttle and Progress flights. The Progress is the 

unmanned Russian resupply vehicle. On each Shuttle and Progress flight, a small quantity of 

fresh food is stowed for transfer to the ISS crew. This typically consists of fresh fruit (apples, 

oranges) and fresh vegetables (carrot sticks, onions, and garlic). These fresh items must be 

consumed fairly quickly by the crew, since they cannot be refrigerated. 

Although on the early ISS flights crewmembers selected their own menus and all 

attempts were made to satisfy crew preferences for both the U.S. and Russian foods, launch 

logistics often created situations where the menu planned for a given crewmember was not 

available. Also, foods are typically consumed on a first-in, first-eaten basis, and if food 

remains after a previous crewmember has left, that is consumed first. In 2007, at crew 

request, the U.S. switched to providing a standardized menu for all crewmembers. Each 

crewmember was allowed to select not only a monthly bonus container, but also a 

“preference” container, with items from the standard food list that could help offset items on 

the standard menu that were less desired by that crewmember. 

Because of the length of the ISS missions, crewmembers typically settle into a more 

normal eating pattern than is possible on a hectic Shuttle flight. For this reason, food 

consumption rates are much higher on the ISS, but still not up to the level observed during the 

Skylab program. A recurring comment is that greater variety is beneficial to food intake. One 

of the ways this continues to improve is through the development and provision of foods from 

the other partners in the ISS program. The Canadian, European, and Japanese Space Agencies 

are all developing foods, either for inclusion in the crews’ “bonus” food containers or for 

eventual inclusion in the standard food list. 

III. NUTRITIONAL REQUIREMENTS

NASA’s first space flight-specific nutrient requirements were established for the longduration missions of the 1990s. Nutrient requirements for other programs (Shuttle and earlier) 

had been based on Earth-based requirements of the day [14]. 

Nutritional requirements for space crews on long-duration missions (> 30 days of flight) 

were initially defined in 1991, for planned Space Station Freedom missions of up to 120 days 

[457]. In 1992, plans for this U.S. space station were abandoned, and collaboration with the 

Russian space program was reinvigorated with flights on Shuttle, Mir, and ultimately the 

International Space Station. An updated set of requirements was developed for the Mir flights 

in collaboration with Russian partners in 1995 [458]. 

The nutrient requirements for ISS missions of up to 360 d [350, 458] are shown in Table 

1. With a few exceptions (most notably vitamin D insufficiency, and iron and sodium excess), 

the actual menus meet these requirements [612]. As discussed below, vitamin D supplements 

are provided to mitigate the dietary insufficiency. 

In 1999, all ISS International Partners—the Canadian Space Agency, the European Space 

Agency, the Japanese Space Agency (NASDA, later JAXA), the Russian Space Agency, and 

the U.S. space agency, NASA—held discussions to review ISS nutrient requirements. 

Additional reviews have been conducted since then, but a formal, signed agreement for 

updated nutritional requirements has yet to be established. 

Table 1. Planned (menu) and required nutrient intake on International Space Station 

missions.1

 Menu Content2 ISS Nutrient Requirements 

[458] 

NASA Exploration 

Mission Requirements 

[460] 

Energy, kcal/d 2877 ± 1673 Based on WHO [736] Based on DRI [279] 

Energy, % WHO 99 ± 13 

Total carbohydrate, % of kcal 50 ± 3 50–55 50–55 

Total protein, g/d 126 ± 10 0.8 g/kg BW, NTE 35% of 

calories 

Total protein, % of kcal 17 ± 1 12–15 

Animal protein, g/d 72 ± 7 60% 2/3 

Vegetable protein, g/d 33 ± 3 40% 1/3 

Total fat, % of kcal 31 ± 1 30–35 25–35 
14 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

Table 1. (Continued) 

 Menu Content2 ISS Nutrient Requirements 

[458] 

NASA Exploration 

Mission Requirements 

[460] 

Total dietary fiber, g/d 33 ± 4 10–25 10–14 g/1000 kcal 

Retinol equivalents, μg/d 1420 ± 205 1000 700–900 

Vitamin D, μg/d (IU) 4.2 ± 1.0 10 (400 IU) 25 (1000 IU) 

Vitamin E (total α-tocopherol 

equivalents), mg/d 12.1 ± 1.9 20 15 

Vitamin K (phylloquinone), 

μg/d 105 ± 19 80 90 (women) 120 (men) 

Vitamin C (ascorbic acid), 

mg/d 191 ± 39 100 90 

Thiamin, mg/d 2.0 ± 0.1 1.5 1.1 (women) 1.2 (men) 

Riboflavin, mg/d 2.2 ± 0.2 2.0 1.3 

Niacin, mg/d 29.8 ± 1.9 20 mg niacin equivalents 16 

Pantothenic acid, mg/d 5.1 ± 0.8 5.0 

Vitamin B6, mg/d 2.3 ± 0.2 2.0 1.7 

Total folate, μg/d 434 ± 53 400 400 

Vitamin B12 (cobalamin), μg/d 4.6 ± 0.7 2.0 2.4 

Biotin, μg/d 30 

Pantothenic acid, mg/d 30 

Calcium, mg/d 1020 ± 109 1000–1200 1200–2000 

Phosphorus, mg/d 1856 ± 165 1000–1200 (NTE 1.5 × Ca) 700 (NTE 1.5 × calcium) 

Phosphorus:calcium ratio 1.83 ±0.17 < 1.5 < 1.5 

Magnesium, mg/d 424 ± 40 350 320 (women) 420 (men) 

Iron, mg/d 22.7 ± 4.5 10 8–10 

Copper, mg/d 3.6 ± 0.9 1.5–3.0 0.5–9.0 

Zinc, mg/d 22.1 ± 6.2 15 11 

Manganese, mg/d 5.7 ± 0.7 2–5 1.8 (women) 2.3 (men) 

Selenium, μg/d 146 ± 16 70 55–400 

Iodine, mg/d 1.0 ± 2.8 0.15 0.15 

Fluoride, mg/d 3 (women) 4 (men) 

Chromium, μg/d 35 

Sodium, mg/d 5625 ± 531 < 3500 1500–2300 

Potassium, mg/d 3995 ± 360 3500 4700 

Water, g/d 2155 ± 206 1 mL/kcal, > 2 liters per day 1.0–1.5 mL/kcal, NLT 

2000 mL/d 

BW, body weight; DRI, dietary reference intake; NLT, not less than; NTE, not to exceed; WHO, World 

Health Organization. 1

Table adapted from Smith and Zwart [612] and [460]. 

2

Menu data are derived from either proximate analysis of space foods (macronutrients, most minerals) 

or estimations (animal protein, vegetable protein, all vitamins, selenium) from similar items in the 

Nutrition Data System for Research (NDS-R) database, versions 4.03/31, 4.05/33, 4.06/34, 5.0/35, 

2005, and 2006, developed by the Nutrition Coordinating Center, University of Minnesota, 

Minneapolis, MN, USA [562]. 3

All data are mean ± SD, and represent the average from menus of 19 ISS astronauts. 
Nutritional Requirements 15

For some missions, detailed dietary intakes were recorded by crews during flight, 

typically in conjunction with life sciences research. These data are compiled in Table 2. 

Table 2. In-flight dietary intake of Apollo, Skylab, and Shuttle crewmembers. 

 Apollo Skylab Shuttle 

Number of subjects 33 9 32 

Energy, kcal/d 1880 ± 415 1 2897 ± 447 2090 ± 440 

Energy, % WHO 64.2 ± 13.6 99.1 ± 8.2 74.2 ± 16.0 

Protein intake, g/d 76.1 ± 18.7 111.0 ± 18.4 78.0 ± 18.8 

Protein intake, % of kcal 16.3 ± 2.1 15.7 ± 2.1 14.9 ± 2.4 

Carbohydrate intake, g/d 268.9 ± 49.1 413.3 ± 59.3 304.0 ± 67.3 

Carbohydrate intake, % of kcal 58.1 ± 7.1 57.5 ± 9.1 58.4 ± 5.0 

Fat intake, g/d 61.4 ± 21.4 83.2 ± 13.8 64.0 ± 17.8 

Fat intake, % of kcal 28.9 ± 5.5 26.8 ± 8.6 27.2 ± 4.4 

Calcium, mg/d 774 ± 212 894 ± 142 826 ± 207 

Phosphorus, mg/d 1122 ± 325 1760 ± 267 1216 ± 289 

Magnesium, mg/d 310 ± 58 294 ± 74 

Iron, mg/d 15.0 ± 3.9 

Zinc, mg/d 12.0 ± 2.9 

Sodium, mg/d 3666 ± 890 5185 ± 948 3984 ± 853 

Potassium, mg/d 2039 ± 673 3854 ± 567 2391 ± 565 

Water, g/d 1647 ± 188 2 2829 ± 529 2223 ± 669 

1

All data are mean ± SD. Empty cells (Apollo magnesium, Apollo and Skylab iron and zinc) show 

where data were not available. 2 n = 3 for water intake during Apollo missions. 

Adequate intake and recommended dietary allowance (RDA) of many nutrients, as 

defined by the Institute of Medicine [276-280], are given in this book for comparison with 

space flight nutritional requirements [458-460]. The RDA (a recommendation issued by the 

U.S. government) is calculated from the estimated average requirement (EAR), which is 

based on scientific evidence. Adequate intake is an estimate that is used when not enough 

evidence exists about a nutrient to calculate an EAR. 

IV. SOURCES OF NUTRITION DATA AND GAPS IN 

NUTRITION KNOWLEDGE

In addition to establishing requirements for nutrient intake of astronauts, NASA requires 

crewmembers to participate in evaluations of their health; these are called Medical 

Requirements. One such evaluation is the “Clinical Nutritional Assessment” [459], in which 

all U.S. crewmembers on ISS missions are required to participate. The findings from this 

assessment are included in the sections on findings from space flight and ground-based 

research, to provide background information about the changes seen in flights of 4 to 6 

months (during which time resupply by at least one Progress vehicle occurred). 

In many cases in this book, we have extrapolated from ground-based space analog 

studies—studies performed in a laboratory on Earth under conditions that simulate some of 

the conditions found during space flight. In others we have only the ground-based nutrition 

literature for support, knowing nothing of the effects of space travel. We have pointed out the 

areas where we are at highest risk of being wrong, with little or no evidence base to support 

nutritional requirements and recommendations for space flight. 

In 2006, the NASA Human Research Program created the Human Health and 

Countermeasures Element Small Assessment Team, a group of individuals representing the 

Human Adaptation and Countermeasures Division, the Space Medicine Division, and the 

Astronaut Office. The review and final report of the team listed 15 specific gaps in knowledge 

about the risk of inadequate nutrition during long-term space travel. Five of these pertained to 

specific nutrients and will be discussed under those nutrients, but the other 10 are more 

general and are listed here: 

1. Are nutrients in food stable during space flight? 

2. How do nutritional status and nutrition requirements change during space flight? 

3. Do countermeasures to other physiological effects of space flight affect nutrition? 

4. What impact does flight have on oxidative damage to nutrients? 

5. How much energy and how much of which nutrients are required for crewmembers 

to perform extravehicular activity? What is the best system for delivering these 

nutrients? 

6. Can nutritional countermeasures mitigate muscle loss? 

7. What are the risks of the release of minerals and metals from bone? 

8. Can the risk that a crewmember will develop a renal stone be decreased using 

nutritional countermeasures? 

9. What nutritional countermeasures can mitigate bone loss? 
18 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

10. Can generally good nutrition or particular nutrients mitigate the risks that oxygen and 

radiation pose to health? 
V. FOOD, ENERGY, AND MACRONUTRIENTS

In this section, the longest in this book, we review available information about individual 

nutrients and human requirements for them, and the evidence base of existing ground-based 

and space flight research and clinical findings. 

A. FOOD AND ENERGY

1. Background 

Ensuring that the spacecraft food systems provide palatable, safe, and nutritious foods is 

obviously critical for any space mission. The longer space station missions have included 

semi-closed food systems, with periodic resupply and transient exposure to unique and fresh 

foods [62, 242, 353, 504]. Exploration missions will have a more closed food system 

(because of the difficulty of resupply and shelf-life requirements). The food system on these 

missions is likely to be supplemented with food grown on a planetary surface or even 

potentially on the spacecraft [62, 353, 504]. 

From the early days of the space program [250, 251, 321, 322, 340, 596], development of 

foods for space flight has proven a significant challenge, yet the design criteria have changed 

little since then: minimal crumbling, ease of preparation and consumption in microgravity, 

minimal trash volume, and high palatability. With one exception, the food systems used in 

every space program to date have been entirely shelf-stable, and they are composed primarily 

of rehydratable or thermostabilized (heat-treated) food items [62, 353]. Although these foods 

are known to have lower hedonistic value (palatability) than fresh or frozen foods, groundbased studies have clearly shown that the Shuttle food system can adequately support most 

nutritional requirements [214]. Skylab is the only U.S. program that has included frozen 

foods [62, 353]. 

Energy itself is not readily stored in the body, but the substrates for energy are. Energy in 

the form of heat is obtained by oxidizing carbohydrates, fats, proteins, and alcohol; this 

energy is also known as the heat of combustion. Fat provides the most energy of these 

sources, at about 9 kcal/g. Carbohydrates and proteins provide about 4 kcal/g, and alcohol 

about 7 kcal/g. Because the body can adapt to different energy sources, large variations in 

intake of macronutrients (carbohydrates, fats, proteins) are generally well tolerated. Adipose 

tissue is the only viable long-term source of stored energy. Carbohydrate stored as glycogen 

in liver and muscle provides a transient (hours) source of carbohydrate. Protein can be broken 
20 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

down to release amino acids, but this is done at the expense of muscle tissue. 

The small amount of starvation data available suggest that for every 500 kcal consumed 

per day, about 1% of body mass can be conserved every 12 days. It would not be acceptable, 

however, to use these numbers for a long-term (> 21 days) prediction of body mass loss or 

conserved body mass loss because after 21 days of starvation the basal metabolic rate of the 

body decreases [74, 492]. This can be and has been accounted for using a mathematical 

model to predict body mass loss given changes in basal metabolic rate [492], with results 

estimating that survival on 1000 kcal/d could exceed 3 years (compared with only 6 months 

without accounting for decreased metabolic rate). 

2. Findings from Space Flight and Ground-Based Research 

Despite indications that energy requirements are similar before and during flight [348, 

736], energy intake during flight is commonly lower than the estimated requirements for 

individual crewmembers [14, 242, 243, 292, 348, 365, 526, 527, 604, 609, 610, 626] (Figure 

9). From the Apollo program through the more recent flights, crewmember dietary intakes 

during flight have averaged about 70% of predicted requirements [610]. 

Apollo Skylab Shuttle Mir ISS

0

25

50

75

100

125

% WHO-predicted

Figure 9. In-flight dietary intake of crewmembers in different space programs. Data are expressed as 

percentage of energy requirements predicted by the World Health Organization (WHO) [736]. Apollo n

= 33, Skylab n = 9, Shuttle n = 32, Mir n = 7, ISS n = 23. Apollo and Skylab data are from Bourland et 

al. [62]. Figure is adapted from Smith and Lane [611], with additional data from Smith et al., 2005 and 

Smith and Zwart, 2008 [610, 612]. 

Exceptions to the average inadequate intakes do exist. A number of ISS crewmembers 

have been able to consume recommended dietary intake requirements and maintain body 

mass [610]. In some cases, such as during Skylab [361, 524] and European flights to the Mir 

space station [146], metabolic experiments have required crewmember subjects to consume a 

eucaloric diet, with the goal of weight maintenance. These crewmembers ate essentially 100% 

of their recommended energy requirements. It is difficult to determine if 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 generally beneficial. 
Food, Energy and Macronutrients 21

Anecdotal reports from crewmembers on long-duration missions indicate that 

crewmembers who had lost a significant amount of body mass on orbit had a rebound gain in 

body mass after landing, but in general, the data do not support this finding (Figure 10). 

R+0 AME1 AME2 

-10

-5

0

5

BW (% change from preflight)

Figure 10. Postflight body weight (BW) of Mir and ISS crewmembers (n = 20). Data are expressed as 

mean ± SD of the percent change from preflight body weight. R+0 = landing day, AME1 = first annual 

medical exam after return from the mission, and AME2 = second exam. 

The cause of reduced dietary intake during flight is unknown, but many potential 

explanations have been proposed [292, 350, 596]. A common cause of reduced dietary intake 

during the first days of a mission [246] is space motion sickness [246, 341, 467, 535, 569]. 

The effects of space motion sickness typically pass after the first several days of flight, but 

the decreased dietary intake can extend beyond the first week [350]. 

Anecdotal reports of appetite 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 [2]. 

Food palatability is occasionally reported as a cause of reduced in-flight intake, and many 

anecdotal reports exist of changes in taste and aroma of food during flight [35, 488, 569]. One 

hypothesis is that fluid shifts and congestion associated with the first days of microgravity 

can alter taste and odor perception. Other possibilities exist as well, including effects of 

atmospheric contaminants, stress, radiation, and psychological factors [488]. Experimental 

research has not been able to clearly document changes in taste or olfaction during space 

flight or head-down-tilt bed rest [75, 488, 715]. 

When tongue taste perception was measured before, during, and after a 30-day –6° headdown bed rest period, subjects reported decreased appetite and lack of taste early in the bed 

rest phase [75, 338]. By day 13 of the bed rest phase, for all tastes (sweet, salt, acidic, bitter), 

the threshold for taste sensitivity had increased. In contrast, a more recent study found no 

changes in odor and taste perception after 14 days of head-down bed rest [537], suggesting 

that multiple factors are likely involved in this process. 

Flight-related changes in gastrointestinal function may also occur. Fluid shifts, in 

combination with reduced fluid intake, would tend to decrease gastrointestinal motility. 

Gastrointestinal transit time has not been systematically studied during flight, but during 10 

days of –6° head-down bed rest, mouth-to-cecum transit time was significantly longer than 

during ambulatory control periods [344]. However, because the Skylab astronauts and others 
22 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

were able to maintain a eucaloric diet in space, hypotheses regarding 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 gastrointestinal function 

during actual and simulated space flight, in humans and in animal models, have previously 

been reviewed [593]. 

The obvious and immediate reason for concern about reduced dietary intake is the risk of 

body mass loss, and more specifically, loss of lean and bone tissue. Body mass losses of 1% 

to 5% of preflight body mass have been a typical finding in the history of space flight, 

although some crewmembers have been able to maintain body mass [610]. In-flight and 

postflight losses of body mass are compiled in Figure 11, Figure 12, and Figure 13. 

Documented weight losses have occurred on short- and long-duration flights in both the U.S. 

and Russian space programs [292, 340, 343, 387]. Indeed, all crewmembers on Gemini, 

Apollo, Skylab, and Apollo-Soyuz Test Project missions lost body mass [369]; thus, ingestion 

of the prescribed energy intake on the U.S. Skylab missions did not ensure maintenance of 

body mass [524]. In one study of 13 male Shuttle crewmembers, body mass losses ranged 

from 0 to 3.9 kg [348]. Body mass loss has been observed to reach 10% to 15% of preflight 

body mass [603]. Crewmembers on the ISS have shown similar patterns of mass loss during 

and after flight. 

0 10 20 30

-15

-10

-5

0

5

Week of flight

Body mass (%

Δ from preflight)

Figure 11. In-flight body mass measurement data from ISS crewmembers. Data are expressed as 

percent change from preflight values. Data collection was scheduled every 2 weeks, but complete data 

for all crewmembers were not always available. Each line represents data for 1 crewmember. 

Data relating reduced dietary intake to loss of body mass were collected from 2 groundbased studies in which subjects were semi-starved. In the first study [74], 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 other study, starved subjects lost 9% of 

their body mass after 11 days, 15% by day 18, and 18% by day 43 [158]. 
Food, Energy and Macronutrients 23

0 20 40 60 80 100 120 140 160 180 200 220

-15

-10

-5

0

5

10

Mission duration (days)

Body weight (% Δ from preflight)

Figure 12. Changes in body weight on the day of landing. Data are expressed as percent change from 

preflight values. Each symbol represents 1 crewmember from a Shuttle (open circles), Skylab (open 

triangles), Mir (filled squares), or ISS (filled circles) mission. Duration data have been adjusted slightly 

to ensure anonymity. From Lane et al., Food and nutrition for the moon base: what have we learned in 

45 years of spaceflight. Nutr Today 2007;42(3):102-10 [353], adapted with permission. 

F-0 R+0

50

60

70

80

90

100

Body weight (kg)

Figure 13. Body weight of Apollo crewmembers (Apollo 7 through 17) before (F–0) and after (R+0) 

flight. Data are from Johnston et al., 1975 [295]. 

Only about 1% of the loss of body mass can be explained by loss of body water [365]; 

most of the observed loss of body mass is accounted for by loss of muscle and fat tissue [291, 

349]. The water loss may be confounded by lean tissue loss, as metabolic water loss will be 

associated with depletion of glycogen stores and protein catabolism, both of which occur with 

inadequate intake. Inadequate energy intake is associated not only with loss of fat tissue 

(Figure 14) but also with decreased protein synthesis [627] (in flight), increased protein 

catabolism [50] (in bed rest), and subsequent loss of lean tissue mass. 

Besides the obvious concerns about body mass loss and dehydration [710], 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 European Space Agency 

(ESA) to evaluate the impact of hypocaloric nutrition on multiple systems. A crossover 

design was used, with hypocaloric and eucaloric phases, and bed rest and ambulatory phases. 

Results for protein metabolism (Figure 15) document the fact that undernutrition exacerbates 

the negative effects of bed rest. 
24 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

20 30 40 50

-1

0

1

2

3

INFLIGHT ENERGY DEFICIT

(100 X ENERGY DEFICIT/ENERGY EXPENDITURE) BODY FAT OXIDIZED (kg)

Figure 14. In-flight oxidation of body fat related to in-flight energy deficit. Stein et al., Am J Physiol 

Regul Integr 1999 [628], adapted with permission. 

Ambulatory Bed rest

0.0

0.1

0.2

0.3

Eucaloric diet

Hypocaloric diet

Leucine oxidation

(μmol/kg LBM/min)

Figure 15. Leucine oxidation (an index of net protein catabolism) in a crossover-design bed rest study 

to evaluate the impact of hypocaloric nutrition on integrated physiology. There was a significant (P = 

0.04) interaction between bed rest and diet. Data are from Biolo et al. [50]. LBM, lean body mass. 

Undernutrition has also been found to impair cardiovascular performance (orthostatic 

tolerance) in controlled bed rest settings [176] and after space flight (William Carpentier, 

personal communication). The mechanism for this energy-cardiovascular connection has been 

hypothesized to involve multiple functions of many endocrine factors, including insulin, 

leptin, and growth hormone [57]. 

Besides undernutrition, another possible explanation for loss of body mass is altered 

energy expenditure. According to early hypotheses, energy expenditure during flight would 

be less than on the ground, because of the relative hypokinesia in space [596]. Lower energy 

expenditure was observed during extravehicular activity (EVA) on the lunar surface than 

during similar activities at 1 G [712] (Figure 16 and Figure 17). However, studies of Space 

Shuttle crewmembers during in-flight EVA [349] and non-EVA (that is, intravehicular 

activity, or IVA) [348] showed that in-flight energy expenditure was unchanged from 

preflight levels (Figure 18). More recent studies have even shown greater energy expenditure 

during flight than before flight, most likely as a result of increased exercise [628]. 

These recent studies involved Shuttle astronauts and indirect calorimetry techniques to 

determine total energy expenditure (TEE) over several days. The doubly-labeled water (water 

enriched with deuterium and 18O) technique was used to determine oxygen consumption 

[564]. The benefits of this technique are that it is noninvasive and it takes into account the 
Food, Energy and Macronutrients 25

energy cost of all activities for several days. The drawback of the method is that information 

about the individual components of TEE (such as resting, sleep, and exercise) is not available. 

The wide range of differences between preflight and in-flight TEE makes it important to have 

information about the components of TEE. Although it is assumed that moving the body mass 

around the cabin requires less expenditure of energy during weightlessness than at 1 G, other 

metabolic activities, such as maintaining resting metabolic rate and responding to stress, may 

require increased energy expenditure during weightlessness. 

In ground-based studies, resting energy expenditure did not change, but TEE was less 

during bed rest than before bed rest [215]. Because (except during lunar EVA) TEE during 

flight is unchanged [348] from preflight levels or increased [628], 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 difference between bed rest and space flight is 

the lack of a metabolic response to stress during bed rest [630]. 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 space flight on energy and fuel metabolism [400]. 

0 2 4 6

0

200

400

600

Subject 1

Subject 2

Traverse rate on lunar surface (km/h)

Metabolic rate (kcal/h)

Figure 16. Metabolic rate of Apollo 14 astronauts while they traversed the lunar surface on foot during 

EVA. Data are from Waligora and Horrigan [712]. 

Pre-egress Ops (12 min)

Egress (8 min)

TV deployment (12 min)

LRV offloading (21 min)

LRV config (73 min)

LRV traverse (26 min)

Station 1 acitivities (18 min)

Station 2 activities (51 min)

LRV traverse 2 (34 min)

ALSEP offloading (24 min)

ALSEP traverse (9 min)

Heat flow exp deployment (51 min)

Laser ranging deployment (9 min)

Photography (5 min) 

LRV traverse (5 min)

EVA closeout (15 min)

EVA termination (13 min)

0

100

200

300

400

500

Avg metabolic rate (kcal/hr)

Figure 17. Metabolic expenditures of the first Apollo 15 lunar EVA in chronological order (durations of 

each activity are noted in parentheses). The average total energy expenditure during the EVA was 1800 

kcal. ALSEP = Apollo Lunar Surface Experiments Package, EVA = extravehicular activity, LRV = 

Lunar Roving Vehicle, TV = television. Data are from Waligora and Horrigan [712]. 
26 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

Intake

EE

WHO

0

5

10

15

20

*

MJ/d

Figure 18. Energy intake, energy expenditure (EE), and WHO-predicted energy requirements (WHO) 

of Space Shuttle crewmembers before (checked bars) and during (open bars) space flight. Data are from 

Lane et al., 1997 and Lane et al., 1999 [348, 351]. 

3. Dietary Intake and Requirements 

The estimated energy requirements (EERs) for space missions are based on total energy 

expenditure (TEE) as calculated from the 2002 Institute of Medicine Dietary Reference Intake 

reports [279], using an activity factor of 1.25 (active) along with the individual’s age, body 

mass (kg), and height (m) in the following calculations: 

EER for men 19 years and older 

EER = 622 – 9.53 × Age [y] + 1.25 × (15.9 × Mass [kg] + 539.6 × Height [m]) 

EER for women 19 years and older 

EER = 354 – 6.91 × Age [y] + 1.25 × (9.36 × Mass [kg] + 726 × Height [m]) 

For historical reference, the daily energy requirements for male and female astronauts 

were defined in 1991 [457], and again in 1995 [458], and are as follows: 

Missions of 30–120 days: Energy consumption should be sufficient to maintain weight 

and body composition, with continuous monitoring during space flight. A 70-kg man 

exercising 1 to 2 hours per day is expected to require about 3,000 calories/day [457]. 

Missions up to 360 days: Intake of energy should be sufficient to maintain body weight 

and composition, and the extensive activities planned for International Space Station crew 

members. Energy requirements will be calculated for each individual by using the World 

Health Organization [736] equations: 

Men 

3⁄4 18-30 y: 1.7 (15.3W + 679) = calories/day required 

3⁄4 30-60 y: 1.7 (11.6W + 879) = calories/day required 

Women 

3⁄4 18-30 y: 1.6 (14.7W + 496) = calories/day required 
Food, Energy and Macronutrients 27

3⁄4 30-60 y: 1.6 (8.7W + 829) = calories/day required 

3⁄4 where W = weight in kg 

These equations are to be used for moderate levels of activity. The original space flight 

requirements included an additional 500 calories/d that would be supplied to the diet during 

the period when end-of-mission countermeasures (such as more intensive exercise) are being 

conducted. 

On the basis of results from previous space missions, it was also recommended that an 

additional 500 calories/d be supplied to crew members on days of extravehicular activity 

(EVA); the extra energy should be similar in nutrient composition to the rest of the diet [458]. 

4. Risks on Exploration Missions 

It is imperative that adequate resources be provided to support food consumption on 

exploration missions. A reliable food system must include a variety of palatable foods and the 

means to process them (such as rehydration, heating, and cooling). Time (for meal 

preparation, consumption, and cleanup) is another limited resource that often hinders dietary 

intake during space flight. 

The availability of freezers and refrigerators for food storage and preparation would 

provide a more palatable food system, which would increase dietary intake as well as provide 

added psychological support. 

Deficiency of dietary energy intake leads to wasting and ultimately tissue breakdown, or 

even death. The loss of lean body mass during space flight is significant, and is associated 

with increased proteolysis and catabolism related to metabolic stress [170]. Inadequate energy 

intake can also have negative effects on bone, exacerbated by exercise [28, 275]. This 

highlights the interaction between systems, and the fact that exercise regimens must be 

coordinated with energy provision. 

It is difficult to predict the impact of suboptimal (or lack of) energy intake on otherwise 

healthy individuals. One issue is that the energy equivalent of the lost mass changes with 

time, as different body fuels are used at different times during semi-starvation [74, 492]. With 

partial rations available (1000 calories per day), it is reasonable to expect that a person could 

survive for more than 4 to 6 months, potentially longer if the metabolic rate were to decrease 

because of decreased intake. If energy availability were restricted further, survivability would 

range between this amount of time and the 1 to 2 months possible with no food. 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 [331, 384]. 

Other possible effects of long-term low intake of calories include decreased motor and 

cognitive function, each of which could impair an astronaut’s ability to perform work-related 

tasks necessary for landing. According to military survival studies, astronauts would be 

expected to experience decreased endurance early on, and the decrease in strength would 

parallel the decrease in lean body mass [507]. During total fasting, degradation of 

coordination, speed, and cognitive function would be evident within the first 2 weeks [507]. 

The metabolic condition of ketosis, which would be expected to result from starvation, 
28 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

not only would have metabolic effects (including decreased appetite), but might also affect 

other aspects of the mission (for example, the life-support systems might not be able to 

remove the ketones from the air). Ketoacidosis can obviously have negative effects on acidbase balance, which in turn can affect bone, muscle, and other systems. 

It is speculated that a crew could survive on a spacecraft or planetary base for 40 to 60 

days without food. With limited rations (1000 calories/d), a crew could survive 4 to 6 months 

(although physical performance capability might be severely degraded). The high-stress 

environment of a contingency during transit or on a planetary surface would likely exacerbate 

the basic effects of limited rations, and would shorten projections of survivability estimated 

from ground-based studies. 

Insufficient dietary intake and subsequent loss of body mass are significant not only for 

crew health but also for medical operations and research studies, in which clear interpretation 

of essentially all other physiological data is impossible when subjects are malnourished. That 

is to say that virtually all space flight data collected on Shuttle, Mir, and ISS missions are 

confounded by inadequate dietary intake. Investigators who have studied bone and muscle, 

cardiovascular function, immune response, and other systems during space flight cannot say 

to what degree undernutrition affected their findings. 

5. Remaining Questions 

Further research is warranted to better understand why astronauts typically do not 

consume 100% of their recommended daily energy intake. Decreased energy intake has 

numerous negative implications for the body, and is often associated with decreased intake of 

other nutrients. 

Studies of energy expenditure have been conducted only on short-duration (Shuttle) 

flights [348, 628]. Whether the same trends continue on longer flights is not known (an ESAsponsored study of energy expenditure on ISS missions is currently in development). The 

health implications of decreased energy expenditure need to be determined, and ways to 

prevent both in-flight loss and postflight gain of body mass need to be evaluated. 

At least 2 approaches exist to controlling body mass and composition while studying 

human adaptation to bed rest: maintaining body mass (as is typically done in the U.S.) or 

allowing subjects to lose total mass while keeping fat mass constant (and thus losing lean 

tissue). While this latter approach sounds intriguing, implementing it has proven very 

difficult, given the difficulties in measuring fat mass and adapting intake in a timely manner. 

Nonetheless, Biolo and colleagues have recently reported data suggesting that the more the fat 

mass increases during bed rest, the more lean tissue is lost [51], and that this is confounded by 

increasing oxidative and inflammatory damage markers [51]. Altered fuel homeostasis has 

been documented in other bed rest studies [56] and animal studies [635, 636], and remains to 

be fully elucidated, in bed rest or space flight [636, 745]. 
Food, Energy and Macronutrients 29

B. PROTEIN AND MUSCLE

1. Background 

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 in its amino-acid building blocks makes protein, 

along with nucleic acids, one of the major nitrogen-containing macromolecules. The type of 

protein, such as animal or vegetable protein, incorporated into the diet may be an important 

factor to consider in determining protein requirements. 

Protein is one of the most important limiting factors when the body is deprived of energy, 

because essential amino acids are not stored in 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 [589]. Loss of more than 40% to 50% of 

initial body mass is not compatible with life [194, 507]. 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 

[331, 384]. 

2. Findings from Space Flight and Ground-Based Research 

Blood concentrations of total protein and albumin were elevated at landing after Skylab 

missions (Figure 19). Urinary albumin has been shown to be reduced during space flight and 

bed rest [100-102]. Measurements of urinary albumin excretion, which are typically low in 

healthy individuals, have not been reported after landing. 

Potassium and nitrogen balances became increasingly negative throughout the Skylab 

flights, but urinary creatinine (a product of muscle protein breakdown) did not change [361, 

725] despite losses of leg volume [524, 666]. Nitrogen balance has also been shown to be 

negative during Shuttle flights [625]. 

Preflight

R+0R+1

R+3/4

R+14

6.0

6.5

7.0

7.5

8.0

Protein (g %)

Preflight

R+0R+1

R+3/4

R+14

3.5

4.0

4.5

5.0

Albumin (g %)

Figure 19. Plasma total protein (left panel) and albumin (right panel) in Skylab crewmembers before 

and after flight. Data are from Leach and Rambaut [361]. 
30 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

Exposure to microgravity reduces muscle mass, volume, and performance, especially in 

the legs, on both long [19, 31, 174, 430, 524, 746] and short flights [1, 133, 174, 219, 375, 

524]. Muscle biopsy studies demonstrated that the cross-sectional area of type II (fast-twitch) 

but not type I muscle fibers decreased after landing. Type II is the muscle fiber type that 

responds to resistive exercise [128]. 

Disuse atrophy of muscle in space may be related to changes in turnover of protein in the 

whole body. The results of one ground-based study showed that whole-body protein synthesis 

decreased about 13% during 2 weeks of bed rest, and that half of that decrease could be 

accounted for by the leg muscles [168]. This bed rest study did not include exercise, and body 

mass was maintained during the bed rest period. In the same study, excretion of 4-pyridoxic 

acid, a vitamin B6 metabolite, increased during bed rest [106], suggesting that metabolically 

active muscle tissue was lost. 

Turnover studies with stable isotopes indicate that during short-term space flight, wholebody protein turnover increases. Protein synthesis increases, but protein breakdown increases 

even more [623, 625]. The increase in synthesis is hypothesized by Stein et al. [632] to be 

related to physiological stress, as indicated by generally (but not consistently) increased 

urinary cortisol during flight [365, 630, 631]. These findings are similar to those found in 

catabolic patients, those undergoing metabolic breakdown. Decreased prostaglandin secretion 

has also been implicated in the loss of muscle tissue during space flight, secondary to 

decreased mechanical stress on muscle [631]. 

On long-duration Mir flights, conversely, investigators have noted decreased rates of 

protein synthesis [628]. Protein synthesis was directly correlated with energy intake (Figure 

20), suggesting that the reduced protein synthesis was related to inadequate energy intake 

[627]. 

40 50 60 70 80 90 100 110 120

20

40

60

80

Energy intake during flight

(% of preflight)

Protein synthesis during flight

(% of preflight)

Figure 20. Protein synthesis and energy deficit. Stein et al. , Am J Physiol Endocrinol Metab 1999 

[627], adapted with permission. 

Evaluation of plasma and urinary amino acids often does not provide a clear picture of 

muscle metabolism. However, an increase in plasma amino acids was noted in cosmonauts 

after flight [687, 688]. Limited Shuttle flight data indicate a tendency for plasma branchedchain amino acids to be increased during flight, compared to preflight levels [629]. Data from 
Food, Energy and Macronutrients 31

short-duration Shuttle flights reveal little or no change in urinary amino acid profiles [626]. 

Apollo (Figure 21) [366] and Skylab studies did reveal increases in excretion of the amino 

acid metabolites creatinine, sarcosine, and 3-methylhistidine [362], suggesting that contractile 

proteins of skeletal muscle are degraded in weightlessness. 

Preflight Postflight

0

20

40

60

100

200

300

400 Phosphoethanolamine

Taurine

Glycine

Alanine

Tyrosine

β-Alanine

+18%

+140%

-15%

-15%

-9%

+13%

Amino acid excretion (mg/d)

Figure 21. Urinary amino acid excretion by Apollo crewmembers (n = 12) before and after flight. Data 

are from Leach et al. 1975 [366]. 

Some data suggest that during the recovery period after short-duration Shuttle flights, 

protein is a limiting nutrient, and that competition for substrate to replenish plasma proteins 

and muscle mass strains the system [637]. This has not been tested experimentally, but clearly 

good nutrition is required for rapid return to optimal health. 

3. Muscle – Comparison of Space Flight and Bed Rest 

Although, as described above, both space flight and bed rest studies have shown 

decrements in muscle strength and volume, the mechanisms by which these decrements occur 

seem to be different in the two types of studies. Differences between flight and ground studies 

may relate to a number of variables, in addition to potential shortcomings of the analog 

studies. Dietary intake is one major difference between the two types of studies. On the SLS 

missions, in-flight intakes of protein and energy were about 20% less than preflight intakes, 

and crewmembers lost approximately 1 to 1.5% of their body mass [625]. Ground-based 

studies typically have prescribed and controlled dietary intakes or are designed to maintain 

body mass. Variability in stress levels might explain some of the variability in the results 

from this type of study, both flight and ground-based. An increase in stress level is typically 

associated with the initial days of space flight. In many cases, urinary cortisol levels return to 

preflight levels after 5 to 9 days, although this phenomenon has yet to be fully characterized 

or generalized to all crews. Ground-based studies have the potential for stress to increase, but 

this is not an entirely consistent finding. Some studies have shown no change, or even a 

downward trend, in cortisol excretion during bed rest [434]. As seen with studies of energy 

metabolism, administration of exogenous cortisol or thyroid hormone induces metabolic 
32 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

stress, which produces a more accurate ground-based model of protein metabolism during 

space flight [175, 400, 495, 496]. Ground-based rodent studies generally show increased 

proteolysis along with reduced synthesis [31], a pattern similar to that seen in studies of 

humans during flight, described above. 

4. Muscle Loss Countermeasures 

A. Mechanical 

Exercise is the most common first-pass approach to maintaining muscle mass and 

strength [1, 33, 34, 136, 677]. The exercise regimens tested as countermeasures to date have 

not succeeded in maintaining muscle mass or strength (or bone mass) during space flight 

[677]. On Mir flights, crewmembers differed significantly with respect to in-flight exercise 

frequency and intensity (related to such factors as mission requirements and personal habits). 

However, losses of leg muscle volume, detected immediately after flight by magnetic 

resonance imaging, were almost 20% in all subjects [377]. Similar findings (wide variations 

in exercise, lack of difference in bone loss) have also been documented for bone loss [603]. 

Many types of resistive exercise and combination resistive and aerobic exercise protocols 

have been proposed to aid in the maintenance of both muscle and bone during flight [11, 12, 

169, 212, 232, 410, 432, 532, 543, 567, 578, 661], but these have yet to be fully tested on 

orbit. 

Vibration has also received much attention recently in the hope that it can provide a 

viable musculoskeletal countermeasure [44, 58, 550], but initial reports have found it to be 

ineffective for muscle [747]. 

B. Pharmacological 

Exogenous testosterone administration during bed rest studies has maintained muscle 

mass and protein balance, but with no effect on muscle strength [744]. Because of the 

necessary route of administration (injection) and other issues, this has not been vigorously 

pursued. Testosterone has also been suggested as a bone loss countermeasure for animal 

models [734, 735], because a reduction in testosterone concentrations has been observed 

during flight in humans, animals, and cellular models of space flight [640-647]. A potential 

confounding factor is the drop in testosterone that has been observed in exercising bed rest 

subjects (but not controls) [711]. 

C. Nutritional 

Use of protein and amino acid supplementation has long been studied as a potential 

means to mitigate muscle loss associated with space flight [18, 49, 72, 175, 494, 678], but 

results have been inconclusive. Oral doses of branched-chain amino acids had little effect on 

leg-muscle protein kinetics in ambulatory male subjects [167], whereas feeding a bed rest 

group adequate energy with excess protein reversed nitrogen losses [649]. However, feeding 

Skylab crewmen energy and protein equivalent to those given to the bed rest group did not 

prevent negative nitrogen balance and loss of leg muscle strength during flight [430, 666, 

725]. In another bed rest study, a leucine-enriched, high-protein diet failed to mitigate muscle 

loss, and in some sites exacerbated loss [678]. It remains unclear whether nutritional 
Food, Energy and Macronutrients 33

measures beyond the consumption of adequate energy and protein would be beneficial in 

reducing muscle atrophy. 

5. Protein and Bone 

The interrelation of protein and bone health is complex, and often seemingly 

contradictory. In certain populations (such as growing children), protein is essential for bone 

growth. However, in some cases, high protein intakes can be detrimental to bone [126], a fact 

confounded by the type of protein (and amino acids) consumed and by their relation to other 

dietary factors [127, 523]. 

High-protein diets lead to hypercalciuria, and increase the risk of fracture and the risk of 

renal stone formation [127, 249]. In one 5-year study of 120 men, the relative risk of stone 

formation on a restricted protein (52 g/d) and salt (50 mEq/d) diet was found to be half that of 

men on a calcium-restricted diet (400 mg/d) [61]. The reason for the decreased risk of renal 

stones on a low-protein diet is not well understood, but several potential mechanisms have 

been postulated. It is generally well accepted that high-protein diets induce hypercalciuria, 

and this can contribute to formation of calcium oxalate or calcium phosphate stones. One 

hypothesis to explain protein-induced hypercalciuria is related to the “acid-ash” hypothesis 

that excessive intake of animal protein provides excess sulfur-containing amino acids that are 

metabolized to sulfuric acid. Since bone is a large reservoir of base, it can be broken down to 

provide carbonate or phosphate to neutralize fixed acid loads. Furthermore, low urinary pH 

decreases urinary excretion of citrate, which is a potent inhibitor of stone formation. In 

addition, dietary animal protein represents a rich source of purines that may raise uric acid 

excretion, which could increase the risk of forming uric acid stones [750]. 

Protein-induced hypercalciuria may also be detrimental to bone [497]. Some studies show 

that high-protein diets increase intestinal absorption of calcium [312], but this has not been 

widely accepted. The key to understanding the interrelationship of protein and bone may lie 

in understanding the complexities of these types of studies, which may require a full 

accounting of many nutrients and environmental factors [355, 356]. 

Several studies show that animal protein increases acid load more than vegetable protein 

because of the higher sulfur content per serving of food. Vegetable protein itself does not 

necessarily have less sulfur per gram of protein, but a larger mass of foods containing 

vegetable protein would have to be consumed to get the same amount of protein as from 

foods containing animal protein. It can be assumed that foods containing vegetable protein 

contain less sulfur than foods containing animal protein. In studies with controlled dietary 

intakes with varying sulfur content, diets consisting of animal protein yielded greater urinary 

calcium excretion and lower urinary pH than similar diets consisting mainly of vegetable 

protein [70]. The results of another study comparing the effects of 2 sources of protein (meat 

and soy protein), with and without additional supplementation with sulfur amino acids, 

indicated that dietary meat elicited a greater positive association between protein intake and 

urinary calcium, sulfur, ammonia, and titratable acids than dietary soy elicited [302]. When 

the soy diet was supplemented with sulfur amino acids, urinary calcium and acid excretion 

increased. Conversely, the addition of dietary potassium (as fruit or K+

 supplement) to both 

diets decreased urinary calcium and acid excretion [302]. Other studies have shown that 

greater amounts of protein or higher ratios of animal protein to potassium are more 
34 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

detrimental when bone health is already compromised (such as during bed rest, and 

potentially during space flight) [756, 757]. 

Dietary intake of protein, specific types of protein, and patterns of acid and base 

precursors have recently been associated with the concentrations of urinary markers of bone 

resorption during bed rest [756, 758, 759]. In one study with male identical twins, the 

relationships between acid and base precursors in the diet and markers of bone and calcium 

metabolism during bed rest were investigated [607]. With regard to dietary intake patterns, a 

strong positive correlation existed between markers of bone resorption (n-telopeptide [NTX], 

deoxypyridinoline, and pyridinoline) and the ratio of animal protein to potassium intake 

during bed rest. Figure 22 shows that a positive correlation existed between urinary NTX 

excretion and the ratio of animal protein to potassium intake during 4 weeks of bed rest. No 

relationship was found between the ratio of vegetable protein to potassium and markers of 

bone metabolism. There tended to be a positive association between these variables before 

bed rest and during weeks 1 and 2 of bed rest, but the relationship was not significant, likely 

because of high variability among the population and small sample size [756]. 

0.5 0.6 0.7 0.8

0

500

1000

1500

2000

Apro/K (g/mEq)

N-telopeptide (nmol/d)

Figure 22. The bone resorption marker n-telopeptide (NTX) was positively correlated with the ratio of 

animal protein to potassium intake (APro/K) during week 4 of bed rest (solid line, squares), while no 

relationship was observed in ambulatory subjects (dashed line, circles). Adapted from Zwart et al. 

[756]. 

The results above, showing that the ratio of animal protein to potassium intake was less 

related to bone metabolism markers in the exercising group and more related to bone markers 

at the end of bed rest, when calcium excretion was highest, support the argument 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 have a more detrimental effect on bone, similar 

to what has been observed in other studies of the effect of high-protein diets on bone [126, 

127]. 

The idea that the levels of acid and base precursors in the diet can affect bone and 

calcium metabolism is supported by the results of studies testing the ability of a supplement 

containing essential amino acids and carbohydrate (45 g/d essential amino acids and 90 g/d 

sucrose) to mitigate muscle loss [757]. The supplement contained 1.5 g methionine, which is 

about 1.13 times the recommended daily intake (supplementing the amount of methionine 

provided in the diet). The sulfur in methionine is converted in the body to sulfuric acid, and 

thus methionine is an acid precursor in the diet. It was evident that more methionine was 

broken down than was used by the body because urine pH decreased in the amino acid-
Food, Energy and Macronutrients 35

supplemented group (Figure 23). It was hypothesized that this low-grade metabolic acidosis 

[708] contributed to the higher urinary concentrations of bone resorption markers (Figure 24) 

and calcium excretion (Figure 25) in the supplemented group. 

Pre Wk 1 Wk 2 Wk 3 Wk 4

5.5

6.0

6.5

7.0

7.5

* * *

#

Urine pH

Figure 23. Urine pH (mean ± SD) of amino acid-supplemented (■) and placebo (○) groups during 4 

weeks of bed rest. *Significantly different from before bed rest (Pre), P < 0.05. #

Significant difference 

between groups, P < 0.05. Figure is from Zwart et al., J Appl Physiol 2005 [757]. 

Pre Wk 1 Wk 2 Wk 3 Wk 4

0

350

700

1050

1400 * * * *

Urinary NTX (nmol/d)

Figure 24. Urinary n-telopeptide (NTX) excretion (mean ± SD) of amino acid-supplemented (■) and 

placebo (○) groups during 4 weeks of bed rest. *Significantly different from before bed rest, P < 0.05 

(no significant differences between groups). Figure is from Zwart et al., J Appl Physiol 2005 [757]. 

Pre Wk 1 Wk 2 Wk 3 Wk 4

0

5

10

15

#

# # #

Urinary calcium (mmol/d)

Figure 25. Urinary calcium excretion (mean ± SD) of amino acid-supplemented (AA, ■) and placebo 

(○) groups during 4 weeks of bed rest. #

AA values were significantly different from pre-bed rest values, 

P < 0.05. Figure is from Zwart et al., J Appl Physiol 2005 [757]. 
36 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

In a separate study, 13 volunteers were subjected to 60 to 90 days of 6o head-down-tilt 

bed rest [761]. Net acid excretion, as determined by dietary acid and base components, was 

positively correlated with NTX during but not before bed rest (Zwart et al., unpublished data). 

Net acid excretion has also been associated with calcium loss using meta-analysis techniques 

[164]. 

6. Dietary Intake and Requirements 

Maintaining a proper protein intake is vital, as both low-protein and high-protein diets 

can cause harm (and, at the extreme, death). A low-protein diet (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 [307, 308]. The impact of 

chronically low protein intake is not well understood; however, several studies suggest that 

low-protein diets are associated with loss of bone density [187, 520]. 

The current documented space flight requirement for protein intake is 0.8 g/kg per day, 

not to exceed 35% of the total daily energy intake [460]. About 2/3 of the total amount of 

protein is to be provided in the form of animal protein, and 1/3 of the total should be in the 

form of vegetable protein. In the U.S., the recommended dietary allowances (RDAs) for those 

in the age range of the astronaut population are 56 g/d for men and 46 g/d for women [279]. 

The acceptable range for protein intake is 10% to 35% of total energy intake [279]. For 

historical reference, the space flight daily protein requirements were defined in 1991 for 

missions of 30 to 120 days, and were defined similarly in 1995 for missions up to 360 days as 

10% to 15% of total energy intake [457, 458]. 

Actual intakes of protein typically exceed these recommendations, as shown in Table 2 

(page 15). European studies have shown that on long missions reaching (or exceeding) 

nominal protein intakes is common, but that on short flights (Shuttle missions) protein intake 

is less than the recommended amount because of insufficient food intake [242]. 

7. Risks on Exploration Missions 

The risks associated with protein intake come from deficiency or excess. 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. Low-protein diets can have 

negative consequences for bone [307, 309-311]. Excess protein exacerbates increased 

excretion of calcium and the risk of renal stone formation, and is detrimental to bone. Specific 

amino acids may additionally increase these risks. 

8. Remaining Questions 

Research continues on the effects of amino-acid supplementation as a means to mitigate 

muscle loss. This needs to continue in order to refine the details (such as dose and timing) and 

assess the viability of this countermeasure. 
Food, Energy and Macronutrients 37

Further research is also required to better understand the effects of protein source (animal 

vs. vegetable, and the effect of sulfur amino acid content) on bone loss and renal stone risk 

[460, 758]. The concept of using these effects as nutritional countermeasures has long been 

advocated [171], but it has yet to be evaluated. 

C. CARBOHYDRATE

1. Background 

Carbohydrates play an important role in the body because they supply the primary source 

of energy as well as a readily available source. This energy is oxidized and used by various 

organs and cells in the body, particularly the brain and red blood cells, which depend solely 

on carbohydrate for energy. 

Dietary carbohydrates are classified into a number of different categories, all based on the 

number of sugar units present. Monosaccharides are composed of only 1 sugar unit, such as 

glucose or fructose. Disaccharides are composed of 2 sugar units; examples are sucrose 

(glucose + fructose) and lactose (glucose + galactose). Longer chains of sugar units, up to 10, 

are known as oligosaccharides, and polysaccharides contain more than 10 sugar units. 

Examples of polysaccharides are starch and glycogen, which are the storage forms of 

carbohydrate for plants and animals, respectively. 

The human body stores about 150 to 500 g of carbohydrate as glycogen, in the liver and 

skeletal muscle [388]. Most of the body’s glycogen is in skeletal muscle. Muscle glycogen 

stores 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 [650]. Liver stores of glycogen are depleted after 12 

to 18 hours of fasting [388]. In skeletal muscle, glycogen synthesis is triggered by a rise in 

insulin after the consumption of carbohydrates. De novo synthesis of glucose from 

noncarbohydrate precursors can and does occur in the body, if needed. This allows 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 utilize 

glucose. 

As long as the intake of protein and fat is adequate, the lower limit of dietary 

carbohydrate that is compatible with life is zero. The level of carbohydrate required to 

provide optimal health is not as clearly defined. 

2. Findings from Space Flight and Ground-Based Research 

Carbohydrate should make up the most significant portion of the diet because it is the 

main energy source. Requirements for carbohydrate in space are thought to be similar to those 

on Earth. However, to date, few investigations have been conducted on the effects of 

microgravity on the metabolism of dietary carbohydrate, and those studies have had 

conflicting results. 
38 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

Early studies documented increases in blood concentrations of both insulin and glucose at 

landing after Apollo (Figure 26) and Skylab (Figure 27, Figure 28) flights. 

Preflight Postflight

0

5

10

15

20

25

90

95

100

105

110

115

Insulin

Glucose

+32%

+10%

Insulin (

μU/mL)

Glucose (mg/dL)

Figure 26. Plasma insulin (n = 22) and glucose (n = 33) in Apollo crewmembers before and after flight. 

Data are from Leach et al., 1975 [366]. 

Preflight

FD3/4FD5/6

FD13/14FD20/21FD27/30

FD38

FD45/48FD58/59

FD73FD82

R+0R+1

R+3/4

R+14

70

80

90

100

110

Plasma glucose (mg %)

Figure 27. Plasma glucose in Skylab crewmembers (n = 9) before, during, and after flight. Data are 

from Leach and Rambaut, 1977 [361] . 

Preflight

FD3/4FD5/6

FD13/14FD20/21FD27/30

FD38

FD45/48FD58/59

FD73FD82

R+0R+1

R+3/4

R+14

0

10

20

30

Insulin (μU/mL)

Figure 28. Plasma insulin in Skylab crewmembers (n = 9) before, during, and after flight. Data are from 

Leach and Rambaut, 1977 [361]. 
Food, Energy and Macronutrients 39

On the Shuttle, studies by German investigators showed no impact of 7 days of flight on 

glucose tolerance tests [406]. Additionally, 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 [6, 592]. Insulin resistance (lack of 

sensitivity to insulin) has been found to result from simulated weightlessness (bed rest) [49, 

56, 648, 696]. Using C-peptide excretion as a proxy, Stein et al. found evidence of insulin 

resistance during actual and simulated spaceflight [624]. Efforts to maintain muscle mass 

(and presumably correct the insulin resistance) continue, but little research has been done to 

pursue this as a nutritional issue. 

3. Dietary Intake and Requirements 

The current documented requirement for carbohydrate intake during space flight is 50% 

to 55% of the total daily energy intake. In the U.S., the acceptable macronutrient distribution 

range for dietary carbohydrate is defined as 45% to 65% of the total dietary energy intake 

[558]. A minimum intake of 140 g/d is required to maintain the needs of organs that require 

carbohydrate for energy production [408]. For reference, the daily carbohydrate requirement 

for male and female astronauts was originally defined in 1991 for missions of 30 to 120 days 

as 50% of total energy intake [457], and in 1995 for missions up to 360 days as 50% to 55% 

of total energy intake [458]. The 1995 requirement included an admonition that most of the 

carbohydrate should be provided as complex carbohydrates, with less than 10% of total 

carbohydrate provided as simple sugars. 

Macronutrient intake by space crews is relatively high in protein and carbohydrate 

content (close to 60% of calories) [350], as shown in Table 2 on page 15. Some have 

speculated that this may represent a shift in macronutrient preferences, but it may also simply 

be related to the high sugar content of many of the available beverages in the U.S. food 

supply [346]. 

4. Risks on Exploration Missions 

Suboptimal carbohydrate intake before and during space flight may have consequences 

for the crew’s productivity and impede their ability to respond in emergency situations [345]. 

Deficiency of carbohydrate leads to ketosis. A ketotic state would likely impair performance 

of crewmembers, as seen in studies conducted by the military [507], as well as increase renal 

stone risk secondary to reduced urinary pH [508, 509, 751]. Other aspects of the mission 

would also be at risk (for example, the life-support systems may not be able to remove 

exhaled ketones from the air). Toxicity of carbohydrate has not been well studied, and would 

likely be an issue only because it would displace other nutrients (protein and fat) from the 

diet. 
40 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

5. Remaining Questions 

Few data are currently available to assess the impact of space flight on carbohydrate 

metabolism. Observations from space flight as well as ground-based bed rest studies show 

subtle changes in insulin secretion, insulin resistance, and glucose intolerance [142, 393, 648, 

696]. Even subtle changes in such important metabolic processes make it critically important 

to consider the likelihood, nature, and consequences of altered carbohydrate and insulin 

metabolism for exploration missions. 

D. DIETARY FIBER

1. Background 

Dietary fiber consists of nondigestible food components that are typically carbohydrate 

and plant-based. Nonstarch polysaccharides, including cellulose, gums, pectins, mixedlinkage β-glucans, and hemicelluloses, are the major components of dietary fiber. Lignan is 

also included even though it is a noncarbohydrate component. 

Evidence exists that dietary fiber plays a role in decreasing plasma cholesterol, modifying 

the response of blood glucose to food (the glycemic response), improving large-bowel 

function, and decreasing the bioavailability of some nutrients. Epidemiological evidence also 

points to relationships between diets high in fiber and decreased incidence of cardiovascular 

disease and bowel cancer [287]. 

2. Findings from Space Flight and Ground-Based Research 

Changes in gastrointestinal function and gut transit time during space flight have been 

described. Because mouth-to-cecum transit times are slower on orbit [345], adequate dietary 

fiber will be essential to maintain gastrointestinal function and decrease the incidence of 

constipation. 

3. Dietary Intake and Requirements 

The current documented requirement for dietary fiber intake in space flight is 10 to 14 

g/1000 kcal. In the U.S., acceptable daily requirements for dietary fiber intake [279] are, for 

those aged 19 to 50 years, 38 g/d for men and 25 g/d for women, and for individuals aged 51 

to 70 years, 30 g/d for men and 21 g/d for women. 

For reference, the daily total fiber requirements for male and female astronauts were 

defined in 1991 for missions of 30 to 120 days as 10 to 15 g, in soluble and insoluble forms 

[457], and in 1995 for missions up to 360 days as 10 to 25 g, in soluble and insoluble forms 

[458]. 
Food, Energy and Macronutrients 41

4. Risks on Exploration Missions 

Inadequate dietary fiber, in combination with low fluid intake, may lead to constipation. 

An open question exists about the effect of fiber on vitamin K synthesis by colon microflora 

(and its availability) during space flight (see vitamin K section). 

5. Remaining Questions 

Several studies have shown that specific dietary fatty acids and types of dietary fiber can 

reduce animals’ risk of getting radiation-induced cancer [122, 682]. Further research is 

warranted to investigate the potential protective effects of fiber on the risk of radiationinduced cancer in humans exposed to high-linear energy transfer radiation during space flight. 

E. FAT

1. Background 

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 3 fatty acids attached. Many types of fatty acid exist, 

including saturated, monounsaturated, polyunsaturated, and trans. Dietary fat assists in the 

absorption of fat-soluble vitamins and supplies the body with the 2 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. 

Body stores of fat are located mainly in adipose tissue as triacylglycerols. Adipose tissue 

is dispersed throughout the human body, its distribution differing slightly between genders. 

According to case studies, people following fat-free diets can exhibit symptoms of 

essential fatty acid deficiencies after only 1 month. An infant consuming fat-free total 

parenteral nutrition for 3 months developed skin lesions and had polyunsaturated fatty acid 

levels less than 10% of control values [501]. In another study, an adult who consumed fat-free 

total parenteral nutrition for 7 months developed a severe dermatitis by the end of the first 

month. Omega-3 (n-3) fatty acids made up 0.01% of the fatty acids of this person’s plasma 

phospholipids, which means that the patient was almost completely depleted of n-3 fatty acids 

[266]. 
42 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

2. Findings from Space Flight and Ground-Based Research 

While few, if any, studies have been conducted to look at dietary fat, plasma lipid levels, 

and related factors in space flight, voluminous data exist from routine medical examinations 

conducted before and after flight, along with annual medical exams (Figure 29, Figure 30, 

Figure 31). 

Skylab

Preflight

R+0R+1

R+3/4

R+14

60

80

100

120

140

160

Triglycerides (mg %)

Figure 29. Plasma triglycerides in Skylab crewmembers (n = 9) before and after flight. Data are from 

Leach and Rambaut, 1977 [361]. 

Preflight Postflight 0

20

40

60

80

100

Landing day collection

>2mo postflight collection

HDL (mg/dL)

Figure 30. Serum high-density lipoproteins (HDL) in ISS crewmembers (n = 12) before and after flight. 

Postflight data are from landing day or 2 to 12 months after flight. Because HDL is not a routine 

measurement at landing, some data were available only at the next medical exam. 

Preflight Postflight

80

100

120

140

160

Landing day collection

>2mo postflight collection

LDL (mg/dL)

Figure 31. Serum low-density lipoprotein (LDL) in ISS crewmembers (n = 12) before and after flight. 

Postflight data are from landing day or 2 to 12 months after flight. Because LDL is not a routine 

measurement at landing, some data were available only at the next medical exam. 
Food, Energy and Macronutrients 43

Contrary to the typical lipoprotein response to weight loss, low-density lipoprotein (LDL) 

concentrations tended to increase in long-duration crewmembers who lost weight during the 

flight. This relationship seemed to return to normal by the subsequent medical exam 

(according to available data, 50 to 257 days after landing) (Figure 32). 

-12.5 -10.0 -7.5 -5.0 -2.5 0.0 2.5 5.0 7.5

-35

-30

-25

-20

-15

-10

-5

0

5

10

15

20

25

30

35

R+50-257

R+0

BW (%Δ from preflight)

LDL (%

Δ from preflight)

Figure 32. Relationship between the loss of body mass observed after landing and the change in serum 

LDL in ISS crewmembers (n = 12). Because LDL is not a routine measurement at landing, some data 

were available only at the next medical exam, which ranged from 50 to 257 days after landing. 

Bed rest studies have documented alterations in fuel homeostasis, including gender 

differences [56]. Specifically, lipogenesis was increased during bed rest, to a greater extent in 

women than in men. Additionally, men had increased carbohydrate oxidation [56]. Given 

these data, and the insulin, leptin, and other endocrine changes noted in bed rest and space 

flight [409, 630, 631], changes in fuel homeostasis in bed rest clearly warrant additional 

investigation. 

3. Dietary Intake and Requirements 

The current documented space flight requirement is for dietary intake of fat to make up 

25% to 35% of the total daily energy intake [460]. Dietary intake of n-6 and n-3 fatty acids is 

to be 14 g/d and 1.1 to 1.6 g/d, respectively. Saturated fat should be < 7% of total calories, 

trans fatty acids < 1% of calories, and cholesterol intake < 300 mg per day. In the U.S., 

currently no RDA or adequate intake level has been set for total fat because data are 

insufficient to determine the level of dietary fat that may put one at risk for inadequacy or 

may contribute to the prevention of chronic disease [279]. The acceptable distribution range 

for fat intake is 20% to 35% of total energy intake [279]. For reference, the daily total fat 

requirement for male and female astronauts was defined in 1991 for missions of 30 to 120 

days to be 30% to 35% of total energy intake [457], and in 1995 for missions up to 360 days 

to be 30% to 35% of total energy intake [458]. 

Actual in-flight intakes of total fat are typically 25% to 30% of calories, as shown in 

Table 2 (page 20). Intake of specific types of fat has yet to be documented during flight. 
44 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

4. Risks on Exploration Missions 

Deficiency of fat leads to essential fatty acid deficiency and ultimately death. Toxic 

levels of fat lead to high serum cholesterol, obesity, atherosclerotic plaques, and ultimately 

coronary heart disease, and ultimately death. 

5. Remaining Questions 

Alterations in fuel homeostasis and regulatory hormones have been noted in space flight 

and ground-based studies. The implications of these findings in long-duration exposures are 

not well understood. 

The role of n-3 fatty acids in cancer prevention is currently being investigated in animal 

models of space flight radiation effects [122]. Not only do n-3 fatty acids (in combination 

with pectin) show promise in alleviating cancer risk [94, 122, 267, 557, 682], but these fatty 

acids also have well-documented cardiovascular benefits. Abundant data show that 

eicosapentaenoic acid can successfully prevent muscle atrophy in other muscle-wasting 

circumstances, such as cancer or sepsis [40, 595, 672-675, 727, 728, 732, 733], indicating the 

likelihood is high that eicosapentaenoic acid will have the same beneficial effects on muscle 

atrophy during space flight or in ground-based analogs including bed rest. Thus, further 

research on eicosapentaenoic acid is warranted. 

Recent preliminary analysis of data from bed rest studies has revealed a negative 

correlation between n-3 fatty acids and bone loss during bed rest. Although this is still being 

evaluated, it provides additional evidence of the importance of evaluating fish oils as a 

countermeasure for muscle, bone, and radiation risks of space flight. 

F. FLUID

1. Background 

Adequate fluid intake is necessary to maintain the body’s normal hemodynamic state and 

normal fluid osmolality, which is 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 may be lost from the body by 

a variety of routes and for a variety of reasons. They are excreted in sweat, urine, and feces, 

and in abnormal situations excessive amounts can be lost by these routes and others. 

Significant losses may occur through the gastrointestinal tract as a result of diarrhea, 

vomiting, or gastric drainage. Loss through the skin increases with fever, increased 

metabolism, sweating, and burns [485]. 

Total body water makes up about 50% to 70% of body mass [561]. Fluid requirements 

increase with metabolic rate and heat stress. Death from dehydration can occur within weeks 

of depriving the body of all water [655]. 
Food, Energy and Macronutrients 45

2. Findings from Space Flight and Ground-Based Research 

Fluid and electrolyte homeostasis is significantly altered during space flight, and this has 

been extensively reviewed [130, 145, 146, 365, 367, 368, 370, 371, 373, 601]. The hypothesis 

originally proposed to explain this was that upon entering weightlessness, the human body 

would experience a headward shift of fluids, with subsequent diuresis and dehydration. A 

series of flight experiments was conducted to assess fluid and electrolyte homeostasis during 

space flight; 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 

space flight [145, 198, 365, 480, 481, 601]. 

Within hours of the onset of weightlessness (the earliest available data point), a reduction 

in both plasma volume and extracellular fluid volume had occurred, accompanied by the 

“puffy” faces typically observed early in flight [365, 468]. Initially, the decrement in plasma 

volume (~17%) was larger than the decrement in extracellular fluid volume (~10%), 

suggesting that interstitial fluid volume (the other four-fifths of extracellular fluid) is 

conserved proportionally more than plasma volume [365]. The idea that interstitial fluid 

volume is conserved is supported by rapid decreases in total circulating protein, specifically 

albumin [365], indicating that protein, and associated oncotic pressure, shifted from the 

intravascular to the extravascular space. This would have facilitated the initial changes in 

plasma volume [365]. 

Following the initial adaptation, extracellular fluid volume further decreased 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 [365]. Plasma volume was partially restored during this 

period, from the initial ~17% below preflight levels to ~11% below preflight levels [365], and 

it has been found to remain 10% to 15% below preflight levels even for extended-duration 

flights [290]. 

It is 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, with a loss of oncotic force and a resulting decreased 

extracellular fluid volume and increased plasma volume [365, 481]. This loss of extracellular 

protein (intra- and extravascular) and the associated decreased oncotic potential probably play 

a role in postflight orthostatic intolerance, which has been considered to result partly from 

reduced plasma volume at landing [77]. Furthermore, the loss of protein may in part explain 

why fluid loading alone does not restore circulatory volume [274, 698], as no additional 

solute load exists to maintain the fluid volume. Another potential (or perhaps partial) 

explanation for the failure of fluid loading is that because astronauts’ diets are high in sodium, 

additional salt cannot help increase plasma volume or extracellular fluid volume. This has 

been documented in bed rest [Heer et al., 2009]. 

The effect of space flight on total body water has been evaluated to assess hydration. 

Shuttle and Skylab astronauts had decreases of about 1% in total body water during flight 

[364, 365, 665], and the percentage of body mass represented by water did not change. Thus, 

the often-proposed weightlessness-induced dehydration does not exist. This has also been 

shown by European investigators on Shuttle and Mir missions [144, 145, 480-482]. 

Diuresis is also typically not observed during flight [32, 144, 196, 197, 291, 373, 480, 

481, 601], for a number of possible reasons. Operational constraints have made it difficult to 
46 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

document urine volume accurately on the first day of space flight. 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 [365]. Urine volumes on a week-long flight to Mir were also less than preflight 

volumes [196]. During the first week of the 59- and 84-d Skylab flights [361], urine volume 

was less than it was before flight, and for the remainder of the missions it was unchanged 

from preflight levels. Decreased fluid intake likely accounts 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 [226, 729-731]. 

As mentioned above, the percent of body mass represented by total body water is 

relatively unchanged during flight [365]. However, on a volume basis, the change in 

extracellular fluid volume was found to be greater than the change (or lack of change) in total 

body water [365]. Thus, by difference, intracellular fluid volume increased during space 

flight. This had been previously hypothesized from ground-based studies [211] and observed 

in postflight studies of Apollo crewmembers [291]. The mechanism for a space flight-induced 

increase in intracellular fluid volume is unknown. One possible explanation is that a shift in 

fuel utilization results in increased glycogen storage, a condition known to increase cellular 

water content. 

Diuresis has been documented to occur in bed rest studies [478, 479, 697]. Urinary 

albumin, a marker of kidney function, has been shown to be reduced in both space flight 

(compared to before flight) and bed rest (compared to the ambulatory state) [100-102]. 

However, space flight, but not bed rest, results in reduced urine flow rates [480]. Taken 

together, these data suggest that differences in fluid metabolism exist between analog studies 

and actual space flight [145, 197, 198, 478, 480-482]. Such differences do not seem to be a 

simple effect of abnormal renal function, and thus require further investigation [533]. 

3. Dietary Intake and Requirements 

In the U.S., the recommended total intake of water (including that contained in food, 

beverages, and drinking water) is 3.7 L/d for men (19 years and older), and 2.7 L/d for 

women (19 years and older) [280]. This is considered “adequate intake.” Since 1991 [457, 

458], the space flight requirement for fluid has been 1 to 1.5 mL/kcal, with a minimum intake 

of 2000 mL/d. Actual fluid intakes meet this minimum (> 2 L) requirement on average, but 

every crewmember does not meet it every day, as shown in Table 2 (page 15). 

4. Risks on Exploration Missions 

Although no space flight-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. In closed flight vehicles, water is 

often a limiting resource, but rationing of water should be avoided. 
Food, Energy and Macronutrients 47

Deficiency of fluid leads to dehydration and ultimately death. Likewise, an excess of 

fluid intake leads to water intoxication and ultimately death. Obviously, the risk of this 

occurring during space flight, where water is a limited commodity, is extremely low. 

5. Remaining Questions 

Decreased fluid intake during space flight may be a consequence of reduced thirst during 

flight [345], but the reason for reduced thirst is unknown. 

Studies described above have documented that total body water is unchanged during 

flight, but apparently a shift of fluid from the extracellular to the intracellular compartment 

occurs. The effect of this on cell size and cell function (such as the effect of a change in the 

density of receptors on cell membranes) has not been evaluated. This might be responsible for 

some of the microgravity-induced changes noted in other systems (such as the endocrine, 

cardiovascular, and immune systems). 

G. SODIUM AND CHLORIDE

1. Background 

Sodium is the major cation of extracellular fluid [485]. Together with chloride, sodium is 

utilized by the body to maintain normal water distribution, osmotic pressure, and anion-cation 

balance in the extracellular fluid compartment [669]. Electrolyte concentrations in the body 

are essential for proper cardiovascular function and are under renal and hormonal control 

[516]. 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 percent of total sodium resides in bone, with the balance found 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 [512]. Exchangeable sodium becomes available by 

diffusion when plasma sodium levels become low, and 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 [405]. During acute starvation, urinary sodium excretion decreases 

to less than 0.2 g within 10 days [45], and can be affected by the amount of sweat [313]. 

Plasma sodium levels are maintained fairly well during acute starvation: an initial decrease is 

followed by a return toward normal values [193]. Maintenance of blood sodium is also 

observed 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) [313]. 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 [313]. 
48 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

2. Findings from Space Flight and Ground-Based Research 

Pre-, in-, and postflight plasma sodium and chloride data are available from Apollo 

(Figure 33, Figure 34), Skylab (Figure 35, Figure 36), and Shuttle (Figure 37) flights, and 

have been reviewed extensively [198, 239, 242, 481, 601]. 

Preflight Postflight 

0

50

100

150

Serum sodium (mEq/L)

Preflight Postflight

0

50

100

150

200

-49%

Urinary sodium (mEq/24 h)

Figure 33. Serum (n = 33) and urinary (n = 30) sodium from Apollo crewmembers. Numbers in bars 

represent the percent change from preflight values. Adapted from Leach et al., 1975 [366]. 

0

50

100

150

Preflight Postflight

Serum chloride (mEq/L)

0

50

100

150

200

Preflight Postflight

-61%

Urinary chloride (mEq/24 h)

Figure 34. Serum (n = 33) and urinary (n = 30) chloride from Apollo crewmembers. Numbers in bars 

represent the percent change from preflight values. Adapted from Leach et al., 1975 [366]. 

Preflight

FD3/4FD5/6

FD13/14FD20/21FD27/30

FD38

FD45/48FD58/59

FD73FD82

R+0R+1

R+3/4

R+14

125

130

135

140

145

150

Plasma sodium (mEq/L)

Figure 35. Plasma sodium of Skylab crewmembers (n = 9) before, during, and after flight. Data are 

from Leach and Rambaut, 1977 [361]. 
Food, Energy and Macronutrients 49

Preflight

FD3/4FD5/6

FD13/14FD20/21FD27/30

FD38

FD45/48FD58/59

FD73FD82

R+0R+1

R+3/4

R+14

85

90

95

100

105

Plasma chloride (mEq/L)

Figure 36. Plasma chloride of Skylab crewmembers (n = 9) before, during, and after flight. Data are 

from Leach and Rambaut, 1977 [361]. 

FD2 FD4 FD6 FD7 R+0 R+3 R+10 -10

-5

0

5

10

Serum sodium

(% Δ from preflight)

FD2 FD4 FD6 FD7 R+0 R+3 R+10 -10

-5

0

5

10

Serum chloride

(% Δ from preflight)

Figure 37. Serum sodium (left panel) and chloride (right panel) of Shuttle crewmembers (n = 2 to 6) 

during and after flight, expressed as a percent change from preflight values. Data are from LeachHuntoon et al., 1987 [359]. 

In-flight sodium intakes (Figure 38) during Skylab and Shuttle missions averaged 4 to 5 

g, and were similar to the astronauts’ preflight intakes [62]. The current food system is high in 

dietary sodium, and typical intakes on the ISS have been in excess of 4.5 g, even with 

suboptimal food intake [610]. Intakes as high as 7 to 10 g of sodium per day have been 

observed. Sodium homeostasis and blood sodium levels are maintained during real and 

simulated space flight [352], but the high sodium content of the current space food system 

makes it important to monitor and restrict dietary sodium intake of astronauts to maintain 

their bone and renal health. 

Apollo Skylab Shuttle Mir ISS

0

1000

2000

3000

4000

5000

6000

7000

mg

Figure 38. In-flight dietary sodium intake (mg/d) across space programs. Apollo n = 33, Skylab n = 9, 

Shuttle n = 32, Mir n = 7, ISS n = 23. Apollo and Skylab data are from Bourland et al., 2000 [62]. 

Figure is adapted from Smith and Lane, 2008 [611], with additional data from Smith et al., 2005, and 

Smith and Zwart, 2008 [610, 612]. 
50 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

European studies with Mir crewmembers documented positive sodium balance during 

space flight, in a non-osmotic fashion (that is, without a concomitant increase in fluid 

compartments) [198, 242, 481]. These data were confirmed in a series of ground-based 

studies, documenting an increase in mRNA expression of some of the enzymes required for 

glycosaminoglycan syntheses in the skin, the displacement of sodium by hydrogen in the 

glycosaminoglycans, and a subsequent acidosis [248]. 

On Earth, excessive sodium intake has been associated with increased bone turnover 

[155, 207, 208]. Dietary sodium is known to affect calcium homeostasis [92, 107, 238, 259, 

472, 474]. 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 [318]. This 

phenomenon is expressed at high levels of dietary sodium. 

Over 90% of dietary sodium is absorbed, even when intake is high [240]. Sodium is 

excreted mostly in the urine, but about two-thirds of the sodium filtered by the kidney is 

reabsorbed by mechanisms thought to involve solvent drag and electrochemical gradients. 

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, and 

ultimately leads to increased calcium loss secondary to increased sodium excretion. In the 

distal tubule, calcium is preferentially reabsorbed, an event stimulated by parathyroid 

hormone (PTH) and cyclic adenosine monophosphate (cAMP) [3]. Cyclic AMP also 

influences reabsorption of sodium [110]. 

A small amount of sodium is excreted in feces. When 500 mmol sodium was ingested 

each day for 7 days, the average fecal excretion was 1.8 ± 0.4% of the total dose, and when 

smaller amounts of sodium were ingested (50 mmol/d), an average of 6.0 ± 1.0% was 

excreted in the feces (Figure 39). 

0 1 2 3 4 5 6 7 8

0

5

10

15

** **

++ ++

Time (d)

Sodium in feces (mmol/d)

Figure 39. Fecal sodium excretion in 4 groups with different sodium intake (∆: 50 mmol NaCl/d; □: 200 

mmol NaCl/d; ○: 400 mmol NaCl/d; ■: 550 mmol NaCl/d). Values are mean ± SEM (n = 8). Fecal 

sodium excretion increased significantly with increasing sodium intake. **Significantly different from 

the 50 mmol NaCl/d group. ++Significantly different from the 200 mmol NaCl/d group (P < 0.01). 

Adapted from Heer, 1996 [240]. 

Salt loading alone increases intestinal calcium absorption. In hypoparathyroid patients, 

dietary salt increased intestinal calcium absorption in one study by Meyer [427] but not in 

another study by Breslau [69]. In Breslau’s study, calcium absorption correlated with serum 

1,25-dihydroxyvitamin D. Thus, conclusions about the role of PTH in the increase in 

intestinal calcium absorption after a sodium load are speculative. 
Food, Energy and Macronutrients 51

Studies in premenopausal women suggest that increased intestinal calcium absorption, 

rather than increased bone resorption, compensates for sodium-induced hypercalciuria in 

subjects whose adaptive processes related to bone metabolism are intact [201, 392]. Ginty et 

al. [201] examined the effects of 7 days of high or low dietary sodium on bone markers in 

young women. Although urinary calcium was increased with high (180 mmol/d) sodium 

intakes, the effect of high sodium on markers of bone resorption was not different from the 

effect of low (80 mmol/d) sodium intakes. Lietz et al. [392] also found no effect of intakes of 

170 mmol/d or 60 mmol/d of sodium for 8 days on bone resorption markers in 

postmenopausal women. However, Evans et al. [155] reported that postmenopausal women 

ingesting 300 mmol sodium per day for 7 days had greater excretion of bone resorption 

markers than those ingesting 50 mmol sodium per day. These differences were not observed 

in a premenopausal group [155]. 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. 

Data from human and animal studies suggest that high dietary sodium chloride leads to 

bone loss due to increased bone resorption [54, 227-229, 419, 420, 573], and even that 

restriction of dietary sodium will reduce bone resorption [475]. In a review of the interactions 

between dietary salt, calcium, and bone, Massey and Whiting [420] suggested that habitual 

excessive salt intake contributes to bone loss. Other reviewers have come to the conclusion 

that increased dietary sodium chloride intake negatively affects acid-base balance, with 

subsequent loss of calcium [132, 184]. 

Massey and Whiting [420] found that the effect of excessive salt intake on bone loss is 

modulated in specific subpopulations. For example, people who tend to form renal calcium 

stones are more responsive to changes in dietary salt than are non-stone formers. Although 

sodium intakes of stone formers are typically similar to those of controls [163, 679], the 

detrimental effects of high sodium intakes on renal stone risk have been well documented [54, 

132, 573]. Increasing sodium intake 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 [554]. 

Work by Goulding [207, 208] and Matkovic [421] has generated interest in the effect of 

dietary sodium on 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 [134]. Work by Dr. Heer’s group has 

also documented the resorptive response to high dietary sodium, and the role of acid-base 

balance in this process [188]. 

Dietary sodium also seems to exacerbate the calciuric responses to musculoskeletal 

unloading in weightlessness. Bed rest subjects consuming a low-sodium diet (100 mmol/d) 

had no change in urinary calcium, while those on a high-sodium diet (190 mmol/d) had 

hypercalciuria [23]. A more recent bed rest study by Heer et al. documented that the highsodium-induced increase in bone resorption exceeded the bed rest-induced increase, through a 

mechanism mediated by acid-base balance [188-190]. A symposium was held recently in 

Germany (and proceedings published in 2008) regarding the impact of acid-base balance on 

health issues [708], including the role of sodium in bone loss [24, 78, 185]. 
52 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

3. Dietary Intake and Requirements 

In the U.S., the recommendation for adequate intake of sodium for men and women ages 

19 to 50 years is 1.5 g/d, and for men and women ages 51 to 70 years it is 1.3 g/d [280]. The 

current documented space flight requirement for dietary sodium is 1500 to 2300 mg/d (1.5 to 

2.3 g/d) for both women and men. The ISS sodium requirement was slightly higher at 3500 

mg [458] (Table 1), although typical intakes exceeded this (Table 2). 

4. Risks on Exploration Missions 

High sodium intakes in flight can exacerbate bone loss and lead to increased risk of renal 

stone formation. In and of itself, excess sodium can lead to hypernatremia, hypertension, and 

even death. Although it has not been a concern to date, too little sodium or a deficiency of this 

electrolyte during flight could lead to hyponatremia, hypotension, and even death. 

5. Remaining Questions 

Further research is required to investigate potential effects of high sodium intake during 

space flight, since the space food system currently has very high sodium levels. The impact of 

high sodium intake on bone, calcium, and pH is not well understood, and 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. This may prove to be an 

area where nutrition and cardiovascular effects of space flight may interact, and study of the 

interaction may produce a dietary countermeasure. 

H. POTASSIUM

1. Background 

As the major intracellular cation, potassium has a significant role in several physiological 

processes [516]. It is crucial to regulation of acid-base balance, energy metabolism, blood 

pressure, membrane transport, and fluid distribution within the body. It is also involved in the 

transmission of nerve impulses and cardiac function [320]. Potassium metabolism that is 

disordered because of excessive or deficient circulating levels has negative consequences for 

cardiac, muscle, and neurological function. 

Total body potassium averages 45 mmol/kg body weight, totaling about 3150 mmol 

(1230 g) of potassium in a reference 70-kg person. Two percent of body potassium (~60 

mmol) is distributed in the extracellular fluid, and intracellular fluid levels are typically 

maintained at 140 to 150 mmol/L). 

Potassium levels cannot be maintained at intakes under 10 to 20 mmol/d [505]. Moderate 

depletion of potassium in humans is associated with clinically significant impaired active 

relaxation of the left ventricle [621]. In the referenced study, healthy adults were placed on a 
Food, Energy and Macronutrients 53

potassium-depletion diet for 7 days. At the end of that time, isovolumic relaxation time and 

deceleration time of flow through the mitral valve were significantly increased. 

Deficiency of potassium leads to hypokalemia, muscle weakness, constipation, and 

fatigue, or even death. There is no evidence of adverse effects associated with toxicity of 

potassium from naturally occurring sources. However, supplemental intake may cause 

hyperkalemia (and associated weakness, cardiac arrest, and paralysis), metabolic acidosis 

[708], decreased neuromuscular function, or even death. 

2. Findings from Space Flight and Ground-Based Research 

Serum and urinary levels of potassium were both decreased after space flight on Apollo 

(Figure 40) [366], and there is evidence of a similar decrease on Skylab [361]. 

Preflight Postflight

0

1

2

3

4

5

-7.3%

Serum potassium (mEq/L)

Preflight Postflight

0

20

40

60

80

100

-47%

Urinary potassium (mEq/24 h)

Figure 40. Serum (n = 33) and urinary (n = 30) potassium of Apollo crewmembers. Numbers in bars 

represent the percent change from preflight values. Adapted from Leach et al., 1975 [366]. 

Potassium loss (both total body potassium and exchangeable potassium) was observed in 

Apollo crewmembers (Figure 41) [366]. Increased levels of urinary potassium during space 

flight may be related to muscle disuse atrophy and inadequate intake [352]. In the initial days 

of bed rest, excess dietary sodium was shown to be potassium-depleting (Heer et al., 

unpublished observations). 

24 48

-20

-15

-10

-5

0

5

Apollo 15

Apollo 16

Apollo 17

Dilution time in hours

Mean %

Δ in total mEq potassium

Figure 41. Exchangeable potassium of Apollo 15, 16, and 17 crewmembers after flight, as the percent 

change from preflight values. Data are from Leach et al., 1975 [366]. 
54 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

Preflight

FD3/4FD5/6

FD13/14FD20/21FD27/30

FD38

FD45/48FD58/59

FD73FD82

R+0R+1

R+3/4

R+14

3.0

3.5

4.0

4.5

5.0

Plasma potassium (mEq/L)

Figure 42. Plasma potassium of Skylab crewmembers (n = 9) before, during, and after flight. Data are 

from Leach and Rambaut, 1977 [361] . 

FD2 FD4 FD6 FD7 R+0 R+3 R+10

-25

-15

-5

5

15

25

Serum potassium

(%

Δ from preflight)

Figure 43. Serum potassium of Shuttle crewmembers (n = 2-6) during and after flight, expressed as the 

percent change from preflight values. Data are from Leach-Huntoon et al. 1987 [359]. 

3. Dietary Intake and Requirements 

Dietary intake of potassium for long-duration ISS crewmembers is, on average, 3.2 g per 

day, which is lower than the recommended daily amount of 3.5 g for ISS crewmembers. The 

current documented space flight requirement for potassium is 4.7 g/d, the same as the U.S. 

recommendation for adequate intake of potassium for men and women 19 to 70 years [280]. 

The ISS potassium requirement was slightly lower at 3.5 g [458] (Table 1). 

4. Risks on Exploration Missions 

Loss of lean body mass, along with high sodium intake, may result in potassium 

depletion. As mentioned on page 52, the implications of potassium depletion for cardiac, 

musculoskeletal, and other systems are extremely serious. 
Food, Energy and Macronutrients 55

5. Remaining Questions 

The relationship between bone health and the protein:potassium ratio in the diet needs to 

be further investigated, along with the role of potassium in cardiovascular health during 

flight. 

VI. FAT-SOLUBLE VITAMINS

A. VITAMIN A 

1. Background 

Less concern is expressed about adequacy of fat-soluble vitamin intake than about intake 

of water-soluble vitamins because the body can store larger quantities of fat-soluble vitamins. 

However, recent findings about previously unknown functions of some of these vitamins, as 

well as unique aspects of space flight, provide specific challenges for maintaining optimum 

status of these nutrients. 

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, αcarotene, β-carotene, and retinyl palmitate. Trans-retinol is the primary biologically active 

form of vitamin A. Many carotenoids, including β-carotene, can be converted to trans-retinol 

and thus contribute to vitamin A activity. Collectively, these carotenoids are termed 

provitamin A carotenoids and they are measured in retinol equivalents (REs). 

Vitamin A is directly involved in vision, gene expression, reproduction, embryonic 

development, and immunity. Vitamin A and β-carotene serve as biological antioxidants and 

have been shown in multiple studies to reduce the risk of cancer and coronary heart disease 

[325, 693]. Vitamin A also plays a role, albeit sometimes indirectly, in the function of almost 

all of the body’s organs [490]. 

Vitamin A is stored mainly (80%) in the liver, with the remainder stored in peripheral 

organs and tissues. Total body stores range from 1.05 to 3.14 nmol (300 to 900 mg) in normal 

adults [618]. 

Liver stores of vitamin A are severely depleted when their content is less than 20 μg 

[549]. A study of vitamin A depletion in baboons found a 59% decrease in hepatic vitamin A 

after 4 months of a chronic ethanol diet [386]. After 24 to 48 months, the researchers found a 

95% decrease in hepatic vitamin A stores, accompanied by fibrosis and cirrhosis of the liver. 

Alcoholism is often associated with vitamin A deficiency because retinol and ethanol are 

competing substrates for the same enzymes [385]. 

Deficiency of vitamin A leads to xerophthalmia, loss of appetite, drying and 

keratinization of membranes, infection, or even death. Acute toxicity of vitamin A leads to 
58 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

nausea, vomiting, headache, blurred vision, and muscular incoordination. Chronic toxicity of 

vitamin A leads to rapid reduction in bone mineral density, liver abnormalities, or even death. 

2. Findings from Space Flight and Ground-Based Research 

There is a significant interaction between the effects of landing site and space flight on 

serum levels of both retinol and retinol-binding protein (Figure 44) [610]. Russian landings 

are different from U.S. landings in that blood samples are usually collected several hours later 

because of the logistics of the landing site. 

Preflight Postflight

0.0

0.5

1.0

1.5

2.0

2.5

Serum retinol (

μmol/L)

Preflight Postflight

0

20

40

60

80

Serum retinol-binding protein (mg/L)

Figure 44. Serum retinol (n = 23) and retinol-binding protein (n = 18) in ISS crewmembers before and 

after long-duration space flight. Data are from Smith et al., 2005 [610]. 

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 U.S. Similarly, retinol-binding protein decreased from 61.4 ± 5.6 to 50.92 ± 8.41 

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 U.S. 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 a difference in the stress response at different sites. These data, however, do 

not seem to provide clear evidence that there is a deficiency of any sort for vitamin A. 

3. Dietary Intake and Requirements 

In the U.S., the recommended dietary allowance for vitamin A is 900 μg RE/d for men 

aged 19 and older, and 700 μg RE/d for women aged 19 and older [181]. Upper limits also 

exist for vitamin A (3000 μg RE/d), and β-carotene supplementation is advised only in 

situations where there is a risk of vitamin A deficiency. The current documented space flight 

requirement for vitamin A intake is 700 to 900 μg/d. 
Fat-Soluble Vitamins 59

4. Risks on Exploration Missions 

Oxidative stress is increased during space flight, and this could affect cardiovascular 

health and cancer risk. Vitamin A status may play a critical role in maintaining antioxidant 

health during space flight. 

As with many antioxidants, the desire to supplement with high doses in the hope of 

staving off one disease is high, but 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 [284, 426, 429, 497]. 

5. Remaining Questions 

Vitamin A content and stability in the space food supply should be determined. The role 

of vitamin A as an antioxidant has not been investigated. 

B. VITAMIN D 

1. Background 

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. Typically the goldstandard measurement for determining vitamin D status (Figure 45), 25-hydroxyvitamin D is 

converted to 1,25-dihydroxyvitamin D in the kidney, and from there it is transported 

systemically to target organs. Classic target organs include bone, intestine, and kidney. 

In recent years, noncalcitropic functions of vitamin D have been identified [48, 237, 431, 

477, 713]. Although 1,25-dihydroxyvitamin D is the biologically active form for these 

pathways also, 25-hydroxyvitamin D must be available in sufficient quantities for the 

1-hydroxylase enzyme in nonrenal tissues to synthesize 1,25-dihydroxyvitamin D. Besides 

kidney cells, other cell types, including epithelial cells, monocytes, and antigen-presenting 

cells, also synthesize 1,25-dihydroxyvitamin D [257]. Numerous tissues are affected by 

vitamin D status because their cell nuclei contain receptors for 1,25-dihydroxyvitamin D [48]. 

Some of these tissues are adipose tissue, bone marrow, brain, breast, cancer cells, cartilage, 

lung, muscle, ovary, placenta, prostate, stomach, testis, thymus, and uterus [476]. 

It has been suggested that the newly discovered functions of vitamin D help elucidate the 

relationship between 25-hydroxyvitamin D levels and many chronic diseases not normally 

associated with its calcitropic functions, such as cancer, diabetes, and multiple sclerosis [220, 

230, 262, 265, 657]. Similarly, the noncalcitropic functions of vitamin D may help explain 

why a robust set of reproducible data shows an inverse correlation between sun exposure and 

several types of cancer [5, 209, 210]. 

People who are normally exposed to sunlight make vitamin D in their skin (Figure 45). 

Ultraviolet B light, a component of sunlight, converts 7-dehydrocholesterol to 25-

hydroxyvitamin D3 in the skin [263]. Although sunlight has a positive effect on health 
60 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

through its role in making vitamin D, caution must still be exercised to avoid too much sun 

exposure [199, 200, 445]. 

7,8-dehydrocholesterol pre-vitamin D3 vitamin D3 skin

25(OH)D

1,25(OH)2D 1,25(OH)2D

kidney prostate, breast, 

colon, immune 

cells, β cells, skin

liver

Endocrine 

actions

Intestinal Ca transport 

Bone metabolism 

Renal Ca reabsorption 

Blood pressure 

Autocrine/paracrine 

actions

Inhibition of cell proliferation 

Promotion of cell differentiation 

Immune regulation

Figure 45. Vitamin D synthesis, activation, and catabolism. Dusso et al., Am J Physiol Renal Physiol 

2005 [149], adapted with permission. 

In the U.S., the recommendation for adequate intake (AI) of vitamin D by the 1998 Food 

and Nutrition Board of the Institute of Medicine was 200 IU/d (5 μg/d) for adults < 51 years. 

For adults > 51 years, the AI was defined as 400 IU/d (10 μg/d) [179]. The 2005 Dietary 

Guidelines for Healthy Americans report that optimal serum 25-hydroxyvitamin D levels 

should be at least 80 nmol/L, the level that maximally suppresses serum parathyroid hormone 

concentration [137]. These guidelines recommend that people in high-risk groups (such as 

those who are elderly, have dark skin, or are exposed to little sunlight) need to have 

substantially higher intakes of vitamin D (25 μg or 1000 IU) to maintain serum 25-

hydroxyvitamin D values at 80 nmol/L [137]. Increasing serum 25-hydroxyvitamin D levels 

to 80 nmol/L from < 50 nmol/L is associated with not only serum parathyroid hormone 

suppression, but also a two-thirds greater calcium absorption efficiency, a one-third decrease 

in osteoporotic fracture risk, greater bone mineral density, and reduced rates of bone 

resorption and loss [52, 96, 235, 570]. 

Since the discovery of vitamin D, a vitamin D “deficiency” has been defined with the 

endpoints of rickets or osteomalacia. Today, it is clear that serum 25-hydroxyvitamin D must 

be high enough to allow 1,25-dihydroxyvitamin D production in kidney and other cells, and 

the disease index for vitamin D should not be limited to short-latency diseases such as rickets. 

From the large body of data relating parathyroid hormone concentrations to circulating 25-

hydroxyvitamin D [97, 153, 662], the general consensus is that the lower end of an acceptable 

normal range for 25-hydroxyvitamin D should be defined as ~80 nmol/L. 

2. Findings from Space Flight and Ground-Based Research 

Spacecraft typically shield crewmembers from the ultraviolet B radiation that forms 25-

hydroxyvitamin D3 in the skin (the only exception being the rare quartz windows). 

Crewmembers on the longest Skylab mission (Skylab 4, 84 days), but not the shorter missions 
Fat-Soluble Vitamins 61

(28 and 59 days), had decreased serum 25-hydroxyvitamin D at landing [361] despite taking 

daily 400-IU vitamin D supplements (Figure 46). Supplementation with this amount of 

vitamin D also did not prevent a decrease in vitamin D status after flight in ISS crewmembers 

[610]. 

Preflight

R+0R+1

R+3/4

R+14

0

50

100

150

25-hydroxyvitamin D (nmol/L)

Figure 46. Plasma 25-hydroxyvitamin D of Skylab crewmembers (n = 9) before and after flight. Data 

are from Leach and Rambaut, 1977 [361]. 

Indeed, decreased vitamin D status is one of the most striking nutritional changes that 

occurs during space flight [609, 610]. The mean preflight serum 25-hydroxyvitamin D 

concentration for U.S. ISS crewmembers is 62 ± 14 nmol/L (Figure 47). In several studies, 

crewmembers on the Russian space station Mir had serum 25-hydroxyvitamin D3

concentrations that were 32% to 36% less during and after long-duration (3- to 4-month) 

missions than before the missions [603, 609]. The serum 25-hydroxyvitamin D concentrations 

of ISS astronauts have typically been 25% to 30% lower after 4- to 6-month space flights 

[610], and in several ISS crewmembers, serum 25-hydroxyvitamin D has decreased to levels 

considered clinically significant (Figure 47) [610]. 

25(OH) vitamin D

Pre mean R+0

0

50

100

150

nmol/L

Figure 47. Serum 25-hydroxyvitamin D concentrations before and after 4- to 6-month space flights on 

the International Space Station (n = 23). Each line represents 1 crewmember. The “Pre mean” point on 

each line is the average of data collected about 6 months and about 6 weeks before launch. R+0 = 

Recovery plus zero days, that is, landing day. These samples are typically collected 2 to 8 hours after 

landing. Adapted from Smith and Zwart, Adv Clin Chem 2008 [612]. 
62 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

Another important observation from the ISS nutritional status assessment was related to 

the relationship between parathyroid hormone (PTH) and 25-hydroxyvitamin D before and 

after ISS missions. Before launch, 25-hydroxyvitamin D was inversely correlated with PTH 

(r = –0.72, P < 0.05) (Figure 48), but this relationship was not evident after landing, 

suggesting that the body’s normal response to changes in vitamin D was altered [610]. 

Preflight

0 20 40 60 80 100

0

50

100

150

iPTH (pg/mL)

25(OH) vitamin D (nmol/L)

Postflight

0 50 100 150 200

0

50

100

150

iPTH (pg/mL)

25(OH) vitamin D (nmol/L)

Figure 48. Serum 25-hydroxyvitamin D and parathyroid hormone concentrations before (average of 

data from samples collected about 6 months and 6 weeks before launch) and after (landing day, 

typically collected 2 to 8 hours after landing) 4- to 6-month space flights on the International Space 

Station. Each symbol represents 1 crewmember. Adapted from Smith and Zwart, Adv Clin Chem 2008 

[612]. 

Results from ground-based studies of bed rest subjects [607] and subjects living in 

closed-chamber facilities or submarines for extended periods suggest that these subjects are 

also at high risk of having vitamin D deficiency [140, 148, 604]. Ground-based models with 

limited sunlight exposure are valuable for performing vitamin D supplementation trials. 

Perhaps an ideal ground-based model for individuals lacking ultraviolet light exposure is 

the Antarctic, where winter levels of ultraviolet B radiation are essentially zero. We recently 

completed a study at McMurdo Station, Antarctica, to determine the daily dose of vitamin D 

needed to sustain serum levels of 25-hydroxyvitamin D during a 5- to 6-month period when 

there is little to no ultraviolet B (UV-B) exposure [613]. 

The environment in the Antarctic is quite unique. Seasonal changes in ultraviolet B light 

exposure are more extreme than in any other part of the world. The sun does not rise for 42 

days during winter (June 1 to July 12), and the sun does not set for 60 days during the 

summer months (Nov 22 to Jan 20). During the Antarctic winter, scientists and visitors are 

typically isolated, and no fresh fruits or vegetables are available. As a result of being in close 

quarters and having limited food choices throughout the year, most scientists at a particular 

research station have homogeneous food intakes and physical activities. Not only is 

Antarctica a good model for studying vitamin D metabolism because of the limited sunlight 

exposure [281], but also the Antarctic science station model has been used successfully as a 

ground-based analog for space flight in studies of behavior, immune response, and latent 

virus reactivation [451, 452, 585]. 

It is well documented that vitamin D status is decreased among subjects who live in 

Antarctica for an extended period [395, 489, 511, 741, 748]. One research group examined 
Fat-Soluble Vitamins 63

25-hydroxyvitamin D status of 31 members of an Antarctic wintering team who stayed at the 

Japanese Antarctic station, Syowa, for 14 months. For 1 week in May and 1 week in July, 

food items were weighed before they were cooked and vitamin D intake was estimated to be 

488 IU/d. Serum 25-hydroxyvitamin D was lowest during April to October (~19.0 ± 4.4 

ng/mL, or ~47.5 nmol/L) [741]. Because the subjects had no source of UV-B during the 

winter months, it can be concluded from this study that 488 IU/d is not enough to prevent a 

decrease in serum 25-hydroxyvitamin D levels. Olvieri and colleagues also studied bone 

metabolism in wintering individuals for 1 year and found that the mean 25-hydroxyvitamin D 

level in Argentine Antarctic wintering researchers was 10 ng/mL (25 nmol/L) during the 

winter months [489]. On a different 1-year expedition to Antarctica, both 25-hydroxyvitamin 

D and 1,25-dihydroxyvitamin D were significantly decreased about 25% during the winter 

months [748]. 

To our knowledge, only 1 supplementation trial has successfully maintained serum 25-

hydroxyvitamin D in subjects living in Antarctica during the summer [395]. Despite the 

sunlight in the summer, temperatures still keep skin exposure to the sun at a minimum. 

Twenty-two healthy males were randomly divided into 2 groups: supplemented with 1000 IU 

vitamin D3 per day, and nonsupplemented controls. Both groups ingested less than 500 mg/d 

calcium. Blood was sampled at intervals of 22 days during the Antarctic summer months. 

Serum 25-hydroxyvitamin D levels were significantly decreased in the control group but did 

not change in the supplemented group. In the latter group, however, a significant decrease in 

PTH occurred. This study showed that 1000 IU/d vitamin D was enough to maintain vitamin 

D status during the summer months in Antarctica. 

Although these data suggest that 1000 IU/d vitamin D may be enough to offset changes 

in vitamin D status in subjects with limited sun exposure such as astronauts, they shed no 

light on the efficacy of 1000 IU/d during the winter months in Antarctica, the time when 

Antarctica most closely models space flight. In the winter months, there is little to no UV-B 

exposure. The mean monthly amount of total UV-B radiation at the Syowa station in 

Antarctica is greatest in December (49,540 J/m2

) and smallest in June and July (0 J/m2) [741]. 

In Tsukuba, Japan, which is similar in latitude to the Midwest in the United States, the 

maximum UV-B total daily is about 20,550 J/m2

 and the lowest is about 5,010 J/m2 [741]. 

Astronauts aboard the International Space Station and those who will travel to Mars will not 

be exposed to any UV-B because spacecraft successfully block UV-B radiation [536]. The 

zero UV-B radiation exposure and zero availability of fresh fruits and vegetables due to 

forced isolation makes the winter months in Antarctica a better model for space flight than the 

summer months, when many researchers work outdoors (temperatures range from – 5 to +6 

°C). 

In addition to a decrease in vitamin D status, wintering residents in Antarctica show signs 

of impaired cognitive function and changes in psychosocial behavior [162, 531]. Although 

there is some evidence that a vitamin D deficiency may be related to changes in cognitive 

function [204], further research is needed to determine if these changes are related to 

nutritional issues or other reasons. 

Glerup and colleagues compared vitamin D status in sunlight-deprived individuals (veiled 

Arab women living in Denmark, veiled Danish Muslim women, and nonveiled Danish 

women) and found a severe vitamin D deficiency among veiled Arab women (serum 25-

hydroxyvitamin D was 7.1 ± 1.1 nmol/L) [203]. Twenty-six percent of the veiled Arab 
64 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

women reported a change in gait compared with 9% of nonveiled Danish controls, and 

muscle pain was felt by 88% of Arab women. These women had a very low vitamin D intake 

(1.04 μg/d) and limited sun exposure. Veiled Danish Muslims had a high vitamin D intake 

[13.53 μg/d, (~600 IU/d)] but limited sun exposure, and they were still vitamin D deficient 

(serum 25-hydroxyvitamin D was 17.5 ± 2.3 nmol/L). These data suggest that 600 IU/d 

vitamin D is not enough to maintain 25-hydroxyvitamin D levels in individuals with little or 

no sun exposure. In another study with 51 submariners on deployment, 400 IU vitamin D was 

not enough to prevent a decrease in vitamin D status after 76 days [148]. 

One Russian study of the effects of gamma or proton radiation on vitamin D showed a 

slight (2.3% and 4.6%, respectively) decrease in vitamin D content of supplements [80] after 

irradiation. 

3. Dietary Intake and Requirements 

As mentioned above, the 1998 Food and Nutrition Board of the Institute of Medicine 

defined an adequate intake of vitamin D at 200 IU/d (5 μg/d) for adults < 51 years, and for 

adults > 51 years, the AI was defined as 400 IU/d (10 μg/d) [179]. The 2005 Dietary 

Guidelines for Healthy Americans recommended substantially higher intakes of vitamin D 

(25 μg or 1000 IU). Given the volume of data reported on vitamin D and health in recent 

years, a call has gone out for reconsideration and reevaluation of these recommendations 

[739]. 

The current documented space flight requirement for dietary intake of vitamin D is 25 μg 

per day [460], an increase from the original ISS recommendation of 10 μg per day [458] 

(Table 1). The ISS food system provides less than half of this amount (4 μg per day on 

average, Table 1). Given this shortfall, and because astronauts in space are shielded from 

sunlight, considering them to be in a high-risk group seems appropriate. It is currently 

recommended that ISS crewmembers take 800 IU of vitamin D per day during long-duration 

space flight. 

4. Risks on Exploration Missions 

Deficiency of vitamin D leads to osteomalacia and osteoporosis, which could lead to lifethreatening fractures and even death. Furthermore, decreased vitamin D status has been 

associated with increased risk for multiple diseases, including cancer, cardiovascular disease, 

diabetes, multiple sclerosis, and infections [4, 125, 141, 237, 262, 431, 471, 510, 615, 713]. 

This is likely related to the fact that cells in a variety of tissues contain 1,25-dihydroxyvitamin 

D3 nuclear receptors [99, 446]. 

As noted above, vitamin D deficiency is linked to calcium metabolism, and in severe 

cases leads to osteomalacia and osteoporosis in adults (and rickets in children). Throughout 

the ISS program, supplemental vitamin D has been provided to astronauts to ensure optimal 

vitamin D status. 

Efforts to provide vitamin D supplements are misinterpreted to infer that this might be a 

viable bone loss countermeasure, but this is not the case. Even when vitamin D stores during 
Fat-Soluble Vitamins 65

flight are adequate, the circulating concentration of the active form of vitamin D, 1,25-

dihydroxyvitamin D, is decreased [603, 609]. As described in the section on calcium, 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. 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, soft 

tissue 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 compared to placebo) for 6 

months. Little effect was found on parathyroid hormone, and no effect on bone markers [53]. 

In a similar 40-week trial of 1000 IU of vitamin D2 or D3 (two groups), neither had an effect 

on bone markers [619]. The problem of weightlessness-induced bone loss must be solved, but 

vitamin D is not the answer. Nevertheless, even if bone loss is not stemmed, ensuring an 

adequate amount of vitamin D will remain important. 

Since the current space food system includes very few dietary sources of vitamin D, and 

vitamin D cannot be synthesized endogenously due to lack of UV light, decreased vitamin D 

status is a serious concern for exploration missions that could last 1000 days.

Toxicity of vitamin D is typically less likely to occur than a deficiency [231, 668, 703, 

704], but use of supplements would increase its likelihood. Excessive blood levels of vitamin 

D can lead to hypercalcemia, which can lead to nephrocalcinosis, arteriosclerosis, irreversible 

calcification of soft tissue, or even death. 

5. Remaining Questions 

Vitamin D levels in the food system need to be determined, and the stability of vitamin D 

in the food system needs to be investigated. Additional research is needed to understand 

whether supplementation (and what level of supplementation) can maintain vitamin D stores. 

This is very important for long-duration crewmembers, and is of the utmost importance for 

exploration-class missions. 

C. VITAMIN E 

1. Background 

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: 4 tocopherol derivatives (α-, γ-, δ-, and β-tocopherol) 

and 4 tocotrienol derivatives (α-, γ-, δ-, and β-tocotrienol) [676]. The tocopherols that are 

most abundant in biological systems are α- and γ-tocopherol, but small amounts of δtocopherol and α-tocopheryl quinine are also present. About 90% of the tocopherol found in 

human plasma is in the form of α-tocopherol [278]. 

Vitamin E helps protect cell membranes in the early stages of free-radical attack because 

of its free-radical-quenching activity. Free radicals attack polyunsaturated fatty acids found in 
66 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

membrane phospholipids, causing damage to cellular membranes and possibly cell death. The 

interception of a free radical by vitamin E produces a tocopheroxyl radical that can be 

reduced by vitamin C or another reducing agent to return vitamin E to its reduced state. The 

extent of regeneration and recycling of vitamin E in human tissue has not been well 

established [617, 676]. 

Vitamin E is stored mainly in adipose tissue but is also found in phospholipid 

membranes. Results of studies conducted to determine vitamin E tissue levels have shown 

that tissue α-tocopherol concentrations are largely reflected by changes in plasma αtocopherol concentrations [304]. 

Vitamin E deficiencies in humans are rare; however, fat malabsorption syndromes, 

genetic abnormalities, and protein-energy malnutrition are specific conditions in which a 

vitamin E deficiency is likely to occur. Symptoms include neurological problems associated 

with nerve degeneration in the extremities [278]. Vitamin E depletion has been detected when 

markers of lipid peroxidation were elevated. However, the lowering of levels of these lipid 

peroxidation markers has not been shown to have any health benefits, and therefore they have 

not been used to establish α-tocopherol requirements. 

Deficiency of vitamin E leads to neurological disorders, hemolytic anemia, retinopathy, 

and abnormal platelets and lymphocytes, or even death. Toxicity of vitamin E from naturally 

occurring sources has not been shown to occur. 

2. Findings from Space Flight and Ground-Based Research 

After ISS crewmembers had spent 4 to 6 months in space, their plasma γ-tocopherol was 

50% less than preflight levels [610]. No change in α-tocopherol occurred in these subjects. 

Recent animal studies have documented the ability of vitamin E to mitigate muscle 

atrophy, apparently through genetic regulation of proteolysis [576]. Additionally, animal 

hindlimb unloading studies have shown that supplemental vitamin E can have a positive 

influence on bone, potentially through the vitamin’s antioxidant properties [594]. Although, 

as always, such results are intriguing, the ability of these studies to translate into effectiveness 

in humans has yet to be determined. 

3. Dietary Intake and Requirements 

The current documented space flight requirement for dietary intake of vitamin E is 15 

mg/d for men and women, the same as the U.S. recommendation for adequate intake of 

vitamin E. No upper limit has been established because the highest level of daily intake is not 

likely to pose serious health risks to the majority of individuals [278]. Although no striking 

changes occurred in plasma vitamin E concentrations, the space flight menus provide only 

about 60% of the documented requirement for vitamin E (see Table 1, page 18). 
Fat-Soluble Vitamins 67

4. Risks on Exploration Missions 

Oxidative stress can increase in microgravity and high-radiation environments [161, 633, 

634], and the antioxidant properties of vitamin E may help to counteract the free-radical 

damage caused by high-linear energy transfer radiation in space. Pretreatment with 

antioxidants may help decrease radiation damage during missions [503], and it may be 

necessary to provide enough vitamin E for astronauts’ blood levels of the vitamin to be higher 

during space flight than on Earth. However, knowledge gaps weaken the evidence for use of 

vitamin E as a countermeasure (see below). 

5. Remaining Questions 

Vitamin E content of space foods, along with the stability of vitamin E in these foods, 

needs to be determined. After learning about the promising antioxidant effects of 

supplemental vitamin E, many people on Earth did not hesitate to take vitamin E supplements 

to prevent cancer. But the protective effects were not borne out in controlled studies, 

highlighting the difficulties of defining a specific antioxidant countermeasure for space 

travelers without the luxury of having data from epidemiological studies to provide an 

evidence base for space flight. 

D. VITAMIN K 

1. Background 

Vitamin K occurs naturally in 2 forms: phylloquinone (vitamin K1) and menaquinone 

(vitamin K2). Menaquinones are produced by bacteria, while phylloquinone is synthesized in 

plants. Phylloquinone represents the main source of dietary vitamin K in Western countries 

[491]. 

The function of vitamin K was originally assumed to be strictly limited to involvement in 

blood coagulation, but an increasing amount of evidence indicates that this vitamin affects 

multiple physiological systems. Vitamin K is a cofactor in the posttranslational synthesis of γcarboxyglutamic acid (GLA). γ-Carboxyglutamic acid is a constituent of all vitamin Kdependent proteins, and its role is related to increasing the affinity of the proteins for calcium 

[166]. Vitamin K-dependent proteins include blood coagulation proteins (prothrombin; 

factors VII, IX, and X; and proteins C and S) and bone proteins (osteocalcin, matrix GLA 

protein, and protein S). 

The main storage depot for vitamin K in the body is the liver. Large amounts of vitamin 

K are also present in cortical and trabecular bone [260]. However, vitamin K stores are very 

small compared to those of other fat-soluble vitamins, and hepatic vitamin K is rapidly 

depleted when dietary vitamin K is restricted [689]. 

Anticoagulants such as warfarin, a coumarin-based anticoagulant, are administered to 

create a partial vitamin K deficiency to reduce risks of abnormal blood clotting [417]. Dosing 

with warfarin must be closely monitored for optimal efficacy and safety. High or low intake 
68 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

of vitamin K can interact with the actions of warfarin to yield nontherapeutic anticoagulation 

or life-threatening hemorrhagic complications [233, 305]. 

2. Findings from Space Flight and Ground-Based Research 

Data from 11 U.S. astronauts on ISS 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 (Figure 49), whereas urinary γ-carboxyglutamic acid 

did not change [610]. In one study, undercarboxylated osteocalcin was elevated (a sign of 

vitamin K insufficiency) as early as the 8th day of space flight, and remained high during 21- 

and 180-d missions [85]. Studies on the EuroMir 95 mission showed that markers of vitamin 

K status were decreased after 12.5 weeks of space flight, and vitamin K supplementation (10 

mg/d for 6 weeks) reversed these effects [695]. Vitamin K supplementation elevated γcarboxyglutamic acid and decreased undercarboxylated osteocalcin, suggesting that vitamin 

K status was lower during space flight and was improved by supplementation [85, 695]. 

Pre mean R+0

0

1

2

3

4

5

nmol/L

Figure 49. Serum phylloquinone before and after 4- to 6-month space flights on the International Space 

Station. Each line represents 1 crewmember (n = 15). The “Pre Mean” point on each line is the average 

of data collected about 6 months and about 6 weeks before launch. R+0 = Recovery plus zero days, that 

is, landing day. These samples are typically collected 2 to 8 hours after landing. Data are from Smith et 

al. [610]. 

Elevated undercarboxylated osteocalcin has been associated with increased fracture risk 

in certain populations, and evidence exists that vitamin K antagonists increase the risk of 

fracturing vertebrae and ribs in a time-dependent manner [90, 582]. 

Recent publications have shown a link between carboxylation of osteocalcin and insulin 

resistance and energy metabolism. Space flight has been shown to increase the percentage of 

undercarboxylated osteocalcin [85, 694, 695], which according to Lee and Karsenty [383] 

should increase insulin sensitivity. However, space flight or disuse is accompanied by an 

increase in insulin resistance (decrease in insulin sensitivity). Yashida et al. [743] have 

reported that daily supplementation of 500 μg of vitamin K decreases insulin resistance. The 
Fat-Soluble Vitamins 69

nature of any relationship between insulin sensitivity and the carboxylation of osteocalcin 

must be considered unknown for now, and it could be a concern for exploration missions. 

3. Dietary Intake and Requirements 

The current documented space flight requirements for dietary intake of vitamin K are 90 

and 120 μg per day for women and men, respectively. These are the same as the U.S. 

adequate intake recommendations for vitamin K [181]. No upper limit has been established. 

4. Risks on Exploration Missions 

Decreased vitamin K status has serious implications for space flight because it is related 

to bone health. Space flight data, including data from Mir [85, 694] and ISS crewmembers 

[610], suggest that vitamin K status during long-duration space flight is suboptimal. 

5. Remaining Questions 

Deficiency of vitamin K is not common in adults, as the intestinal microflora synthesize 

vitamin K. The reliability of this source of vitamin K during flight is unknown, and expert 

panels have recommended having higher intake requirements because of this uncertainty 

[460]. It has been hypothesized that microflora production of vitamin K may be altered in 

space, but few or no data are available to support this. The use of vitamin K as a bone loss 

countermeasure has been proposed and is under investigation [243, 652]. Given that the 

amount of space flight data documenting the improvement in bone marker status with vitamin 

K supplementation is limited, clearly more needs to be known before exploration missions are 

undertaken. Furthermore, the vitamin K content of the space food system and its stability 

should be determined. 

VII. WATER-SOLUBLE VITAMINS

Water-soluble vitamins are a key concern for space travelers, because of the limited 

endogenous storage of many of these nutrients. They must be replenished from food that may 

have been stored for a long time (9 to 18 months) under suboptimal conditions, including the 

space radiation environment. 

A. FOLATE

1. Background 

Folate is the general term used to describe folic acid and compounds that have activity 

similar to that of folic acid [30]. Folic acid is the form of the vitamin used in vitamin 

supplements and fortified food products, but it is rarely found to occur naturally in food. 

About 50% of all folate is stored in the liver. The average liver concentration of folate is 

about 8 μg/g [268]. Estimated total body folate stores are 12 to 28 mg [277]. Very little folate 

is excreted in the urine or feces. Most of the absorbed folate is secreted by the liver into the 

bile, which is then reabsorbed through enterohepatic recirculation. Most of the folate excreted 

in feces is synthesized by intestinal bacteria. 

The reduction of folic acid and dihydrofolate by a cytosolic enzyme produces the active 

form of folate, tetrahydrofolate (THF). Tetrahydrofolate accepts single-carbon groups from 

reactions in amino acid metabolism to form active derivatives of THF [30]. These derivatives 

function in amino acid metabolism, specifically in the reversible reactions of serine synthesis 

from glycine, methionine synthesis from homocysteine, and histidine metabolism. Folate is 

essential in cell division because the THF derivatives play important roles in purine and 

pyrimidine synthesis. Tetrahydrofolate derivatives play a major role in the formation of 

thymidylate, which is a substrate needed for DNA synthesis [30]. 

Radiation exposure and inadequate dietary consumption can lead to inadequate intake of 

folate [277]. Deficiency of folate leads to megaloblastic anemia or even death. Low folate 

intake will cause red blood cell 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 [218]. Folate deficiency in humans has 

been described as a 4-stage process [254, 255], including changes in serum folate (Stage 1), 

changes in red blood cell folate (Stage 2), defective DNA synthesis and elevated 

homocysteine (Stage 3), and clinical folate deficiency (Stage 4), manifested by 
72 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

macroovalocytosis (many large, oval cells in the blood), elevated mean corpuscular (red 

blood cell) volume, and large, nucleated embryonic cells. 

Folate deficiency is associated with irritability, forgetfulness, and hostile or paranoid 

behavior [255]. It has been suggested that folate may influence the metabolism of certain 

neurotransmitters, but this may be related to the neurotoxicity of homocysteine, which is 

elevated in folate deficiency. Hyperhomocysteinemia also has detrimental cognitive and 

neurodegenerative effects [256]. 

2. Findings from Space Flight and Ground-Based Research 

It is evident that folate status is decreased after long-duration space flight (4 to 6 months) 

(Figure 50) [604, 610]. To date, only pre- and postflight assessments of nutrient status have 

been possible, although the recently initiated Nutritional Status Assessment Supplemental 

Medical Objective experiment will provide in-flight data as well [612]. 

Folate

Pre mean R+0

0

500

1000

1500

ng/mL

Figure 50. Red blood cell folate concentrations before and after 4- to 6-month space flights on the 

International Space Station (n = 23). Each line represents 1 crewmember. The “Pre mean” point is the 

average of data collected about 6 months and 6 weeks before launch. R+0 = Recovery plus zero days, 

that is, landing day. These samples are typically collected 2 to 8 hours after landing. Adapted from 

Smith and Zwart, 2008 [612]. 

Recent bed rest studies did not document any change in red blood cell folate status during 

or after short (3-week, [762]) or long (60- to 90-day [761]) bed rest. A 14-day exposure to 

increased atmospheric pressure (saturation diving) did not significantly affect red blood cell 

folate [608]. 

3. Dietary Intake and Requirements 

The current documented space flight requirement for folate intake is 400 μg/d [460], 

unchanged from ISS requirements [458] (Table 1). In the U.S., the RDA for all individuals 

aged 14 and older is 400 μg/d of dietary folate equivalents (DFEs). Using DFEs adjusts for 
Water-Soluble Vitamins 73

the 50% reduction in food folate bioavailability compared to that of folic acid: 1 μg DFE = 

0.6 μg of folic acid from fortified food, or as a supplement taken with meals; 1 μg DFE = 1 

μg of food folate = 0.5 μg of a supplement taken on an empty stomach. An upper limit of 

folate intake during space flight is set at 1000 μg/d. 

4. Risks on Exploration Missions 

As with many nutrients, folate deficiency on an exploration mission would be 

catastrophic. Animal studies have shown that low folate status increases chromosome damage 

resulting from radiation exposure [42, 115, 151, 152]; however, it should be noted that 

excessive folate supplementation provided no additional benefit [151]. Similarly, cell models 

have shown that folic acid deficiency increases sensitivity to chromosome breakage from 

ionizing radiation [42]. Antioxidant properties of folate have been studied, and folate was 

found to scavenge a diverse array of reactive oxygen species efficiently [299]. Cell models 

also show the ability of folate to reduce iron toxicity in cases of iron overload, by oxidizing 

free or chelated iron [299]. Folate status may be even more important during exploration 

missions than on the ISS because of known increases in iron storage during long-duration 

space flight [610] and exposure to ionizing radiation. 

5. Remaining Questions 

It is unknown whether the decrease in folate status during space flight is related to the 

folate content of food, the stability of folate in food during flight, or alterations in absorption, 

metabolism, or excretion. Folate levels in the space food system need to be determined. If the 

diet does in fact provide 400 μg/d, then further research should be done to understand the 

stability of folate during radiation exposure. If neither folate content of food nor folate 

stability in food is an issue, then evaluations of folate metabolism during space flight are 

warranted to ensure that the body’s requirements are understood. 

B. THIAMIN

1. Background 

Thiamin functions as a coenzyme in the metabolism of carbohydrates and branched-chain 

amino acids [39]. The coenzyme form of thiamin, thiamin pyrophosphate, functions in the 

decarboxylation of pyruvate and α-ketoglutarate. Without these decarboxylations, synthesis 

of both adenosine triphosphate (ATP) and acetyl-coenzyme A would be inhibited. Thiamin 

pyrophosphate also functions as part of the hexose monophosphate shunt, the pathway by 

which 6-carbon sugars are converted to pentoses and NADPH (the reduced form of 

nicotinamide adenine dinucleotide phosphate) [39]. Thiamin pyrophosphate is also involved 

with neural function, although the mechanism is not completely understood [39]. 
74 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

About 30 mg of thiamin is stored in the human body [277]. About half of the body’s 

thiamin is stored in the skeletal muscle, with the rest being stored in the heart, liver, kidney, 

and brain. Thiamin in excess of tissue needs and storage capacity is excreted in the urine. The 

biological half-life of thiamin is in the range of 9 to 18 days. 

Deficiency of thiamin ultimately leads to beriberi (enlarged heart, muscle weakness, 

anorexia, apathy, reduction in nerve impulse transmission) or even death. No toxicity 

symptoms of excess thiamin are known. 

2. Findings from Space Flight and Ground-Based Research 

Evaluation of erythrocyte transketolase activity, an index of thiamin status [81], before 

and after space flight did not yield any abnormal data [610]. 

3. Dietary Intake and Requirements 

The current documented space flight requirement for dietary intake of thiamin is 1.2 and 

1.1 mg/d for men and women, respectively [460] (Table 1), the same as the U.S. RDAs for 

men aged 19 and older and for women [277]. The ISS thiamin requirements were slightly 

higher at 1.5 mg, and without gender differences [458] (Table 1). 

4. Risks on Exploration Missions 

It is well known that thiamin is highly susceptible to destruction by radiation [80, 183, 

706] and processing in foods [79]. It will be crucial to determine if thiamin can survive a 3-

year-plus mission to deep space. 

5. Remaining Questions 

The thiamin levels in the space food supply and their stability need to be determined, 

particularly since thiamin is highly susceptible to degradation from radiation exposure. 

C. NIACIN

1. Background 

The term “niacin” includes nicotinamide, nicotinic acid, and their derivatives that have 

the biological activity of nicotinamide [277, 286]. In its coenzyme forms, nicotinamide 

adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), 

niacin has many different metabolic roles in the human body. The nicotinamide moiety 

accepts hydride ions in numerous biological redox reactions. NAD functions in respiration 

and as a co-dehydrogenase with enzymes involved in the oxidation of fuel molecules [286]. 
Water-Soluble Vitamins 75

NAD is converted to NADH, which transfers electrons from the Krebs cycle through the 

electron transport chain. NAD also acts as a donor of adenine dinucleotide phosphate-ribose 

for the posttranslational modification of proteins [218]. The coenzyme NADP has a role in 

fatty acid, cholesterol, and steroid syntheses, and as a co-dehydrogenase in the pentose 

phosphate pathway. Conversion of folate to its active forms also requires NADP. 

Niacin is stored in the liver as NAD. This stored NAD can result from conversion of 

tryptophan, nicotinic acid, or plasma nicotinamide. 

Limited data show that after 80 to 135 days of ingesting a low-niacin diet, subjects’ 

urinary excretion of N1

-methylnicotinamide is at a level representing deficiency status [180]. 

On a niacin-deficient diet, symptoms begin to appear after 50 to 60 days [286]. 

Deficiency of niacin leads to dermatitis, glossitis, growth retardation, pellagra and its 

associated three “d”s (diarrhea, dermatitis, dementia), and ultimately death. Niacin deficiency 

has also been associated with increased damage to DNA after an oxidative stress, but it was 

not related to glutathione peroxidase levels [659]. 

Niacin in the amount of 3 g/d or more has been associated with toxic effects [277]. 

Niacin toxicity from mega doses of niacin can cause vasodilatory effects (flushing), 

gastrointestinal distress, hepatotoxicity, glucose intolerance, and blurred vision [286]. 

However, many of these toxic effects have been shown to occur only after treatment over 

long periods and in amounts that far exceed the RDA. The tolerable upper intake limit is 

defined as 35 mg of niacin equivalents per day. This is the upper limit of where no risks or 

adverse effects are expected [286]. 

2. Findings from Space Flight and Ground-Based Research 

Niacin status of astronauts during and after flight has not been measured. 

3. Dietary Intake and Requirements 

The current documented space flight requirement for dietary intake of niacin is 16 mg 

niacin equivalents/d (NE/d) [460], slightly lower than the originally defined ISS requirement 

of 20 mg NE/d (Table 1) [458]. The ISS menu was estimated to provide intakes of almost 30 

mg NE/d on average (Table 1). In the U.S., the niacin requirement for men aged 19 and older 

is 16 mg/d of niacin equivalents, and for women aged 19 and older the requirement is 14 

mg/d of niacin equivalents [277]. One niacin equivalent is equal to about 60 mg of the amino 

acid tryptophan and can be obtained from 6 grams of high-quality protein [218]. The RDA for 

niacin can be met from the actual niacin content of the diet or by metabolic conversion of 

tryptophan in the diet. 

4. Risks on Exploration Missions 

Very little is known about niacin metabolism during space flight. One concern for 

exploration missions is the stability of niacin in the food system, particularly because of 
76 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

reports showing that the niacin content of foods decreases after exposure to 6 kGy of 

radiation [129]. 

5. Remaining Questions 

Niacin content and stability in the space food supply need to be determined. The role of 

niacin in protection from oxidative damage should also be evaluated as part of a larger search 

for an oxidative damage countermeasure. 

D. RIBOFLAVIN

1. Background 

Riboflavin’s primary role in the body, like that of many water-soluble vitamins, is as a 

coenzyme [544]. The most important biologically active forms of riboflavin are flavin 

mononucleotide and flavin adenine dinucleotide (FAD). These cofactors participate in a range 

of redox reactions in numerous metabolic pathways [514, 544]. Some of these pathways are 

niacin-dependent and niacin-independent dehydrogenations, reactions with sulfur-containing 

compounds, hydroxylations, oxidative decarboxylations, dioxygenations, and reduction of 

oxygen to hydrogen peroxide [544]. The riboflavin cofactors also play a role in the formation 

and function of some other vitamins, including folate, vitamin B12, and vitamin B6 [514]. 

Unbound flavins are labile and are rapidly hydrolyzed to release free riboflavin. Excess 

free riboflavin is excreted in the urine [514]. 

The highest concentrations of stored riboflavin are found in the liver, kidneys, and heart 

[277], and almost all riboflavin in tissues is enzyme-bound, such as FAD covalently bound to 

succinic dehydrogenase [590]. The total body stores of riboflavin are enough to meet the 

demands of the body for 2 to 6 weeks [277]. 

Riboflavin deficiency affects ferritin iron mobilization and iron absorption. Symptoms of 

riboflavin deficiency include peripheral nerve demyelination, neurologic abnormalities, and 

anemia. 

2. Findings from Space Flight and Ground-Based Research 

After flight on the International Space Station, erythrocyte glutathione reductase (EGR) 

activation, an index of riboflavin status [81], was unchanged compared to preflight values 

[610]. 

A 14-day exposure to increased atmospheric pressure (saturation diving) did not have a 

statistically significantly effect on EGR activation, but activation values during and after the 

dive tended (P = 0.07) to be lower than before the dive [608]. 
Water-Soluble Vitamins 77

3. Dietary Intake and Requirements 

The current documented space flight requirement for dietary intake of riboflavin is 1.3 

mg/d [460], lower than the initial requirements of 2.0 mg/d defined for ISS crewmembers 

[458]. Regardless of the requirement, the menu provides about 2.2 mg/d on average (Table 1). 

In the U.S., the RDAs for riboflavin for men and women aged 19 and older are 1.3 and 1.1 

mg/d, respectively [277]. 

4. Risks on Exploration Missions 

Cataract incidence is higher in space travelers than in the general population [119, 297], 

and cataracts have also been described in riboflavin-deficient animal models [270, 514]. 

Although no evidence exists to date that riboflavin status changes during space flight, the 

possibility that this nutrient could be involved in cataract formation cannot be ignored. 

Riboflavin is relatively heat-stable, but it is readily degraded by light [38, 514]. It does 

not seem to be degraded by gamma irradiation of foods [183, 342], which reduces concern 

about long-term stability. 

5. Remaining Questions 

No evidence exists that riboflavin status is altered during 4- to 6-month space flights 

[610]; however, riboflavin content in the space food supply needs to be investigated to ensure 

that a) enough is available, and b) riboflavin will not degrade during long-duration storage. 

E. VITAMIN C 

1. Background 

The term “vitamin C” actually refers to 2 different compounds, both of which have 

activity against scurvy: ascorbic acid and dehydroascorbic acid [294]. Vitamin C functions as 

an antioxidant because it acts as a reducing agent for most physiologically relevant reactive 

oxygen species, reactive nitrogen species, singlet oxygen, and hypochlorite. It serves as a 

cofactor for enzymes involved in the biosynthesis of collagen, carnitine, and 

neurotransmitters [294]. Vitamin C also provides antioxidant protection by returning αtocopherol to its biologically active state during lipid oxidation. The reducing agents 

glutathione and either reduced nicotinamide adenine dinucleotide (NADH) or reduced 

nicotinamide adenine dinucleotide phosphate (NADPH) regenerate the oxidation products of 

ascorbate [294]. 

It has been suggested that vitamin C requirements should be greater for 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 [278]. 
78 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

The total body pool of vitamin C varies with intake. Higher concentrations are found in 

the pituitary and adrenal glands, liver, spleen, heart, kidneys, lungs, pancreas, leukocytes, eye 

tissues and humors, and the brain, while lower concentrations are found in the saliva, muscle, 

and plasma. Blood cell and tissue concentrations become saturated at intakes from 100 to 140 

mg/d, and steady-state plasma vitamin C concentrations occur with intakes of 200 mg/d. 

Catabolic turnover varies from 10 to 45 mg/d, and with low intake, turnover is reduced. 

Maximum body pools of ascorbate are ~2 grams. 

Vitamin C has been related to cataract and cancer incidence [663, 716, 742], both of 

concern for space travelers. Although higher vitamin C intake in the Framingham Study was 

found to be associated with lower bone mass [553], the significance of this association was 

marginalized when adjusted for potassium intake. This suggests that vitamin C may be a 

secondary factor related to fruit and vegetable reduction in bone loss [356, 407, 465, 466], as 

described elsewhere in this text. 

Vitamin C deficiency most commonly presents itself as any of an array of symptoms 

commonly referred to as scurvy. Scurvy is seen in adults within 45 to 80 days of stopping 

vitamin C intake. Intake below the RDA can cause a deficiency once the body pools fall 

below ~300 mg of ascorbic acid. The length of time until scurvy symptoms develop when 

intake is suboptimal depends on the size of the individual’s body pool of vitamin C before 

intake was decreased. 

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 [66]. Toxicity of vitamin C leads to gastrointestinal distress, and has been 

reported in subjects consuming more than 1000 mg/d [663]. 

2. Findings from Space Flight and Ground-Based Research 

Vitamin C status of crewmembers has not been reported to date, at least not to our 

knowledge. Vitamin C assessments of ISS crewmembers have been initiated, but have yet to 

be reported. A recent short-duration bed rest study documented no statistically significant 

change in vitamin C (Figure 51), but results showed a trend for an increase, which might be 

related to dietary intake during the study compared to the subjects’ nominal intake [762]. 

The stability of vitamin C has been studied in food supplies, and it is generally unstable 

at a neutral or alkaline pH, and in high-oxygen environments [253]. Vitamin C is also 

unstable when exposed to light or heat [253], and in irradiated foods [160, 555]. Salem [555] 

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 [86]. Exposure of these spices to gamma rays 

for > 3 months resulted in a marked increase in quinone radicals. 
Water-Soluble Vitamins 79

0 10 20 30

-10

0

10

20

30

Bed rest Recovery

Vitamin C (% change)

Figure 51. Plasma vitamin C in 7 subjects during 21 days of bed rest. Data, from Zwart et al. [762], are 

expressed as percent change from before bed rest. 

3. Dietary Intake and Requirements 

The current documented space flight requirement for dietary intake of vitamin C is 90 

mg/d (Table 1). In the U.S., the RDAs for vitamin C for men and women aged 19 and older 

are 90 mg/d and 75 mg/d, respectively. They are set by assuming a coefficient of variation of 

10 percent because information about the standard deviation is unavailable. The RDA is 

defined as equal to the estimated average requirement (EAR) plus twice the coefficient of 

variation, to cover the needs of at least 98% of the population [278]. Because of the increased 

level of stress predicted for orbiting crews, the requirement for vitamin C in space crews was 

initially defined as 100 mg/d for males and females [457, 458], at a time when the U.S. RDA 

was 60 mg/d. 

4. Risks on Exploration Missions 

A major concern for space flight is the possibility that vitamin C could be degraded in 

foods during extended-duration missions when space foods are exposed to large amounts of 

radiation and undergo long-term storage (foods may be sent to Mars in advance of the crew, 

and left there for up to 5 y). This could be catastrophic. 

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 [82, 

288]. Just as important to consider, however, is the possibility that vitamin C could induce 

DNA damage. Cai and colleagues [82] found that vitamin C can act as an antioxidant to 

prevent DNA damage caused by ionizing radiation, but in the presence of copper, it can also 

act as a reducing agent to induce DNA damage. Because vitamin C can reduce redox-active 

metals such as iron and copper, this “antioxidant” can increase the pro-oxidant chemistry of 
80 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

these metals [76]. Thus, vitamin C can serve as both a pro-oxidant 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). 

5. Remaining Questions 

Vitamin C content and stability in the space food supply need to be determined. 

Evaluation of the impact of vitamin C supplementation during exposure to oxygen or highlinear energy transfer 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. After data have been gathered regarding vitamin C 

status during and after flight, and preferably after data are available regarding the influence of 

space flight-induced stress on vitamin C, an evaluation of intake requirements needs to be 

made. 

F. VITAMIN B6

1. Background 

Vitamin B6 comprises a group of 3 compounds and their 5′-phosphates (P): pyridoxal 

(PL) and PLP, pyridoxine (PN) and PNP, and pyridoxamine (PM) and PMP [423]. These 

“vitamers” of B6 serve as coenzymes in many transamination reactions by forming a Schiff’s 

base with the ε-amino group of lysine and the carbonyl group of PLP [277, 423]. They can 

also function in decarboxylation reactions, such as the formation of γ-aminobutyric acid from 

glutamate and serotonin from 5-hydroxytryptophan, and they function in trans- and 

desulfhydration, by which cysteine is synthesized from methionine and pyruvate is generated 

from cysteine, respectively. The vitamers also function in cleavage reactions, racemization of 

D- and L-amino acids, synthesis of multiple compounds, glycogen catabolism (where vitamin 

B6 is required for the activity of glycogen phosphorylase), and steroid hormone action (where 

the vitamers decrease the actions of steroids) [218]. 

About 80% of vitamin B6 is stored in muscle tissue and 10% is stored in the liver, with 

the rest being stored in the blood plasma pool. Research data have shown that total body 

stores are about 1,000 μmol or 167 mg [277]. Overall body half-lives of the vitamers of 

vitamin B6 are about 25 days [277, 580]. 

Deficiency of vitamin B6 leads to dermatitis, microcytic anemia, convulsions, altered 

mental status, hyperhomocysteinemia, or even death. Toxicity of vitamin B6 leads to sensory 

neuropathy or even death. 

2. Findings from Space Flight and Ground-Based Research 

The variables used to assess vitamin B6 status are red blood cell transaminase, plasma 

PLP, and urinary 4-pyridoxic acid. No change occurred in the activation of red blood cell 
Water-Soluble Vitamins 81

transaminase of astronauts on 4- to 6-month space flights [610]. To date, plasma PLP has not 

been determined after long-duration space flight or bed rest. 

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 [333]. Since vitamin B6 is stored 

mainly in muscle tissue [105], 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- [762] and long-duration bed rest studies [106], likely 

reflects this loss of muscle stores of vitamin B6. 

3. Dietary Intake and Requirements 

The current documented space flight requirement for dietary intake of vitamin B6 is 1.7 

mg/d [460], slightly lower than the original requirement defined for ISS missions [458]. In 

the U.S., the vitamin B6 requirement for all adults over age 19 years is 1.3 mg/d [277]. The 

ISS food system is estimated to provide adequate (2.3 mg/d average) vitamin B6 (Table 1). 

4. Risks on Exploration Missions 

Given the changes observed in vitamin B6 metabolism during bed rest, vitamin B6 status 

during and after long-duration space flight warrants further attention. A deficiency in vitamin 

B6 causes a decrease in the synthesis of serotonin and catecholamines, which has been shown 

to be associated with depression [272]. Excess vitamin B6 can lead to neuropathy [37, 195, 

303]. 

5. Remaining Questions 

Vitamin B6 levels and stability in the space food supply need to be determined, along 

with an assessment of its stability in an environment with increased levels of radiation. 

G. VITAMIN B12

1. Background 

Vitamin B12 functions in many enzymatic reactions, and deficiencies result in anemia, as 

well as neurological disorders. Vitamin B12 functions as a coenzyme in 2 metabolic forms: 

adenosylcobalamin and methylcobalamin [622]. Vitamin B12 works as a cofactor for 3 

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 β-leucine. Vitamin B12 deficiency may cause the accumulation 

of folate in the serum because of a reduction in B12-dependent methyltransferase, also known 
82 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

as the methyl-folate trap [584]. 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, but smaller amounts can also be found in the muscles, 

kidneys, bones, heart, brain, and spleen. About 2 to 5 mg of vitamin B12 is stored in the body 

[277]. 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 [277]. 

No evidence of toxicity has been found with vitamin B12 supplementation in amounts 

greater than the RDA [277], and no adverse effects are reported to be caused by an excess of 

vitamin B12. 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 [691]. Deficiency of 

vitamin B12 leads to pernicious anemia and demyelination of the central nervous system, and 

can lead to death [622]. 

2. Findings from Space Flight and Ground-Based Research 

No data are available on vitamin B12 status during or after long-duration space flight, 

although the recently initiated Nutritional Status Assessment Supplemental Medical Objective 

experiment will provide determinations of homocysteine, methylmalonic acid, and related 

metabolites. These determinations will allow not only diagnosis of vitamin B12 deficiency, 

but also differentiation between vitamin B12 and folate deficiencies. 

3. Dietary Intake and Requirements 

The current documented space flight requirement for dietary intake of vitamin B12 is 2.4 

μg/d [460], slightly higher than the original requirement defined for ISS missions [458]. This 

is the defined required amount of vitamin B12 in the U.S. for both men and women aged 19 

years and older [277]. The ISS food system is estimated to provide 4.6 μg vitamin B12 per day 

(Table 1). 

4. Risks on Exploration Missions 

Virtually nothing is known about the status of vitamin B12 during or after space flight, or 

its relationship to other factors. Alterations in the metabolism of this vitamin or the 

requirements for it during long-duration flights could have critical health implications for 

crewmembers. 
Water-Soluble Vitamins 83

5. Remaining Questions 

Determinations of homocysteine (and related metabolites) before, during, and after flight 

should help resolve (or increase) any concerns about vitamin B12 in space crews. Vitamin B12

concentrations and stability in the space food supply should be determined. 

H. BIOTIN

1. Background 

Biotin is a required cofactor for pyruvate carboxylase, acetyl-CoA carboxylase isoforms 

1 and 2, propionyl-CoA carboxylase, and β-methylcrotonyl-CoA carboxylase [88]. The 5 

biotin-dependent enzymes are involved in carbohydrate, fatty acid, and amino acid 

metabolism [88]. 

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 [440]. 

Low-biotin diets administered to 10 healthy subjects who also consumed large amounts 

of avidin (an egg-white protein that binds biotin very tightly) showed signs of decreased 

biotin status by the third day [444]. At that time urinary excretion of 3-hydroxyisovaleric acid 

had increased significantly. Urinary excretion of biotin and its metabolites decreased 

significantly only after 7 to 17 days. Serum biotin did not decrease significantly, and it was 

suggested that serum biotin is not a sensitive indicator of marginal biotin deficiency [442]. 

The earliest and most sensitive indicator of a biotin deficiency is 3-hydroxyisovaleric acid 

excretion. Urinary biotin excretion, however, was used in animal studies as an indicator of a 

biotin deficiency, generally reported to occur about 2 to 3 weeks after beginning consumption 

of a biotin-free diet [389, 443]. 

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 [334, 441, 530]. 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 [59, 120, 411]. 

Frank biotin deficiencies are associated with neurological and dermatological 

manifestations, which are likely caused by the loss of function of biotin-dependent enzymes. 

Seizures, hearing loss, optic atrophy, dermatitis, and aciduria (associated with elevated blood 

concentrations of organic acids) are common symptoms of a frank biotin deficiency. There is 

no evidence of toxicity of biotin at high intake levels.

2. Findings from Space Flight and Ground-Based Research 

No data currently exist regarding biotin intake or status during or after space flight. 
84 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

3. Dietary Intake and Requirements 

The current documented requirement for dietary intake of biotin during space flight is 30 

μg/d. In the U.S., the dietary reference intake for biotin has been based only on adequate 

intake (AI) data [180]. To date, no RDA has been reported for biotin due to lack of data and a 

general consensus that colon bacteria synthesize biotin that contributes to the daily supply. 

Because microbial synthesis of biotin takes place in the lower part of the intestine, where 

nutrient absorption is limited, controversy exists about how much of the biotin produced by 

colon bacteria is available for host metabolism. The AI for adults is extrapolated from the AI 

for healthy infants consuming breast milk, and has been determined to be 30 μg/d for men 

and women > 19 years. 

4. Risks on Exploration Missions 

Nothing is known about biotin as related to space flight. While risk of deficiency on 

Earth is rare, alterations in synthesis metabolism or requirements during long-duration flights, 

or the occurrence of drug/nutrient interactions, could have significant health implications for 

the crew. 

5. Remaining Questions 

Biotin levels in the space food system need to be determined. Biotin status of astronauts 

during and after flight, and the fact that gastrointestinal changes during space flight may lead 

to changes in microbial synthesis of biotin, warrant further study. Furthermore, the interaction 

of biotin with some pharmacological agents (such as phenobarbital) included in the medical 

kit supplied to astronauts during space flight has been shown to yield biotin deficiencies in 

other populations [334]. 

I. PANTOTHENIC ACID

1. Background 

The primary function of pantothenic acid is in its role as a precursor of coenzyme A and 

as a component of acyl carrier protein [433]. Pantothenic acid, in the form of coenzyme A and 

acyl carrier protein, is required for numerous lipid, carbohydrate, and protein metabolic 

reactions. Coenzyme A is necessary for acetyl and acyl transfer reactions associated with 

catabolism, and it acts as a precursor to acyl carrier protein. Acyl carrier protein is also a 

coenzyme in fatty acid synthase complex. 

Free pantothenic acid is found in various parts of the body: 10 to 15 μmol/L in the liver, 

~100 μmol/L in the heart, 1 to 5 μmol/L in plasma, 50 to 100 μmol/L as coenzyme A, and 10 

μmol/L as acyl carrier protein. About 70% to 90% of coenzyme A is found in the 

mitochondria. Any excess pantothenic acid is excreted in urine [433]. 
Water-Soluble Vitamins 85

Since pantothenic acid is widely distributed in foods of both plant and animal origin, 

deficiencies have been reported only in cases where semisynthetic diets or antagonists to the 

vitamin were used, or in cases of multiple nutrient deficiencies [433]. Individuals became 

deficient after 63 days on a diet virtually devoid of pantothenic acid [191]. Deficiency of the 

vitamin is frequently associated with multi-nutrient deficiencies, making it difficult to detect 

specific symptoms of pantothenic acid deficiency [433]. There is no conclusive evidence that 

adverse effects occur from high intakes of pantothenic acid [433]. 

The requirement for pantothenic acid in a variety of metabolic reactions explains why a 

deficiency of the vitamin can cause neurological, immunological, hematological, 

reproductive, and gastrointestinal dysfunctions. Specific symptoms include dermatitis, growth 

retardation, numbness and burning of hands and feet, impaired antibody production, 

headache, fatigue, insomnia, increased sensitivity to insulin, and intestinal disturbances [433]. 

2. Findings from Space Flight and Ground-Based Research 

No data regarding pantothenic acid intake or status during or after space flight are 

currently available. 

3. Dietary Intake and Requirements 

The current documented requirement for dietary intake of pantothenic acid during space 

flight is 30 mg/d [460]. In the U.S., the dietary reference intake for pantothenic acid has been 

based only on adequate intake (AI) data [180]. No RDA has been reported for pantothenic 

acid. The AI for adults is based on mean intakes and is 5 mg/d for men and women > 19 

years. No upper limit has been reported for pantothenic acid, but doses of the vitamin as high 

as 10 to 20 g/d have been well tolerated, with occasional diarrhea reported [433]. Estimates of 

pantothenic acid in the ISS food system indicate that the requirements are being met (Table 

1). 

4. Risks on Exploration Missions 

The stability of pantothenic acid under conditions of long-term space flight (such as 

extended storage time and exposure to high-linear energy transfer radiation) will have to be 

determined in order to minimize risk for pantothenic acid deficiency symptoms. 

5. Remaining Questions 

Pantothenic acid levels in the space food system should be determined. Given the lack of 

information, and rarity of deficiency, at this point, no specific research is required. 

VIII. MINERALS

A. CALCIUM AND BONE

1. Background 

Calcium is essential for maintaining the body’s structural and mechanical functions, and 

it makes up 37% to 40% of the bone mineral hydroxyapatite in the body [234, 719]. In 

addition to its obvious role in the musculoskeletal system, calcium has a critical role in 

modulating the function of important proteins and regulating metabolic processes. Calcium 

binding is responsible for the activation of a wide range of proteins, including those involved 

in cell motility, blood coagulation, muscle contraction, neural transmission, glandular 

secretion, and cell division [559, 717, 719]. Circulating calcium levels are under tight control 

and are maintained within a narrow range [473]. 

Bone acts as the body’s reserve for calcium, and contains almost 99% of the calcium in 

the body [719]. Total skeletal calcium is on average 1100 to 1500 g, and inadequate calcium 

intake has significant impact on adult bone [276]. About 1% of the body’s calcium stores 

resides in the intracellular structures, cell membranes, and extracellular fluids [559]. 

During acute starvation, urinary calcium remains constant; the largest amounts of calcium 

loss occur in feces, with much of the mineral lost apparently coming from bone [313]. Blood 

calcium levels are extremely resistant to starvation, with no change found after 4 days of 

starvation in children [193], or 44 days of total fasting [285]. Studies in dogs and cats indicate 

that significant changes occur only when more than 35% of body mass is lost [448]. Blood 

calcium levels in humans after chronic semi-starvation are variable, but most studies indicate 

that plasma or serum calcium levels decrease [313]. Controlled calcium balance studies 

during semi-starvation provide more variable results, with individual calcium balances 

ranging from positive to negative [313]. 

Calcium depletion is not uncommon in many subgroups of the population. Calcium 

absorption may be decreased in a variety of disease states, including Crohn’s disease, 

diabetes, chronic renal failure, and malabsorption syndromes [559]. Although the daily 

calcium intake requirement rises with age, many elderly people and those in other population 

groups have inadequate intakes. Assessment of calcium deficiency by clinical laboratory 

analyses is difficult because circulating calcium is tightly regulated over a wide range of 

intakes [559, 719]. Imaging techniques (such as dual-energy X-ray absorptiometry and 
88 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

quantitative computed tomography) that enable determination of bone mineral content may 

provide a good indicator of long-term calcium nutritional status. 

Deficiency of calcium leads to reduced bone mass and osteoporosis. An excess of 

absorbed calcium leads to kidney stones, hypercalcemia, and ultimately renal insufficiency or 

even death. Increased dietary (as opposed to absorbed) calcium intake is not only not related 

to increased renal stone risk, it has been associated with reduced risk [236]. Intakes up to 

2500 mg/d are considered safe under normal conditions [559, 719]. 

2. Findings from Space Flight and Ground-Based Research 

Bone loss is a significant health concern for long-duration space flight [91, 261, 382, 

588]. As a result of skeletal unloading during flight [378, 484, 528, 598, 651, 726], bone 

mineral is lost, leading to increased urinary excretion of calcium [598, 725, 726]. It is often 

estimated that the rate of bone mineral loss during space flight is about 0.5% to 1% per month 

[379, 702, 718]. Averaged losses across all sites were estimated to be 2% to 9% [586]. The 

bone loss and an increased risk of renal stone formation during and after flight [508, 509, 729, 

730, 750] are significant. 

The Skylab studies showed that during space flight, bone mineral was not uniformly lost 

from all parts of the skeleton. Loss of bone tissue was greatest in weight-bearing bones such 

as the os calcis. Of the 3 men aboard the 59-day Skylab 3 mission, 1 lost a significant amount 

of os calcis bone mineral (–7.4%) but the other 2 did not (+2.3% and +1.4 %). Calcium 

excretion in the urine was 200% of the preflight value for the man who lost os calcis mineral 

and 50% of the preflight values for the other 2 men [598]. This subject-to-subject variability 

remains a hallmark of space flight-induced bone loss [382], and may provide insight to 

finding a means to mitigate this loss. 

Negative calcium balance was observed during the Skylab [361, 498, 598, 722, 724-726] 

and Mir [603, 609] missions. During the 84-d Skylab 4 mission, calcium balance was –200 

mg/d [498, 525, 725], but no significant calcium losses occurred during the 28-d Skylab 2 

mission [598, 718]. Increased urinary and fecal calcium excretion accounts for most of the 

deficit in calcium [361, 598, 603, 609, 722, 725, 726, 730]. During the Skylab 4 mission, 

calcium losses correlated roughly with mineral losses in the os calcis [723] and increases in 

the excretion of hydroxyproline [382, 525]. 

Preflight

FD3/4FD5/6

FD13/14FD20/21FD27/30

FD38

FD45/48FD58/59

FD73FD82

R+0R+1

R+3/4

R+14

8.5

9.0

9.5

10.0

10.5

11.0

11.5

Plasma calcium (mg %)

Figure 52. Plasma calcium of Skylab crewmembers (n = 9) before and after flight. Data are from Leach 

and Rambaut, 1977 [361]. 
Minerals 89

FD2 FD4 FD6 FD7 R+0 R+3 R+10

-25

-15

-5

5

15

25

Serum calcium

(%

Δ from preflight)

Figure 53. Serum calcium of Shuttle crewmembers (n = 2-6) during and after flight, expressed as a 

percent change from preflight values. Data are from Leach-Huntoon et al., 1987 [359]. 

Preflight

FD3/4FD5/6

FD13/14FD20/21FD27/30

FD38

FD45/48FD58/59

FD73FD82

R+0R+1

R+3/4

R+14

0

10

20

30

PTH (ng/mL)

Figure 54. Plasma parathyroid hormone (PTH) concentrations of Skylab crewmembers (n = 9) before 

and after flight. Data are from Leach and Rambaut, 1977 [361]. 

Because of the nature of calcium metabolism, the source of calcium loss from bone and 

increased urinary calcium excretion cannot easily be identified. Calcium excretion can be 

affected by dietary changes, alterations in absorption of calcium from the diet, secretion of 

calcium into the gastrointestinal tract, the rate of bone calcium deposition (that is, bone 

formation), and bone resorption. For space flight-induced bone loss to be mitigated, the 

mechanism must be known. Although early animal studies suggested that the primary change 

in bone metabolism was related to bone formation, the identification of markers specific to 

bone resorption in the late 1980s [156, 684] and the availability of commercial immunoassays 

in the 1990s [546, 577] allowed resolution of this matter: bone resorption increases during 

space flight and bone formation decreases or does not change significantly. 
90 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

3. Bone 

Bone resorption increases during space flight, as shown by the concentrations of bone 

resorption markers [84, 108, 575, 602] and by the results of calcium tracer kinetic studies 

[603, 609]. Urinary hydroxyproline was elevated during short-duration Shuttle flights [575] 

and longer duration Skylab flights [361, 362, 725]. Urinary collagen crosslinks, also markers 

of bone resorption [571], were elevated > 100% during space flight compared to preflight 

levels [602, 603]. Calcium tracer kinetics data indicated that bone resorption increased about 

50% during flight [603]. 

Bone formation either remains unchanged or decreases during space flight [603, 609, 

718]. As indicated by serum concentrations of bone-specific alkaline phosphatase and 

osteocalcin, bone formation was unchanged during Mir flights, but increased 2 to 3 months 

after landing [603, 609]. Trends toward decreased levels of bone formation markers were 

noted in 2 Mir studies with 1 subject each [84, 108]. The results of studies, using calcium 

tracer techniques, of bone formation in 3 Mir crewmembers [603, 609] were equivocal 

(formation unchanged or decreased). Together, increased resorption and decreased or 

unchanged formation yield an overall negative calcium balance [603, 609]. 

Preflight

R+0R+1

R+3/4

R+14

15

20

25

30

Alkaline phosphatase (IU)

Figure 55. Plasma total alkaline phosphatase of Skylab crewmembers (n = 9) before and after flight. 

Data are from Leach and Rambaut, 1977 [361]. 

A number of related factors likely contribute to the loss of bone mineral during 

weightlessness. Mir astronauts were observed to have decreased calcium absorption [603, 

609], which likely resulted from the decreased concentration of circulating 1,25-

dihydroxyvitamin D that was also observed in these crewmembers [603, 609]. Although it is 

believed to be important to maintain calcium intake during flight, the lower calcium 

absorption during flight suggests that maintaining or increasing calcium intake is not a viable 

countermeasure for weightlessness-induced bone loss, a fact proven in bed rest studies [244, 

619]. 

Space flight analog studies (such as bed rest) with humans have shown qualitative effects 

on bone and calcium homeostasis similar to those shown in flight studies [382, 502], with 

quantitative effects generally being of smaller magnitude. Effects include loss of bone mass 

[380, 620, 701, 749], decreased calcium absorption [376], increased urinary excretion of 

calcium and biochemical markers of resorption [22, 138, 143, 224, 245, 273, 374, 376, 620, 

721, 726], increased risk of renal stone formation [138, 273, 751], and decreased serum 

concentrations of parathyroid hormone [22, 607] and 1,25-dihydroxyvitamin D [21, 22, 376, 

607]. 
Minerals 91

That bone resorption increases during bed rest has been shown by histomorphometry 

[300, 701] and measurement of biochemical markers. Excretion of hydroxyproline [143, 224, 

376] increases during bed rest, and excretion of collagen crosslinks [376, 602, 607, 620] is 

elevated about 50% above control levels, compared with the increase of greater than 100% 

during flight [602, 603]. 

The concentrations of biochemical markers [376, 607, 749] indicate that bone formation 

is unchanged during bed rest, but histomorphometry data from bone biopsies show that bone 

formation decreases [22, 300, 701]. This difference likely reflects the difference between sitespecific (biopsy) and systemic (biochemical markers) indices of bone formation. After 

ambulation begins following bed rest, bone formation generally increases [376, 749]. 

Bone loss and altered calcium metabolism occur in paralyzed individuals (as reviewed by 

Elias and Gwinup [150]), and a number of similarities can be found between these changes 

and those associated with space flight [319, 428, 454, 638]. The loss of bone that occurs after 

spinal cord injury seems to stabilize after about 25 weeks [438]. Studies of bone metabolism 

have not been possible during space missions of this duration, and the limited postflight bone 

assessment does not allow determination of the rate of loss. 

If the rate of bone calcium loss is constant throughout a flight (a reasonable assumption 

judging by collagen crosslink excretion data [602, 603, 609]), then about 250 mg of bone 

calcium is lost per day during flight [217, 603, 609, 725]. 

Long-term follow-up data on bone recovery are far from complete [587, 670]. However, 

if the rate of postflight recovery estimated from biochemical data is also assumed to be 

constant (reasonable according to ground-based [380] and flight [603, 609] data), then the 

rate of recovery is about +100 mg/d [603, 609]. By these estimates, on flights up to about 6 

months, it takes 2 to 3 times the mission duration to recover the lost bone. A recent analysis 

of bone recovery data from dual-energy x-ray absorptiometry analyses suggests that a 50% 

recovery of bone mass occurs in the initial 9 months after flight [587]. For longer exploration 

missions, however, the usefulness of these assumptions comes into question, as space flight 

data are not available for these durations. Although more data clearly are required to validate 

this hypothesis, it nevertheless has significant implications as mission durations increase. 

4. Bone Loss Countermeasures 

Many countermeasures to bone loss have been proposed and tested, from mechanical to 

pharmacological to nutritional forms. 

A. Mechanical 

Exercise countermeasures have been implemented during flight as far back as the Skylab 

missions (Skylab was the first vehicle to allow enough room for exercise). In addition to 

flight experiments, extensive ground-based testing has been done to evaluate the effectiveness 

of exercise as a countermeasure for muscle, bone, and cardiovascular maladaptations that 

occur during flight [112, 232, 502, 563]. For bone, the challenge remains to attain the force 

required to stimulate bone sufficiently to mitigate loss. Many types of exercises and devices 

have been studied, alone or in rare cases in combination, with mixed results. Although 

ground-based studies have demonstrated positive effects of exercise (for example, treadmill, 

flywheel, and weight stacks) on bone (assessed by various means from densitometry to 
92 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

biochemistry) [47, 216, 542, 578, 607, 664, 714, 759], flight validation has not been achieved 

to date [354]. Many factors contribute to this lack of success, including the quantitative 

difference between bone loss during bed rest and space flight and the function, availability, 

and utilization of on-orbit hardware. The question of whether the same degree of exercise 

effectiveness can be reached during flight as in ground analogs is yet to be answered. 

Vibration has also received much attention recently in the hope that it can provide a 

viable musculoskeletal countermeasure [44, 58, 550], and the initial ground-based evaluations 

are underway. As with all proposed countermeasures, vibration must first be proven effective 

in ground analog studies (such as bed rest), and if it is clearly successful, then in-flight 

validation studies can be conducted. 

Under the assumption that lack of gravity is the stimulating factor in the bone loss of 

space flight, replacement of gravity by centrifugation (“artificial gravity”) has been proposed 

as a countermeasure for multiple body systems [104, 700], particularly for bone. Some of the 

artificial-gravity studies have relied on short-radius centrifuges [213], others on rotating 

exercise devices [737, 738] intended to provide gravitational impact as well as physical 

exercise. Artificial gravity or hypergravity has been shown to positively affect bone, in 

human and some animal studies [283, 463, 464]. Vernikos and colleagues reported that 

intermittent exposure to 1 Gz (by standing or walking) during a 4-d head-down-tilt bed rest 

was effective in preventing the increase in urinary calcium that typically occurs during bed 

rest [699]. In a recent study, 1 hour per day of centrifugation resulting in 1 Gz at the heart and 

2.5 Gz at the feet was ineffective for bone [614]. The optimal artificial gravity prescription for 

bone, including dose, duration, and frequency of centrifugation, remains to be clarified [103], 

along with its potential impact on nutrition and related systems [247]. 

B. Pharmacological 

Pharmacological agents, the most common being the bisphosphonates, have also been 

tested for their ability to mitigate weightlessness-induced bone loss. Many ground analog 

studies of bisphosphonates (including bed rest studies and studies of patients immobilized 

because of spinal cord injury or other reasons) have been conducted, with generally positive 

findings [95, 216, 282, 381, 397, 415, 439, 487, 563, 581, 664, 701, 714]. However, ongoing 

discussion and debate surround the relative safety of these compounds for use in otherwise 

healthy individuals (astronauts), as opposed to the target population for whom the drugs were 

developed (patients with disorders such as osteoporosis). In addition to resolving safety 

concerns, investigators have yet to determine the optimal drug, dose, and schedule of 

administration during space flight. As noted above with exercise, given that the bone loss of 

bed rest is about half that of space flight, there is little reason to believe that the same dose of 

drug will have the same effectiveness in both environments. Moreover, data from animal 

studies suggest that the disuse- or space flight-induced increase in bone resorption cannot 

fully, or chronically, be mitigated by bisphosphonates [390, 391]. 

Endocrine therapies, including exogenous calcitonin administration [224, 563], have also 

been attempted, albeit unsuccessfully. In animal models, testosterone has also been suggested 

as a bone loss countermeasure [734, 735] because data have documented a reduction in 

testosterone concentrations during flight in human, animal, and cellular models [640-642, 

644-647]. 
Minerals 93

C. Nutritional 

One of the most obvious nutritional countermeasures—providing calcium—does not 

protect against bone loss [755]. This result is likely related to the decreased calcium 

absorption seen during bed rest [376] and space flight [603, 609, 754]. Phosphate 

supplementation, used in an attempt to reduce calcium excretion, was also ineffective [271]. 

Combination therapy with calcium and phosphorus was also unsuccessful at mitigating bone 

loss and hypercalciuria [224]. 

Other nutrients, specifically sodium, protein, potassium, vitamin K, and omega-3 fatty 

acids, have also been proposed and/or tested as bone loss countermeasures [758]. These are 

discussed in detail in other sections of this book. 

5. Dietary Intake and Requirements 

The current documented space flight requirement for dietary intake of calcium during 

flight is 1200 to 2000 mg/d [460], higher than the initial ISS requirements of 1000-1200 mg/d 

[458]. In the U.S., adequate intake is defined as 1000 mg for men and women ages 31 through 

50 years and 1200 mg for men and women 51 years and older [462]. The ISS menu provides 

about 1000 mg calcium/d, meeting the existing requirement. Meeting the higher intake 

requirement of 1200 to 2000 mg/d defined in 2005 [460] would help reduce the 

phosphorus:calcium ratio from the existing ratio of 1.8 (Table 1), a negative factor for bone 

health (see the Phosphorus section). 

6. Risks on Exploration Missions 

The ability to understand and counteract weightlessness-induced bone mineral loss will 

be vital to crew health and safety during and after extended-duration space station and 

exploration missions [20, 241, 447, 563, 587, 588, 612]. Changes in the endocrine regulation 

of bone metabolism seem to reflect adaptation to the weightless environment. Decreases in 

calcium absorption and plasma levels of parathyroid hormone and 1,25-dihydroxyvitamin D 

are responses that would be expected to occur if the resorption of bone increases as the body 

adapts to an environment in which bones bear less weight than on Earth. The evidence for 

these responses, and the lack of improvement provided by earlier dietary countermeasures, 

indicate that supplementation of the diet with nutrients such as calcium and vitamin D will 

not correct this problem [244]. Several other nutrients (for example, sodium, 

protein:potassium ratios, n-3 fatty acids, and vitamin K) do show promise as nutritional 

countermeasures, and both ground and flight testing of these are underway. In any event, 

adequate nutrition will be a required component in the success of whatever countermeasures 

are identified and implemented [239, 241]. 

For planetary missions, the ability of a partial terrestrial G force (such as Mars’ 0.38 G) 

to reduce bone loss, or even allow recovery to begin, is unknown. Although no data on 

responses to partial G are available, the general consensus among investigators is that forces 

less than 0.5 G are likely to be of little value. 
94 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

7. Remaining Questions 

The effect of near-weightlessness on the human skeletal system is one of the greatest 

concerns in safely extending space missions [20, 241, 261, 282, 447, 486, 563, 587, 588, 606, 

612]. Adequate intake of dietary calcium will be crucial for maintaining skeletal health. Both 

dietary protein (amount and type) and dietary sodium affect calcium metabolism. In addition, 

the use of pharmacological countermeasures against bone loss may have implications for 

calcium homeostasis. Specifically, the bisphosphonates exert their effects by inhibiting 

osteoclast-mediated bone resorption, and this inhibition lowers serum calcium in subjects 

who are normocalcemic or hypercalcemic [68]. It is recommended that subjects receiving 

bisphosphonates have adequate vitamin D status before therapy, and that their calcium status 

be monitored [46, 67, 506]. 

Although it is unlikely that diet is solely responsible for the bone mineral loss associated 

with space flight, even modest protective effects from a balanced diet would benefit crew 

health. Using diet modification as a countermeasure has several advantages, including no 

additional costs and no additional time required of astronauts during flight. The ratio of acid 

and base precursors in the diet could be an important predictor for the extent of bone loss 

during space flight, and could be determined from the menu choices before flight. 

Maintaining a diet balanced in acid and base precursors would involve food choices, and 

could be done with the help of a dietitian planning the menus. Furthermore, until in-flight 

resources for research are available, a pre- and postflight investigation of the relationship 

between diet and bone metabolism could provide a basis for defining optimal nutritional 

recommendations during recovery after space flight. 

B. PHOSPHORUS

1. Background 

Phosphorus is an important component of cell membranes and bone mineral. Phosphate 

accounts for about 60% of bone mineral [234], and most (85%) of the body’s extracellular 

phosphorus is in bone [16]. Phosphorus is also an essential element of most enzymes, cellular 

messengers, and carbohydrate fuels. 

Deficiency of phosphorus leads to hypophosphatemia, which causes cellular dysfunction 

and can lead to anorexia, muscle weakness, bone pain, and ultimately rickets, or even death. 

Osteomalacia, a defect in bone mineralization, often occurs as a result of long-term 

phosphorus deficiencies. Inadequate intake of phosphorus can cause the release of calcium 

from bone, cardiomyopathy, and a reduction in chemotactic, phagocytic, and bactericidal 

properties of granulocytes [324]. An excess of phosphorus leads to hyperphosphatemia, 

ectopic calcification of the kidney, or even death. Excessive phosphorus intake has been 

shown to affect calcium absorption by increasing excretion of endogenous calcium in the 

feces [123]. 

Human studies show that phosphorus can be depleted by daily antacid treatment with 

either magnesium-aluminum hydroxide (60 mL, 4 times per day) or aluminum hydroxide (30 

mL, 4 times per day) [399]. Serum calcium of these subjects was elevated within 12 days of 
Minerals 95

treatment, and by day 20 phosphorus balance was negative [399]. Animal studies have 

demonstrated that removal of phosphate from the diet rapidly produces hypercalcemia, 

hypercalciuria, and hypophosphaturia. Rats fed a low-phosphate diet showed signs of 

deficiency after 11 days [289]. 

2. Findings from Space Flight and Ground-Based Research 

Plasma phosphate was determined in Skylab crewmembers before, during, and after 

flight (Figure 56), and showed a tendency for increased circulating concentrations during 

flight. 

Preflight

FD3/4FD5/6

FD13/14FD20/21FD27/30

FD38

FD45/48FD58/59

FD73FD82

R+0R+1

R+3/4

R+14

2.0

2.5

3.0

3.5

4.0

4.5

Plasma phosphate (mg %)

Figure 56. Plasma phosphate of Skylab crewmembers (n = 9) before, during, and after flight. Data are 

from Leach and Rambaut, 1977 [361]. 

Long-duration ISS space flight data showed that urinary phosphorus concentrations were 

about 45% less after landing than before launch (Figure 57) [610].

Preflight Postflight

0

500

1000

1500

Urinary phosphorus (mg/d)

Figure 57. Urinary phosphorus of ISS crewmembers (n = 23) before and after long-duration space 

flight. Data are from Smith et al., 2005 [610]. 

Excretion of phosphorus during untreated bed rest was not changed [761] from 

ambulatory conditions. An earlier study of 3 subjects revealed increased urinary phosphorus 

and negative phosphorus balance [143]. In bed rest studies, investigators have attempted to 

use combination therapy with calcium and phosphorus to mitigate bone loss and 

hypercalciuria, with trends in the right direction but no significant changes [224]. 
96 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

3. Dietary Intake and Requirements 

In the U.S., the RDA for phosphorus [276] is 700 mg/d for men and women 19 years of 

age and older. The current documented space flight requirement for dietary intake of 

phosphorus during flight is 700 mg/d, and phosphorus intake is not to exceed 1.5 times the 

calcium intake [460]. Although the ratio is the same as in initial ISS requirements, the 

phosphorus recommendation has been reduced [458]. The ISS menu provides an excess of 

phosphorus, with an average of 1856 mg phosphorus per day, and a phosphorus:calcium ratio 

of 1.8 (Table 1). Actual intakes from Apollo, Skylab, and Shuttle crews were closer to the 

desired 1.5 P:Ca ratio (Table 2). 

4. Risks on Exploration Missions 

Adequate phosphorus intake before and during flight will be crucial for preserving bone 

quality and quantity. In addition, a dietary phosphorus:calcium ratio greater than 1.5 is known 

to decrease calcium absorption, which could impair skeletal integrity. Serum phosphorus rises 

with increasing phosphorus intake, and if hyperphosphatemia occurs, it can result in 

calcification of the kidney. For this reason, ensuring optimal phosphorus intake during flight 

becomes very important [718]. Because phosphorus deficiency can cause muscle weakness 

and osteomalacia, maintaining adequate status of phosphorus during flight will be vitally 

important for preventing impaired performance on landing, which could limit crew capability 

for getting out of the spacecraft in an emergency. 

5. Remaining Questions 

Nominal determinations of phosphorus content of the space food system are required, as 

well as further investigation of the mechanism and implications of decreased phosphorus 

excretion after long-duration space flight. The implications of the existing dietary 

phosphorus:calcium ratio exceeding the guidelines should be evaluated. 

C. MAGNESIUM

1. Background 

Magnesium is the fourth most abundant cation in the body, and within the cell is second 

only to potassium [436, 707]. It is required as a cofactor for more than 300 enzyme systems 

and serves as a substrate for phosphate transfer reactions in all cells [707]. More than half of 

the body’s magnesium is in bone, about 30% in muscle, and the remainder mostly in soft 

tissue [583]. 

While magnesium deficiency can be induced by many causes (from drug-nutrient 

interactions to plain inadequate intake), few studies have addressed experimental magnesium 

depletion in humans. Consuming a diet containing 10 mg/d for 110 days led to a steady 
Minerals 97

decline in plasma magnesium to levels 10% to 30% of control values, and urinary magnesium 

levels were negligible (< 1 mEq/d) within 7 days [583]. Abnormal neuromuscular signs 

occurred in 5 of 7 subjects after 25 to 110 days of magnesium deficiency [583]. Deficiency of 

magnesium leads to neuromuscular hyperexcitability, seizures, cardiac complications, or even 

death [276]. Adequate intake of magnesium is necessary to prevent hypocalcemia, resistance 

to vitamin D, and resistance to parathyroid hormone. 

No evidence has been reported of adverse effects associated with toxicity from naturally 

occurring sources of magnesium, but very large doses may cause gastrointestinal distress. 

Furthermore, excessive intake from supplements has been shown to impair calcium 

absorption [583]. 

2. Findings from Space Flight and Ground-Based Research 

Decreased urinary magnesium after flight, compared to before flight, seems to be a 

hallmark of space flight. Apollo serum and urinary magnesium are shown in Figure 58 [366]. 

Serum magnesium trends downward, as seen with in-flight and postflight Shuttle data shown 

in Figure 59. 

Preflight Postflight 0.0

0.5

1.0

1.5

2.0

2.5

-4.5%

Serum magnesium (mg/100 mL)

Preflight Postflight

0

2

4

6

8

10

-36%

Urinary magnesium (mg/24 h

Figure 58. Serum (n = 32) and urinary (n = 23) magnesium from Apollo crewmembers. Numbers in 

bars represent the percent change from preflight values. Adapted from Leach et al., 1975 [366].

FD2 FD4 FD6 FD7 R+0 R+3 R+10

-10

-5

0

5

10

Serum magnesium

(%

Δ from preflight)

Figure 59. Serum magnesium of Shuttle crewmembers (n = 2-6) during and after flight, expressed as a 

percent change from preflight values. Data are from Leach-Huntoon et al., 1987 [359]. 
98 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

At landing, crewmembers on Skylab flights had lower plasma magnesium (Figure 60), 

but it had returned to normal by 2 weeks after landing. 

Skylab

Preflight

R+0R+1

R+3/4

R+14

1.8

1.9

2.0

2.1

2.2

2.3

Plasma magnesium (mg %)

Figure 60. Plasma magnesium of Skylab crewmembers (n = 9) before and 0, 1, 3-4, and 14 days after 

flight. Data from Leach and Rambaut, 1977 [361]. 

Several studies show that magnesium metabolism may be altered during and after longduration space flight [361, 372, 610]. After crewmembers had spent 4 to 6 months in space, 

their urinary magnesium was about 45% less than it was before flight [610]. The causes and 

implications of this are being evaluated in ongoing ground-based and flight studies. 

Pre mean R+0

1.50

1.75

2.00

2.25

2.50

2.75

Serum magnesium (mg/dL)

Pre mean R+0

0

50

100

150

200

Urinary magnesium (mg/d)

Figure 61. Serum (left panel) and urinary (right panel) magnesium before and after 4- to 6-month space 

flights on the International Space Station. Each line represents 1 crewmember. The “Pre mean” point on 

each line is the average of data collected about 6 months and about 6 weeks before launch. R+0 = 

Recovery plus zero days, that is, landing day. These samples are typically collected 2 to 8 hours after 

landing. Data are from Smith et al., 2005 [610]. 

A Russian report on the impact of space flight on the magnesium content of bones 

documented 12% to 32% lower concentrations in the compact layer of the femoral epiphysis 

and diaphysis, vertebral body, and sternum of Salyut-1 space station crewmembers than in 

nonflight controls [519]. These changes were reported as appearing “with a high degree of 

certainty.” No changes were observed in the calcaneus. (Note: This study reported on the 

autopsy results after the tragic end of the 24-d Salyut-1 mission, compared to controls.) 

Magnesium balance was slightly negative during extended-duration bed rest studies 

conducted in Russia [216], with little effect of exercise or bisphosphonate. Recent studies 
Minerals 99

conducted in the U.S. have shown a decrease in magnesium excretion in short- and longduration bed rest [761, 762]. Artificial gravity had no effect on magnesium [762]. 

Magnesium shows promise for reducing the risk of renal stone formation [568]. In 

ground-based studies, potassium-magnesium citrate has proven effective in reducing bed restinduced risk [751], but flight validation tests have yet to be conducted. 

3. Dietary Intake and Requirements 

The current documented requirement for dietary intake of magnesium during space flight 

is 420 and 320 mg/d for men and women respectively [460], compared to the original ISS 

requirement of 350 mg [458]. In the U.S., the RDA for magnesium [276] for men aged 19 to 

30 years is 400 mg/d, and for men 31 to 70 years it is 420 mg/d. For women aged 19 to 30 

years the RDA is 310 mg/d, and for those 31 to 70 years it is 320 mg/d. The ISS food system 

provides an average of 424 mg/d (Table 1). 

4. Risks on Exploration Missions 

Adequate magnesium intake before and during flight will be needed to reduce the 

potential for altered magnesium status, and to help preserve bone quality and quantity. 

Maintaining adequate magnesium status during flight will be critical for maintaining 

musculoskeletal structure and function and thus for preventing impaired performance on 

landing, which might limit crew capability for getting out of the spacecraft in an emergency. 

5. Remaining Questions 

Nominal determinations of magnesium content of the space food system are required. 

The significant decrease in urinary magnesium excretion after space flights (described above) 

also warrants further investigation. 

D. IRON AND HEMATOLOGY

1. Background 

Iron is an essential element involved in oxygen transport, oxidative phosphorylation in 

carbohydrate and lipid metabolism, and electron transport in cytochromes and cytochrome 

oxidase [41, 159]. 

Body iron is composed of essential iron compounds (70% of the total), which include 

hemoglobin (59%), functional tissue iron (myoglobin and metalloenzymes, 13%), and 

transport iron (bound to transferrin, < 0.1%); and nonessential storage iron (30%), which 

includes ferritin and hemosiderin [41]. Serum ferritin has been shown to be a sensitive 

indicator of iron stores [435]. Ferritin is exponentially correlated with storage iron, as 
100 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

determined by quantitative phlebotomy in patients with iron overload [517]. Most 

investigators have looked at ferritin as an indicator of iron depletion, and it has been 

hypothesized to represent a rapidly mobilized iron pool, with hemosiderin being mobilized as 

the ferritin pool becomes depleted [435]. 

Iron is also thought to be involved in immune system function. Changes in serum ferritin 

and transferrin are observed during infection and as part of the inflammatory response. The 

inflammatory response is characterized by increased clearance of iron from plasma, increased 

uptake of iron by the reticuloendothelial system, and increased ferritin synthesis, inducing 

elevated serum ferritin levels [26]. The upper limit of serum ferritin in the presence of 

inflammation has been reported to be between 50 and 100 μg/L [55, 394]. 

Iron deficiency is the most common nutritional deficiency worldwide, but iron toxicity is 

also worthy of concern. Deficiency of iron leads to anemia, fatigue, reduced work capacity, 

impaired behavior and intellectual performance, cognitive deficits and memory loss, heart 

palpitations, impaired thermoregulation, decreased immune function, or even death [121, 402, 

705]. Toxicity of iron may lead to tissue damage or cancer. High iron intakes have also been 

related to gastrointestinal distress. The toxic potential of iron derives from its ability to exist 

in 2 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 [740]. The distinct relationship between iron stores and 

oxidative damage is clear [680]. Anemia has also been associated with inflammation [529]. 

Adaptation of iron metabolism in humans typically allows the maintenance of normal 

body iron in spite of disparate physiological requirements and dietary supply [113]. Body 

iron, about 4 g in the adult human, is determined by physiological iron demands, dietary 

supply, and adaptation [41, 113, 172]. Dietary iron is a function of both content and 

bioavailability of total food iron; bioavailability is lower in nonheme than in heme iron 

sources. Dietary factors that inhibit iron absorption include tea, coffee, bran, calcium, 

phosphate, egg yolk, polyphenols, and certain forms of dietary fiber [41]. Conversely, meat, 

fish, poultry, and ascorbic acid will enhance the bioavailability of nonheme iron. 

Adaptation to variations in iron demand and supply is well documented [41, 172] in 

situations of iron deficiency and overload, and is regulated by alterations in transport, 

absorption, and storage of iron. Daily dietary iron absorption is 1 to 3 mg [41, 178], but the 

internal iron requirement is far in excess of this, with significant flux of iron through the 

system. Because a large percentage of body iron circulates in the red blood cells (RBCs), 

disordered RBC metabolism can cause marked changes in iron kinetics and metabolism. 

Transferrin saturation is primarily a gauge of iron supply to tissues, but this test is subject 

to the large biological variation that occurs in serum iron concentration [41]. The delivery of 

iron to the erythroblast (RBC precursor) is mediated by the interaction of plasma transferrin 

with transferrin receptors located on the cell surface [114, 269]. The number of transferrin 

receptors is regulated by both iron status and formation of RBCs [43, 667]. Although ~80% 

of the transferrin receptors are located in the bone marrow where RBCs are formed, a 

truncated form of the receptor has been identified in human serum and plasma, and has been 

shown to be a reliable index of iron status [522]. Serum transferrin receptors may reflect the 

availability of iron for erythropoiesis (formation of RBCs) [165, 177, 317, 591]. Unlike serum 

ferritin, serum transferrin receptors are not influenced by infection or chronic inflammation 

[317, 339, 667]. Moreover, serum transferrin receptors have been shown to be sensitive to 
Minerals 101

(that is, decreased in the presence of) iron deficiency, inefficient erythropoiesis, and iron 

overload [43, 339]. 

Intracellular iron homeostasis requires coordination of processes of iron uptake, 

intracellular storage, and utilization [337]. Studies have shown that these processes occur 

under the aegis of regulatory factors that exert reciprocal control of the transferrin receptor 

and ferritin mRNA expression [337]. Storage (ferritin) and utilization (erythropoietic) 

pathways are stimulated and uptake pathways are depressed when intracellular iron status is 

replete, with the reverse occurring in the presence of intracellular iron depletion [337]. 

2. Findings from Space Flight and Ground-Based Research 

Decreased red blood cell (RBC) mass is a consistent finding after short- and long-term 

flights [8, 290, 293, 347, 363, 683]. This “space flight anemia” was observed as early as 

Gemini missions in the 1960s [173]. The initial decrease in RBC mass occurs at a rate slightly 

greater than 1% per day, with an eventual loss of 10% to 15% within 10 to 14 days of flight 

[8, 363, 683]. During the first several days of space flight, hematocrit is either unchanged 

[600] or slightly elevated [8, 363, 683]. When elevation is noted, it is not as great as would be 

predicted from the decrease in plasma volume [365]. 

An early hypothesis for the cause of decreased RBC mass was that RBC synthesis in 

space was understimulated compared to synthesis on the ground [293]. Decreased release of 

mature RBCs into the circulation is associated with a decrease in circulating erythropoietin 

concentrations. Serum erythropoietin decreases in the first few days of space flight, but it 

returns to preflight levels later and iron turnover is unchanged during flight [8, 683], 

indicating that synthesis of RBCs and hemoglobin is unchanged. 

0 20 40 60 80 100 120

-30

-20

-10

0

10

Mission duration (days)

%

Δ from preflight

Figure 62. Red blood cell mass (mL/kg body mass) after space flight. Each point represents 1 

crewmember. Data are expressed as percent change from preflight values. Adapted from Smith, 2002 

[605]. 

Nevertheless, the release of new red cells is halted upon entry into weightlessness [7, 8, 

540, 683], and newly released RBCs are selectively removed from the circulation [7]. These 
102 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

nascent cells are larger than the more mature circulating RBCs, allowing them to be 

selectively destroyed [7]. Removal of mature red cells from the circulation is unchanged 

during flight [8]. 

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, so that a 

dilutional “anemia” often occurs after flight [600]. For example, a 3% to 5% decrease in 

hematocrit between landing (R+0 days) and R+3 days is common after both short- and longduration flights [600]. 

Although the in-flight decrease in RBC mass is significant, the efficient postflight 

recovery suggests that it represents an adaptation to weightlessness. After the first weeks of 

flight, RBC mass and body fluid volumes reach new plateaus (lower than on Earth), as shown 

by data from long-duration flights [111, 347, 350, 360]. The triggering mechanism for these 

changes is unknown. One hypothesis is that the body senses a decreased requirement for 

blood volume and adapts accordingly. This may be related to changes in fluid (circulatory) 

dynamics and reduced gravitational strain on the circulatory system during flight, which may 

result in easier delivery of oxygen to tissues, or to the decreased plasma volume and increased 

concentration of RBCs in the first few days of space flight. The decrease in RBC mass has no 

documented functional consequences. 

Serum iron concentrations are normal or elevated during and after flight [8, 683]. Serum 

ferritin concentrations increase during and after both short- and long-duration flights [10, 

605]. 

Bed rest studies have not proven to be consistently reliable models for the hematological 

changes of space flight. Early bed rest studies showed a decrease in RBC mass during bed 

rest, but erythropoietin was unchanged and hematocrit increased [147], suggesting that the 

mechanisms that bring about hematological changes during bed rest are different from those 

that act during flight. If the reduced RBC mass during flight is caused by the reduced 

gravitational load on the circulatory system, it is reasonable to assume that bed rest alone 

would not alleviate these forces, but would only reposition them. More recent studies have 

shown small changes in iron status measurements, the most consistent being a drop in 

hematocrit and hemoglobin after reambulation [761, 762], suggesting an impact of plasma 

volume replacement, with a smaller role of hematopoiesis. 

Preflight Postflight

0

10

20

30

Serum iron (μmol/L)

Preflight Postflight

0

100

200

300

400

Serum ferritin (μg/L)

Figure 63. Serum iron and ferritin in ISS crewmembers (n = 23) before and after long-duration space 

flight. Data are from Smith et al., 2005 [610]. 
Minerals 103

Another model is provided in studies involving changes in altitude, where the descent 

from high to low altitude induces changes similar to those observed for space flight 

(decreased red cell mass, increased iron storage) [539]. Exogenous erythropoietin prevented 

the changes [539], suggesting that it is involved in the regulating mechanism, as it may be in 

the initial change in space flight. 

The NASA Extreme Environment Mission Operations (NEEMO) undersea environment 

provides an excellent space flight analog, specifically with respect to the environment in the 

NEEMO habitat [608]. Because of the increased air pressure in the habitat, crewmembers are 

exposed to higher oxygen pressures, which increase their risk for oxidative damage to DNA, 

proteins, and lipids [13, 27, 139, 548]. Probably because of the increased pressure and greater 

oxygen availability, newly formed red blood cells are destroyed in a process called 

neocytolysis (which also occurs in space flight) [9, 131, 538, 540], and body iron stores are 

elevated [605, 610]. As discussed above, excess iron can act as an oxidant and cause tissue 

damage [71, 202]. 

3. Dietary Intake and Requirements 

The current documented space flight requirement for dietary intake of iron is 8 to 10 

mg/d for men and women. In the U.S., the RDA for men 19 to 70 years is 8 mg/d, and for 

women aged 19 to 50 years it is 18 mg/d, dropping to 8 mg/d in women over 50. Historical 

space flight iron requirements for missions of 12 to 30 days were less than 10 mg/d [457, 

458], matching the RDA at the time. 

Dietary iron provided by the space food system has always exceeded the requirement, 

and intakes have often been much higher (intakes as high as 20 to 25 mg iron per day have 

been observed, and the menu provides an average of over 22 mg/d, Table 1). This gives 

reason for concern because of the potential for elevated tissue iron to cause deleterious 

effects, including oxidative damage [680]. This is a rare gender-based effect: women, who are 

at increased risk of iron deficiency on Earth, may actually be protected against iron overload 

during flight [226]. 

4. Risks on Exploration Missions 

One consequence of the decreased RBC mass during space flight is that the iron released 

when new RBCs are destroyed is processed for storage. Increased iron storage and excess 

dietary iron intake during long-duration exploration missions pose a risk of iron toxicity and 

other effects of iron overload. Iron-related radical ions could form during iron-overload 

situations, and this could confound damage induced by ionizing radiation and inflammatoryimmune injury [178]. Serum concentrations of ferritin and soluble transferrin receptor have 

been linked to evidence of DNA damage in ground-based models [680]. Furthermore, the 

formation of free radicals subsequent to elevation of iron stores has also been linked on Earth 

to cardiovascular disease and cancer. Although aspects of some of the evidence supporting 

this thesis contradict each other [25, 574], a correlation between coronary heart disease and 

iron status has been described in a number of recent studies [357, 556, 654], and an 

association between increased incidence of myocardial infarction and increased iron stores (as 
104 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

measured by serum ferritin) has been observed [556, 653]. In a prospective Finnish study, 

increased risk of all cancer types combined and colorectal cancer in particular was associated 

with high iron stores [323]. The relationship between iron, lipids, and cancer has also been 

documented in the Framingham study [416]. A relationship has also been indicated between 

excessive iron stores and ascorbic acid deficiency; when reductions in ascorbic acid occur, 

vitamin A and selenium tend to exacerbate iron-induced peroxidation processes [565]. These 

data suggest that the alterations in erythropoiesis and iron metabolism that occur in 

microgravity could cause significant changes affecting crew health. 

5. Remaining Questions 

Better characterization of iron metabolism during flight is warranted because of the high 

levels of dietary iron and the potential for iron to act as an oxidizing agent during space flight, 

complicated by increased radiation levels. Iron absorption has yet to be determined during 

flight. Additionally, the relationship between iron storage and oxidative damage during flight 

has not been fully elucidated. 

E. COPPER

1. Background 

Copper is an essential cofactor for enzymes involved in energy production, metabolism 

of oxygen and iron, maturation of the extracellular matrix and neuropeptides, and 

neuroendocrine signaling [518]. Deficiencies in copper have implications for bone health, the 

nervous system, immune function, the cardiovascular system, and lipid metabolism [518]. 

Copper is involved in bone health, specifically related to lysyl oxidase function and collagen 

synthesis [497, 518]. 

Copper is not usually stored in tissues, but liver, brain, and kidney typically contain the 

largest amounts per unit tissue mass [518]. Total body copper is about 50 to 120 mg (0.79 to 

1.9 mmol) [124]. Copper transport and regulation involve the blood protein ceruloplasmin. 

Frank copper deficiency is rare in human populations consuming a normal diet; however, 

copper deficiencies have been noted in infants fed milk formulas, infants recovering from 

malnutrition and fed cow’s milk, and patients receiving total parenteral nutrition for a 

prolonged period [181]. Six patients fed (through the gastrointestinal tract) a diet containing 

15 μg copper/100 kcal for 12 to 66 mo [258] developed a copper deficiency. 

When copper deficiency occurs it leads to normocytic, hypochromic anemia, decreased 

production of leukocytes and neutrophils, defects in connective tissue (specifically in collagen 

synthesis) that can lead to vascular and skeletal problems and central nervous system 

dysfunction, or even death [181]. Heartbeat irregularities have also been reported in cases of 

copper deficiency [437]. 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 [258]. Toxic concentrations of 

copper lead to oxidative damage, gastrointestinal distress, liver damage, or even death [518]. 
Minerals 105

2. Findings from Space Flight and Ground-Based Research 

Serum copper and ceruloplasmin of ISS crews have been determined as part of the 

medical requirement to assess nutritional status in long-duration crewmembers [459, 610]. 

Pre mean R+0

0

10

20

30

μmol/L

Figure 64. Serum copper before and after 4- to 6-month missions on the International Space Station. 

Each line represents 1 crewmember. The “Pre Mean” point for each line is the average of data collected 

about 6 months and about 6 weeks before launch. R+0 = Recovery plus zero days, that is, landing day. 

These samples are typically collected 2 to 8 hours after landing. Data are from Smith et al., 2005 [610]. 

Pre Mean R+0

0

10

20

30

40

50

60

70

mg/dL

Figure 65. Serum ceruloplasmin before and after 4- to 6-month missions on the International Space 

Station. Each line represents 1 crewmember. The “Pre Mean” point on each line is the average of data 

collected about 6 months and about 6 weeks before launch. R+0 = Recovery plus zero days, that is, 

landing day. These samples are typically collected 2 to 8 hours after landing. Data are from Smith et al., 

2005 [610]. 

One Russian report on the effect of space flight on copper content of bones [519] 

documented “non-uniform changes” in copper content of bone from different regions after 

flight compared to nonflight controls. Copper content of the femoral epiphysis was 81-159% 

greater, while the amounts of copper in the vertebral body and sternum were 36% and 58% 

less, respectively. (Note: This study reported on the autopsy results after the tragic end of the 

24-d Salyut-1 mission, compared to controls.) 

During a 17-week bed rest study, copper balance was unchanged, but after re-ambulation 

it increased [336]. During and after 3 weeks of bed rest, serum copper and ceruloplasmin 

were unchanged [762]. After 90 days of bed rest, serum copper was slightly elevated, but the 

change was statistically significant [761]. In 60- and 90-day bed rest studies, ceruloplasmin 

was unchanged [761]. 
106 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

3. Dietary Intake and Requirements 

The current documented space flight requirement for dietary intake of copper is 0.5 to 9 

mg/d [460], a wider range than the original ISS requirement of 1.5 to 3.0 mg/d (Table 1, 

[458]). In the U.S., the recommended dietary allowance for copper in men and women aged 

19 to 70 years is 0.9 mg/d [181]. The ISS food system provides 3.6 mg/d on average (Table 

1). 

4. Risks on Exploration Missions 

Changes in copper status could contribute to the effects of space flight on bone, red blood 

cells, and iron status. The changes in bone during space flight, described in this volume, could 

be exacerbated by copper deficiency and impaired collagen synthesis. Anemia of space flight 

is manifested as a reduction in circulating red blood cell mass with elevations in serum 

ferritin and iron concentrations [8, 350]. Since copper is required for iron mobilization and 

absorption, alterations in copper status may affect iron and red blood cell changes during 

flight. 

Appropriate amounts of certain nutrients, copper in particular [65], are vital for 

maintaining normal immune function. The immune system seems to be altered during space 

flight [60, 118, 388, 660, 671], and this may have direct or indirect (when alterations are 

induced by stress or radiation) implications for nutrition and nutritional status as possible 

causes or effects [60, 135]. 

5. Remaining Questions 

No information about copper absorption and metabolism during space flight is available, 

but, given the available ground data, obtaining such information is not a high priority at this 

point. Ensuring adequate copper content of the diet and verifying that the flight copper status 

data follow ground trends are important monitoring steps.

F. MANGANESE

1. Background 

Manganese can function as an enzyme activator and as part of metalloenzymes. It 

becomes involved in activating enzyme-catalyzed reactions by causing conformational 

changes in the enzyme that it binds to. Manganese can also bind directly to the substrate. 

All transferases, including kinases, hydrolases, oxidoreductases, ligases, and lyases, can 

be activated by manganese. However, in the presence of a manganese deficiency, these 

enzymes can be activated by other divalent cations. Activating these enzymes gives 

manganese a role in formation of components of connective tissue, urea formation, arginase 

activity, gluconeogenesis, the prevention of lipid peroxidation by superoxide radicals in the 
Minerals 107

mitochondria, and the conversion of pyruvate to oxaloacetate in the tricarboxylic acid cycle. 

Studies are currently being conducted to look at the role that manganese may play in secondmessenger pathways in tissues and the regulation of calcium-dependent processes [218]. 

Only trace amounts of manganese are found in animal tissues. Humans store about 10 to 

20 mg of the nutrient. Although it is found in most organs and tissues, the highest 

concentrations are in bone and in the liver, pancreas, and kidneys [218]. 

Signs of a manganese deficiency in humans have not been firmly established, partly 

because other cations can perform the same role. In one study, when adult men were fed a 

purified diet with only 0.11 mg manganese per day for 39 days, all of them developed a finely 

scaling rash, along with decreased serum cholesterol, increased serum calcium and 

phosphorus, and increased alkaline phosphatase [186]. 

It was initially believed that manganese was one of the least toxic trace minerals when 

taken orally. However, recent evidence shows a correlation between brain MRI manganese 

signals and neurological symptoms, including sleep disorders, found in patients with chronic 

liver disease [469]. The tolerable upper intake limit was based on these findings, and for 

adults that limit is 11 mg/d [181, 469]. 

Manganese and iron compete for binding sites. At low iron intakes, manganese is 

absorbed at a greater rate than at higher iron intakes, so that higher iron intake inhibits 

manganese absorption. Likewise, higher manganese intake can inhibit iron absorption. 

2. Findings from Space Flight and Ground-Based Research 

One Russian report on the effect of space flight on manganese content of bones [519] 

documented generally greater regional bone manganese content (26-187%) after flight than in 

nonflight controls. (Note: This study reported on the autopsy results after the tragic end of the 

24-d Salyut-1 mission, compared to controls.) 

3. Dietary Intake and Requirements 

The current documented space flight requirement for dietary intake of manganese is 2.3 

and 1.8 mg/d for men and women respectively, the same as the adequate intake of manganese 

for men and women aged 19 years and older [181]. 

4. Risks on Exploration Missions 

Considering manganese’s function in preventing lipid peroxidation and the increase in 

lipid peroxidation that occurs during space flight, ensuring adequate manganese intake on 

long space flights is vital to preventing and/or minimizing oxidative stress. Given the narrow 

range between adequate intake and toxicity concerns, however, crewmembers who select 

multivitamins need to take care to ensure that manganese intake is not excessive. 
108 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

5. Remaining Questions 

Existing knowledge of manganese metabolism seems adequate; other than the nominal 

determinations of manganese content of the space food system, no other specific research is 

required. 

G. FLUORIDE

1. Background 

Fluoride in bone exists in a rapidly exchangeable pool and a slowly exchangeable pool. 

In the rapidly exchangeable pool, fluoride is in the hydration shell on bone crystallites, where 

it is exchanged isoionically or heteroionically with other ions nearby [462]. The slowly 

exchangeable pool is mobilized during the process of bone remodeling. Fluoride has also 

been shown to influence the function of osteoblasts, enabling new bone to be made. An 

increase in fluoride absorption increases the amount absorbed by the hard tissue, but urinary 

excretion also increases. 

Ninety-nine percent of fluoride is stored in mineralized tissues, predominantly in bone 

[469]. Because specific signs of fluoride deficiency have not been fully elucidated for higher 

animals and humans, it is not possible to estimate a relative time to depletion. 

Fluoride deficiency increases the development of dental caries and may reduce the 

integrity of skeletal tissue [218]. Supplementation of fluoride (5 or 10 mg per day) in 

ambulatory subjects was shown to have no impact on calcium homeostasis, but did result in 

positive fluoride balance [413]. 

Toxicity with fluoride supplementation is rare but can occur with fluoride intakes greater 

than 10 mg/d for at least 10 years [276]. Toxicity of fluoride leads to fluorosis of the tooth 

enamel and skeleton, and osteosclerosis. High doses (> 40 mg per day) also result in side 

effects including bone pain and gastric irritation [541]. 

2. Findings from Space Flight and Ground-Based Research 

No information about the effect of space flight on fluoride status of astronauts is 

available. Bed rest studies have documented that simulated weightlessness had no effect on 

fluoride balance [412], but this was in subjects consuming less than the recommended 

amounts of fluoride. Another study with similarly low fluoride intakes showed the same 

effect: bed rest alone does not affect fluoride balance [415], but balance is negative with 

insufficient intake. 

In a follow-up study, fluoride supplementation was evaluated as a countermeasure for 

bone loss of osteoporosis and simulated space flight (bed rest). Although fluoride balance was 

positive when subjects were supplemented with 10 mg per day, there was no impact on 

calcium homeostasis, and both the fluoride-treated and untreated groups lost calcium during 

bed rest [414]. 
Minerals 109

3. Dietary Intake and Requirements 

The current documented space flight requirement for dietary intake of fluoride is 4 mg/d 

for men and 3 mg/d for women, the same as adequate intake of fluoride for men and women 

aged 19 years and older [181]. 

4. Risks On Exploration Missions 

Care needs to be taken to ensure adequate, but not excessive, intake of fluoride. 

5. Remaining Questions 

Existing knowledge of fluoride metabolism seems adequate. Beyond the nominal 

determinations of fluoride content of the space food system (including water), no other 

specific research is required. 

H. ZINC

1. Background 

Zinc is a component of many enzymes, which depend on it for their catalytic activity. 

RNA polymerases, alcohol dehydrogenase, carbonic anhydrase, and alkaline phosphatase are 

all zinc metalloenzymes [116]. Tissue and cell growth, cell replication, skin integrity, cellmediated immunity, and generalized host defense are all functions of zinc. Zinc is involved in 

bone metabolism, being required for bone formation and alkaline phosphatase activity, as 

well as collagen synthesis [497]. In tissue growth, zinc is involved directly with the regulation 

of protein synthesis. Cell membranes require zinc for protein-to-protein interactions and 

membrane proteins’ conformation. Zinc may also affect the activity of enzymes attached to 

plasma membranes. Zinc prevents oxidation of the membrane by occupying sites that might 

otherwise be occupied by pro-oxidant metals and protects against oxidation by its role in the 

protein metallothionein. Zinc is an integral part of the hormone insulin and plays a role in 

carbohydrate metabolism. 

About 1.5 to 2.5 grams of zinc is stored in the human body [181]. It is found 

intracellularly in all organs, tissues, and body fluids, but mostly in bone, liver, kidneys, 

muscle, and skin [116, 218]. More than 85% of zinc is found in skeletal muscle and bone 

[218, 315]. Even when dietary zinc is suboptimal, the zinc stored in muscle, brain, lung, and 

heart is not released. The apatite of bones releases zinc slowly, and this release does not 

greatly affect the zinc supply [181]. The greatest losses of zinc occur through the intestine. In 

men, the average daily loss of zinc from sources other than the intestine remains relatively 

constant at 1.27 mg/d, even when individuals consume an inadequate amount of the nutrient. 

For women, calculation of this value has been based on the difference in average surface area 

and menstruation, and is 1.0 mg/d [181]. 
110 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

Because the stores of zinc in the body are small, inadequate intake can quickly lead to 

exhaustion of the zinc supply. When this happens, plasma enzymes containing zinc and 

metallothionein are catabolized to provide the necessary zinc [116, 181], and this brings about 

a decrease in enzyme activity [218]. Zinc deficiency can also cause decreased glucose 

tolerance by decreasing insulin response. Basal metabolic rate has been shown to be 

decreased in individuals who were receiving a zinc-deficient diet [709]. Deficiency of zinc 

leads to arrested growth and development and decreased immune function. 

There is currently no evidence of adverse effects associated with toxicity from naturally 

occurring sources of zinc. However, supplemental intake may cause suppression of immune 

response, decreased circulating high-density lipoprotein (HDL) cholesterol, reduced copper 

status, or even death. Acute toxicity has been shown to produce metallic taste, nausea, 

vomiting, epigastric pain, abdominal cramps, and bloody diarrhea. Long-term toxicity can 

cause copper deficiency because zinc and copper compete for absorption by the intestine 

[218]. 

2. Findings from Space Flight and Ground-Based Research 

Zinc status of astronauts, as assessed by serum zinc and urinary zinc excretion, did not 

change after long-duration space flight (Figure 66, [610]). Circulating zinc levels are an 

imperfect tool to evaluate zinc status, as other physiological factors may affect them [116]. 

However, to increase the reliability of zinc status evaluation, more intensive and/or invasive 

techniques would be required. 

Preflight Postflight

0

5

10

15

20

25

Serum zinc (

μmol/L)

Preflight Postflight

0

5

10

15

20

Urine zinc (

μmol/d)

Figure 66. Serum and urinary zinc status from 11 ISS crewmembers before and after flight. Data are 

from Smith et al., 2005 [610]. 

The release of zinc from bones (as a result of demineralization) has been noted in bed rest 

studies [335, 336], and a similar increase in excretion of zinc was noted in Wistar rats flown 

during COSMOS 1129 (a 20-d space flight) [89]. This release of zinc associated with 

demineralization has raised concern that other metals, including lead, could also be released 

secondary to weightlessness-induced bone resorption [327, 328]. 
Minerals 111

3. Dietary Intake and Requirements 

The current documented space flight requirement for dietary intake of zinc is 11 mg/d 

[460], the same as the U.S. adequate intake for men (adequate intake is 8 mg/d for women) 

[181]. The space food system provides about 22 mg/d in the planned menu (Table 1), but 

actual in-flight intakes of Shuttle crewmembers are lower (12 mg/d on average) (Table 2, 

page 20). 

4. Risks on Exploration Missions 

Many compounds exist in food that can complex with zinc and decrease its absorption. 

Phytates, oxalates, polyphenols, fibers, and other nutrients including vitamins can all inhibit 

zinc absorption. In view of zinc’s role in metabolism, ensuring that requirements are 

understood, and met, will be crucial on long-duration exploration missions. 

Increases in urinary zinc with increased muscle catabolism have been noted in cases of 

starvation or trauma [181]. The importance of this phenomenon for space flight has not been 

evaluated (nor has the release of other heavy metals [such as lead] from bone during flight, 

although this has been modeled and proposed as a concern [327, 328]). 

5. Remaining Questions 

Existing knowledge of zinc metabolism seems adequate. Beyond the nominal 

determination of zinc content of the space food system, no specific research is required. 

I. SELENIUM

1. Background 

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 [656]. Selenium is also a cofactor for glutathione peroxidase 

(GPX). GPX plays a role in the reduction of organic peroxides and hydrogen peroxide. 

Selenium has also been shown to be necessary for iodine metabolism. 

Total body selenium stores are in the amount of about 15 mg [218]. There are 2 selenium 

pools in the body: the selenium in selenomethionine and the selenium in GPX. Selenium 

absorption can be increased by vitamins A, C, and E and reduced glutathione, and decreased 

by chelation and precipitation of the mineral by heavy metals, such as mercury, and phytates. 

Deficiency of selenium leads to decreased selenoenzyme activity, which may lead to 

biochemical changes that predispose to illness or even death. Selenium deficiency has been 

associated with Keshan disease, characterized by cardiomyopathy and heart tissue necrosis, 

and with Kashin-Beck’s disease, characterized by osteoarthropathy of the joints and 

epiphyseal-plate cartilages of the legs and arms [218]. In rats, symptoms of acute selenium 
112 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

deficiency have been shown to appear as early as 2 days after withholding selenium. The 

deficiency was shown as a reduction in GPX activity, but no change in blood enzymes was 

seen [278]. 

Selenium status has been related to cancer risk [656, 692], leading to much speculation 

about the ability of selenium supplementation to prevent cancer. 

Toxicity of selenium is called selenosis. Nausea, vomiting, fatigue, hair and nail 

brittleness and loss, changes in nail beds, interference in sulfur metabolism, and inhibition of 

protein synthesis have all been demonstrated to result from selenium toxicity [656]. 

2. Findings from Space Flight and Ground-Based Research 

The Clinical Nutritional Assessment profile [459] has documented a significant (10%) 

reduction in serum selenium concentrations after flight [610]. Whether this is related to intake 

or metabolism is not known. 

3. Dietary Intake and Requirements 

The current documented requirement for dietary intake of selenium during space flight is 

70 μg/d. In the U.S., the recommended dietary allowance for men and women aged 19 years 

and older is 55 μg/d [278]. The space food system provides approximately double this amount 

(Table 1). 

4. Risks on Exploration Missions 

Deficiency of selenium can lead to impaired immune function, illness (Keshan disease 

and Kashin-Beck’s disease, mentioned above), or even death. Excess of selenium can lead to 

problems affecting gastrointestinal, neurological, cardiopulmonary, and renal systems [656]. 

However, toxicity is not likely to occur except when selenium is consumed in large amounts 

in dietary supplements. Despite the relationship of selenium to cancer risk and antioxidant 

status, care must be taken to avoid toxicity. 

5. Remaining Questions 

Selenium levels in the space food system need to be determined. The potential role for 

selenium in protecting against oxidative stress during space flight should be further 

investigated. 
Minerals 113

J. IODINE

1. Background 

Iodine performs its main function in its ionic form, iodide, as part of the thyroid 

hormones (triiodothyronine, or T3, and tetraiodothyronine, T4). About 15 to 20 mg of iodide is 

stored in the human body [753]. The thyroid gland traps the iodide, and it is here that 70 to 80 

percent of the total body iodide is stored. The rest is stored in the salivary and gastric glands, 

with some iodide being found in the mammary glands, ovaries, placenta, and skin. 

Iodine deficiency causes the iodine deficiency disorders, which include mental 

retardation, hypothyroidism, goiter (enlargement of the thyroid gland), cretinism, and other 

growth and development abnormalities, or even death [753]. During a 4-week study in which 

rats were subjected to varying degrees of iodine deficiency, the most severely depleted rats 

showed an increase in thyroid mass after 4 days [453]. 

No toxic side effects have been reported when 2.0 mg of iodine per day was ingested 

[218]. However, with intake greater than 18 mg/d for a prolonged period, the risk of goiter 

increases, as does the risk of thyroid cancer [181, 462]. Other symptoms of iodine toxicity, 

which occur when intake is on the order of several grams per day, include gastrointestinal 

distress, thyroiditis, goiter, sensitivity reactions, thyroid papillary cancer, or even death [462]. 

2. Findings from Space Flight and Ground-Based Research 

Iodine intake on Shuttle missions has often been very high because iodine is used as a 

bactericidal agent in the water system [560]. Some changes in thyroid status that were 

potentially related to iodine excess were observed in ground studies and flight crews [424, 

425, 456]. As a result, in the late 1990s a system to remove iodine from water was deployed 

on most missions. Iodine is not added to the ISS water, and as a result, pre- and postflight 

urinary iodine are similar (Figure 67). 

Preflight Postflight

0

2

4

6

Urinary iodine (μmol/d)

Figure 67. Urinary iodine excretion of ISS crewmembers before and after long-duration space flight (n

= 23). Data are from Smith et al., 2005 [610]. 
114 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

3. Dietary Intake and Requirements 

The current documented space flight requirement for the dietary intake of iodine during 

flight is 150 μg/d [460], the same as the U.S. recommended dietary allowance for iodine for 

men and women aged 19 years and older [181]. The tolerable upper intake level for iodine in 

adults is 1100 μg/d [181]. 

4. Risks on Exploration Missions 

Although providing adequate amounts of dietary iodine is not a critical issue with regard 

to space flight, the possible effects of the iodine used in spacecraft water systems (where 

iodine is often used as a bactericide) are much discussed [425]. In earlier Shuttle missions and 

space programs, NASA used iodine concentrations in drinking water of 2 mg/L [560]. A 

report from the Food and Nutrition Board of the National Academy of Sciences states that in 

adults, daily iodine intake ranging from 50 to 2000 μg/d has no adverse effect [461]. With 

iodine as a bactericidal agent in the water, depending on water intake, iodine intake could 

easily exceed 2 mg/d. Given the current state of knowledge, it is assumed that iodine will not 

be used in exploration spacecraft water systems, or that these systems will be designed so that 

iodine will be removed before the water is consumed, or that levels of iodine will be used that 

would allow the iodine intake of crewmembers to remain below defined toxicity limits. 

5. Remaining Questions 

Existing knowledge of iodine metabolism seems adequate. It would be prudent to know 

precise iodine intake levels of crewmembers (from the diet and drinking water) so that 

potential hazards associated with iodine excess could be avoided. 

K. CHROMIUM

1. Background 

Chromium is thought to complex with nicotinic acid and amino acids to form glucose 

tolerance factor, which initiates the disulfide bridging between insulin and its receptor [218, 

639]. This allows the insulin hormone to be more effective and therefore increases cellular 

glucose uptake and intracellular carbohydrate and lipid metabolism. Chromium may also play 

a role in pancreatic insulin secretion, internalization of insulin through decreasing membrane 

fluidity, and regulation of the insulin receptor. It also may increase sensitivity of tissues to 

insulin by activating insulin receptor kinase [639]. 

The human body can store 4 to 6 mg of chromium. Tissues having the greatest amounts 

of chromium are the liver, kidney, muscle, spleen, heart, pancreas, and bone [639]. It is 

possible that chromium is stored along with ferric iron because of its transport by transferrin, 

which can bind chromium as well as iron. 
Minerals 115

Deficiency of chromium leads to impaired glucose tolerance, or even death. Chromium 

deficiency may result in insulin resistance, which is characterized by hyperinsulinemia. This 

has been shown to be a risk factor for coronary heart disease. Several months of suboptimal 

chromium intake will lead to deficiency symptoms such as hyperglycemia and glycosuria 

[73]. One study found that 9 weeks on a low-chromium diet (5 μg/1000 kcal) was long 

enough to yield changes in glucose tolerance [17]. Severe trauma and stress may increase the 

need for chromium. Stress causes release of the stress hormones, including cortisol and 

glucagon. These hormones alter glucose metabolism and, in effect, chromium metabolism. 

Toxicity of chromium leads to chronic renal failure, hepatic dysfunction, rhabdomyolysis 

(a disease of skeletal muscle), or even death. When they are ingested orally, Cr6+ is more 

toxic than Cr3+. Liver damage, skin ulcerations, dermatitis, and respiratory disease may all 

result from a chromium intake greater than 1,000 μg/d [218]. 

2. Findings from Space Flight and Ground-Based Research 

Little or nothing is known about chromium in space travelers. Chromium potentiates the 

action of insulin [403], and insulin resistance has been observed after space flight or bed rest 

[49, 648, 696]. Whether the insulin resistance associated with space flight is related to 

chromium is unknown. 

3. Dietary Intake and Requirements 

The current documented space flight requirement for dietary intake of chromium is 35 

μg/d. 

In the U.S., adequate intake of chromium is defined for men aged 19 to 50 years as 35 

μg/d, and for those 51 years and older as 30 μg/d. Adequate intake is defined for women aged 

19 to 50 years as 25 μg/d, and for those 51 years and older as 20 μg/d [181]. 

4. Risks on Exploration Missions 

Although it may be plausible that changes in glucose metabolism during space flight are 

in part related to chromium, given that nothing is known about chromium during space flight, 

it seems premature to raise concerns about chromium at this point. Additionally, iron excess, 

in hemochromatosis, may affect chromium homeostasis [639], another reason to be concerned 

about iron excess during space travel. 

5. Remaining Questions 

Beyond the nominal determinations of chromium content of the space food system, no 

other specific research is required given the current state of knowledge. 
116 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

L. OTHER TRACE ELEMENTS

No nutrition text would be complete without the acknowledgment that a handful of 

ultratrace elements have been studied and are proposed to play a required role in the human 

body. These include boron, vanadium, aluminum, and others [469]. While we do not dispute 

these findings, at this point their potential for having an impact on space missions would be 

extremely speculative. 
IX. NUTRITIONAL ISSUES FOR 

EXTRAVEHICULAR ACTIVITY

Extravehicular activity (EVA), or spacewalking, is a unique situation from a nutritional 

perspective, because the EVA suit does not easily allow food consumption. On early Shuttle 

missions, a 165-kcal fruit bar was custom-made to fit in the EVA suit, but it was typically not 

consumed, and is no longer included. Crewmembers can go without food for as long as 8 to 

10 hours while they are preparing for and performing EVA. Nutritional recommendations for 

EVA were designed to help maximize crew performance and efficiency. When nutrition for 

EVA was reviewed in 1991, the recommendation for EVA crewmembers was that they 

should consume an additional 500 kcal on days of EVA [457]. This was designed to account 

for the metabolic cost of EVA (~200 kcal/h). 

In 2000, another review of this situation was requested by NASA’s Flight Medicine 

Division. The resulting recommendation was to provide food items for consumption during 

EVA preparation (as close as possible to the donning of helmets). The food items should 

contain 300 to 500 kcal, with about 70 to 100 g of carbohydrate and a high content of soluble 

fiber. Candidate items are reviewed to ensure that in the attempt to meet the basic criteria, 

undesirable nutrients or additives are not included, and that crew preferences are accounted 

for. It was also recommended that crewmembers reconsider use of the in-suit food bar, or that 

alternatives be sought. 

Fluid intake during EVA is also a topic of concern. Crewmembers lose 6 to 8 oz fluid/h 

(177 to 237 mL) during an EVA. The current EVA suit contains a 24- or 32-ounce drink bag 

(710 or 946 mL). Only water is used (early EVAs included flavored beverages, but a problem 

during a lunar EVA resulted in a programmatic decision to include only water). Provision of 

in-suit fluid is an important factor in suit design. For the current suit, use of the 32-ounce 

drink bag is recommended. The development of a larger, disposable drink bag is highly 

encouraged. The disposable drink bag should be designed so that a flavored drink (such as the 

current Shuttle food system beverages) could be used to increase palatability and intake, 

assuming that the technical concerns can be eliminated. 

The issue of nutritional support during EVA was reviewed only briefly at the 2005 

Standards and Operating Bands meeting, and no recommendations were made to change the 

2000 guidelines. As suits are developed for exploration mission transit and planetary EVAs, 

following the suggestions above would alleviate problems deemed too complicated to solve 

by changing the existing suit used on the Shuttle and ISS. 

Along with food and fluid issues associated with EVA, the hyperoxic environment of 

EVA has the potential for causing additional damage to the body. The pre-EVA protocol for 
118 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

U.S. astronauts typically includes a 2.5-h “prebreathe” of 95% to 100% oxygen [422] to 

reduce the risk of decompression sickness. After the prebreathe, astronauts are typically 

exposed to hypobaric 100% oxygen for 6 to 10 hours during EVA. Studies from saturation 

dives show that oxidative damage occurs under conditions similar to those of EVA [608]. 

Judging by the results of numerous ground-based studies with hyperoxia, including data from 

a NASA Extreme Environment Mission Operations (NEEMO) 14-d saturation dive [608, 

760], the potential exists for nutritional countermeasures to mitigate some of the oxidative 

damage [470, 658, 720]. 

REMAINING QUESTIONS

Because, according to proposed plans for lunar EVAs, they will be similar in duration (8 

to 10 h) to current ISS EVAs but more frequent (2 to 3 times per week), there is a clear need 

for development of nutrition support during EVAs. A nutrition support system will need to fit 

the lunar suit design. The definition of the optimal nutrition support system will need to be 

based on the results of ground studies designed to optimize performance, minimize fatigue, 

and minimize oxidative damage from a high partial pressure of oxygen in the suit. 
X. ANTIOXIDANTS

A. SOURCES OF OXIDATIVE STRESS

Space flight inevitably increases astronauts’ likelihood of having cellular oxidative 

damage occur because the space environment is associated with numerous sources of 

oxidative stress. Some of these are hyperoxic (100% oxygen) conditions during EVA, 

exercise, high-linear energy transfer radiation exposure, and acute gravitational stress of 

reentry, all of which have been associated with initiating reactive oxygen species and 

oxidative damage in both human and animal ground-based studies [117, 329, 330, 534, 685].

1. Hyperoxic Conditions 

Currently astronauts are exposed to hypobaric hyperoxic conditions when they perform 

EVA (6 to 8 h). The pre-EVA protocol for U.S. astronauts typically includes a 2.5-h 

prebreathe of 95% to 100% oxygen [422] to reduce the risk of decompression sickness. After 

the prebreathe, astronauts are exposed to hypobaric 100% oxygen for 6 to 10 hours during 

EVA. Future lunar EVAs are expected to be longer in duration and more frequent than those 

performed now on the ISS. 

The literature is replete with studies showing injury to virtually all organ systems after 

sufficient exposure to hyperoxia [109, 515]. A hyperoxic environment can induce oxidative 

damage and decrease antioxidant capacity, as demonstrated in numerous ground-based 

experiments using both normobaric and hypobaric hyperoxic conditions. Under physiological 

conditions (21% O2), about 2% to 3% of the oxygen consumed by the body is converted into 

oxygen-derived reactive oxygen species [616]. Human antioxidant defenses are designed to 

protect against 21% oxygen, but these defenses are easily overwhelmed in hyperoxic 

environments. 

It was first suggested in the 1950s that a hyperoxic environment may be toxic, because of 

eye damage among premature infants in incubators with high oxygen concentrations [87, 316, 

500]. Evidence exists that acute exposure to > 95% oxygen is followed by increased lipid 

peroxidation. Increased lipid peroxidation (measured by urinary n-pentane) occurs in humans 

within 30 minutes of breathing 100% O2 [449]. In another study, elevated plasma 

malondialdehyde (MDA) was reported in healthy humans after 125 min of normobaric 

exposure to 100% oxygen [398]. Animal studies support the human data [332, 681]. The 
120 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

accuracy of n-pentane as a marker of lipid peroxidation is debated [83, 326], but this and 

increased MDA provide evidence that lipid peroxidation increases during hyperoxia. 

Hyperoxic conditions are also found to increase vasoconstriction in humans [418], deplete 

pulmonary extracellular superoxide dismutase (SOD) in mice [493], and increase apoptosis in 

PC12 cells [658], all of which indicate that hyperoxia can induce cellular oxidative damage. 

2. Generation of Reactive Oxygen Species During Exercise 

Exercise-induced fatigue and muscle atrophy are also mediated in part by reactive oxygen 

species (ROS). Electron spin resonance spectroscopy technology confirmed earlier findings 

from the 1950s suggesting that short-lived reactive intermediate molecules like ROS are 

present in skeletal muscle after exercise [534]. Since then, numerous studies support a role of 

ROS in skeletal muscle fatigue [483, 534, 686]. ROS denature proteins directly associated 

with the sarcoplasmic reticulum Ca2+ release mechanism [154], 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 [358]. Furthermore, decreased antioxidant status lowers exercise 

capacity and increases onset of fatigue in human and animal studies [483, 534]. 

Astronauts perform extensive upper-body exercise during EVA activity, and 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. 

3. Radiation Exposure 

Astronauts are exposed to highly ionizing radiation, in addition to secondary radiations 

resulting from interactions with shielding materials or the human body. Biological effects of 

radiation include damage to DNA from a direct hit from an ion track, oxidative damage from 

generated ROS, and oxidative damage induced by a bystander effect [298, 306, 682]. A 

bystander effect occurs when cells damaged by radiation particles secrete cytokines or other 

proteins that can generate ROS in cells that are not destroyed [396]. 

B. OXIDATIVE DAMAGE MARKERS DURING 

SPACE FLIGHT AND IN GROUND ANALOGS

A number of studies show that astronauts have elevated levels of markers of oxidative 

damage after space flight. Plasma MDA, 8-iso-prostaglandin F2α, and urinary 8-hydroxy-2′-

deoxyguanosine (8OHdG) have been measured during and after flight as indicators of lipid 

peroxidation (MDA and PGF2α) and DNA damage (8OHdG) [604, 633]. A significant 

elevation of urinary 8OHdG has been noted after long-duration missions (Mir and ISS) [610]. 

These data are supported by results from the ground-based analog, NEEMO, in which 

crewmembers underwent 10- to 14-day saturation dives [608, 760]. Similarly, urinary 8-iso-
Antioxidants 121

prostaglandin F2α was significantly decreased during flight but elevated about 2.5-fold after 

flight [633], and plasma MDA was increased both during and after flight [633]. In a Russian 

120-day bed rest study, increased concentrations of markers of lipid peroxidation were found 

in subjects, and this increase was mitigated with vitamin E [752]. 

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 [314, 521], but evidence exists that 

downregulation of antioxidant defense systems occurs during space flight [264]. Along with 

increases in markers of oxidative damage and decreases in antioxidant defense systems, a 

decrease in total antioxidant capacity also occurs. 

XI. SUPPLEMENTS

The issue of supplement use arises with discussion of nutrient requirements for space 

travelers and the use of nutrients as countermeasures to the negative effects of space flight, 

especially oxidative damage and radiation-induced cancer risk. It is generally agreed that 

nutrients should be provided to astronauts in standard foods, as opposed to supplements [350, 

457, 458, 460, 599]. This is essential, as natural foods also provide non-nutritive substances 

such as fiber, carotenoids, and flavonoids, as well as a sense of palatability and psychological 

well-being that will be important during long missions. The need for more detailed 

information about the “psychophysiology of hunger and eating” was noted decades ago 

during the early space programs [596], but this topic has yet to be studied in detail. It is clear 

from astronauts’ experience on the Mir that when humans are in an isolated environment far 

from home, food becomes a very supportive psychological factor. 

NASA currently does not recommend that astronauts take general nutritional supplements 

during flight, for several reasons. Experience to date indicates that crewmembers do not 

consume the recommended amount of energy intake, and 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, they are not metabolized by the body as they are when in foods [15]. 

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, 1 

supplement has met this standard, and that is 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 [610], but recently this was raised to 800 IU per day of supplementation [460]. 

REMAINING QUESTIONS

Before a supplement is recommended, a clear deficit of that nutrient in the space food 

system must be identified, 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 
124 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

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 

space flight 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 [205]. 
XII. NUTRIENT-DRUG INTERACTIONS

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. The most common studies of nutrient-drug 

interactions concern their effects on a nutrient or drug’s absorption, distribution, 

biotransformation, and excretion. 

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 watersoluble by biotransformation. For most drugs, this process yields a water-soluble compound 

that is less active than the original compound. Biotransformation occurs in 2 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, but CYP1, CYP2, and CYP3 are the forms most commonly used 

in drug metabolism [225]. Cytochrome P450 enzymes are unique in their ability to use a wide 

range of substrates [222]. Phase II biotransformation involves the conjugation of the parent 

compound to a polar group (acetate, glucuronides, sulfates, amino acids, glutathione), which 

inactivates most drugs. Biotransformation of drugs is influenced by several factors that could 

be affected by space flight and the space food system: dietary factors, nutrient metabolism, 

monoamine oxidase inhibitors, and antacids and proton pump inhibitors. 

A. DIETARY FACTORS

Dietary factors (either an excess or deficiency) can influence both phases of drug 

biotransformation. In phase I, 3 factors are required: a sufficient energy source (because of 

the high energy demands of this system), a protein source for enzyme formation, and iron for 

cytochrome formation [690]. Phase II requires glucose, sulfur-containing amino acids, and 

glutathione [690]. 

The effects of nutrients on drug metabolism have been well studied in animal models; 

however, relatively few dietary factors have been studied in humans [221, 690]. 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 [29, 301]. Flavonoid compounds such as naringin, naringenin, 

limonin, and obacunone, which are present in grapefruit juice, act as substrates for particular 
126 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

intestinal cytochrome P450 enzymes (CYP3A4 and CYP1A2). Within hours of ingestion, 

grapefruit juice decreases CYP3A4 protein expression for up to 24 hours [401, 404]. The 

decrease in CYP3A4 is associated with a decreased capability for drug metabolism, and 

therefore increased drug bioavailability. 

Other foods, nutrients, or supplements known to affect phase I and II biotransformations 

and cytochrome P450 enzymes include protein, carbohydrates, lipids, certain vitamins, 

minerals, char-broiled foods, red wine, monosodium glutamate and aspartate, and herbs such 

as St. John’s wort [93, 192, 221, 513, 547, 690]. 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 [221]. 

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 [157]. 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, and activity of 

this enzyme is enhanced in the presence of highly polyunsaturated fatty acids such as fish 

oils. 

B. NUTRIENT METABOLISM

Some nutrients are metabolized by cytochrome P450 enzymes; therefore, drugs or other 

nutrients that alter the activity of these enzymes can alter nutrient metabolism. Vitamin D and 

vitamin A are 2 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 [552]. CYP3A4 has been found to 

be a 25-hydroxylase as well [223]. 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. 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 [566]. 

Certain drugs are known to activate CYP24 activity, including rifampin, isoniazid, and 

phenobarbital [499, 572]. Several studies show a relationship between the use of these drugs 

and osteomalacia [206, 579], 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 

vitamin D metabolism of numerous drugs, including inducers or inhibitors of this enzyme (for 

example, grapefruit juice, erythromycin, omeprazole, carbamazepine, and dexamethasone), or 

implicate them in unexplained effects on vitamin D metabolism. 
Nutrient-Drug Interactions 127

Vitamin A metabolism involves the actions of CYP1A2 and CYP4A4 in the conversion 

of retinol to retinoic acid [98, 545]. Inducers of CYP1A2 (cigarette smoke, cruciferous 

vegetables, broiled beef, rifampin) may affect vitamin A metabolism. 

C. 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, and therefore the compounds are taken up in the brain. In the brain, 

tyramine displaces norepinephrine from storage vesicles, 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 [690]. Fermented foods and protein-rich foods that 

have begun to spoil are rich in phenylethylamines [690]. 

D. 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, and vitamin A [182, 450, 690]. Antacids can precipitate folic acid at a 

pH greater than 4.0, thus rendering it insoluble and not available for absorption [551]. A high 

pH also affects thiamin bioavailability because the vitamin is not stable at high pH [690]. 

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 accumulates in the stomach, which can increase the 

likelihood that potentially carcinogenic N-nitroso compounds will be formed [450]. These 

changes are observed mostly in subjects who are infected by Helicobacter pylori and are 

taking proton-pump inhibitors [450]. 

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 [182]. 

This would be particularly harmful if vitamin B12 stores were low before initiation of therapy. 

E. REMAINING QUESTIONS

Currently no data are available that pertain to specific drug-nutrient interactions during 

space flight. The main concerns for a long-duration mission involve use of pharmacological 

agents that are taken chronically. Side effects will be especially harmful if the status of all 
128 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

nutrients is not adequate at the beginning of a long-duration mission. Addressing these 

concerns of drug-nutrient interactions will be especially crucial for crewmembers who 

embark on exploration-class missions lasting several years. 
XIII. LOOKING FORWARD

NASA has undertaken an exploration initiative that will return humans to the Moon and 

eventually take them to Mars. Although the first missions to the Moon are projected to be 

short and will not require significant, if any, modifications to the food system, the initial 

round trip to Mars using current propulsion technology is projected to take 3 years. This will 

require a food system with items having even longer shelf lives than those currently available 

for the ISS missions [353, 504]. As NASA designs the vehicles for these missions, the 

challenges for the food system will be very 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. Acceptability of the food items will 

become even more important on a 3-year mission. New challenges for this exploration food 

system will include the need for a 3- to 5-year shelf life and the possibility that the increased 

radiation encountered on a trip to Mars might affect the nutritional content and quality of the 

food over time. 

Long-term plans for exploration include the establishment of habitats on the Moon 

(Figure 68) and eventually on Mars (Figure 69) for long-duration stays [353, 504]. The lunar 

habitats will be used to test technologies needed for a mission to Mars. Most of the plans for 

habitats include the growing of plants to aid in the recycling of air and water within the 

habitat [36]. These crops will be available for use in the food system. The presence of partial 

gravity on both the Moon and Mars will allow crops to be processed into ingredients (for 

example, milling wheat into flour) and then used to prepare menu items for crew consumption 

[353]. 

The long-term missions, either months living on the Moon or years going to and from 

Mars, 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. In light of the duration of a Mars mission, a chronic 

deficiency, potentially even a marginal 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 

understanding their stability in the space environment (for the months to years waiting to be 

consumed) will be critical. Just as for the sailors who left Europe in sailing ships, it is not 

enough to have food; one must have the right food. 
130 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

Figure 68. Artist’s image of the next-generation lunar landing. Credit: NASA. 

Figure 69. Artist’s concept of Martian habitat and exploration vehicles. Credit: NASA. 
XIV. CONCLUSION

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 health. The ability of nutrients and nutrition to mitigate negative effects 

of space travel is far from being fully explored. Ground-based evidence is being amassed but 

is yet to be fully tested. In many ways, nutrition offers a suite of countermeasures that require 

no more crew time than that already allotted for meals. While care clearly needs to be taken to 

avoid excess amounts of any nutrient, the risks of using nutritional countermeasures 

compared to those of using pharmacological countermeasures are negligible. 

This document details the evidence collected to date that shows why inadequate nutrition 

is a risk during long-term space travel. The evidence is substantial, and drives a significant 

ongoing effort to optimize nutrition for space travelers and to use nutrition as a tool to 

mitigate the health risks of microgravity exposure. 

XV. REFERENCES

[1] Adams GR, Caiozzo VJ, Baldwin KM. Skeletal muscle unweighting: spaceflight and 

ground-based models. J Appl Physiol. 2003 Dec;95(6):2185-201. 

[2] Agureev AN, Kalandarov S, Segal DE. [Optimization of cosmonauts' nutrition during 

the period of acute adaptation and at the closing stage of the mission]. Aviakosm 

Ekolog Med. 1997;31(6):47-51. 

[3] Agus ZS, Goldfarb S. Renal regulation of calcium balance. In: Seldin DW, Giebisch G, 

eds. The kidney: physiology and pathophysiology. New York, NY: Raven Press; 

1985:1323-35. 

[4] Ahn J, Peters U, Albanes D, et al. Serum vitamin D concentration and prostate cancer 

risk: a nested case-control study. J Natl Cancer Inst. 2008 Jun 4;100(11):796-804. 

[5] Ahonen MH, Tenkanen L, Teppo L, Hakama M, Tuohimaa P. Prostate cancer risk and 

prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control. 

2000 Oct;11(9):847-52. 

[6] Alexandrov A, Gharib C, Grigoriev AI, et al. [Oral glucose tolerance tests in man 

during a space flight of 150 days (Salyut 7-Soyuz T9)]. C R Seances Soc Biol Fil. 

1985;179:192-5. 

[7] Alfrey CP, Udden MM, Huntoon CL, Driscoll T. Destruction of newly released red 

blood cells in space flight. Med Sci Sports Exerc. 1996;28(10 Suppl):S42-4. 

[8] Alfrey CP, Udden MM, Leach-Huntoon C, Driscoll T, Pickett MH. Control of red 

blood cell mass in spaceflight. J Appl Physiol. 1996;81:98-104. 

[9] Alfrey CP, Rice L, Udden MM, Driscoll TB. Neocytolysis: physiological downregulator of red-cell mass. Lancet. 1997 May 10;349(9062):1389-90. 

[10] Alfrey CP, Rice L, Smith SM. Iron metabolism and the changes in red blood cell 

metabolism. In: Lane HW, Schoeller DA, eds. Nutrition in spaceflight and 

weightlessness models. Boca Raton, FL: CRC Press; 2000:203-11. 

[11] Alkner BA, Berg HE, Kozlovskaya I, Sayenko D, Tesch PA. Effects of strength 

training, using a gravity-independent exercise system, performed during 110 days of 

simulated space station confinement. Eur J Appl Physiol. 2003 Sep;90(1-2):44-9. 

[12] Alkner BA, Tesch PA. Knee extensor and plantar flexor muscle size and function 

following 90 days of bed rest with or without resistance exercise. Eur J Appl Physiol. 

2004 Dec;93(3):294-305. 

[13] Alleva R, Nasole E, Di Donato F, Borghi B, Neuzil J, Tomasetti M. alpha-Lipoic acid 

supplementation inhibits oxidative damage, accelerating chronic wound healing in 
134 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

patients undergoing hyperbaric oxygen therapy. Biochem Biophys Res Commun. 2005 

Jul 29;333(2):404-10. 

[14] Altman PL, Talbot JM. Nutrition and metabolism in spaceflight. J Nutr. 1987;117:421-

7. 

[15] American Dietetic Association. Position of the American Dietetic Association: 

fortification and nutritional supplements. J Am Diet Assoc. 2005 Aug;105(8):1300-11. 

[16] Anderson JJB, Klemmer PJ, Watts MLS, Garner SC, Calvo MS. Phosphorus. In: 

Bowman BA, Russell RM, eds. Present knowledge in nutrition, Vol I. 9th ed. 

Washington, DC: ILSI Press; 2006:383-99. 

[17] Anderson RA, Polansky MM, Bryden NA, Canary JJ. Supplemental-chromium effects 

on glucose, insulin, glucagon, and urinary chromium losses in subjects consuming 

controlled low-chromium diets. Am J Clin Nutr. 1991 Nov;54(5):909-16. 

[18] Antonione R, Caliandro E, Zorat F, Guarnieri G, Heer M, Biolo G. Whey protein 

ingestion enhances postprandial anabolism during short-term bed rest in young men. J 

Nutr. 2008 Nov;138(11):2212-6. 

[19] Antonutto G, Capelli C, Girardis M, Zamparo P, di Prampero PE. Effects of 

microgravity on maximal power of lower limbs during very short efforts in humans. J 

Appl Physiol. 1999 Jan;86(1):85-92. 

[20] Arnaud SB, Schneider VS, Morey-Holton E. Effects of inactivity on bone and calcium 

metabolism. In: Sandler H, Vernikos J, eds. Inactivity: physiological effects. Orlando, 

FL: Academic Press, Inc.; 1986:49-76. 

[21] Arnaud SB, Fung P, Popova IA, Morey-Holton ER, Grindeland RE. Circulating 

parathyroid hormone and calcitonin in rats after spaceflight. J Appl Physiol. 1992 

Aug;73(2 Suppl):169S-73S. 

[22] Arnaud SB, Sherrard DJ, Maloney N, Whalen RT, Fung P. Effects of 1-week headdown tilt bed rest on bone formation and the calcium endocrine system. Aviat Space 

Environ Med. 1992;63:14-20. 

[23] Arnaud SB, Wolinsky I, Fung P, Vernikos J. Dietary salt and urinary calcium excretion 

in a human bed rest spaceflight model. Aviat Space Environ Med. 2000;71:1115-9. 

[24] Arnett TR. Extracellular pH regulates bone cell function. J Nutr. 2008 

Feb;138(2):415S-8S. 

[25] Ascherio A, Willett WC. Are body iron stores related to the risk of coronary heart 

disease? (Editorial). N Engl J Med. 1994;330:1152-4. 

[26] Aufricht C, Ties M, Wimmer M, Haschke F, Pietschnig B, Herkner K. Iron 

supplementation in children after cardiopulmonary bypass for surgical repair of 

congenital heart disease. Pediatr Cardiol. 1994 Jul-Aug;15(4):167-9. 

[27] Bader N, Bosy-Westphal A, Koch A, Mueller MJ. Influence of vitamin C and E 

supplementation on oxidative stress induced by hyperbaric oxygen in healthy men. Ann 

Nutr Metab. 2006;50(3):173-6. 

[28] Baek K, Barlow AA, Allen MR, Bloomfield SA. Food restriction and simulated 

microgravity: effects on bone and serum leptin. J Appl Physiol. 2008 Apr;104(4):1086-

93. 

[29] Bailey DG, Spence JD, Edgar B, Bayliff CD, Arnold JM. Ethanol enhances the 

hemodynamic effects of felodipine. Clin Invest Med. 1989 Dec;12(6):357-62. 
References 135

[30] Bailey LB, Gregory III JF. Folate. In: Bowman BA, Russell RM, eds. Present 

knowledge in nutrition, Vol I. 9th ed. Washington, DC: International Life Sciences 

Institute; 2006:278-301. 

[31] Bajotto G, Shimomura Y. Determinants of disuse-induced skeletal muscle atrophy: 

exercise and nutrition countermeasures to prevent protein loss. J Nutr Sci Vitaminol 

(Tokyo). 2006 Aug;52(4):233-47. 

[32] Balakhovskiy I, Natochin Y. [Metabolism under the extreme conditions of spaceflight 

and during its simulation], Vol 22. Moscow: Nauka Press; 1973. 

[33] Baldwin KM. Future research directions in seeking countermeasures to weightlessness. 

J Gravit Physiol. 1995;2(1):P51-3. 

[34] Baldwin KM. Effect of spaceflight on the functional, biochemical, and metabolic 

properties of skeletal muscle. Med Sci Sports Exerc. 1996 Aug;28(8):983-7. 

[35] Baranski S, Kubiczkowa J, Piorko A, et al. Electrogustometric investigations during 

manned space flight. Aviat Space Environ Med. 1983 Jan;54(1):1-5. 

[36] Barta DJ, Henninger DL. Regenerative life support systems - why do we need them? 

Adv Space Res. 1994;14(11):40-3. 

[37] Bassler KH. Use and abuse of high dosages of vitamin B6. Int J Vitam Nutr Res Suppl. 

1989;30:120-6. 

[38] Bates CJ, Liu DS, Fuller NJ, Lucas A. Susceptibility of riboflavin and vitamin A in 

breast milk to photodegradation and its implications for the use of banked breast milk in 

infant feeding. Acta Paediatr Scand. 1985 Jan;74(1):40-4. 

[39] Bates CJ. Thiamin. In: Bowman BA, Russell RM, eds. Present knowledge in nutrition, 

Vol I. 9th ed. Washington, DC: International Life Sciences Institute; 2006:242-9. 

[40] Bayram I, Erbey F, Celik N, Nelson JL, Tanyeli A. The use of a protein and energy 

dense eicosapentaenoic acid containing supplement for malignancy-related weight loss 

in children. Pediatr Blood Cancer. 2008 Dec 17. 

[41] Beard JL. Iron. In: Bowman BA, Russell RM, eds. Present knowledge in nutrition, Vol 

I. 9th ed. Washington, DC: International Life Sciences Institute; 2006:430-44. 

[42] Beetstra S, Thomas P, Salisbury C, Turner J, Fenech M. Folic acid deficiency increases 

chromosomal instability, chromosome 21 aneuploidy and sensitivity to radiationinduced micronuclei. Mutat Res. 2005 Oct 15;578(1-2):317-26. 

[43] Beguin Y. The soluble transferrin receptor: biological aspects and clinical usefulness as 

quantitative measure of erythropoiesis. Haematologica. 1992;77:1-10. 

[44] Belavy DL, Hides JA, Wilson SJ, et al. Resistive simulated weightbearing exercise with 

whole body vibration reduces lumbar spine deconditioning in bed-rest. Spine. 2008 Mar 

1;33(5):E121-31. 

[45] Benedict FG. A study of prolonged fasting, Vol Washington Publ N0 203: Carnegie 

Institute; 1915. 

[46] Berenson J, Hirschberg R. Safety and convenience of a 15-minute infusion of 

zoledronic acid. Oncologist. 2004;9(3):319-29. 

[47] Berg HE, Eiken O, Miklavcic L, Mekjavic IB. Hip, thigh and calf muscle atrophy and 

bone loss after 5-week bedrest inactivity. Eur J Appl Physiol. 2007 Feb;99(3):283-9. 

[48] Bikle D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab. 2009 Jan;94(1):26-

34. 

[49] Biolo G, Ciocchi B, Stulle M, et al. Metabolic consequences of physical inactivity. J 

Ren Nutr. 2005 Jan;15(1):49-53. 
136 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[50] Biolo G, Ciocchi B, Stulle M, et al. Calorie restriction accelerates the catabolism of 

lean body mass during 2 wk of bed rest. Am J Clin Nutr. 2007 Aug;86(2):366-72. 

[51] Biolo G, Agostini F, Simunic B, et al. Positive energy balance is associated with 

accelerated muscle atrophy and increased erythrocyte glutathione turnover during 5 wk 

of bed rest. Am J Clin Nutr. 2008 Oct;88(4):950-8. 

[52] Bischoff-Ferrari HA, Dietrich T, Orav EJ, Dawson-Hughes B. Positive association 

between 25-hydroxy vitamin D levels and bone mineral density: a population-based 

study of younger and older adults. Am J Med. 2004 May 1;116(9):634-9. 

[53] Bjorkman M, Sorva A, Risteli J, Tilvis R. Vitamin D supplementation has minor effects 

on parathyroid hormone and bone turnover markers in vitamin D-deficient bedridden 

older patients. Age Ageing. 2008 Jan;37(1):25-31. 

[54] Blackwood AM, Sagnella GA, Cook DG, Cappuccio FP. Urinary calcium excretion, 

sodium intake and blood pressure in a multi-ethnic population: results of the 

Wandsworth Heart and Stroke Study. J Hum Hypertens. 2001 Apr;15(4):229-37. 

[55] Blake DR, Waterworth RF, Bacon PA. Assessment of iron stores in inflammation by 

assay of serum ferritin concentrations. Br Med J (Clin Res Ed). 1981 Oct 

31;283(6300):1147-8. 

[56] Blanc S, Normand S, Pachiaudi C, Fortrat JO, Laville M, Gharib C. Fuel homeostasis 

during physical inactivity induced by bed rest. J Clin Endocrinol Metab. 2000 

Jun;85(6):2223-33. 

[57] Blanc S, Somody L, Gharib C. Are energy metabolism alterations involved in 

cardiovascular deconditioning after weightlessness? An hypothesis. Pflugers Arch. 

2000;441(2-3 Suppl):R39-47. 

[58] Bleeker MW, De Groot PC, Rongen GA, et al. Vascular adaptation to deconditioning 

and the effect of an exercise countermeasure: results of the Berlin Bed Rest study. J 

Appl Physiol. 2005 Oct;99(4):1293-300. 

[59] Borboni P, Magnaterra R, Rabini RA, et al. Effect of biotin on glucokinase activity, 

mRNA expression and insulin release in cultured beta-cells. Acta Diabetol. 1996 

Jul;33(2):154-8. 

[60] Borchers AT, Keen CL, Gershwin ME. Microgravity and immune responsiveness: 

implications for space travel. Nutrition. 2002 Oct;18(10):889-98. 

[61] Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of 

recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002;346(2):77-84. 

[62] Bourland C, Kloeris V, Rice B, Vodovotz Y. Food systems for space and planetary 

flights. In: Lane HW, Schoeller DA, eds. Nutrition in spaceflight and weightlessness 

models. Boca Raton, FL: CRC Press; 2000:19-40. 

[63] Bourland CT, Rapp RM, Smith MC. Space Shuttle food system. Food Technol. 

1977;31:40-5. 

[64] Bourland CT, Fohey MF, Kloeris VL, Rapp RM. Designing a food system for Space 

Station Freedom. Food Technol. 1989 February;43(2):76-81. 

[65] Bourre JM. Effects of nutrients (in food) on the structure and function of the nervous 

system: update on dietary requirements for brain. Part 1: micronutrients. The journal of 

nutrition, health & aging. 2006 Sep-Oct;10(5):377-85. 

[66] Bown SR. Scurvy. New York, NY: St. Martin's Press; 2003. 

[67] Breay S. Hypocalcaemia after intravenous bisphosphonate: read the product 

information first. BMJ. 2004 Jun 12;328(7453):1439; author reply -40. 
References 137

[68] Breen TL, Shane E. Prolonged hypocalcemia after treatment with zoledronic acid in a 

patient with prostate cancer and vitamin D deficiency. J Clin Oncol. 2004 Apr 

15;22(8):1531-2. 

[69] Breslau MA, McGuire J, Zerwekh J, Pak CYC. The role of dietary sodium on renal 

excretion and intestinal absorption of calcium and on vitamin D metabolism. J Clin 

Endocrinol Metab. 1982;55:369-73. 

[70] Breslau NA, Brinkley L, Hill KD, Pak CY. Relationship of animal protein-rich diet to 

kidney stone formation and calcium metabolism. J Clin Endocrinol Metab. 1988 

Jan;66(1):140-6. 

[71] Britton RS, Leicester KL, Bacon BR. Iron toxicity and chelation therapy. Int J Hematol. 

2002 Oct;76(3):219-28. 

[72] Brooks N, Cloutier GJ, Cadena SM, et al. Resistance training and timed essential amino 

acids protect against the loss of muscle mass and strength during 28 days of bed rest 

and energy deficit. J Appl Physiol. 2008 Jul;105(1):241-8. 

[73] Brown RO, Forloines-Lynn S, Cross RE, Heizer WD. Chromium deficiency after longterm total parenteral nutrition. Dig Dis Sci. 1986 Jun;31(6):661-4. 

[74] Brozek J, Grande F, Taylor HL, Anderson JT, Buskirk ER, Keys A. Changes in body 

weight and body dimensions in men performing work on a low calorie carbohydrate 

diet. J Appl Physiol. 1957;10(3):412-20. 

[75] Budylina SM, Khvatova VA, Volozhin AI. Effect of orthostatic and antiorthostatic 

hypokinesia on taste sensitivity in men. Kosm Biol Aviakosm Med. 1976;10:27-30. 

[76] Buettner GR, Jurkiewicz BA. Catalytic metals, ascorbate and free radicals: 

combinations to avoid. Radiat Res. 1996 May;145(5):532-41. 

[77] Bungo MW, Johnson PC, Jr. Cardiovascular examinations and observations of 

deconditioning during the space shuttle orbital flight test program. Aviat Space Environ 

Med. 1983 1983;54:1001-4. 

[78] Burckhardt P. The effect of the alkali load of mineral water on bone metabolism: 

interventional studies. J Nutr. 2008 Feb;138(2):435S-7S. 

[79] Burger IH, Walters CL. The effect of processing on the nutritive value of flesh foods. 

Proc Nutr Soc. 1973 May;32(1):1-8. 

[80] Bychkov VP, Kozar MI, Popov VI, Boiko NN, Kolchin EV. [Experimental data on the 

effect of proton and gamma radiation on food products]. Kosm Biol Aviakosm Med. 

1974 May-Jun;8(3):6-10. 

[81] Caballero B, Allen L, Prentice A. Encyclopedia of human nutrition. 2nd ed. Oxford, 

UK; 2005. 

[82] 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 Jul 31;137(1):75-

88. 

[83] Cailleux A, Allain P. Is pentane a normal constituent of human breath? Free Radic Biol 

Med. 1993;18(6):323-7. 

[84] Caillot-Augusseau A, Lafage-Proust MH, Soler C, Pernod J, Dubois F, Alexandre C. 

Bone formation and resorption biological markers in cosmonauts during and after a 

180-day space flight (Euromir 95). Clin Chem. 1998 Mar;44(3):578-85. 

[85] Caillot-Augusseau A, Vico L, Heer M, et al. Space flight is associated with rapid 

decreases of undercarboxylated osteocalcin and increases of markers of bone resorption 
138 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

without changes in their circadian variation: observations in two cosmonauts. Clin 

Chem. 2000;46:1136-43. 

[86] Calucci L, Pinzino C, Zandomeneghi M, et al. Effects of gamma-irradiation on the free 

radical and antioxidant contents in nine aromatic herbs and spices. J Agric Food Chem. 

2003 Feb 12;51(4):927-34. 

[87] Campbell K. Intensive oxygen therapy as a possible cause of retrolental fibroplasia: a 

clinical approach. Med J Aust. 1951;2:48-50. 

[88] Camporeale G, Zempleni J. Biotin. In: Bowman BA, Russell RM, eds. Present 

knowledge in nutrition, Vol I. 9th ed. Washington, DC: ILSI Press; 2006:314-26. 

[89] Cann CE, Adachi RR. Bone resorption and mineral excretion in rats during spaceflight. 

Am J Physiol. 1983;13:R327-31. 

[90] Caraballo PJ, Heit JA, Atkinson EJ, et al. Long-term use of oral anticoagulants and the 

risk of fracture. Arch Intern Med. 1999 Aug 9-23;159(15):1750-6. 

[91] Carmeliet G, Vico L, Bouillon R. Space flight: a challenge for normal bone 

homeostasis. Crit Rev Eukaryot Gene Expr. 2001;11(1-3):131-44. 

[92] Castenmiller JJM, Mensink RP, van der Heijden L, et al. The effect of dietary sodium 

on urinary calcium and potassium excretion in normotensive men with different 

calcium intakes. Am J Clin Nutr. 1985;41:52-60. 

[93] Chan WK, Nguyen LT, Miller VP, Harris RZ. Mechanism-based inactivation of human 

cytochrome P450 3A4 by grapefruit juice and red wine. Life Sci. 1998;62(10):PL135-

42. 

[94] Chapkin RS, Davidson LA, Ly L, Weeks BR, Lupton JR, McMurray DN. 

Immunomodulatory effects of (n-3) fatty acids: putative link to inflammation and colon 

cancer. J Nutr. 2007 Jan;137(1):200S-4S. 

[95] Chappard D, Alexandre C, Palle S, et al. Effects of a bisphosphonate (1-hydroxy 

ethylidene-1,1 bisphosphonic acid) on osteoclast number during prolonged bed rest in 

healthy humans. Metabolism. 1989 Sep;38(9):822-5. 

[96] Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip 

fractures in the elderly women. N Engl J Med. 1992 Dec 3;327(23):1637-42. 

[97] Chapuy MC, Preziosi P, Maamer M, et al. Prevalence of vitamin D insufficiency in an 

adult normal population. Osteoporos Int. 1997;7(5):439-43. 

[98] Chen H, Howald WN, Juchau MR. Biosynthesis of all-trans-retinoic acid from alltrans-retinol: catalysis of all-trans-retinol oxidation by human P-450 cytochromes. Drug 

Metab Dispos. 2000 Mar;28(3):315-22. 

[99] Chen TC, Holick MF. Vitamin D and prostate cancer prevention and treatment. Trends 

Endocrinol Metab. 2003 Nov;14(9):423-30. 

[100] Cirillo M, De Santo NG, Heer M, et al. Urinary albumin in space missions. J Gravit 

Physiol. 2002 Jul;9(1):P193-4. 

[101] Cirillo M, Stellato D, Heer M, Drummer C, Bellini L, De Santo NG. Urinary albumin in 

head-down bed rest. J Gravit Physiol. 2002 Jul;9(1):P195-6. 

[102] Cirillo M, De Santo NG, Heer M, et al. Low urinary albumin excretion in astronauts 

during space missions. Nephron Physiol. 2003;93(4):102-5. 

[103] Clement G, Pavy-Le Traon A. Centrifugation as a countermeasure during actual and 

simulated microgravity: a review. Eur J Appl Physiol. 2004 Jul;92(3):235-48. 

[104] Clément G, Bukley AP, eds. Artificial gravity New York: Springer; 2007. 
References 139

[105] Coburn SP, Lewis DL, Fink WJ, Mahuren JD, Schaltenbrand WE, Costill DL. Human 

vitamin B-6 pools estimated through muscle biopsies. Am J Clin Nutr. 1988 

Aug;48(2):291-4. 

[106] Coburn SP, Thampy KG, Lane HW, et al. Pyridoxic acid excretion during low vitamin 

B-6 intake, total fasting, and bed rest. Am J Clin Nutr. 1995;62(5):979-83. 

[107] Cohen AJ, Roe FJ. Review of risk factors for osteoporosis with particular reference to a 

possible aetiological role of dietary salt. Food Chem Toxicol. 2000 Feb-Mar;38(2-

3):237-53. 

[108] Collet P, Uebelhart D, Vico L, et al. Effects of 1- and 6-month spaceflight on bone 

mass and biochemistry in two humans. Bone. 1997;20:547-51. 

[109] Conklin JJ, Walker RI. Military radiobiology. Orlando: Academic Press; 1987. 

[110] Constanzo LS, Windhager EE. Effects of PTH, ADH and cyclic AMP on distal tubular 

Ca and Na reabsorption. Am J Physiol. 1980;239:F478-F85. 

[111] Convertino VA. Clinical aspects of the control of plasma volume at microgravity and 

during return to one gravity. Med Sci Sports Exerc. 1996 Oct;28(10 Suppl):S45-52. 

[112] Convertino VA. Planning strategies for development of effective exercise and nutrition 

countermeasures for long-duration space flight. Nutrition. 2002 Oct;18(10):880-8. 

[113] Cook JD. Adaptation in iron metabolism. Am J Clin Nutr. 1990 Feb;51(2):301-8. 

[114] Cook JD, Skikne MD, Baynes RD. Serum transferrin receptor. Annu Rev Med. 

1993;44:63-74. 

[115] 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 Jan;18(1):209-11. 

[116] Cousins RJ. Zinc. In: Bowman BA, Russell RM, eds. Present knowledge in nutrition, 

Vol I. 9th ed. Washington, DC: ILSI Press; 2006:445-57. 

[117] Crespo ME, Bicho MP. Membrane-mediated effects of catecholamines on the DNA of 

human leukocytes: the role of reactive oxygen species. Biol Signals. 1995 MarApr;4(2):78-85. 

[118] Crucian BE, Stowe RP, Pierson DL, Sams CF. Immune system dysregulation following 

short- vs long-duration spaceflight. Aviat Space Environ Med. 2008 Sep;79(9):835-43. 

[119] ucinotta FA, Manuel FK, Jones J, et al. Space radiation and cataracts in astronauts. 

Radiat Res. 2001;156(5 Pt 1):460-6. 

[120] Dakshinamurti K, Li W. Transcriptional regulation of liver phosphoenolpyruvate 

carboxykinase by biotin in diabetic rats. Mol Cell Biochem. 1994 Mar 30;132(2):127-

32. 

[121] Dallman PR. Iron deficiency and the immune response. Am J Clin Nutr. 1987;46:329-

34. 

[122] Davidson LA, Nguyen DV, Hokanson RM, et al. Chemopreventive n-3 polyunsaturated 

fatty acids reprogram genetic signatures during colon cancer initiation and progression 

in the rat. Cancer Res. 2004 Sep 15;64(18):6797-804. 

[123] Davies KM, Rafferty K, Heaney RP. Determinants of endogenous calcium entry into 

the gut. Am J Clin Nutr. 2004 Oct;80(4):919-23. 

[124] Davis AT, Franz FP, Courtnay DA, Ullrey DE, Scholten DJ, Dean RE. Plasma vitamin 

and mineral status in home parenteral nutrition patients. Jpen. 1987 Sep-Oct;11(5):480-

5. 
140 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[125] Davis CD. Vitamin D and cancer: current dilemmas and future research needs. Am J 

Clin Nutr. 2008 Aug;88(2):565S-9S. 

[126] Dawson-Hughes B. Interaction of dietary calcium and protein in bone health in humans. 

J Nutr. 2003 Mar;133(3):852S-4S. 

[127] Dawson-Hughes B. Calcium and protein in bone health. Proc Nutr Soc. 2003 

May;62(2):505-9. 

[128] Day MK, Allen DL, Mohajerani L, Greenisen MC, Roy RR, Edgerton VR. Adaptations 

of human skeletal muscle fibers to spaceflight. J Gravit Physiol. 1995;2(1):P47-50. 

[129] De Groot AP, Van der Mijll Dekker LP, Slump P, Vos HJ, Willems JJL. Composition 

and nutritive value of radiation-pasteurized chicken. The Netherlands: Central Institute 

for Nutrition and Food Research; 1972. 

[130] De Santo NG, Christensen NJ, Drummer C, et al. Fluid balance and kidney function in 

space: introduction. Am J Kidney Dis. 2001 Sep;38(3):664-7. 

[131] De Santo NG, Cirillo M, Kirsch KA, et al. Anemia and erythropoietin in space flights. 

Semin Nephrol. 2005 Nov;25(6):379-87. 

[132] de Wardener HE, MacGregor GA. Harmful effects of dietary salt in addition to 

hypertension. J Hum Hypertens. 2002 Apr;16(4):213-23. 

[133] Desplanches D. Structural and functional adaptations of skeletal muscle to 

weightlessness. Int J Sports Med. 1997 Oct;18 Suppl 4:S259-64. 

[134] Devine A, Criddle RA, Dick IM, Kerr DA, Prince RL. A longitudinal study of the 

effect of sodium and calcium intakes on regional bone density in postmenopausal 

women. Am J Clin Nutr. 1995;62:740-5. 

[135] Devine A, Hodgson JM, Dick IM, Prince RL. Tea drinking is associated with benefits 

on bone density in older women. Am J Clin Nutr. 2007 Oct;86(4):1243-7. 

[136] di Prampero PE, Narici MV. Muscles in microgravity: from fibres to human motion. J 

Biomech. 2003 Mar;36(3):403-12. 

[137] Dietary Guidelines Advisory Committee. Dietary guidelines for Americans, 2005. 6th 

ed: U.S. Department of Health and Human Services and U.S. Department of 

Agriculture; 2005. Report No.: 0160723981. 

[138] Dietrick JE, Whedon GD, Shorr E. Effects of immobilization upon various metabolic 

and physiologic functions of normal men. Am J Med. 1948;4:3-36. 

[139] Djurhuus R, Segadal K, Svardal AM. Glutathione in blood cells decreases without 

DNA breaks after a simulated saturation dive to 250 msw. Aviat Space Environ Med. 

2006 Jun;77(6):597-604. 

[140] Dlugos DJ, Perrotta PL, Horn WG. Effects of the submarine environment on renalstone risk factors and vitamin D metabolism. Undersea Hyperb Med. 1995 

Jun;22(2):145-52. 

[141] Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-

hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and 

cardiovascular mortality. Arch Intern Med. 2008 Jun 23;168(12):1340-9. 

[142] Dolkas CB, Greenleaf JE. Insulin and glucose responses during bed rest with isotonic 

and isometric exercise. J Appl Physiol. 1977 Dec;43(6):1033-8. 

[143] Donaldson C, Hulley S, Vogel J, Hattner R, Bayers J, McMillan D. Effect of prolonged 

bed rest on bone mineral. Metabolism. 1970;19:1071-84. 

[144] Drummer C, Heer M, Dressendörfer RA, Strasburger CJ, Gerzer R. Reduced natriuresis 

during weightlessness. Clin Investig. 1993;71:678-86. 
References 141

[145] 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(2-3 Suppl):R66-72. 

[146] Drummer C, Hesse C, Baisch F, et al. Water and sodium balances and their relation to 

body mass changes in microgravity. Eur J Clin Invest. 2000 Dec;30(12):1066-75. 

[147] Dunn CDR, Lange RD, Kimzey SL, Johnson PC, Leach CS. Serum erythropoietin titers 

during prolonged bedrest; relevance to the "anaemia" of space flight. Eur J Appl 

Physiol. 1984;52:178-82. 

[148] Duplessis CA, Harris EB, Watenpaugh DE, Horn WG. Vitamin D supplementation in 

underway submariners. Aviat Space Environ Med. 2005 Jun;76(6):569-75. 

[149] Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol. 2005 

Jul;289(1):F8-28. 

[150] Elias AN, Gwinup G. Immobilization osteoporosis in paraplegia. J Am Paraplegia Soc. 

1992;15:163-70. 

[151] 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 Apr;82(4):223-30. 

[152] 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 Jan;83(1):65-71. 

[153] Erkal MZ, Wilde J, Bilgin Y, et al. High prevalence of vitamin D deficiency, secondary 

hyperparathyroidism and generalized bone pain in Turkish immigrants in Germany: 

identification of risk factors. Osteoporos Int. 2006;17(8):1133-40. 

[154] Essig DA, Nosek TM. Muscle fatigue and induction of stress protein genes: a dual 

function of reactive oxygen species? Can J Appl Physiol. 1997 Oct;22(5):409-28. 

[155] Evans CE, Chughtai AY, Blumsohn A, Giles M, Eastell R. The effect of dietary sodium 

on calcium metabolism in premenopausal and postmenopausal women. Eur J Clin Nutr. 

1997;51(6):394-9. 

[156] Eyre DR, Dickson IR, Van Ness K. Collagen cross-linking in human bone and articular 

cartilage. Biochem J. 1988;252:405-500. 

[157] Fagan TC, Walle T, Oexmann MJ, Walle UK, Bai SA, Gaffney TE. Increased clearance 

of propranolol and theophylline by high-protein compared with high-carbohydrate diet. 

Clin Pharmacol Ther. 1987 Apr;41(4):402-6. 

[158] Faintuch J, Soriano FG, Ladeira JP, Janiszewski M, Velasco IT, Gamma-Rodrigues JJ. 

Changes in body fluid and energy compartments during prolonged hunger strike. Rev 

Hosp Clin Fac Med Sao Paulo. 2000;55(2):47-54. 

[159] Fairbanks VF. Iron in medicine and nutrition. In: Shils ME, Olson JA, Shike M, Ross 

AC, eds. Modern nutrition in health and disease. 9th ed. Baltimore, MD: Lippincott 

Williams & Wilkins; 1999:193-221. 

[160] Fan X, Thayer DW. gamma-Radiation influences browning, antioxidant activity, and 

malondialdehyde level of apple juice. J Agric Food Chem. 2002 Feb 13;50(4):710-5. 

[161] Fang Y, Yang S, Wu G. Free radicals, antioxidants, and nutrition. Nutrition. 

2002;18:872-9. 

[162] Farrace S, Cenni P, Tuozzi G, Casagrande M, Barbarito B, Peri A. Endocrine and 

psychophysiological aspects of human adaptation to the extreme. Physiol Behav. 1999 

Jun;66(4):613-20. 

[163] Fellstrom B, Danielson BG, Karlstrom B, Lithell H, Ljunghal S, Vessby B. Dietary 

habits in renal stone patients compared with healthy subjects. Br J Urol. 1989;63:575-

80. 
142 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[164] Fenton TR, Eliasziw M, Lyon AW, Tough SC, Hanley DA. Meta-analysis of the 

quantity of calcium excretion associated with the net acid excretion of the modern diet 

under the acid-ash diet hypothesis. Am J Clin Nutr. 2008 Oct;88(4):1159-66. 

[165] Ferguson BJ, Skikne BS, Simpson KM, Baynes RD, D CJ. Serum transferrin receptor 

distinguishes the anemia of chronic disease from iron deficiency anemia. J Lab Clin 

Med. 1992;119(4):385-90. 

[166] Ferland G. Vitamin K. In: Bowman BA, Russell RM, eds. Present knowledge in 

nutrition. 9th ed. Washington, DC: ILSI Press; 2006:220-30. 

[167] Ferrando AA, Williams BD, Stuart CA, Lane HW, Wolfe RR. Oral branched-chain 

amino acids decrease whole-body proteolysis. Jpen. 1995 Jan-Feb;19(1):47-54. 

[168] Ferrando AA, Lane HW, Stuart CA, Davis-Street J, Wolfe RR. Prolonged bed rest 

decreases skeletal muscle and whole body protein synthesis. Am J Physiol Endocrinol 

Metab. 1996 Apr;270(4 Pt 1):E627-33. 

[169] Ferrando AA, Tipton KD, Bamman MM, Wolfe RR. Resistance exercise maintains 

skeletal muscle protein synthesis during bed rest. J Appl Physiol. 1997 Mar;82(3):807-

10. 

[170] Ferrando AA, Paddon-Jones D, Wolfe RR. Alterations in protein metabolism during 

space flight and inactivity. Nutrition. 2002 Oct;18(10):837-41. 

[171] Fettman MJ. Dietary instead of pharmacological management to counter the adverse 

effects of physiological adaptations to space flight. Pflugers Arch. 2000;441(2-3 

Suppl):R15-20. Review. 

[172] Finch CA, Huebers HA. Perspectives in iron metabolism. N Engl J Med. 

1982;306:1520-8. 

[173] Fischer CL, Johnson PC, Berry CA. Red blood cell mass and plasma volume changes in 

manned space flight. JAMA. 1967;200:579-83. 

[174] Fitts RH, Riley DR, Widrick JJ. Invited review: microgravity and skeletal muscle. J 

Appl Physiol. 2000 Aug;89(2):823-39. 

[175] Fitts RH, Romatowski JG, Peters JR, Paddon-Jones D, Wolfe RR, Ferrando AA. The 

deleterious effects of bed rest on human skeletal muscle fibers are exacerbated by 

hypercortisolemia and ameliorated by dietary supplementation. Am J Physiol Cell 

Physiol. 2007 Jul;293(1):C313-20. 

[176] Florian J, Curren M, Baisch F, Pawelczyk J. Caloric restriction decreases orthostatic 

tolerance. FASEB J. 2004;18:478.6. 

[177] Flowers CH, Skikne BS, Covell AM, D CJ. The clinical measurement of serum 

transferrin receptor. J Lab Clin Med. 1989;114(4):368-77. 

[178] Fontecave M, Pierre JL. Iron: metabolism, toxicity and therapy. Biochimie. 

1993;75:767-73. 

[179] Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes: a risk 

assessment model for establishing upper intake levels for nutrients. Washington, DC: 

National Academy Press; 1998. 

[180] Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for thiamin, 

riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and 

choline. Washington, DC: National Academy Press; 2000. 

[181] Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for vitamin 

A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, 
References 143

molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy 

Press; 2001. 

[182] Force RW, Nahata MC. Effect of histamine H2-receptor antagonists on vitamin B12 

absorption. Ann Pharmacother. 1992 Oct;26(10):1283-6. 

[183] Fox JB, Jr., Thayer DW, Jenkins RK, et al. Effect of gamma irradiation on the B 

vitamins of pork chops and chicken breasts. Int J Radiat Biol. 1989 Apr;55(4):689-703. 

[184] Frassetto L, Morris RC, Jr, Sellmeyer DE, Todd K, Sebastian A. Diet, evolution and 

aging--the pathophysiologic effects of the post-agricultural inversion of the potassiumto-sodium and base-to-chloride ratios in the human diet. Eur J Nutr. 2001 

Oct;40(5):200-13. 

[185] Frassetto LA, Morris RC, Jr., Sellmeyer DE, Sebastian A. Adverse effects of sodium 

chloride on bone in the aging human population resulting from habitual consumption of 

typical American diets. J Nutr. 2008 Feb;138(2):419S-22S. 

[186] Freeland-Graves J, Llanes C. Models to study manganese deficiency. In: KlimisTavantzis DJ, ed. Manganese in health and disease. Boca Raton, FL: CRC Press; 

1994:59-86. 

[187] Freudenheim JL, Johnson NE, Smith EL. Relationships between usual nutrient intake 

and bone-mineral content of women 35-65 years of age: longitudinal and crosssectional analysis. Am J Clin Nutr. 1986 Dec;44(6):863-76. 

[188] Frings-Meuthen P, Baecker N, Heer M. Low-grade metabolic acidosis may be the cause 

of sodium chloride-induced exaggerated bone resorption. J Bone Miner Res. 2008 

Apr;23(4):517-24. 

[189] Frings P, Baecker N, Boese A, Heer M. High sodium chloride intake causes mild 

metabolic acidosis: Is this the reason for increased bone resorption? FASEB J. 2005 

Mar;19(5):A1345 (abstract #745.2). 

[190] Frings P, Baecker N, Heer M. High sodium chloride intake exacerbates immobilisation 

induced bone loss. FASEB J. 2007;21:Abstract 548.7. 

[191] Fry PC, Fox HM, Tao HG. Metabolic response to a pantothenic acid deficient diet in 

humans. J Nutr Sci Vitaminol (Tokyo). 1976;22(4):339-46. 

[192] Fujita K. Food-drug interactions via human cytochrome P450 3A (CYP3A). Drug 

Metabol Drug Interact. 2004;20(4):195-217. 

[193] Gamble JL, Ross GS, Tisdall FF. The metabolism of fixed base during fasting. J Biol 

Chem. 1923;57(3):633-95. 

[194] Garrow TS, Fletcher K, Halliday O. Body composition in severe infantile malnutrition. 

J Clin Invest. 1965;44:417-25. 

[195] Gdynia HJ, Muller T, Sperfeld AD, et al. Severe sensorimotor neuropathy after intake 

of highest dosages of vitamin B6. Neuromuscul Disord. 2008 Feb;18(2):156-8. 

[196] Gerzer R, Drummer C, Heer M. Antinatriuretic kidney response to weightlessness. Acta 

Astronaut. 1994 Jul;33:97-100. 

[197] Gerzer R, Heer M, Drummer C. Body fluid metabolism at actual and simulated 

microgravity. Med Sci Sports Exerc. 1996;28(10 Suppl):S32-5. 

[198] Gerzer R, Heer M. Regulation of body fluid and salt homeostasis - from observations in 

space to new concepts on Earth. Curr Pharm Biotechnol. 2005 Aug;6(4):299-304. 

[199] Gilchrest BA. Sun protection and Vitamin D: three dimensions of obfuscation. J Steroid 

Biochem Mol Biol. 2007 Mar;103(3-5):655-63. 
144 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[200] Gilchrest BA. Sun exposure and vitamin D sufficiency. Am J Clin Nutr. 2008 

Aug;88(2):570S-7S. 

[201] Ginty F, Flynn A, Cashman KD. The effect of dietary sodium intake on biochemical 

markers of bone metabolism in young women. Br J Nutr. 1998;79:343-50. 

[202] Glei M, Latunde-Dada GO, Klinder A, et al. Iron-overload induces oxidative DNA 

damage in the human colon carcinoma cell line HT29 clone 19A. Mutat Res. 2002 Aug 

26;519(1-2):151-61. 

[203] Glerup H, Mikkelsen K, Poulsen L, et al. Commonly recommended daily intake of 

vitamin D is not sufficient if sunlight exposure is limited. J Intern Med. 2000 

Feb;247(2):260-8. 

[204] Gloth FM, 3rd, Alam W, Hollis B. Vitamin D vs broad spectrum phototherapy in the 

treatment of seasonal affective disorder. The journal of nutrition, health & aging. 

1999;3(1):5-7. 

[205] Goodman GE, Thornquist MD, Balmes J, et al. The Beta-Carotene and Retinol Efficacy 

Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year 

follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst. 

2004 Dec 1;96(23):1743-50. 

[206] Goraya JS, Gupta PN, Gupta RK, Bahadur R, Parmar VR. Anticonvulsant induced 

osteomalacia. Indian Pediatr. 2000 Mar;37(3):325-9. 

[207] Goulding A. Effects of dietary NaCl supplements on parathyroid function, bone 

turnover and bone composition in rats taking restricted amounts of calcium. Miner 

Electrolyte Metab. 1980;4:203-8. 

[208] Goulding A, Lim PE. Effects of varying dietary salt intake on the fasting urinary 

excretion of sodium, calcium and hydroxyproline in young women. N Z Med J. 

1983;96:853-4. 

[209] Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate 

doses of solar ultraviolet-B radiation. Cancer. 2002 Mar 15;94(6):1867-75. 

[210] Grant WB. An ecologic study of dietary and solar ultraviolet-B links to breast 

carcinoma mortality rates. Cancer. 2002 Jan 1;94(1):272-81. 

[211] Greenleaf JE. Mechanisms for negative water balance during weightlessness: 

immersion or bed rest? Physiologist. 1985;28(6 Suppl):S38-9. 

[212] Greenleaf JE, Bulbulian R, Bernauer EM, Haskell WL, Moore T. Exercise-training 

protocols for astronauts in microgravity. J Appl Physiol. 1989;67(6):2191-204. 

[213] Greenleaf JE, Chou JL, Stad NJ, et al. Short-arm (1.9 m) +2.2 Gz acceleration: isotonic 

exercise load-O2 uptake relationship. Aviat Space Environ Med. 1999 

Dec;70(12):1173-82. 

[214] Gretebeck RJ, Siconolfi SF, Rice B, Lane HW. Physical performance is maintained in 

women consuming only foods used on the U.S. Space Shuttle. Aviat Space Environ 

Med. 1994 Nov;65(11):1036-40. 

[215] Gretebeck RJ, Schoeller DA, Gibson EK, Lane HW. Energy expenditure during 

antiorthostatic bed rest (simulated microgravity). J Appl Physiol. 1995 Jun;78(6):2207-

11. 

[216] Grigoriev AI, Morukov BV, Oganov VS, Rakhmanov AS, Buravkova LB. Effect of 

exercise and bisphosphonate on mineral balance and bone density during 360 day 

antiorthostatic hypokinesia. J Bone Miner Res. 1992 Dec;7 Suppl 2:S449-55. 
References 145

[217] Grigoriev AI, Oganov VS, Bakulin AV, et al. [Clinical and physiological evaluation of 

bone changes among astronauts after long-term space flights]. Aviakosm Ekolog Med. 

1998;32:21-5. 

[218] Groff J, Gropper S. Advanced nutrition and human metabolism. 3rd ed. St. Paul, MN: 

Wadsworth Publishing; 2000. 

[219] Grogor'eva LS, Kozlovskaia IB. [Effect of weightlessness and hypokinesia on the 

velocity-strength properties of human muscles]. Kosm Biol Aviakosm Med. 1987 JanFeb;21(1):27-30. 

[220] Gross MD. Vitamin D and calcium in the prevention of prostate and colon cancer: new 

approaches for the identification of needs. J Nutr. 2005 Feb;135(2):326-31. 

[221] Guengerich FP. Influence of nutrients and other dietary materials on cytochrome P-450 

enzymes. Am J Clin Nutr. 1995 Mar;61(3 Suppl):651S-8S. 

[222] Guengerich FP, Miller GP, Hanna IH, et al. Diversity in the oxidation of substrates by 

cytochrome P450 2D6: lack of an obligatory role of aspartate 301-substrate electrostatic 

bonding. Biochemistry (Mosc). 2002 Sep 10;41(36):11025-34. 

[223] Gupta RP, Hollis BW, Patel SB, Patrick KS, Bell NH. CYP3A4 is a human microsomal 

vitamin D 25-hydroxylase. J Bone Miner Res. 2004 Apr;19(4):680-8. 

[224] Hantman DA, Vogel JM, Donaldson CL, Friedman R, Goldsmith RS, Hulley SB. 

Attempts to prevent disuse osteoporosis by treatment with calcitonin, longitudinal 

compression and supplementary calcium and phosphate. J Clin Endocrinol Metab. 1973 

May;36(5):845-58. 

[225] Hardman J, Limbird L. Goodman and Gilman's the pharmacological basis of 

therapeutics, Vol 9th edition. New York: McGraw Hill; 1996. 

[226] Harm DL, Jennings RT, Meck JV, et al. Invited review: gender issues related to 

spaceflight: a NASA perspective. J Appl Physiol. 2001 Nov;91(5):2374-83. 

[227] Harrington M, Cashman KD. High salt intake appears to increase bone resorption in 

postmenopausal women but high potassium intake ameliorates this adverse effect. Nutr 

Rev. 2003 May;61(5 Pt 1):179-83. 

[228] Harrington M, Bennett T, Jakobsen J, et al. The effect of a high-protein, high-sodium 

diet on calcium and bone metabolism in postmenopausal women and its interaction 

with vitamin D receptor genotype. Br J Nutr. 2004 Jan;91(1):41-51. 

[229] Harrington M, Bennett T, Jakobsen J, et al. Effect of a high-protein, high-salt diet on 

calcium and bone metabolism in postmenopausal women stratified by hormone 

replacement therapy use. Eur J Clin Nutr. 2004 Oct;58(10):1436-9. 

[230] Harris SS. Vitamin D in type 1 diabetes prevention. J Nutr. 2005 Feb;135(2):323-5. 

[231] Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin 

Nutr. 2007 Jan;85(1):6-18. 

[232] Hawkey A. The importance of exercising in space. Interdiscip Sci Rev. 2003 

Jun;28(2):130-8. 

[233] Haywood LJ. Coronary heart disease mortality/morbidity and risk in blacks. I: Clinical 

manifestations and diagnostic criteria: the experience with the Beta Blocker Heart 

Attack Trial. Am Heart J. 1984 Sep;108(3 Pt 2):787-93. 

[234] Heaney RP, McCarron DA, Dawson-Hughes B, et al. Dietary changes favorably affect 

bone remodeling in older adults. J Am Diet Assoc. 1999 Oct;99(10):1228-33. 

[235] Heaney RP. Vitamin D, nutritional deficiency, and the medical paradigm. J Clin 

Endocrinol Metab. 2003 Nov;88(11):5107-8. 
146 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[236] Heaney RP. Calcium supplementation and incident kidney stone risk: a systematic 

review. J Am Coll Nutr. 2008 Oct;27(5):519-27. 

[237] Heaney RP. Vitamin D in health and disease. Clin J Am Soc Nephrol. 2008 

Sept;3(5):1535-41. 

[238] Heer M, Baisch F, Drummer C, Gerzer R. Long-term elevations of dietary sodium 

produce parallel increases in the renal excretion of urodilatin and sodium. In: Sahm PR, 

Keller MH, Schiewe B, eds. Proceedings of the Norderney Symposium on Scientific 

Results of the German Spacelab Mission D-2. Norderney, Germany: Wissenschaftliche 

Projectführung D-2; 1995:708-14. 

[239] Heer M, Zittermann A, Hoetzel D. Role of nutrition during long-term spaceflight. Acta 

Astronaut. 1995 Feb-Mar;35(4-5):297-311. 

[240] Heer M. Einfluss alimentaer erhoehter Kochsalzzufuhr auf den Wasser- und 

Elektrolythaushalt des Menschen: University of Bonn, Germany; 1996. 

[241] Heer M, Kamps N, Biener C, et al. Calcium metabolism in microgravity. Eur J Med 

Res. 1999;4:357-60. 

[242] Heer M, Boerger A, Kamps N, Mika C, Korr C, Drummer C. Nutrient supply during 

recent European missions. Pflugers Arch. 2000;441(2-3 Suppl):R8-14. 

[243] Heer M. Nutritional interventions related to bone turnover in European space missions 

and simulation models. Nutrition. 2002 Oct;18(10):853-6. 

[244] Heer M, Boese A, Baecker N, Smith SM. High calcium intake does not prevent disuseinduced bone loss. In: 24th Annual International Gravitational Physiology Meeting; 

2003 4-9 May, 2003; Santa Monica, CA; 2003. 

[245] Heer M, Baecker N, Mika C, Boese A, Gerzer R. Immobilization induces a very rapid 

increase in osteoclast activity. Acta Astronaut. 2005 Jul;57(1):31-6. 

[246] Heer M, Paloski WH. Space motion sickness: incidence, etiology, and countermeasures. 

Auton Neurosci. 2006 Oct 30;129(1-2):77-9. 

[247] Heer M, Baecker N, Zwart SR, Smith SM. Interactions between artificial gravity, 

affected physiological systems, and nutrition. In: Clement G, Bukley A, eds. Artificial 

gravity. New York: Springer; 2007:249-70. 

[248] Heer M, Frings-Meuthen P, Titze J, et al. Increasing sodium intake from a previous low 

or high intake affects water. Br J Nutr. 2009 May;101(9):1286-94. 

[249] Hegsted M, Linkswiler HM. Long-term effects of level of protein intake on calcium 

metabolism in young adult women. J Nutr. 1981 Feb;111(2):244-51. 

[250] Heidelbaugh ND. Space flight feeding concepts: characteristics, concepts for 

improvement, and public health implications. J Am Vet Med Assoc. 1966;149:1662-71. 

[251] Heidelbaugh ND, Vanderveen JE, Iger HG. Development and evaluation of a simplified 

formula food for aerospace feeding systems. Aerosp Med. 1968 Jan;39(1):38-43. 

[252] Heidelbaugh ND, Smith MC, Jr., Rambaut PC, et al. Clinical nutrition applications of 

space food technology. J Am Diet Assoc. 1973 Apr;62(4):383-9. 

[253] Henshall JD. The effect of processing on the nutritive value of fruit and vegetable 

products. Proc Nutr Soc. 1973 May;32(1):17-22. 

[254] Herbert V. Development of human folate deficiency. In: Picciano MF, Sotokstad ELR, 

Gregory JFI, eds. Folic acid metabolism in health and disease. New York: Wiley-Liss; 

1990:195-210. 

[255] Herbert V. Folic acid. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern 

nutrition in health and disease. Baltimore, MD: Lippincott Williams & Wilkins; 1999. 
References 147

[256] Herrmann W, Herrmann M, Obeid R. Hyperhomocysteinaemia: a critical review of old 

and new aspects. Curr Drug Metab. 2007 Jan;8(1):17-31. 

[257] Hewison M, Zehnder D, Chakraverty R, Adams JS. Vitamin D and barrier function: a 

novel role for extra-renal 1 alpha-hydroxylase. Mol Cell Endocrinol. 2004 Feb 

27;215(1-2):31-8. 

[258] Higuchi S, Higashi A, Nakamura T, Matsuda I. Nutritional copper deficiency in 

severely handicapped patients on a low copper enteral diet for a prolonged period: 

estimation of the required dose of dietary copper. J Pediatr Gastroenterol Nutr. 1988 

Jul-Aug;7(4):583-7. 

[259] Ho SC, Chen YM, Woo JL, Leung SS, Lam TH, Janus ED. Sodium is the leading 

dietary factor associated with urinary calcium excretion in Hong Kong Chinese adults. 

Osteoporos Int. 2001;12:723-31. 

[260] Hodges SJ, Bejui J, Leclercq M, Delmas PD. Detection and measurement of vitamins 

K1 and K2 in human cortical and trabecular bone. J Bone Miner Res. 1993 

Aug;8(8):1005-8. 

[261] Holick MF. Microgravity-induced bone loss - will it limit human space exploration? 

Lancet. 2000;355:1569-70. 

[262] Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart 

disease, and osteoporosis. Am J Clin Nutr. 2004 Mar;79(3):362-71. 

[263] Holick MF, Chen TC, Lu Z, Sauter E. Vitamin D and skin physiology: a D-lightful 

story. J Bone Miner Res. 2007 Dec;22 Suppl 2:V28-33. 

[264] Hollander J, Gore M, Fiebig R, et al. Spaceflight downregulates antioxidant defense 

systems in rat liver. Free Radic Biol Med. 1998 Jan 15;24(2):385-90. 

[265] Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D 

sufficiency: implications for establishing a new effective dietary intake 

recommendation for vitamin D. J Nutr. 2005 Feb;135(2):317-22. 

[266] Holman RT. Polyunsaturated fatty acid profiles in human disease. In: Bazan NG, 

Paoletti R, Iacono JM, eds. New trends in nutrition, lipid research and cardiovascular 

diseases. New York: Alan R. Liss; 1981:25-42. 

[267] Hong MY, Bancroft LK, Turner ND, et al. Fish oil decreases oxidative DNA damage 

by enhancing apoptosis in rat colon. Nutr Cancer. 2005;52(2):166-75. 

[268] Hoppner K, Lampi B. Folate levels in human liver from autopsies in Canada. Am J Clin 

Nutr. 1980 Apr;33(4):862-4. 

[269] Huebers HA, Finch CA. The physiology of transferrin and transferrin receptors. Physiol 

Res. 1987;67:520-82. 

[270] Hughes SG, Riis RC, Nickum JG, Rumsey GL. Biomicroscopic and histologic 

pathology of the eye in riboflavin deficient rainbow trout (Salmogairdneri). Cornell 

Vet. 1981 Jul;71(3):269-79. 

[271] Hulley SB, Vogel JM, Donaldson CL, Bayers JH, Friedman RJ, Rosen SN. The effect 

of supplemental oral phosphate on the bone mineral changes during prolonged bed rest. 

J Clin Invest. 1971;50:2506-18. 

[272] Hvas AM, Juul S, Bech P, Nexo E. Vitamin B6 level is associated with symptoms of 

depression. Psychother Psychosom. 2004 Nov-Dec;73(6):340-3. 

[273] Hwang TIS, Hill K, Schneider V, Pak CYC. Effect of prolonged bedrest on the 

propensity for renal stone formation. J Clin Endocrinol Metab. 1988;66:109-12. 
148 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[274] Hyatt KH, West DA. Reversal of bedrest-induced orthostatic intolerance by lower body 

negative pressure and saline. Aviat Space Environ Med. 1977 Feb;48(2):120-4. 

[275] Ihle R, Loucks AB. Dose-response relationships between energy availability and bone 

turnover in young exercising women. J Bone Miner Res. 2004 Aug;19(8):1231-40. 

[276] Institute of Medicine. Dietary reference intakes for calcium, phosphorus, magnesium, 

vitamin D, and fluoride. Washington, DC: National Academies Press; 1997. 

[277] Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin 

B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: 

National Academies Press; 1998. 

[278] Institute of Medicine. Dietary reference intakes for vitamin C, vitamin E, selenium, and 

carotenoids. Washington, DC: The National Academies Press; 2000. 

[279] Institute of Medicine. Dietary reference intakes for energy, carbohydrate, fiber, fat, 

fatty acids, cholesterol, protein, and amino acids (macronutrients). Washington, DC: 

The National Academies Press; 2002. 

[280] Institute of Medicine. Dietary reference intakes for water, potassium, sodium, chloride, 

and sulfate. Washington, DC: The National Academies Press; 2004. 

[281] Iuliano-Burns S, Wang XF, Ayton J, Jones G, Seeman E. Skeletal and hormonal 

responses to sunlight deprivation in Antarctic expeditioners. Osteoporos Int. 2009 Jan 

17. 

[282] Iwamoto J, Takeda T, Sato Y. Interventions to prevent bone loss in astronauts during 

space flight. Keio J Med. 2005 Jun;54(2):55-9. 

[283] Iwase S, Takada H, Watanabe Y, et al. Effect of centrifuge-induced artificial gravity 

and ergometric exercise on cardiovascular deconditioning, myatrophy, and osteoporosis 

induced by a -6 degrees head-down bedrest. J Gravit Physiol. 2004 Jul;11(2):P243-4. 

[284] Jackson HA, Sheehan AH. Effect of vitamin A on fracture risk. Ann Pharmacother. 

2005 Dec;39(12):2086-90. 

[285] Jackson JM, Blaine D, Powell-Tuck J, Korbonits M, Carey A, Elia M. Macro- and 

micronutrient losses and nutritional status resulting from 44 days of total fasting in a 

non-obese man. Nutrition. 2006 Sep;22(9):889-97. 

[286] Jacob RA. Niacin. In: Bowman BA, Russell RM, eds. Present knowledge in nutrition, 

Vol I. 9th ed. Washington, DC: ILSI Press; 2006:260-8. 

[287] Jacobs DR, Jr., Gallaher DD. Whole grain intake and cardiovascular disease: a review. 

Curr Atheroscler Rep. 2004 Nov;6(6):415-23. 

[288] 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 May;80(5):347-54. 

[289] Jara A, Lee E, Stauber D, Moatamed F, Felsenfeld AJ, Kleeman CR. Phosphate 

depletion in the rat: effect of bisphosphonates and the calcemic response to PTH. 

Kidney Int. 1999 Apr;55(4):1434-43. 

[290] Johnson P, Driscoll T, LeBlanc A. Blood volume changes. In: Johnston R, Dietlein L, 

eds. Biomedical results from Skylab (NASA SP-377). Washington, DC: National 

Aeronautics and Space Administration; 1977:235-41. 

[291] Johnson PC, Driscoll TB, Alexander WC, Lambertsen CJ. Body fluid volume changes 

during a 14-day continuous exposure to 5.2% O2 in N2 at pressure equivalent to 100 

FSW (4 ata). Aerosp Med. 1973;44:860-3. 
References 149

[292] Johnson PC, Leach CS, Rambaut PC. Estimates of fluid and energy balances of Apollo 

17. Aerosp Med. 1973;44:1227-30. 

[293] Johnson PC. The erythropoietic effects of weightlessness. In: Dunn CDR, ed. Current 

concepts in erythropoiesis. New York: John Wiley & Sons Ltd.; 1983:279-300. 

[294] Johnston CS. Vitamin C. In: Bowman BA, Russell RM, eds. Present knowledge in 

nutrition, Vol I. 9th ed. Washington, DC: ILSI Press; 2006:233-41. 

[295] Johnston RS, Dietlein LF, Berry CA, eds. Biomedical results of Apollo (NASA SP368). Washington, DC: National Aeronautics and Space Administration; 1975. 

[296] Johnston RS. Skylab medical program overview. In: Johnston RS, Dietlein LF, eds. 

Biomedical results from Skylab (NASA SP-377). Washington, DC: National Aeronautics 

and Space Administration; 1977:3-19. 

[297] Jones JA, McCarten M, Manuel K, et al. Cataract formation mechanisms and risk in 

aviation and space crews. Aviat Space Environ Med. 2007 Apr;78(4 Suppl):A56-66. 

[298] Jones JA, Riggs PK, Yang TC, et al. Ionizing radiation-induced bioeffects in space and 

strategies to reduce cellular injury and carcinogenesis. Aviat Space Environ Med. 2007 

Apr;78(4 Suppl):A67-78. 

[299] 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 Jun 15;30(12):1390-9. 

[300] Jowsey J, Riggs BL, Goldsmith RS, Kelly PJ, Arnaud CD. Effects of prolonged 

administration of porcine calcitonin in postmenopausal osteoporosis. J Clin Endocrinol 

Metab. 1971 Nov;33(5):752-8. 

[301] Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc. 2000 

Sep;75(9):933-42. 

[302] Kaneko K, Masaki U, Aikyo M, et al. Urinary calcium and calcium balance in young 

women affected by high protein diet of soy protein isolate and adding sulfur-containing 

amino acids and/or potassium. J Nutr Sci Vitaminol (Tokyo). 1990 Apr;36(2):105-16. 

[303] Katan MB. [How much vitamin B6 is toxic?]. Ned Tijdschr Geneeskd. 2005 Nov 

12;149(46):2545-6. 

[304] Kayden HJ, Traber MG. Absorption, lipoprotein transport, and regulation of plasma 

concentrations of vitamin E in humans. J Lipid Res. 1993 Mar;34(3):343-58. 

[305] Kempin SJ. Warfarin resistance caused by broccoli. N Engl J Med. 1983 May 

19;308(20):1229-30. 

[306] Kennedy AR, Ware JH, Guan J, et al. Selenomethionine protects against adverse 

biological effects induced by space radiation. Free Radic Biol Med. 2004 Jan 

15;36(2):259-66. 

[307] Kerstetter JE, Caseria DM, Mitnick ME, et al. Increased circulating concentrations of 

parathyroid hormone in healthy, young women consuming a protein-restricted diet. Am 

J Clin Nutr. 1997 Nov;66(5):1188-96. 

[308] Kerstetter JE, O'Brien KO, Insogna KL. Dietary protein affects intestinal calcium 

absorption. Am J Clin Nutr. 1998 Oct;68(4):859-65. 

[309] Kerstetter JE, Looker AC, Insogna KL. Low dietary protein and low bone density. 

Calcif Tissue Int. 2000 Apr;66(4):313. 

[310] Kerstetter JE, Svastisalee CM, Caseria DM, Mitnick ME, Insogna KL. A threshold for 

low-protein-diet-induced elevations in parathyroid hormone. Am J Clin Nutr. 2000 

Jul;72(1):168-73. 
150 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[311] Kerstetter JE, O'Brien KO, Insogna KL. Low protein intake: the impact on calcium and 

bone homeostasis in humans. J Nutr. 2003 Mar;133(3):855S-61S. 

[312] Kerstetter JE, O. OBK, Caseria DM, Wall DE, Insogna KL. The impact of dietary 

protein on calcium absorption and kinetic measures of bone turnover in women. J Clin 

Endocrinol Metab. 2005 Jan;90(1):26-31. 

[313] Keys AB, Brozek J, Henschel A. The biology of human starvation Vol 1. Minneapolis: 

University of Minnesota Press; 1950. 

[314] Kiefer J, Pross HD. Space radiation effects and microgravity. Mutat Res. 1999 Dec 

6;430(2):299-305. 

[315] King JC, Keen CL. Zinc. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern 

nutrition in health and disease. 9th ed. Baltimore, MD: Lippincott Williams & Wilkins; 

1999:223-39. 

[316] Kinsey VE. Retrolental fibroplasia: cooperative study of retrolental fibroplasia and the 

use of oxygen. Arch Ophthalmol. 1956;56:481-543. 

[317] Kivivuori SM, Heikinheimo M, Teppo AM, Simes MA. Early rise in serum 

concentration of transferrin receptor induced by recombinant human erythropoietin in 

very-low-birth-weight infants. Pediatr Res. 1994;36(1 Pt 1):85-9. 

[318] Kleeman CR, Bohannan J, Bernstein D, Long S, Maxwell MH. Effect of variations in 

sodium intake on calcium excretion in normal humans. Proc Soc Exp Biol Med. 

1964;115:29-32. 

[319] Klein L, van der Noort S, DeJak JJ. Sequential studies of urinary hydroxyproline and 

serum alkaline phosphatase in acute paraplegia. Med Serv J Can. 1966 JulyAugust;22(7):524-33. 

[320] Kleinman LI, Lorenz JM. Physiology and pathophysiology of body water and 

electrolytes. In: Kaplan LA, Pesce AJ, eds. Clinical chemistry: theory, analysis, and 

correlation. St. Louis, MO: CV Mosby Company; 1984:363-86. 

[321] Klicka MV. Development of space foods. J Am Diet Assoc. 1964;44:358-61. 

[322] Klicka MV, Hollender HA, Lachance PA. Foods for astronauts. J Am Diet Assoc. 1967 

Sep;51(3):238-45. 

[323] Knekt P, Reunanen A, Takkunen H, Aromaa A, Heliovaara M, Hakulinen T. Body iron 

stores and risk of cancer. Int J Cancer. 1994;56(3):379-82. 

[324] Knochel JP. Phosphorus. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern 

nutrition in health and disease. 9th ed. Baltimore, MD: Lippincott Williams & Wilkins; 

1999:157-67. 

[325] Kohlmeier L, Hastings SB. Epidemiologic evidence of a role of carotenoids in 

cardiovascular disease prevention. Am J Clin Nutr. 1995;62 Suppl:1370S-6S. 

[326] Kohlmuller D, Kochen W. Is n-pentane really an index of lipid peroxidation in humans 

and animals? A methodological reevaluation. Anal Biochem. 1993 May 1;210(2):268-

76. 

[327] Kondrashov V, Rothenberg SJ, Chettle D, Zerwekh J. Evaluation of potentially 

significant increase of lead in the blood during long-term bed rest and space flight. 

Physiol Meas. 2005 Feb;26(1):1-12. 

[328] Kondrashov VS. Cosmonauts and lead: resorption and increased blood lead levels 

during long term space flight. J Med Toxicol. 2006 Dec;2(4):172-3. 
References 151

[329] Konopacka M, Rzeszowska-Wolny J. Antioxidant vitamins C, E and beta-carotene 

reduce DNA damage before as well as after gamma-ray irradiation of human 

lymphocytes in vitro. Mutat Res. 2001 Apr 5;491(1-2):1-7. 

[330] Kopke R, Allen KA, Henderson D, Hoffer M, Frenz D, Van de Water T. A radical 

demise. Toxins and trauma share common pathways in hair cell death. Ann N Y Acad 

Sci. 1999;884:171-91. 

[331] Korcok M. Hunger strikers may have died of fat, not protein, loss. JAMA. 1981 Oct 23-

30;246(17):1878-9. 

[332] Koudelova J, Mourek J. The lipid peroxidation in various parts of the rat brain: effect of 

age, hypoxia and hyperoxia. Physiol Res. 1994;43(3):169-73. 

[333] Kraemer WJ, Staron RS, Gordon SE, et al. The effects of 10 days of spaceflight on the 

shuttle Endeavor on predominantly fast-twitch muscles in the rat. Histochem Cell Biol. 

2000 Nov;114(5):349-55. 

[334] Krause KH, Bonjour JP, Berlit P, Kynast G, Schmidt-Gayk H, Schellenberg B. Effect 

of long-term treatment with antiepileptic drugs on the vitamin status. Drug Nutr 

Interact. 1988;5(4):317-43. 

[335] Krebs JM, Schneider VS, LeBlanc AD. Zinc, copper, and nitrogen balances during bed 

rest and fluoride supplementation in healthy adult males. Am J Clin Nutr. 1988 

Mar;47(3):509-14. 

[336] Krebs JM, Schneider VS, LeBlanc AD, Kuo MC, Spector E, Lane HW. Zinc and 

copper balances in healthy adult males during and after 17 wk of bed rest. Am J Clin 

Nutr. 1993 Dec;58(6):897-901. 

[337] Kuhn LC, Hentze MW. Coordination of cellular iron metabolism by posttranscriptional gene regulation. J Inorg Biochem. 1992 Aug 15-Sep;47(3-4):183-95. 

[338] Kurliandskii V, Khvatova VA, Budylina SM. [Functional mobility of taste receptors of 

the tongue under conditions of prolonged hypodynamia]. Stomatologiia (Mosk). 1974 

Nov-Dec;53(6):13-5. 

[339] Kuvibidila S, Yu LC, Ode DL, Warrier RP, Mbele V. Assessment of iron status of 

Zairean women of childbearing age by serum transferrin receptor. Am J Clin Nutr. 

1994;60(4):603-9. 

[340] LaChance PA, Berry CA. Luncheon in space. Nutr Today 1967 June:2-11. 

[341] Lackner JR, Dizio P. Space motion sickness. Exp Brain Res. 2006 Nov;175(3):377-99. 

[342] Lakritz L, Fox JB, Thayer DW. Thiamin, riboflavin, and alpha-tocopherol content of 

exotic meats and loss due to gamma radiation. J Food Prot. 1998 Dec;61(12):1681-3. 

[343] Lane HW, Schulz LO. Nutritional questions relevant to space flight. Annu Rev Nutr. 

1992 1992;12:257-78. 

[344] Lane HW, LeBlanc AD, Putcha L, Whitson PA. Nutrition and human physiological 

adaptations to space flight. Am J Clin Nutr. 1993;58:583-8. 

[345] Lane HW, Rambaut PC. Nutrition. In: Nicogossian AE, Huntoon CL, Pool SL, eds. 

Space physiology and medicine. 3rd ed. Philadelphia: Lea & Febiger; 1994:305-16. 

[346] Lane HW, Rice B, Kloeris V, et al. Energy intake, body weight, and lean body mass are 

maintained in healthy, active women consuming a US Space Shuttle diet. J Am Diet 

Assoc. 1994;94:87-8. 

[347] Lane HW, Alfrey CP, Driscoll TB, Smith SM, Nyquist LE. Control of red blood cell 

mass during spaceflight. J Gravitational Physiol. 1996 Sep;3(2):87-8. 
152 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[348] 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 Jan;65(1):4-12. 

[349] Lane HW, Gretebeck RJ, Smith SM. Nutrition, endocrinology, and body composition 

during space flight. Nutr Res. 1998 Nov;18(11):1923-34. 

[350] Lane HW, Smith SM. Nutrition in space. In: Shils ME, Olson JA, Shike M, Ross AC, 

eds. Modern nutrition in health and disease. 9th ed. Baltimore, MD: Lippincott 

Williams & Wilkins; 1999:783-8. 

[351] Lane HW, Whitson PA, Putcha L, et al. Regulatory physiology. In: Sawin CF, Taylor 

GR, Smith WL, eds. Extended-Duration Orbiter Medical Project: final report 1989-

1995, Vol NASA SP-1999-534. Houston, TX: NASA Lyndon B. Johnson Space 

Center; 1999:2-1 to 2-10. 

[352] Lane HW, Leach C, Smith SM. Fluid and electrolyte homeostasis. In: Lane HW, 

Schoeller DA, eds. Nutrition in spaceflight and weightlessness models. Boca Raton, FL: 

CRC Press; 2000:119-39. 

[353] 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(3):102-10. 

[354] Lang T, LeBlanc A, Evans H, Lu Y, Genant H, Yu A. Cortical and trabecular bone 

mineral loss from the spine and hip in long-duration spaceflight. J Bone Miner Res. 

2004 June;19(6):1006-12. 

[355] Lanham-New SA. Fruit and vegetables: the unexpected natural answer to the question 

of osteoporosis prevention? Am J Clin Nutr. 2006 Jun;83(6):1254-5. 

[356] Lanham-New SA. The balance of bone health: tipping the scales in favor of potassiumrich, bicarbonate-rich foods. J Nutr. 2008 Jan;138(1):172S-7S. 

[357] Lauffer RB. Iron stores and the international variation in mortality from coronary artery 

disease. Lancet. 1991;2:1288-9. 

[358] Lawler JM, Cline CC, Hu Z, Coast JR. Effect of oxidant challenge on contractile 

function of the aging rat diaphragm. Am J Physiol. 1997 Feb;272(2 Pt 1):E201-7. 

[359] Leach-Huntoon CS, Schneider H, Cintron NM, Landry R. Combined blood 

investigations. In: Bungo MW, Bagian TM, Bowman MA, Levitan BM, eds. Results of 

the life sciences DSOs conducted aboard the Space Shuttle 1981-1986. Houston: Space 

Biomedical Research Institute, Johnson Space Center; 1987:7-11. 

[360] Leach C, Rambaut P. Biochemical observations of long duration manned orbital 

spaceflight. J Am Med Wom Assoc. 1975;30:153-72. 

[361] Leach C, Rambaut P. Biochemical responses of the Skylab crewmen: an overview. In: 

Johnston R, Dietlein L, eds. Biomedical results from Skylab (NASA SP-377). 

Washington, DC: National Aeronautics and Space Administration; 1977:204-16. 

[362] Leach C, Rambaut P, Di Ferrante N. Amino aciduria in weightlessness. Acta Astronaut. 

1979;6:1323-33. 

[363] Leach C, Johnson P. Influence of spaceflight on erythrokinetics in man. Science. 

1984;225:216-8. 

[364] Leach C, Inners L, Charles J. Changes in total body water during spaceflight. J Clin 

Pharmacol. 1991;31:1001-6. 

[365] Leach C, Alfrey C, Suki W, et al. Regulation of body fluid compartments during shortterm spaceflight. J Appl Physiol. 1996;81:105-16. 
References 153

[366] Leach CS, Alexander WC, Johnson PC. Endocrine, electrolyte, and fluid volume 

changes associated with Apollo missions. In: Johnston RS, Dietlein LF, Berry CA, eds. 

Biomedical results of Apollo (NASA SP-368). Washington, DC: National Aeronautics 

and Space Administration; 1975:163-84. 

[367] Leach CS. A review of the consequences of fluid and electrolyte shifts in 

weightlessness. Acta Astronaut. 1979;6:1123-35. 

[368] Leach CS. An overview of the endocrine and metabolic changes in manned space flight. 

Acta Astronaut. 1981;8:977-86. 

[369] Leach CS. Medical results from STS 1-4: analysis of body fluids. Aviat Space Environ 

Med. 1983;54(12 Suppl):S50-S4. 

[370] Leach CS, Johnson PC, Jr. Fluid and electrolyte control in simulated and actual 

spaceflight. Physiologist. 1985;28(6 Suppl):S-34-S-7. 

[371] Leach CS. Fluid control mechanisms in weightlessness. Aviat Space Environ Med. 

1987;58(9 Section II):A74-A9. 

[372] Leach CS. Biochemical and hematologic changes after short-term space flight. 

Microgravity Quarterly. 1992;2:69-75. 

[373] Leach Huntoon CS, Grigoriev AI, Natochin YV. Fluid and electrolyte regulation in 

spaceflight, Vol 94. San Diego: Univelt, Inc.; 1998. 

[374] LeBlanc A, Schneider V, Krebs J, Evans H, Jhingran S, Johnson P. Spinal bone mineral 

after 5 weeks of bed rest. Calcif Tissue Int. 1987;41:259-61. 

[375] LeBlanc A, Rowe R, Schneider V, Evans H, Hedrick T. Regional muscle loss after 

short duration spaceflight. Aviat Space Environ Med. 1995;66:1151-4. 

[376] LeBlanc A, Schneider V, Spector E, et al. Calcium absorption, endogenous excretion, 

and endocrine changes during and after long-term bed rest. Bone. 1995;16(4 

Suppl):301S-4S. 

[377] LeBlanc A, Lin C, Rowe R, et al. Muscle loss after long duration spaceflight on Mir 

18/STS-71 [abstract]. AIAA Life Sciences and Space Medicine Conference; 1996:53-4, 

Abstract 96-LS-71. 

[378] LeBlanc A, Schneider V, Shackelford L, et al. Bone mineral and lean tissue loss after 

long duration space flight. J Bone Miner Res. 1996;11 Suppl 1:S323. 

[379] LeBlanc A, Schneider V, Shackelford L, et al. Bone mineral and lean tissue loss after 

long duration space flight. J Musculoskelet Neuronal Interact. 2000;1:157-60. 

[380] LeBlanc AD, Schneider VS, Evans HJ, Engelbretson DA, Krebs JM. Bone mineral loss 

and recovery after 17 weeks of bed rest. J Bone Miner Res. 1990;5:843-50. 

[381] LeBlanc AD, Driscol TB, Shackelford LC, et al. Alendronate as an effective 

countermeasure to disuse induced bone loss. J Musculoskelet Neuronal Interact. 

2002;2(4):335-43. 

[382] LeBlanc AD, Spector ER, Evans HJ, Sibonga JD. Skeletal responses to space flight and 

the bed rest analog: a review. J Musculoskelet Neuronal Interact. 2007 JanMar;7(1):33-47. 

[383] Lee NK, Karsenty G. Reciprocal regulation of bone and energy metabolism. Trends 

Endocrinol Metab. 2008 Jul;19(5):161-6. 

[384] Leiter LA, Marliss EB. Survival during fasting may depend on fat as well as protein 

stores. JAMA. 1982 Nov 12;248(18):2306-7. 

[385] Leo MA, Lieber CS. Hepatic vitamin A depletion in alcoholic liver injury. N Engl J 

Med. 1982 Sep 2;307(10):597-601. 
154 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[386] Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotene: adverse interactions, 

including hepatotoxicity and carcinogenicity. Am J Clin Nutr. 1999 Jun;69(6):1071-85. 

[387] Leonard JI, Leach CS, Rambaut PC. Quantitation of tissue loss during prolonged space 

flight. Am J Clin Nutr. 1983;38:667-79. 

[388] Levine DS, Greenleaf JE. Immunosuppression during spaceflight deconditioning. Aviat 

Space Environ Med. 1998;69:172-7. 

[389] Lewis B, Rathman S, McMahon R. Dietary biotin intake modulates the pool of free and 

protein-bound biotin in rat liver. J Nutr. 2001 Sep;131(9):2310-5. 

[390] Li CY, Majeska RJ, Laudier DM, Mann R, Schaffler MB. High-dose risedronate 

treatment partially preserves cancellous bone mass and microarchitecture during longterm disuse. Bone. 2005 Sep;37(3):287-95. 

[391] Li CY, Price C, Delisser K, et al. Long-term disuse osteoporosis seems less sensitive to 

bisphosphonate treatment than other osteoporosis. J Bone Miner Res. 2005 

Jan;20(1):117-24. 

[392] Lietz G, Avenell A, Robins SP. Short-term effects of dietary sodium intake on bone 

metabolism in postmenopausal women measured using urinary deoxypyridinoline 

excretion. Br J Nutr. 1997;78:73-82. 

[393] Lipman RL, Ulvedal F, Schnure JJ, Bradley EM, Lecocq FR. Gluco-regulatory 

hormone response to 2-deoxy-d-glucose infusion in normal subjects at bedrest. 

Metabolism. 1970 Nov;19(11):980-7. 

[394] Lipschitz DA, Cook JD, Finch CA. A clinical evaluation of serum ferritin as an index 

of iron stores. N Engl J Med. 1974 1974;290:1213-6. 

[395] Lisbona Gil A, Fernandez Riestra FA, Contreras Fernandez R, Herrero Huertas E, 

Martinez Gomez ME. [Concentrations of 25-hydroxyvitamin D3 in Antarctica]. Med 

Clin (Barc). 1992 Jul 4;99(6):206-9. 

[396] Little JB. Radiation carcinogenesis. Carcinogenesis. 2000 Mar;21(3):397-404. 

[397] Lockwood DR, Vogel JM, Schneider VS, Hulley SB. Effect of the diphosphonate 

EHDP on bone mineral metabolism during prolonged bed rest. J Clin Endocrinol 

Metab. 1975;41:533-41. 

[398] Loiseaux-Meunier MN, Bedu M, Gentou C, Pepin D, Coudert J, Caillaud D. Oxygen 

toxicity: simultaneous measure of pentane and malondialdehyde in humans exposed to 

hyperoxia. Biomed Pharmacother. 2001 Apr;55(3):163-9. 

[399] Lotz M, Zisman E, Bartter FC. Evidence for a phosphorus-depletion syndrome in man. 

N Engl J Med. 1968 Feb 22;278(8):409-15. 

[400] Lovejoy JC, Smith SR, Zachwieja JJ, et al. Low-dose T(3) improves the bed rest model 

of simulated weightlessness in men and women. Am J Physiol Endocrinol Metab. 1999 

Aug;277(2 Pt 1):E370-9. 

[401] Lown KS, Bailey DG, Fontana RJ, et al. Grapefruit juice increases felodipine oral 

availability in humans by decreasing intestinal CYP3A protein expression. J Clin 

Invest. 1997 May 15;99(10):2545-53. 

[402] Lozoff B. Behavioral alterations in iron deficiency. Adv Pediatr. 1988;35:331-59. 

[403] Lukaski HC. Vitamin and mineral status: effects on physical performance. Nutrition. 

2004 Jul-Aug;20(7-8):632-44. 

[404] Lundahl J, Regardh CG, Edgar B, Johnsson G. Relationship between time of intake of 

grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine 

in healthy subjects. Eur J Clin Pharmacol. 1995;49(1-2):61-7. 
References 155

[405] Lynn MP, Fouad F, Cook SA, Napoli CA, Ferrario CM. Alterations in cardiac function 

and cardiopulmonary blood volume in chronic sodium depletion in dogs. Clin Sci 

(Lond). 1980 Dec;59 Suppl 6:393s-5s. 

[406] Maaß H, Raabe W, Wegmann HM. Effects of microgravity on glucose tolerance. In: 

Sahm PR, Keller MH, Schiewe B, eds. Proceedings of the Norderney Symposium on 

Scientific Results of the German Spacelab Mission D-2. Norderney, Germany: 

Wissenschaftliche Projectführung D-2; 1995:732-5. 

[407] Macdonald HM, Black AJ, Aucott L, et al. Effect of potassium citrate supplementation 

or increased fruit and vegetable intake on bone metabolism in healthy postmenopausal 

women: a randomized controlled trial. Am J Clin Nutr. 2008 Aug;88(2):465-74. 

[408] Macdonald I, Williams CA. Effects of ingesting glucose and some of its polymers on 

serum glucose and insulin levels in men and women. Ann Nutr Metab. 1988;32(1):23-9. 

[409] Macho L, Koska J, Ksinantova L, et al. The response of endocrine system to stress 

loads during space flight in human subject. Adv Space Res. 2003;31(6):1605-10. 

[410] Macias BR, Groppo ER, Eastlack RK, et al. Space exercise and Earth benefits. Curr 

Pharm Biotechnol. 2005 Aug;6(4):305-17. 

[411] Maeda Y, Kawata S, Inui Y, Fukuda K, Igura T, Matsuzawa Y. Biotin deficiency 

decreases ornithine transcarbamylase activity and mRNA in rat liver. J Nutr. 1996 

Jan;126(1):61-6. 

[412] Maheshwari UR, Leybin L, Hodge HC, Newbrun E, Schneider VS, McDonald J. 

Comparison of fluoride balances during ambulation and bed rest. Proc West Pharmacol 

Soc. 1981;24:151-3. 

[413] Maheshwari UR, McDonald JT, Schneider VS, et al. Fluoride balance studies in 

ambulatory healthy men with and without fluoride supplements. Am J Clin Nutr. 1981 

Dec;34(12):2679-84. 

[414] Maheshwari UR, Schneider VS, McDonald JT, et al. Fluoride balance studies in healthy 

men during bed rest with and without a fluoride supplement. Am J Clin Nutr. 1982 

Aug;36(2):211-8. 

[415] Maheshwari UR, Leybin L, McDonald JT, Schneider VS, Newbrun E, Hodge HC. 

Effect of dichloromethylene diphosphonate on fluoride balance in healthy men. J Dent 

Res. 1983 May;62(5):559-61. 

[416] Mainous AG, 3rd, Wells BJ, Koopman RJ, Everett CJ, Gill JM. Iron, lipids, and risk of 

cancer in the Framingham Offspring cohort. Am J Epidemiol. 2005 Jun 

15;161(12):1115-22. 

[417] Majerus PW, Broze GJ, Miletech JP, Tollefsen DM. Anticoagulant, thrombolytic, and 

antiplatelet drugs. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. The 

pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990:1311-

31. 

[418] Mallat Z, Philip I, Lebret M, Chatel D, Maclouf J, Tedgui A. Elevated levels of 8-isoprostaglandin F2alpha in pericardial fluid of patients with heart failure: a potential role 

for in vivo oxidant stress in ventricular dilatation and progression to heart failure. 

Circulation. 1998 Apr 28;97(16):1536-9. 

[419] Massey LK, Whiting SJ. Dietary salt, urinary calcium, and stone risk. Nutr Rev. 

1995;53:131-9. 

[420] Massey LK, Whiting SJ. Dietary salt, urinary calcium, and bone loss. J Bone Miner 

Res. 1996;11:731-6. 
156 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[421] Matkovic V, Ilich JZ, Andon MB, et al. Urinary calcium, sodium, and bone mass of 

young females. Am J Clin Nutr. 1995;62:417. 

[422] McBarron JW, 2nd. U.S. prebreathe protocol. Acta Astronaut. 1994 Jan;32(1):75-8. 

[423] McCormick DB. Vitamin B6. In: Bowman BA, Russell RM, eds. Present knowledge in 

nutrition, Vol I. 9th ed. Washington, DC: ILSI Press; 2006:269-77. 

[424] McMonigal K, Sauer RL, Smith SM, et al. Physiological effects of iodinated water on 

thyroid function. In: Lane HW, Sauer RL, Feeback DL, eds. Isolation: NASA 

experiments in closed-environment living. San Diego: Univelt, Inc.; 2002:369-95. 

[425] McMonigal KA, Braverman LE, Dunn JT, et al. Thyroid function changes related to 

use of iodinated water in the U.S. Space Program. Aviat Space Environ Med. 2000 

Nov;71(11):1120-5. 

[426] Melhus H, Michaelsson K, Kindmark A, et al. Excessive dietary intake of vitamin A is 

associated with reduced bone mineral density and increased risk for hip fracture. Ann 

Intern Med. 1998 Nov 15;129(10):770-8. 

[427] Meyer WJ, 3rd, Transbol I, Bartter FC, Delea C. Control of calcium absorption: effect 

of sodium chloride loading and depletion. Metabolism. 1976;9:989-93. 

[428] Meythaler JM, Tuel SM, Cross LL. Successful treatment of immobilization 

hypercalcemia using calcitonin and etidronate. Arch Phys Med Rehabil. 1993;74:316-9. 

[429] Michaelsson K, Lithell H, Vessby B, Melhus H. Serum retinol levels and the risk of 

fracture. N Engl J Med. 2003 Jan 23;348(4):287-94. 

[430] Michel EL, Rummel JA, Sawin CF, Buderer MC, Lem JD. Results of Skylab medical 

experiment M-171 - Metabolic Activity. In: Johnston RS, Dietlein LF, eds. Biomedical 

results of Skylab, Vol NASA SP-377. Washington, DC: NASA; 1977:372-87. 

[431] Michos ED, Melamed ML. Vitamin D and cardiovascular disease risk. Curr Opin Clin 

Nutr Metab Care. 2008 Jan;11(1):7-12. 

[432] Milesi S, Capelli C, Denoth J, Hutchinson T, di Prampero PE, Stussi E. Effects of 17 

days bed rest on the maximal isometric torque of the flexors and extensors of the ankle. 

J Gravit Physiol. 1997 Jul;4(2):P125-6. 

[433] Miller JW, Rogers LM, Rucker RB. Pantothenic acid. In: Bowman BA, Russell RM, 

eds. Present knowledge in nutrition, Vol I. 9th ed. Washington, DC: ILSI Press; 

2006:327-39. 

[434] Millet C, Custaud MA, Maillet A, et al. Endocrine responses to 7 days of head-down 

bed rest and orthostatic tests in men and women. Clin Physiol. 2001 Mar;21(2):172-83. 

[435] Milne DB, Gallagher SK, Nielsen FH. Response of various indices of iron status to 

acute iron depletion produced in menstruating women by low iron intake and 

phlebotomy. Clin Chem. 1990 Mar;36(3):487-91. 

[436] Milne DB. Trace elements. In: Burtis CA, Ashwood ER, eds. Tietz textbook of clinical 

chemistry. 2nd ed. Philadelphia, PA: WB Saunders Company; 1994:1317-347. 

[437] Milne DB. Copper intake and assessment of copper status. Am J Clin Nutr. 1998 

May;67(5 Suppl):1041S-5S. 

[438] Minaire P, Meunier P, Edouard C, Bernard J, Courpron P, Bourret J. Quantitative 

histological data on disuse osteoporosis: comparison with biological data. Calcif Tissue 

Int. 1974;17:57-73. 

[439] Minaire P, Berard E, Meunier PJ, Edouard C, Goedert G, Pilonchery G. Effects of 

disodium dichloromethylene diphosphonate on bone loss in paraplegic patients. J Clin 

Invest. 1981 Oct;68(4):1086-92. 
References 157

[440] Mock DM, Malik MI. Distribution of biotin in human plasma: most of the biotin is not 

bound to protein. Am J Clin Nutr. 1992 Aug;56(2):427-32. 

[441] Mock DM, Stadler DD, Stratton SL, Mock NI. Biotin status assessed longitudinally in 

pregnant women. J Nutr. 1997 May;127(5):710-6. 

[442] Mock DM. Biotin status: which are valid indicators and how do we know? J Nutr. 1999 

Feb;129(2S Suppl):498S-503S. 

[443] Mock NI, Mock DM. Biotin deficiency in rats: disturbances of leucine metabolism are 

detectable early. J Nutr. 1992 Jul;122(7):1493-9. 

[444] Mock NI, Malik MI, Stumbo PJ, Bishop WP, Mock DM. Increased urinary excretion of 

3-hydroxyisovaleric acid and decreased urinary excretion of biotin are sensitive early 

indicators of decreased biotin status in experimental biotin deficiency. Am J Clin Nutr. 

1997 Apr;65(4):951-8. 

[445] Mohr SB, Garland CF, Gorham ED, Grant WB, Garland FC. Relationship between low 

ultraviolet B irradiance and higher breast cancer risk in 107 countries. Breast J. 2008 

May-Jun;14(3):255-60. 

[446] Moon SJ, Fryer AA, Strange RC. Ultraviolet radiation: effects on risks of prostate 

cancer and other internal cancers. Mutat Res. 2005 Apr 1;571(1-2):207-19. 

[447] Morey-Holton E, Whalen R, Arnaud S, Van Der Meulen M. The skeleton and its 

adaptation to gravity. In: Fregly M, Blatteis C, eds. Environmental physiology, Vol 1. 

New York: Oxford University Press; 1996:691-719. 

[448] Morgulis S. Chemical changes in the blood during fasting and subsequent refeeding. II. 

Inorganic constituents. Am J Physiol. 1928;84:350-62. 

[449] Morita S, Snider MT, Inada Y. Increased N-pentane excretion in humans: a 

consequence of pulmonary oxygen exposure. Anesthesiology. 1986 Jun;64(6):730-3. 

[450] Mowat C, McColl KE. Alterations in intragastric nitrite and vitamin C levels during 

acid inhibitory therapy. Best Pract Res Clin Gastroenterol. 2001 Jun;15(3):523-37. 

[451] Muller HK, Lugg DJ, Quinn D. Cell mediated immunity in Antarctic wintering 

personnel; 1984-1992. Immunol Cell Biol. 1995 Aug;73(4):316-20. 

[452] Muller HK, Lugg DJ, Ursin H, Quinn D, Donovan K. Immune responses during an 

Antarctic summer. Pathology (Phila). 1995 Apr;27(2):186-90. 

[453] Naeije R, Vanhaelst L, Golstein J. Pituitary-thyroid axis during short term, mild and 

severe, iodine depletion in the rat. Horm Metab Res. 1978 Nov;10(6):521-5. 

[454] Naftchi NE, Viau AT, Sell GH, Lowman EW. Mineral metabolism in spinal cord 

injury. Arch Phys Med Rehabil. 1980;61:139-42. 

[455] Nanz RA, Michel EL, Lachance PA. Evolution of space feeding concepts during the 

Mercury and Gemini space programs. Food Technol. 1967;21:52-8. 

[456] National Aeronautics and Space Administration. Medical effects of iodine: proceedings 

of NASA/JSC conference. Houston, TX: Lyndon B. Johnson Space Center; 1998. 

Report No.: JSC 28379. 

[457] 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). Houston, TX: National Aeronautics and Space Administration 

Lyndon B. Johnson Space Center; 1993. Report No.: JSC-32283. 

[458] National Aeronautics and Space Administration Johnson Space Center. Nutritional 

requirements for International Space Station (ISS) missions up to 360 days. Houston, 
158 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

TX: National Aeronautics and Space Administration Lyndon B. Johnson Space Center; 

1996. Report No.: JSC-28038. 

[459] National Aeronautics and Space Administration Johnson Space Center. Nutritional 

status assessment for extended-duration space flight. JSC Document #28566, Revision 

1. Houston, TX: NASA; 1999. 

[460] National Aeronautics and Space Administration Johnson Space Center. Nutrition 

Requirements, Standards, and Operating Bands for Exploration Missions. JSC 

Document #63555. Houston, TX: NASA; 2005. 

[461] National Research Council. Recommended dietary allowances. 10th ed. Washington, 

DC: National Academy Press; 1989. 

[462] National Research Council. Dietary Reference Intakes for calcium, phosphorus, 

magnesium, vitamin D, and fluoride. Washington, DC: The National Academy Press; 

2000. 

[463] Naumann FL, Bennell KL, Wark JD. The effects of +Gz force on the bone mineral 

density of fighter pilots. Aviat Space Environ Med. 2001 Mar;72(3):177-81. 

[464] Naumann FL, Grant MC, Dhaliwal SS. Changes in cervical spine bone mineral density 

in response to flight training. Aviat Space Environ Med. 2004 Mar;75(3):255-9. 

[465] New SA, Bolton-Smith C, Grubb DA, Reid DM. Nutritional influences on bone mineral 

density: a cross-sectional study in premenopausal women. Am J Clin Nutr. 1997 

Jun;65(6):1831-9. 

[466] New SA, Robins SP, Campbell MK, et al. Dietary influences on bone mass and bone 

metabolism: further evidence of a positive link between fruit and vegetable 

consumption and bone health? Am J Clin Nutr. 2000 Jan;71(1):142-51. 

[467] Nicogossian A. Medicine and space exploration. Lancet. 2003 Dec;362 Suppl:s8-9. 

[468] Nicogossian AE, Sawin CF, Huntoon CL. Overall physiologic response to space flight. 

In: Nicogossian AE, Huntoon CL, Pool SL, eds. Space physiology and medicine. 3rd 

ed. Philadelphia, PA: Lea & Febiger; 1994:213-27. 

[469] Nielson FH. Boron, manganese, molybdenum, and other trace elements. In: Bowman 

BA, Russell RM, eds. Present knowledge in nutrition, Vol I. 9th ed. Washington, DC: 

ILSI Press; 2006:506-26. 

[470] Niki E. Interaction of ascorbate and alpha-tocopherol. Ann N Y Acad Sci. 

1987;498:186-99. 

[471] Nnoaham KE, Clarke A. Low serum vitamin D levels and tuberculosis: a systematic 

review and meta-analysis. Int J Epidemiol. 2008 Feb;37(1):113-9. 

[472] Nordin B, Need A, Morris H, Horowitz M, Cochran M. Sodium and osteoporosis. In: 

Lesourd B, Rapin C, Sachet P, eds. Osteoporose: pour une prevention nutritionelle du 

risque? Paris: CERIN; 1992:117. 

[473] Nordin BE. Calcium homeostasis. Clin Biochem. 1990 Feb;23(1):3-10. 

[474] Nordin BE, Need AG, Morris HA, Horowitz M. The nature and significance of the 

relationship between urinary sodium and urinary calcium in women. J Nutr. 

1993;123:1615-22. 

[475] Nordin BE, Need AG, Steurer T, Morris HA, Chatterton BE, Horowitz M. Nutrition, 

osteoporosis, and aging. Ann N Y Acad Sci. 1998 Nov 20;854:336-51. 

[476] Norman AW. Vitamin D. In: Bowman BA, Russell RM, eds. Present knowledge in 

nutrition. 8th ed. Washington, DC: ILSI Press; 2001. 
References 159

[477] Norman AW. A vitamin D nutritional cornucopia: new insights concerning the serum 

25-hydroxyvitamin D status of the US population. Am J Clin Nutr. 2008 

Dec;88(6):1455-6. 

[478] Norsk P, Christensen NJ, Vorobiev D, Suzuki Y, Drummer C, Heer M. Effects of headdown bed rest & microgravity on renal fluid excretion. J Gravit Physiol. 1998 

Jul;5(1):P81-4. 

[479] Norsk P. Renal adjustments to microgravity. Pflugers Arch. 2000;441(2-3 Suppl):R62-

5. 

[480] Norsk P, Christensen NJ, Bie P, Gabrielsen A, Heer M, Drummer C. Unexpected renal 

responses in space. Lancet. 2000 Nov 4;356(9241):1577-8. 

[481] Norsk P, Drummer C, Christensen NJ, et al. Revised hypothesis and future 

perspectives. Am J Kidney Dis. 2001 Sep;38(3):696-8. 

[482] Norsk P. Cardiovascular and fluid volume control in humans in space. Curr Pharm 

Biotechnol. 2005 Aug;6(4):325-30. 

[483] O'Neill CA, Stebbins CL, Bonigut S, Halliwell B, Longhurst JC. Production of 

hydroxyl radicals in contracting skeletal muscle of cats. J Appl Physiol. 1996 

Sep;81(3):1197-206. 

[484] Oganov V, Rakhmanov A, Novikov V, Zatsepin S, Rodionova S, Cann C. The state of 

human bone tissue during space flight. Acta Astronaut. 1991;23:129-33. 

[485] Oh MS, Uribarri J. Electrolytes, water, and acid-base balance. In: Shils ME, Olson JA, 

Shike M, Ross AC, eds. Modern nutrition in health and disease. 9th ed. Baltimore, 

MD: Lippincott Williams & Wilkins; 1999:105-40. 

[486] Ohshima H, Mukai C. [Bone metabolism in human space flight and bed rest study]. 

Clin Calcium. 2008 Sep;18(9):1245-53. 

[487] Okada A, Ohshima H, Itoh Y, Yasui T, Tozawa K, Kohri K. Risk of renal stone 

formation induced by long-term bed rest could be decreased by premedication with 

bisphosphonate and increased by resistive exercise. Int J Urol. 2008 May 8. 

[488] Olabi AA, Lawless HT, Hunter JB, Levitsky DA, Halpern BP. The effect of 

microgravity and space flight on the chemical senses. J Food Sci. 2002 Mar;67(2):468-

78. 

[489] Oliveri MB, Mautalen C, Bustamante L, Gomez Garcia V. Serum levels of 25-

hydroxyvitamin D in a year of residence on the Antarctic continent. Eur J Clin Nutr. 

1994 Jun;48(6):397-401. 

[490] Olson JA. Vitamin A, retinoids, and carotenoids. In: Shils ME, Olson JA, Shike M, eds. 

Modern nutrition in health and disease. 8th ed. Malvern, PA: Lea & Febiger; 1994:287-

307. 

[491] Olson RE. The function and metabolism of vitamin K. Annu Rev Nutr. 1984;4:281-

337. 

[492] Oritsland NA. Starvation survival and body composition in mammals with particular 

reference to Homo sapiens. Bull Math Biol. 1990;52(5):643-55. 

[493] Oury TD, Schaefer LM, Fattman CL, Choi A, Weck KE, Watkins SC. Depletion of 

pulmonary EC-SOD after exposure to hyperoxia. Am J Physiol Lung Cell Mol Physiol. 

2002 Oct;283(4):L777-84. 

[494] Paddon-Jones D, Sheffield-Moore M, Urban RJ, et al. Essential amino acid and 

carbohydrate supplementation ameliorates muscle protein loss in humans during 28 

days bedrest. J Clin Endocrinol Metab. 2004 Sep;89(9):4351-8. 
160 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[495] Paddon-Jones D, Sheffield-Moore M, Urban RJ, Aarsland A, Wolfe RR, Ferrando AA. 

The catabolic effects of prolonged inactivity and acute hypercortisolemia are offset by 

dietary supplementation. J Clin Endocrinol Metab. 2005 Mar;90(3):1453-9. 

[496] Paddon-Jones D, Sheffield-Moore M, Cree MG, et al. Atrophy and impaired muscle 

protein synthesis during prolonged inactivity and stress. J Clin Endocrinol Metab. 2006 

Dec;91(12):4836-41. 

[497] Palacios C. The role of nutrients in bone health, from A to Z. Crit Rev Food Sci Nutr. 

2006;46(8):621-8. 

[498] Parfitt AM. Bone effects of space flight: analysis by quantum concept of bone 

remodelling. Acta Astronaut. 1981;8(9-10):1083-90. 

[499] Pascussi JM, Robert A, Nguyen M, et al. Possible involvement of pregnane X receptorenhanced CYP24 expression in drug-induced osteomalacia. J Clin Invest. 2005 

Jan;115(1):177-86. 

[500] Patz A, Hoeck L, De La Cruz E. Studies on the effect of high oxygen administration in 

retrolental fibroplasia. Am J Ophthalmol. 1952;35:1248-53. 

[501] Paulsrud JR, Pensler L, Whitten CF, Stewart S, Holman RT. Essential fatty acid 

deficiency in infants induced by fat-free intravenous feeding. Am J Clin Nutr. 1972 

Sep;25(9):897-904. 

[502] Pavy-Le Traon A, Heer M, Narici MV, Rittweger J, Vernikos J. From space to Earth: 

advances in human physiology from 20 years of bed rest studies (1986-2006). Eur J 

Appl Physiol. 2007 Sep;101(2):143-94. 

[503] Pence BC, Yang TC. Antioxidants: radiation and stress. In: Lane HW, Schoeller DA, 

eds. Nutrition in spaceflight and weightlessness models. Boca Raton, FL: CRC Press; 

2000:233-52. 

[504] Perchonok M, Bourland C. NASA food systems: past, present, and future. Nutrition. 

2002;18(10):913-20. 

[505] Perez G, Delaney VB, Bourke E. Hypo- and hyperkalemia. In: Preuss HG, ed.

Management of common problems in renal disease. Philadelphia, PA: Field and Wood 

Inc; 1988:109-17. 

[506] Peter R, Mishra V, Fraser WD. Severe hypocalcaemia after being given intravenous 

bisphosphonate. BMJ. 2004 Feb 7;328(7435):335-6. 

[507] Phillips WJ. Starvation and survival: some military considerations. Mil Med. 1994 

Jul;159(7):513-6. 

[508] Pietrzyk RA, Feiveson AH, Whitson PA. Mathematical model to estimate risk of 

calcium-containing renal stones. Miner Electrolyte Metab. 1999 May-Jun;25(3):199-

203. 

[509] Pietrzyk RA, Jones JA, Sams CF, Whitson PA. Renal stone formation among 

astronauts. Aviat Space Environ Med. 2007 Apr;78(4 Suppl):A9-13. 

[510] Pilz S, Marz W, Wellnitz B, et al. Association of vitamin D deficiency with heart 

failure and sudden cardiac death in a large cross-sectional study of patients referred for 

coronary angiography. J Clin Endocrinol Metab. 2008 Oct;93(10):3927-35. 

[511] Pitson GA, Lugg DJ, Roy CR. Effect of seasonal ultraviolet radiation fluctuations on 

vitamin D homeostasis during an Antarctic expedition. Eur J Appl Physiol Occup 

Physiol. 1996;72(3):231-4. 

[512] Pitts RF. Ionic composition of body fluids. The physiological basis of diuretic therapy. 

Springfield, IL: Charles C Thomas Publisher; 1959. 
References 161

[513] Piver B, Berthou F, Dreano Y, Lucas D. Inhibition of CYP3A, CYP1A and CYP2E1 

activities by resveratrol and other non volatile red wine components. Toxicol Lett. 2001 

Dec 15;125(1-3):83-91. 

[514] Powers HJ. Riboflavin (vitamin B-2) and health. Am J Clin Nutr. 2003 Jun;77(6):1352-

60. 

[515] Prasad KN. Handbook of radiobiology. 2nd ed. New York: CRC Press; 1995. 

[516] Preuss HG. Sodium, chloride, and potassium. In: Bowman BA, Russell RM, eds. 

Present knowledge in nutrition. 8th ed. Washington, DC: ILSI Press; 2001:302-10. 

[517] Prieto J, Barry M, Sherlock S. Serum ferritin in patients with iron overload and with 

acute and chronic liver disease. Gastroenterology. 1975;68:525-33. 

[518] Prohaska JR. Copper. In: Bowman BA, Russell RM, eds. Present knowledge in 

nutrition, Vol I. 9th ed. Washington, DC: ILSI Press; 2006:458-70. 

[519] Prokhonchukov AA, Zaitsev VP, Shakhunov BA, Zhizhina NA, Kolesnik AG. [Effect 

of space flight on the concentration of sodium, copper, manganese and magnesium in 

the bones of the skeleton]. Patol Fiziol Eksp Ter. 1978 Nov-Dec(6):65-70. 

[520] Promislow JH, Goodman-Gruen D, Slymen DJ, Barrett-Connor E. Protein consumption 

and bone mineral density in the elderly: the Rancho Bernardo Study. Am J Epidemiol. 

2002 Apr 1;155(7):636-44. 

[521] Pross HD, Casares A, Kiefer J. Induction and repair of DNA double-strand breaks 

under irradiation and microgravity. Radiat Res. 2000 May;153(5 Pt 1):521-5. 

[522] Punnonen K, Irjala K, Rajamaki A. Iron-deficiency anemia is associated with high 

concentrations of transferrin receptor in serum. Clin Chem. 1994 May;40(5):774-6. 

[523] Rafferty K, Heaney RP. Nutrient effects on the calcium economy: emphasizing the 

potassium controversy. J Nutr. 2008 Jan;138(1):166S-71S. 

[524] Rambaut P, Leach C, Leonard J. Observations in energy balance in man during 

spaceflight. Am J Physiol. 1977;233:R208-12. 

[525] Rambaut P, Johnston R. Prolonged weightlessness and calcium loss in man. Acta 

Astronaut. 1979;6:1113-22. 

[526] Rambaut PC, Leach CS, Johnson PC. Calcium and phosphorus change of the Apollo 17 

crew members. Nutr Metab. 1975;18:62-9. 

[527] Rambaut PC, Smith MC, Jr, Wheeler HO. Nutritional studies. In: Johnston RS, Dietlein 

LF, Berry CA, eds. Biomedical results of Apollo (NASA SP-368). Washington, DC: 

National Aeronautics and Space Administration; 1975:277-302. 

[528] Rambaut PC, Goode AW. Skeletal changes during space flight. Lancet. 

1985;2(8463):1050-2. 

[529] Ramel A, Jonsson PV, Bjornsson S, Thorsdottir I. Anemia, nutritional status, and 

inflammation in hospitalized elderly. Nutrition. 2008 Nov-Dec;24(11-12):1116-22. 

[530] Rathman SC, Gregory JF, 3rd, McMahon RJ. Pharmacological biotin supplementation 

maintains biotin status and function in rats administered dietary carbamazepine. J Nutr. 

2003 Sep;133(9):2857-62. 

[531] Reed HL, Reedy KR, Palinkas LA, et al. Impairment in cognitive and exercise 

performance during prolonged antarctic residence: effect of thyroxine supplementation 

in the polar triiodothyronine syndrome. J Clin Endocrinol Metab. 2001 Jan;86(1):110-6. 

[532] Reeves ND, Maganaris CN, Ferretti G, Narici MV. Influence of 90-day simulated 

microgravity on human tendon mechanical properties and the effect of resistive 

countermeasures. J Appl Physiol. 2005 Jun;98(6):2278-86. 
162 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[533] Regnard J, Heer M, Drummer C, Norsk P. Validity of microgravity simulation models 

on earth. Am J Kidney Dis. 2001 Sep;38(3):668-74. 

[534] Reid MB. Muscle fatigue: mechanisms and regulation. In: Sen CK, Packer L, Hänninen 

O, eds. Handbook of oxidants and antioxidants in exercise. Amsterdam: Elsevier 

Science B.V.; 2000:599-630. 

[535] Reschke MF, Bloomberg JJ, Harm DL, Paloski WH. Space flight and neurovestibular 

adaptation. J Clin Pharmacol. 1994 Jun;34(6):609-17. 

[536] Rettberg P, Horneck G, Zittermann A, Heer M. Biological dosimetry to determine the 

UV radiation climate inside the MIR station and its role in vitamin D biosynthesis. Adv 

Space Res. 1998;22(12):1643-52. 

[537] Rice BL, Vickers ZM, Rose MS, Lane HW. Fluid shifts during head-down bed rest do 

not influence flavor sensitivity. In: 67th Annual Scientific Meeting of the Aerospace 

Medical Association; 1996 May 5-9; Atlanta, GA; 1996. 

[538] Rice L, Alfrey CP. Modulation of red cell mass by neocytolysis in space and on Earth. 

Pflugers Arch. 2000;441(2-3 Suppl):R91-4. 

[539] Rice L, Ruiz W, Driscoll T, et al. Neocytolysis on descent from altitude: a newly 

recognized mechanism for the control of red cell mass. Ann Intern Med. 2001 Apr 

17;134(8):652-6. 

[540] Rice L, Alfrey CP. The negative regulation of red cell mass by neocytolysis: 

physiologic and pathophysiologic manifestations. Cell Physiol Biochem. 

2005;15(6):245-50. 

[541] Riggs BL, Jowsey J, Kelly PJ, Hoffman DL. Treatment for postmenopausal and senile 

osteoporosis. Med Clin North Am. 1972 Jul;56(4):989-97. 

[542] Rittweger J, Frost HM, Schiessl H, et al. Muscle atrophy and bone loss after 90 days' 

bed rest and the effects of flywheel resistive exercise and pamidronate: results from the 

LTBR study. Bone. 2005 Jun;36(6):1019-29. 

[543] Rittweger J, Felsenberg D, Maganaris C, Ferretti JL. Vertical jump performance after 

90 days bed rest with and without flywheel resistive exercise, including a 180 days 

follow-up. Eur J Appl Physiol. 2007 Jul;100(4):427-36. 

[544] Rivlin RS. Riboflavin. In: Bowman BA, Russell RM, eds. Present knowledge in 

nutrition, Vol I. 9th ed. Washington, DC: ILSI Press; 2006:250-9. 

[545] Roberts ES, Vaz AD, Coon MJ. Role of isozymes of rabbit microsomal cytochrome P450 in the metabolism of retinoic acid, retinol, and retinal. Mol Pharmacol. 1992 

Feb;41(2):427-33. 

[546] Robins SP, Woitge H, Hesley R, Ju J, Seyedin S, Seibel MJ. Direct, enzyme-linked 

immunoassay for urinary deoxypyridinoline as a specific marker for measuring bone 

resorption. J Bone Miner Res. 1994 Oct;9(10):1643-9. 

[547] Roby CA, Anderson GD, Kantor E, Dryer DA, Burstein AH. St John's Wort: effect on 

CYP3A4 activity. Clin Pharmacol Ther. 2000 May;67(5):451-7. 

[548] Rocco M, Antonelli M, Letizia V, et al. Lipid peroxidation, circulating cytokine and 

endothelin 1 levels in healthy volunteers undergoing hyperbaric oxygenation. Minerva 

Anestesiol. 2001 May;67(5):393-400. 

[549] Ross AC. Vitamin A and retinoids. In: Shils ME, Olson JA, Shike M, Ross AC, eds. 

Modern nutrition in health and disease. 9th ed. Baltimore, MD: Lippincott Williams & 

Wilkins; 1999:305-27. 
References 163

[550] Rubin C, Recker R, Cullen D, Ryaby J, McCabe J, McLeod K. Prevention of 

postmenopausal bone loss by a low-magnitude, high-frequency mechanical stimuli: a 

clinical trial assessing compliance, efficacy, and safety. J Bone Miner Res. 2004 

Mar;19(3):343-51. 

[551] ussell RM, Golner BB, Krasinski SD, Sadowski JA, Suter PM, Braun CL. Effect of 

antacid and H2 receptor antagonists on the intestinal absorption of folic acid. J Lab Clin 

Med. 1988 Oct;112(4):458-63. 

[552] Saarem K, Pedersen JI. Sex differences in the hydroxylation of cholecalciferol and of 5 

beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol in rat liver. Biochem J. 1987 Oct 

1;247(1):73-8. 

[553] Sahni S, Hannan MT, Gagnon D, et al. High vitamin C intake is associated with lower 

4-year bone loss in elderly men. J Nutr. 2008 Oct;138(10):1931-8. 

[554] Sakhaee K, Harvey JA, Padalino PK, Whitson P, Pak CY. The potential role of salt 

abuse on the risk for kidney stone formation. J Urol. 1993;150(2 Pt 1):310-2. 

[555] Salem SA. Effect of gamma radiation on the storage of onions used in the dehydration 

industry. J Sci Food Agric. 1974 Mar;25(3):257-62. 

[556] Salonen JT, Nyyssonen K, Korpela H, Tuomilehto J, Seppanen R, Salonen R. High 

stored iron levels are associated with excess risk of myocardial infarction in eastern 

Finnish men. Circulation. 1992;86(3):803-11. 

[557] Sanders LM, Henderson CE, Hong MY, et al. An increase in reactive oxygen species 

by dietary fish oil coupled with the attenuation of antioxidant defenses by dietary pectin 

enhances rat colonocyte apoptosis. J Nutr. 2004 Dec;134(12):3233-8. 

[558] Sanders LM, Lupton JR. Carbohydrates. In: Bowman BA, Russell RM, eds. Present 

knowledge in nutrition, Vol I. 9th ed. Washington, DC: ILSI Press; 2006:78-88. 

[559] Sauberlich H. Laboratory tests for the assessment of nutritional status. Boca Raton: 

CRC Press; 1999. 

[560] Sauer RL, Janik DS, Thorstenson YR. Medical effects of iodine disinfection products in 

spacecraft water. Warrendale, PA: Society of Automotive Engineers; 1987. 

[561] Sawka MN, Coyle EF. Influence of body water and blood volume on thermoregulation 

and exercise performance in the heat. Exerc Sport Sci Rev. 1999;27:167-218. 

[562] Schakel SF, Sievert YA, Buzzard IM. Sources of data for developing and maintaining a 

nutrient database. J Am Diet Assoc. 1988;88:1268-71. 

[563] Schneider VS, McDonald J. Skeletal calcium homeostasis and countermeasures to 

prevent disuse osteoporosis. Calcif Tissue Int. 1984;36(1 Suppl):S151-44. 

[564] Schoeller DA, Ravussin E, Schutz Y, Acheson KJ, Baertschi P, Jequier E. Energy 

expenditure by doubly labeled water: validation in humans and proposed calculation. 

Am J Physiol Regul Integr Comp Physiol. 1986 May;250(5 Pt 2):R823-30. 

[565] Schreiber WE. Iron, porphyrin, and bilirubin metabolism. In: Kaplan LA, Pesce AJ, 

eds. Clinical chemistry: theory, analysis, and correlation. St. Louis, MO: Mosby-Year 

Books, Inc.; 1996:696-715. 

[566] Schuster I, Egger H, Reddy GS, Vorisek G. Combination of vitamin D metabolites with 

selective inhibitors of vitamin D metabolism. Recent Results Cancer Res. 

2003;164:169-88. 

[567] Schwandt DF, Whalen RT, Watenpaugh DE, Parazynski SE, Hargens AR. 

Development of exercise devices to minimize musculoskeletal and cardiovascular 

deconditioning in microgravity. Physiologist. 1991;34 Suppl 1:S189-90. 
164 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[568] Schwille PO, Schmiedl A, Herrmann U, et al. Magnesium, citrate, magnesium citrate 

and magnesium-alkali citrate as modulators of calcium oxalate crystallization in urine: 

observations in patients with recurrent idiopathic calcium urolithiasis. Urol Res. 1999 

Apr;27(2):117-26. 

[569] Seddon MR, Fettman MJ, Phillips RW. Practical and clinical nutritional concerns 

during spaceflight. Am J Clin Nutr. 1994 Nov;60(5):825S-30S. 

[570] Segersten U, Correa P, Hewison M, et al. 25-hydroxyvitamin D(3)-1alpha-hydroxylase 

expression in normal and pathological parathyroid glands. J Clin Endocrinol Metab. 

2002 Jun;87(6):2967-72. 

[571] Seibel MJ. Biochemical markers of bone turnover. Part I: biochemistry and variability. 

Clin Biochem Rev. 2005 Nov;26(4):97-122. 

[572] Self TH, Chrisman CR, Baciewicz AM, Bronze MS. Isoniazid drug and food 

interactions. Am J Med Sci. 1999 May;317(5):304-11. 

[573] Sellmeyer DE, Schloetter M, Sebastian A. Potassium citrate prevents increased urine 

calcium excretion and bone resorption induced by a high sodium chloride diet. J Clin 

Endocrinol Metab. 2002 May;87(5):2008-12. 

[574] Sempos CT, Looker AC, Gillum RF, Makuc DM. Body iron stores and the risk of 

coronary heart disease. N Engl J Med. 1994;330(16):1119-24. 

[575] Seo H, Itoh T, Murata Y, et al. Changes in urinary excretion of pyridinium cross-links 

during Spacelab-J. Biol Sci Space. 1997 Dec;11(4):321-6. 

[576] Servais S, Letexier D, Favier R, Duchamp C, Desplanches D. Prevention of unloadinginduced atrophy by vitamin E supplementation: links between oxidative stress and 

soleus muscle proteolysis? Free Radic Biol Med. 2007 Mar 1;42(5):627-35. 

[577] Seyedin SM, Kung VT, Daniloff YN, et al. Immunoassay for urinary pyridinoline: the 

new marker of bone resorption. J Bone Miner Res. 1993 May;8(5):635-41. 

[578] Shackelford LC, LeBlanc AD, Driscoll TB, et al. Resistance exercise as a 

countermeasure to disuse-induced bone loss. J Appl Physiol. 2004 July;97(1):119-29. 

[579] Shah SC, Sharma RK, Hemangini, Chitle AR. Rifampicin induced osteomalacia. 

Tubercle. 1981 Sep;62(3):207-9. 

[580] Shane B. Vitamin B6 and blood. In: Human vitamin B6 requirements: proceedings of a 

workshop; 1978; Washington, DC: National Academy Press; 1978. p. 111-28. 

[581] Shapiro J, Smith B, Beck T, et al. Treatment with zoledronic acid ameliorates negative 

geometric changes in the proximal femur following acute spinal cord injury. Calcif 

Tissue Int. 2007 May;80(5):316-22. 

[582] Shearer MJ. Vitamin K. Lancet. 1995 Jan 28;345(8944):229-34. 

[583] Shils ME. Magnesium. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern 

nutrition in health and disease. 9th ed. Baltimore, MD: Lippincott Williams & Wilkins; 

1999:169-92. 

[584] Shin YS, Beuhring KU, Stokstad EL. The relationships between vitamin B12 and folic 

acid and the effect of methionine on folate metabolism. Mol Cell Biochem. 1975 Nov 

14;9(2):97-108. 

[585] Shirai T, Magara KK, Motohashi S, et al. TH1-biased immunity induced by exposure to 

Antarctic winter. J Allergy Clin Immunol. 2003 Jun;111(6):1353-60. 

[586] Sibonga JD, Evans HJ, Spector ER, et al. Skeletal recovery following long-duration 

missions as predicted by preflight and postflight dual-energy x-ray absorptiometry 
References 165

(DXA) scans of 45 crewmembers. J Bone Miner Res. 2005;20 (Suppl 1):1171 

(Abstract). 

[587] Sibonga JD, Evans HJ, Sung HG, et al. Recovery of spaceflight-induced bone loss: 

bone mineral density after long-duration missions as fitted with an exponential 

function. Bone. 2007 Dec;41(6):973-8. 

[588] Sibonga JD, Cavanagh PR, Lang TF, et al. Adaptation of the skeletal system during 

long-duration spaceflight. Clinic Rev Bone Miner Metabol. 2008;5(4):249-61. 

[589] Silber T. Anorexia nervosa: morbidity and mortality. Pediatr Ann. 1984 

Nov;13(11):851, 5-9. 

[590] Singer TP, Kenney WC. Biochemistry of covalently bound flavins. Vitam Horm. 

1974;32:1-45. 

[591] Skikne BS, Flowers CH, Cook JD. Serum transferrin receptor: a quantitative measure of 

tissue iron deficiency. Blood. 1990;75:1870-6. 

[592] Smirnov KV, Rubinova LG, Afonin BV, Noskov VB, Kravchenko VV. [Functional 

carbohydrate test during 237-day space flight]. Kosm Biol Aviakosm Med. 1991 MayJun;25(3):61-2. 

[593] Smirnov KV, Ugolev AM. Digestion and absorption. In: Leach Huntoon CL, Antipov 

VV, Grigoriev AI, eds. Space biology and medicine, humans in spaceflight, Vol 3. 

Reston, VA: American Institute for Aeronautics and Astronautics; 1996:211-30. 

[594] Smith BJ, Lucas EA, Turner RT, et al. Vitamin E provides protection for bone in 

mature hindlimb unloaded male rats. Calcif Tissue Int. 2005 Apr;76(4):272-9. 

[595] Smith HJ, Lorite MJ, Tisdale MJ. Effect of a cancer cachectic factor on protein 

synthesis/degradation in murine C2C12 myoblasts: modulation by eicosapentaenoic 

acid. Cancer Res. 1999 Nov 1;59(21):5507-13. 

[596] Smith MC, Berry CA. Dinner on the moon. Nutr Today. 1969;4:37-42. 

[597] Smith MC, Huber CS, Heidelbaugh ND. Apollo 14 food system. Aerospace Med. 

1971;42:1185-92. 

[598] Smith MC, Jr, Rambaut PC, Vogel JM, Whittle MW. Bone mineral measurement—

experiment M078. In: Johnston RS, Dietlein LF, eds. Biomedical results from Skylab 

(NASA SP-377). Washington, DC: National Aeronautics and Space Administration; 

1977:183-90. 

[599] Smith SM, Davis-Street J, Rice BL, Lane HW. Nutrition in space. Nutrition Today. 

1997 Jan-Feb;32(1):6-12. 

[600] Smith SM, Davis-Street JE, Fontenot TB, Lane HW. Assessment of a portable clinical 

blood analyzer during space flight. Clin Chem. 1997 Jun;43(6 Pt 1):1056-65. 

[601] Smith SM, Krauhs JM, Leach CS. Regulation of body fluid volume and electrolyte 

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

[602] Smith SM, Nillen JL, LeBlanc A, et al. Collagen cross-link excretion during space 

flight and bed rest. J Clin Endocrinol Metab. 1998 Oct;83(10):3584-91. 

[603] Smith SM, Wastney ME, Morukov BV, et al. Calcium metabolism before, during, and 

after a 3-mo spaceflight: kinetic and biochemical changes. Am J Physiol. 1999 

Jul;277(1 Pt 2):R1-10. 

[604] 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 Jul;131(7):2053-61. 
166 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[605] Smith SM. Red blood cell and iron metabolism during space flight. Nutrition. 

2002;18:864-6. 

[606] Smith SM, Heer M. Calcium and bone metabolism during space flight. Nutrition. 

2002;18:849-52. 

[607] Smith SM, Davis-Street JE, Fesperman JV, et al. Evaluation of treadmill exercise in a 

lower body negative pressure chamber as a countermeasure for weightlessness-induced 

bone loss: a bed rest study with identical twins. J Bone Miner Res. 2003;18:2223-30. 

[608] 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. 

[609] Smith SM, Wastney ME, O'Brien KO, et al. Bone markers, calcium metabolism, and 

calcium kinetics during extended-duration space flight on the Mir space station. J Bone 

Miner Res. 2005 Feb;20(2):208-18. 

[610] 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 Mar;135(3):437-43. 

[611] Smith SM, Lane HW. Spaceflight metabolism and nutritional support. In: Barratt MR, 

Pool SL, eds. Principles of clinical medicine for space flight. New York: Springer; 

2008:559-76. 

[612] Smith SM, Zwart SR. Nutritional biochemistry of spaceflight. In: Makowsky G, ed. Adv 

Clin Chem, Vol 46. Burlington: Academic Press; 2008:87-130. 

[613] Smith SM, Gardner KK, Locke J, Zwart SR. Vitamin D supplementation during 

Antarctic winter. Am J Clin Nutr. 2009 Apr;89(4):1092-8. 

[614] Smith SM, Zwart SR, Heer MA, et al. Effects of artificial gravity during bed rest on 

bone metabolism in humans [published online ahead of print December 12, 2008]. J 

Appl Physiol.doi: 10.1152/japplphysiol.91134.2008. 

[615] Smolders J, Menheere P, Kessels A, Damoiseaux J, Hupperts R. Association of vitamin 

D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler. 

2008 Jul 24. 

[616] Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996 

Jul 5;273(5271):59-63. 

[617] Sokol RJ. Vitamin E. In: Ziegler EE, Filer LJ, Jr., eds. Present knowledge in nutrition. 

7th ed. Washington, DC: International Life Sciences Institute; 1996:130-6. 

[618] Solomons NW, Russell RM. "Appropriate technology" for vitamin A field research. 

Am J Clin Nutr. 2001 May;73(5):849-50. 

[619] Sorva A, Valimaki M, Risteli J, et al. Serum ionized calcium, intact PTH and novel 

markers of bone turnover in bedridden elderly patients. Eur J Clin Invest. 1994 

Dec;24(12):806-12. 

[620] Spector ER, Smith SM, Sibonga JD. Skeletal effects of long-duration head-down bed 

rest. Aviat Space Env Med. 2009;80(5 (Supplement)):A23-A8. 

[621] Srivastava TN, Young DB. Impairment of cardiac function by moderate potassium 

depletion. J Card Fail. 1995 Jun;1(3):195-200. 

[622] Stabler SP. Vitamin B12. In: Bowman BA, Russell RM, eds. Present knowledge in 

nutrition, Vol I. 9th ed. Washington, DC: ILSI Press; 2006:302-13. 

[623] Stein TP, Leskiw MJ, Schluter MD. Effect of spaceflight on human protein metabolism. 

Am J Physiol Endocrinol Metab. 1993;264:E824-8. 
References 167

[624] Stein TP, Schulter MD, Boden G. Development of insulin resistance by astronauts 

during spaceflight. Aviat Space Environ Med. 1994 Dec;65(12):1091-6. 

[625] Stein TP, Leskiw MJ, Schluter MD. Diet and nitrogen metabolism during spaceflight on 

the shuttle. J Appl Physiol. 1996;81(1):82-97. 

[626] Stein TP, Schluter MD. Excretion of amino acids by humans during space flight. Acta 

Astronaut. 1998 Jan-Apr;42(1-8):205-14. 

[627] Stein TP, Leskiw MJ, Schluter MD, Donaldson MR, Larina I. Protein kinetics during 

and after long-duration spaceflight on MIR. Am J Physiol Endocrinol Metab. 

1999;276:E1014-21. 

[628] Stein TP, Leskiw MJ, Schluter MD, et al. Energy expenditure and balance during 

spaceflight on the space shuttle. Am J Physiol Regul Integr Comp Physiol. 

1999;276:R1739-48. 

[629] Stein TP, Schluter MD. Plasma amino acids during human spaceflight. Aviat Space 

Environ Med. 1999 Mar;70(3 Pt 1):250-5. 

[630] Stein TP, Schluter MD, Leskiw MJ. Cortisol, insulin and leptin during space flight and 

bed rest. J Gravit Physiol. 1999 Jul;6(1):P85-6. 

[631] Stein TP, Schluter MD, Moldawer LL. Endocrine relationships during human 

spaceflight. Am J Physiol Endocrinol Metab. 1999 Jan;276(1 Pt 1):E155-62. 

[632] Stein TP. Protein and muscle homeostasis: the role of nutrition. In: Lane HW, Schoeller 

DA, eds. Nutrition in spaceflight and weightlessness models. Boca Raton, FL: CRC 

Press; 2000:141-77. 

[633] Stein TP, Leskiw MJ. Oxidant damage during and after spaceflight. Am J Physiol 

Endocrinol Metab. 2000 Mar;278(3):E375-82. 

[634] Stein TP. Space flight and oxidative stress. Nutrition. 2002;18:867-71. 

[635] Stein TP, Schluter MD, Galante AT, et al. Effect of hind limb muscle unloading on 

liver metabolism of rats. The Journal of nutritional biochemistry. 2005 Jan;16(1):9-16. 

[636] Stein TP, Wade CE. Metabolic consequences of muscle disuse atrophy. J Nutr. 2005 

Jul;135(7):1824S-8S. 

[637] Stein TP, Schluter MD. Plasma protein synthesis after spaceflight. Aviat Space Environ 

Med. 2006 Jul;77(7):745-8. 

[638] Stewart AF, Akler M, Byers CM, Segre GV, Broadus AE. Calcium homeostasis in 

immobilization: an example of resorptive hypercalciuria. N Engl J Med. 

1982;306:1136-40. 

[639] Stoecker BJ. Chromium. In: Bowman BA, Russell RM, eds. Present knowledge in 

nutrition, Vol I. 9th ed. Washington, DC: ILSI Press; 2006:498-505. 

[640] Strollo F, Strollo G, Morè M, et al. Space flight induces endocrine changes at both the 

pituitary and peripheral level in the absence of any major chronobiologic disturbances. 

In: Sahm PR, Keller MH, Schiewe B, eds. Proceedings of the Norderney Symposium on 

Scientific Results of the German Spacelab Mission D-2. Norderney, Germany: 

Wissenschaftliche Projectführung D-2; 1995:743-7. 

[641] Strollo F, Strollo G, More M, et al. Changes in human adrenal and gonadal function 

onboard Spacelab. J Gravit Physiol. 1997 Jul;4(2):P103-4. 

[642] Strollo F, Riondino G, Harris B, et al. The effect of microgravity on testicular androgen 

secretion. Aviat Space Environ Med. 1998 Feb;69(2):133-6. 

[643] Strollo F, Strollo G, More M, et al. Hormonal adaptation to real and simulated 

microgravity. J Gravitational Physiol. 1998 Jul;5(1):P89-92. 
168 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[644] Strollo F. Hormonal changes in humans during spaceflight. Adv Space Biol Med. 

1999;7:99-129. 

[645] Strollo F, Barger L, Fuller C. Testosterone urinary excretion rate increases during 

hypergravity in male monkeys. J Gravit Physiol. 2000 Jul;7(2):P181-2. 

[646] Strollo F, Masini MA, Pastorino M, et al. Microgravity-induced alterations in cultured 

testicular cells. J Gravit Physiol. 2004 Jul;11(2):P187-8. 

[647] Strollo F, Boitani C, Basciani S, et al. The pituitary-testicular axis in microgravity: 

analogies with the aging male syndrome. J Endocrinol Invest. 2005;28(11 Suppl 

Proceedings):78-83. 

[648] Stuart CA, Shangraw RE, Prince MJ, Peters EJ, Wolfe RR. Bed-rest-induced insulin 

resistance occurs primarily in muscle. Metabolism. 1988 Aug;37(8):802-6. 

[649] Stuart CA, Shangraw RE, Peters EJ, Wolfe RR. Effect of dietary protein on bed-restrelated changes in whole-body-protein synthesis. Am J Clin Nutr. 1990 Sep;52(3):509-

14. 

[650] Stubbs RJ, Harbron CG, Murgatroyd PR, Prentice AM. Covert manipulation of dietary 

fat and energy density: effect on substrate flux and food intake in men eating ad 

libitum. Am J Clin Nutr. 1995 Aug;62(2):316-29. 

[651] Stupakov GP, Kazeykin VS, Kozlovskiy AP, Korolev VV. [Evaluation of changes in 

human axial skeletal bone structures during long-term spaceflights]. Kosm Biol 

Aviakosm Med. 1984;18(2):33-7. 

[652] Sugiyama T, Kawai S. The use of vitamin K may be a good choice for microgravityinduced bone disorder. J Bone Miner Res. 2001 Apr;16(4):794-5. 

[653] Sullivan JL. The iron paradigm of ischemic heart disease. Am Heart J. 1989;117:1177-

88. 

[654] Sullivan JL. Stored iron and ischemic heart disease: Empirical support for a new 

paradigm (Editorial Comment). Circulation. 1992;86:1036-7. 

[655] Sullivan RJ, Jr. Accepting death without artificial nutrition or hydration. J Gen Intern 

Med. 1993 Apr;8(4):220-4. 

[656] Sunde RA. Selenium. In: Bowman BA, Russell RM, eds. Present knowledge in 

nutrition, Vol I. 9th ed. Washington, DC: ILSI Press; 2006:480-97. 

[657] Tai K, Need AG, Horowitz M, Chapman IM. Vitamin D, glucose, insulin, and insulin 

sensitivity. Nutrition. 2008;24:279-85. 

[658] Takahashi H, Kosaka N, Nakagawa S. alpha-Tocopherol protects PC12 cells from 

hyperoxia-induced apoptosis. J Neurosci Res. 1998 Apr 15;52(2):184-91. 

[659] Tang K, Sham H, Hui E, Kirkland JB. Niacin deficiency causes oxidative stress in rat 

bone marrow cells but not through decreased NADPH or glutathione status. The Journal 

of nutritional biochemistry. 2008 Nov;19(11):746-53. 

[660] Taylor GR, Konstantinova I, Sonnenfeld G, Jennings R. Changes in the immune system 

during and after spaceflight. Adv Space Biol Med. 1997;6:1-32. 

[661] Tesch PA, Ekberg A, Lindquist DM, Trieschmann JT. Muscle hypertrophy following 5-

week resistance training using a non-gravity-dependent exercise system. Acta Physiol 

Scand. 2004 Jan;180(1):89-98. 

[662] Thomas MK, Lloyd-Jones DM, Thadhani RI, et al. Hypovitaminosis D in medical 

inpatients. N Engl J Med. 1998 Mar 19;338(12):777-83. 

[663] Thompson J. Vitamins, minerals and supplements 5: overview of vitamin C. 

Community Pract. 2007 Jan;80(1):35-6. 
References 169

[664] Thomsen JS, Morukov BV, Vico L, Alexandre C, Saparin PI, Gowin W. Cancellous 

bone structure of iliac crest biopsies following 370 days of head-down bed rest. Aviat 

Space Environ Med. 2005 Oct;76(10):915-22. 

[665] Thornton WE, Ord J. Physiological mass measurements in Skylab. In: Johnston RS, 

Dietlein LF, eds. Biomedical results from Skylab (NASA SP-377). Washington, DC: 

National Aeronautics and Space Administration; 1977:175-82. 

[666] Thornton WE, Rummel JA. Muscle deconditioning and its prevention in space flight. 

In: Johnston RS, Dietlein LF, eds. Biomedical results from Skylab (NASA SP-377). 

Washington, DC: NASA; 1977:191-7. 

[667] Thorstensen K, Romslo I. The transferrin receptor: its diagnostic value and its potential 

as therapeutic target. Scand J Clin Lab Invest Suppl. 1993;52 Suppl 215:113-20. 

[668] Thys-Jacobs S, Chan FKW, Koberle LMC, al. e. Hypercalcemia due to vitamin D 

toxicity. In: Feldman D, Glorieux FH, Pike JW, eds. Vitamin D. San Diego, CA: 

Academic Press; 1997:883-901. 

[669] Tietz NW, Pruden EL, Siggaard-Andersen O. Electrolytes. In: Burtis CA, Ashwood ER, 

eds. Tietz textbook of clinical chemistry. 2nd ed. Philadelphia, PA: WB Saunders 

Company; 1994:1887-973. 

[670] Tilton FE, Degioanni JJC, Schneider VS. Long-term follow-up of Skylab bone 

demineralization. Aviat Space Environ Med. 1980;51:1209-13. 

[671] Tipton CM, Greenleaf JE, Jackson CG. Neuroendocrine and immune system responses 

with spaceflights. Med Sci Sports Exerc. 1996 Aug;28(8):988-98. 

[672] Tisdale MJ. Cancer anorexia and cachexia. Nutrition. 2001 May;17(5):438-42. 

[673] Tisdale MJ. Loss of skeletal muscle in cancer: biochemical mechanisms. Front Biosci. 

2001 Feb 1;6:D164-74. 

[674] Tisdale MJ. Molecular pathways leading to cancer cachexia. Physiology (Bethesda). 

2005 Oct;20:340-8. 

[675] Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev. 2009 Apr;89(2):381-410. 

[676] Traber MG. Vitamin E. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern 

nutrition in health and disease. 9th ed. Baltimore, MD: Lippincott Williams & Wilkins; 

1999:347-62. 

[677] Trappe S, Costill D, Gallagher PM, et al. Exercise In Space: Human Skeletal Muscle 

After 6 Months Aboard The International Space Station. J Appl Physiol. 2009 Jan 15. 

[678] Trappe TA, Burd NA, Louis ES, Lee GA, Trappe SW. Influence of concurrent exercise 

or nutrition countermeasures on thigh and calf muscle size and function during 60 days 

of bed rest in women. Acta Physiol (Oxf). 2007 Oct;191(2):147-59. 

[679] Trinchieri A, Mandressi A, Luongo P, Longo G, Pisani E. The influence of diet on 

urinary risk factors for stones in healthy subjects and idiopathic renal calcium stone 

formers. Br J Urol. 1991;67:230-6. 

[680] Tuomainen TP, Loft S, Nyyssonen K, Punnonen K, Salonen JT, Poulsen HE. Body iron 

is a contributor to oxidative damage of DNA. Free Radic Res. 2007 Mar;41(3):324-8. 

[681] Turanlahti M, Pesonen E, Lassus P, Andersson S. Nitric oxide and hyperoxia in 

oxidative lung injury. Acta Paediatr. 2000 Aug;89(8):966-70. 

[682] Turner ND, Braby LA, Ford J, Lupton JR. Opportunities for nutritional amelioration of 

radiation-induced cellular damage. Nutrition. 2002 Oct;18(10):904-12. 
170 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[683] Udden MM, Driscoll TB, Pickett MH, Leach-Huntoon CS, Alfrey CP. Decreased 

production of red blood cells in human subjects exposed to microgravity. J Lab Clin 

Med. 1995;125:442-9. 

[684] Uebelhart D, Gineyts E, Chapuy MC, Delmas PD. Urinary excretion of pyridinium 

crosslinks: a new marker of bone resorption in metabolic bone disease. Bone Miner. 

1990;8(1):87-96. 

[685] Umegaki K, Ikegami S, Inoue K, et al. Beta-carotene prevents x-ray induction of 

micronuclei in human lymphocytes. Am J Clin Nutr. 1994 Feb;59(2):409-12. 

[686] Upton AC. The biological effects of low-level ionizing radiation. Sci Am. 

1982;246(2):41-9. 

[687] Ushakov AS, Vlasova TF. Amino acid spectrum of human blood plasma during space 

flight and in antiorthostatic hypokinesia. Life Sci Space Res. 1976;14:257-62. 

[688] Ushakov AS, Vlasova TF. Free amino acids in human blood plasma during space 

flights. Aviat Space Environ Med. 1976 Oct;47(10):1061-4. 

[689] Usui Y, Tanimura H, Nishimura N, Kobayashi N, Okanoue T, Ozawa K. Vitamin K 

concentrations in the plasma and liver of surgical patients. Am J Clin Nutr. 1990 

May;51(5):846-52. 

[690] Utermohlen V. Diet, nutrition, and drug interactions. In: Shils ME, Olson JA, Shike M, 

Ross AC, eds. Modern nutrition in health and disease. 9th ed. Baltimore, MD: 

Lippincott Williams & Wilkins; 1998. 

[691] van Asselt DZ, van den Broek WJ, Lamers CB, Corstens FH, Hoefnagels WH. Free and 

protein-bound cobalamin absorption in healthy middle-aged and older subjects. J Am 

Geriatr Soc. 1996 Aug;44(8):949-53. 

[692] van den Brandt PA, Zeegers MP, Bode P, Goldbohm RA. Toenail selenium levels and 

the subsequent risk of prostate cancer: a prospective cohort study. Cancer Epidemiol 

Biomarkers Prev. 2003 Sep;12(9):866-71. 

[693] van Poppel G, Goldbohm RA. Epidemiologic evidence for b-carotene and cancer 

prevention. Am J Clin Nutr. 1995;62 Suppl:1393S-402S. 

[694] Vermeer C, Wolf J, Knapen MH. Microgravity-induced changes of bone markers: 

effects of vitamin K-supplementation. Bone. 1997;20(4 Suppl):16S. 

[695] Vermeer C, Wolf J, Craciun AM, Knapen MH. Bone markers during a 6-month space 

flight: effects of vitamin K supplementation. J Gravit Physiol. 1998 Oct;5(2):65-9. 

[696] Vernikos-Danellis J, Leach CS, Winget CM, Goodwin AL, Rambaut PC. Changes in 

glucose, insulin, and growth hormone levels associated with bedrest. Aviat Space 

Environ Med. 1976 Jun;47(6):583-7. 

[697] Vernikos J. Metabolic and endocrine changes. In: Sandler H, Vernikos J, eds. 

Inactivity: physiological effects. Orlando, FL: Academic Press, Inc.; 1986:99-121. 

[698] Vernikos J, Convertino VA. Advantages and disadvantages of fludrocortisone or saline 

load in preventing post-spaceflight orthostatic hypotension. Acta Astronaut. 

1994;33:259-66. 

[699] Vernikos J, Ludwig DA, Ertl AC, Wade CE, Keil L, O'Hara D. Effect of standing or 

walking on physiological changes induced by head down bed rest: implications for 

spaceflight. Aviat Space Environ Med. 1996 Nov;67(11):1069-79. 

[700] Vernikos J. Artificial gravity intermittent centrifugation as a space flight 

countermeasure. J Gravit Physiol. 1997 Jul;4(2):P13-6. 
References 171

[701] Vico L, Chappard D, Alexandre C, et al. Effects of a 120 day period of bed-rest on bone 

mass and bone cell activities in man: attempts at countermeasure. Bone Miner. 

1987;2:383-94. 

[702] Vico L, Collet P, Guignandon A, et al. Effects of long-term microgravity exposure on 

cancellous and cortical weight-bearing bones of cosmonauts. Lancet. 

2000;355(9215):1607-11. 

[703] Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. 

Am J Clin Nutr. 1999 May;69(5):842-56. 

[704] Vieth R. Vitamin D toxicity, policy, and science. J Bone Miner Res. 2007 Dec;22 Suppl 

2:V64-8. 

[705] Viteri FE, Toran B. Anemia and physical work capacity. Clinical Hematology. 

1974;3:609-26. 

[706] Volpe SL, King JC, Coburn SP. Micronutrients: trace elements and B vitamins. In: 

Lane HW, Schoeller DA, eds. Nutrition in spaceflight and weightlessness models. Boca 

Raton, FL: CRC Press; 2000:213-32. 

[707] Volpe SL. Magnesium. In: Bowman BA, Russell RM, eds. Present knowledge in 

nutrition, Vol I. 9th ed. Washington, DC: ILSI Press; 2006:400-8. 

[708] Vormann J, Remer T. Dietary, metabolic, physiologic, and disease-related aspects of 

acid-base balance: foreword to the contributions of the second International Acid-Base 

Symposium. J Nutr. 2008 Feb;138(2):413S-4S. 

[709] Wada L, King JC. Effect of low zinc intakes on basal metabolic rate, thyroid hormones 

and protein utilization in adult men. J Nutr. 1986 Jun;116(6):1045-53. 

[710] Wade CE, Miller MM, Baer LA, Moran MM, Steele MK, Stein TP. Body mass, energy 

intake, and water consumption of rats and humans during space flight. Nutrition. 2002 

Oct;18(10):829-36. 

[711] Wade CE, Stanford KI, Stein TP, Greenleaf JE. Intensive exercise training suppresses 

testosterone during bed rest. J Appl Physiol. 2005 Jul;99(1):59-63. 

[712] Waligora JM, Horrigan DJ. Metabolism and heat dissipation during Apollo EVA 

periods In: Johnston RS, Dietlein LF, Berry CA, eds. Biomedical results of Apollo. 

Washington, DC: NASA; 1975:115-28. 

[713] Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular 

disease. Circulation. 2008 Jan 29;117(4):503-11. 

[714] Watanabe Y, Ohshima H, Mizuno K, et al. Intravenous pamidronate prevents femoral 

bone loss and renal stone formation during 90-day bed rest. J Bone Miner Res. 2004 

Nov;19(11):1771-8. 

[715] Watt DG, Money KE, Bondar RL, Thirsk RB, Garneau M, Scully-Power P. Canadian 

medical experiments on Shuttle flight 41-G. Can Aeronaut Space J. 1985 

Sep;31(3):215-26. 

[716] Watters JL, Satia JA, Kupper LL, Swenberg JA, Schroeder JC, Switzer BR. 

Associations of antioxidant nutrients and oxidative DNA damage in healthy AfricanAmerican and White adults. Cancer Epidemiol Biomarkers Prev. 2007 Jul;16(7):1428-

36. 

[717] Weaver CM, Heaney RP. Calcium. In: Shils ME, Olson JA, Shike M, Ross AC, eds. 

Modern nutrition in health and disease. 9th ed. Baltimore, MD: Lippincott Williams & 

Wilkins; 1999:141-55. 
172 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[718] Weaver CM, LeBlanc A, Smith SM. Calcium and related nutrients in bone metabolism. 

In: Lane HW, Schoeller DA, eds. Nutrition in spaceflight and weightlessness models. 

Boca Raton, FL: CRC Press; 2000:179-201. 

[719] Weaver CM. Calcium. In: Bowman BA, Russell RM, eds. Present knowledge in 

nutrition, Vol I. 9th ed. Washington, DC: ILSI Press; 2006:373-82. 

[720] Wender DF, Thulin GE, Smith GJ, Warshaw JB. Vitamin E affects lung biochemical 

and morphologic response to hyperoxia in the newborn rabbit. Pediatr Res. 1981 

Mar;15(3):262-8. 

[721] Whedon G, Lutwak L, Rambaut P, et al. Effect of weightlessness on mineral 

metabolism; metabolic studies on Skylab orbital flights. Calcif Tissue Res. 1976;21 

Suppl:423-30. 

[722] Whedon G, Lutwak L, Rambaut P, et al. Mineral and nitrogen balance study 

observations: the second manned Skylab mission. Aviat Space Environ Med. 

1976;47:391-6. 

[723] Whedon G, Heaney R. Effects of physical inactivity, paralysis and weightlessness on 

bone growth. In: Hall B, ed. Bone, Vol 7. Boca Raton: CRC Press; 1993:57-77. 

[724] Whedon GD, Lutwak L, Reid J, et al. Mineral and nitrogen metabolic studies on Skylab 

orbital space flights. Trans Assoc Am Physicians. 1974;87:95-110. 

[725] Whedon GD, Lutwak L, Rambaut PC, et al. Mineral and nitrogen metabolic studies, 

experiment M071. In: Johnston RS, Dietlein LF, eds. Biomedical results from Skylab 

(NASA SP-377). Washington, DC: National Aeronautics and Space Administration; 

1977:164-74. 

[726] Whedon GD. Disuse osteoporosis: physiological aspects. Calcif Tissue Int. 

1984;36:S146-50. 

[727] Whitehouse AS, Smith HJ, Drake JL, Tisdale MJ. Mechanism of attenuation of skeletal 

muscle protein catabolism in cancer cachexia by eicosapentaenoic acid. Cancer Res. 

2001 May 1;61(9):3604-9. 

[728] Whitehouse AS, Tisdale MJ. Downregulation of ubiquitin-dependent proteolysis by 

eicosapentaenoic acid in acute starvation. Biochem Biophys Res Commun. 2001 Jul 

20;285(3):598-602. 

[729] Whitson P, Pietrzyk R, Pak C, Cintron N. Alterations in renal stone risk factors after 

space flight. J Urol. 1993;150:803-7. 

[730] Whitson P, Pietrzyk R, Pak C. Renal stone risk assessment during Space Shuttle flights. 

J Urol. 1997;158:2305-10. 

[731] Whitson PA, Pietrzyk RA, Morukov BV, Sams CF. The risk of renal stone formation 

during and after long duration space flight. Nephron. 2001;89:264-70. 

[732] Wigmore SJ, Ross JA, Falconer JS, et al. The effect of polyunsaturated fatty acids on 

the progress of cachexia in patients with pancreatic cancer. Nutrition. 1996 Jan;12(1 

Suppl):S27-30. 

[733] Wigmore SJ, Barber MD, Ross JA, Tisdale MJ, Fearon KC. Effect of oral 

eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer. 

2000;36(2):177-84. 

[734] Wimalawansa SM, Chapa MT, Wei JN, Westlund KN, Quast MJ, Wimalawansa SJ. 

Reversal of weightlessness-induced musculoskeletal losses with androgens: 

quantification by MRI. J Appl Physiol. 1999 Jun;86(6):1841-6. 
References 173

[735] Wimalawansa SM, Wimalawansa SJ. Simulated weightlessness-induced attenuation of 

testosterone production may be responsible for bone loss. Endocrine. 1999 

Jun;10(3):253-60. 

[736] World Health Organization. Energy and protein requirements. Report of a joint 

FAO/WHO/UNU expert consultation. Geneva, Switzerland: WHO; 1985. 

[737] Yang Y, Baker M, Graf S, Larson J, Caiozzo VJ. Hypergravity resistance exercise: the 

use of artificial gravity as potential countermeasure to microgravity. J Appl Physiol. 

2007 Nov;103(5):1879-87. 

[738] Yang Y, Kaplan A, Pierre M, et al. Space cycle: a human-powered centrifuge that can 

be used for hypergravity resistance training. Aviat Space Environ Med. 2007 

Jan;78(1):2-9. 

[739] Yetley EA, Brule D, Cheney MC, et al. Dietary reference intakes for vitamin D: 

justification for a review of the 1997 values. Am J Clin Nutr. 2009 Mar;89(3):719-27. 

[740] Yip R, Dallman PR. Iron. In: Ziegler EE, Filer LJ, Jr., eds. Present knowledge in 

nutrition. 7th ed. Washington, DC: International Life Sciences Institute; 1996:277-92. 

[741] Yonei T, Hagino H, Katagiri H, Kishimoto H. Bone metabolic changes in Antarctic 

wintering team members. Bone. 1999 Feb;24(2):145-50. 

[742] Yoshida M, Takashima Y, Inoue M, et al. Prospective study showing that dietary 

vitamin C reduced the risk of age-related cataracts in a middle-aged Japanese 

population. Eur J Nutr. 2007 Mar;46(2):118-24. 

[743] Yoshida M, Jacques PF, Meigs JB, et al. Effect of vitamin K supplementation on 

insulin resistance in older men and women. Diabetes Care. 2008 Aug 12. 

[744] Zachwieja JJ, Smith SR, Lovejoy JC, Rood JC, Windhauser MM, Bray GA. 

Testosterone administration preserves protein balance but not muscle strength during 28 

days of bed rest. J Clin Endocrinol Metab. 1999 Jan;84(1):207-12. 

[745] Zahariev A, Bergouignan A, Caloin M, et al. Skinfold thickness versus isotope dilution 

for body fat assessment during simulated microgravity: results from three bed-rest 

campaigns in men and women with and without countermeasures. Eur J Appl Physiol. 

2005 Oct;95(4):344-50. 

[746] Zange J, Muller K, Schuber M, et al. Changes in calf muscle performance, energy 

metabolism, and muscle volume caused by long-term stay on space station MIR. Int J 

Sports Med. 1997 Oct;18 Suppl 4:S308-9. 

[747] Zange J, Mester J, Heer M, Kluge G, Liphardt AM. 20-Hz whole body vibration 

training fails to counteract the decrease in leg muscle volume caused by 14 days of 6 

degrees head down tilt bed rest. Eur J Appl Physiol. 2008 Oct 30. 

[748] Zerath E, Holy X, Gaud R, Schmitt D. Decreased serum levels of 1,25-(OH)2 vitamin 

D during 1 year of sunlight deprivation in the Antarctic. Eur J Appl Physiol Occup 

Physiol. 1999 Jan;79(2):141-7. 

[749] Zerwekh JE, Ruml LA, Gottschalk F, Pak CY. The effects of twelve weeks of bed rest 

on bone histology, biochemical markers of bone turnover, and calcium homeostasis in 

eleven normal subjects. J Bone Miner Res. 1998;13:1594-601. 

[750] Zerwekh JE. Nutrition and renal stone disease in space. Nutrition. 2002 

Oct;18(10):857-63. 

[751] Zerwekh JE, Odvina CV, Wuermser LA, Pak CY. Reduction of renal stone risk by 

potassium-magnesium citrate during 5 weeks of bed rest. J Urol. 2007 Jun;177(6):2179-

84. 
174 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

[752] Zezerov AE, Ivanova SM, Morukov BV, Ushakov AS. [Lipid peroxidation in the 

human blood during a 120-day period of anti-orthostatic hypokinesia]. Kosm Biol 

Aviakosm Med. 1989 Mar-Apr;23(2):28-33. 

[753] Zimmermann MB. Iodine and the iodine deficiency disorders. In: Bowman BA, Russell 

RM, eds. Present knowledge in nutrition, Vol I. 9th ed. Washington, DC: ILSI Press; 

2006:471-97. 

[754] Zittermann A, Heer M, Caillot-Augusso A, et al. Microgravity inhibits intestinal 

calcium absorption as shown by a stable strontium test. Eur J Clin Invest. 

2000;30:1036-43. 

[755] Zorbas YG, Kakuris KK, Deogenov VA, Yerullis KB. Inadequacy of calcium 

supplements to normalize muscle calcium deficiency in healthy subjects during 

prolonged hypokinesia. Nutrition. 2008 Mar;24(3):217-23. 

[756] Zwart SR, Hargens AR, Smith SM. The ratio of animal protein intake to potassium 

intake is a predictor of bone resorption in space flight analogues and in ambulatory 

subjects. Am J Clin Nutr. 2004 Oct;80(4):1058-65. 

[757] Zwart SR, Davis-Street JE, Paddon-Jones D, Ferrando AA, Wolfe RR, Smith SM. 

Amino acid supplementation alters bone metabolism during simulated weightlessness. J 

Appl Physiol. 2005 Jul;99(1):134-40. 

[758] Zwart SR, Smith SM. The impact of space flight on the human skeletal system and 

potential nutritional countermeasures. International SportMed Journal. 2005 

Dec;6(4):199-214. 

[759] Zwart SR, Hargens AR, Lee SM, et al. Lower body negative pressure treadmill exercise 

as a countermeasure for bed rest-induced bone loss in female identical twins. Bone. 

2007 Feb;40(2):529-37. 

[760] 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 Jan;139(1):90-

5. 

[761] Zwart SR, Oliver SM, Fesperman JV, et al. Nutritional status assessment before, 

during, and after long-duration head-down bed rest. Aviat Space Environ Med. 

2009;80(5 (Supplement)):A15-A22. 

[762] Zwart SR, Crawford GE, Gillman PL, et al. Effects of 21 days of bed rest, with or 

without artificial gravity, on nutritional status of humans [published online ahead of 

print December 12, 2008]. J Appl Physiol.doi: 10.1152/japplphysiol.91136.2008. 
XVI. AUTHORS

Scott M. Smith is Senior Nutritionist and Manager for Nutritional Biochemistry at the 

NASA Johnson Space Center in Houston, Texas. The primary goal of this group is to 

determine the nutritional requirements for extended-duration space flight. This involves 

conducting both operational and research activities, and has spanned Shuttle, Mir, and ISS 

flight platforms, and planning for lunar exploration missions. Research activities are 

conducted on space missions and in laboratories on the ground; ground-based research 

projects include studies of the effects of simulated weightlessness on calcium and bone 

metabolism, vitamin D supplementation in crews wintering over in Antarctica, and oxidative 

damage in crews living 50 feet below the surface of the ocean, and investigations of dietary 

and other countermeasures for ameliorating space flight-induced changes in human 

physiology. Dr. Smith also participated in the definition of the current nutritional 

recommendations for extended-duration space flight, and is Co-Chair of the Multilateral 

Medical Operations Panel’s Nutrition Working Group for the International Space Station. 

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 space flight, 

including bone loss, changes in iron metabolism, and oxidative damage. She has also worked 

with ground-based analogs of space flight, 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. 

Vickie L. Kloeris is a Food Scientist and Manager of the Space Food Systems Laboratory 

(SFSL) at Johnson Space Center in Houston, Texas. The SFSL is responsible for research and 

development of new space foods and space food packaging, and is also responsible for the 

procurement, processing, packaging, stowing, and shipping of U.S. foods to the International 

Space Station (ISS). In addition, Ms. Kloeris manages the ISS food system and was manager 

of the Shuttle food system for 16 years. 

Martina Heer is Senior Nutritionist and Director of Nutrition Health at Profil Institute for 

Metabolic Research, Neuss, Germany. 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 (in particular the nutrients 

sodium and sodium chloride) with other physiological systems such as the musculoskeletal 

and cardiovascular systems. Her space flight studies started with Shuttle missions and 

missions to the Mir station, and they continue with experiments on the ISS. The space studies 

are combined with extended research in the form of space analog studies on the ground, 
176 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

which take place in the Institute’s clinical research facility. In addition to her position at Profil 

Institute for Metabolic Research, Dr. Heer is adjunct associate professor in Nutrition 

Physiology at the University of 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 and is a member of the ESA Nutrition Expert Committee. 
XVII. EDITOR

Jane M. Krauhs is a Senior Scientist with Wyle Integrated Science and Engineering 

Group in Houston, Texas, and an Editor in the Life Sciences (Diplomate). She has edited 

many technical and nontechnical documents produced by the Nutritional Biochemistry 

Laboratory and other space life science disciplines at the Johnson Space Center. 

XVIII. LIST OF FIGURES

Figure 1. Food kit used by Mercury astronauts. Some packets contained dehydrated 

food that needed water; other foods were ready to eat. A 12-inch 

ruler is shown for scale. Included are packets of mushroom soup, 

orange-grapefruit juice, cocoa beverage, pineapple juice, chicken 

with gravy, pears, strawberries, beef and vegetables, and other 

assorted foods. Photo credit: NASA. 4

Figure 2. An overhead view of the Skylab space station cluster in Earth orbit as 

photographed from the Skylab 4 Command and Service Modules 

(CSM) during the final fly-around by the CSM before it returned 

home. The space station is seen against a cloud-covered Earth. 

Photo credit: NASA. 5

Figure 3. An artist’s concept illustrating an Apollo-type spacecraft (on left) about to 

dock with a Soviet Soyuz-type spacecraft. An agreement between 

the United States and the Union of Soviet Socialist Republics 

provided for the docking in space of the Soyuz and Apollo 

spacecraft in Earth orbit in 1975. The joint venture was known as 

the Apollo-Soyuz Test Project, or in Russia as the Soyuz-Apollo 

Test Project. Photo credit: NASA. 6

Figure 4. A close-up view of cheddar cheese spread, one of the items of food 

selected for the Apollo-Soyuz Test Project mission flown in the 

summer of 1975. This food item was also carried on the Apollo 

missions. Photo credit: NASA. 6

Figure 5. On April 12, 1981, just seconds after 7 a.m., the launch of the first Space 

Shuttle, Columbia, carried astronauts John Young and Robert 

Crippen into an Earth-orbital mission lasting 54 hours. Photo credit: 

NASA. 7

Figure 6. View of the Space Shuttle Orbiter Atlantis on approach to the International 

Space Station (ISS) during the STS-122 mission. Visible in the 

payload bay are the European Laboratory / Columbus module, the 

Integrated Cargo Carrier-Lite, the Orbiter Boom Sensor System, 
180 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

 and the Shuttle Remote Manipulator System. Photo credit: NASA. 8

Figure 7. The International Space Station is seen from Space Shuttle Discovery on 

March 25, 2009. Photo credit: NASA. 10

Figure 8. Astronaut Peggy A. Whitson, Expedition 16 commander, prepares a meal 

at the galley in the Zvezda Service Module of the International 

Space Station. Cosmonaut Yuri I. Malenchenko, flight engineer 

representing Russia’s Federal Space Agency, is visible in the 

background. Photo credit: NASA. 10

Figure 9. In-flight dietary intake of crewmembers in different space programs. Data 

are expressed as percentage of energy requirements predicted by the 

World Health Organization (WHO) [736]. Apollo n = 33, Skylab n

= 9, Shuttle n = 32, Mir n = 7, ISS n = 23. Apollo and Skylab data 

are from Bourland et al. [62]. Figure is adapted from Smith and 

Lane [611], with additional data from Smith et al., 2005 and Smith 

and Zwart, 2008 [610, 612]. 20

Figure 10. Postflight body weight (BW) of Mir and ISS crewmembers (n = 20). Data 

are expressed as mean ± SD of the percent change from preflight 

body weight. R+0 = landing day, AME1 = first annual medical 

exam after return from the mission, and AME2 = second exam. 21

Figure 11. In-flight body mass measurement data from ISS crewmembers. Data are 

expressed as percent change from preflight values. Data collection 

was scheduled every 2 weeks, but complete data for all 

crewmembers were not always available. Each line represents data 

for 1 crewmember. 22

Figure 12. Changes in body weight on the day of landing. Data are expressed as 

percent change from preflight values. Each symbol represents 1 

crewmember from a Shuttle (open circles), Skylab (open triangles), 

Mir (filled squares), or ISS (filled circles) mission. Duration data 

have been adjusted slightly to ensure anonymity. From Lane et al., 

Food and nutrition for the moon base: what have we learned in 45 

years of spaceflight. Nutr Today 2007;42(3):102-10 [353], adapted 

with permission. 23

Figure 13. Body weight of Apollo crewmembers (Apollo 7 through 17) before (F–0) 

and after (R+0) flight. Data are from Johnston et al., 1975 [295]. 23

Figure 14. In-flight oxidation of body fat related to in-flight energy deficit. Stein et 

al., Am J Physiol Regul Integr 1999 [628], adapted with permission. 24

Figure 15. Leucine oxidation (an index of net protein catabolism) in a crossoverdesign bed rest study to evaluate the impact of hypocaloric nutrition 

on integrated physiology. There was a significant (P = 0.04) 

interaction between bed rest and diet. Data are from Biolo et al. 

[50]. LBM, lean body mass. 24
List of Figures 181

Figure 16. Metabolic rate of Apollo 14 astronauts while they traversed the lunar 

surface on foot during EVA. Data are from Waligora and Horrigan 

[712]. 25

Figure 17. Metabolic expenditures of the first Apollo 15 lunar EVA in chronological 

order (durations of each activity are noted in parentheses). The 

average total energy expenditure during the EVA was 1800 kcal. 

ALSEP = Apollo Lunar Surface Experiments Package, EVA = 

extravehicular activity, LRV = Lunar Roving Vehicle, TV = 

television. Data are from Waligora and Horrigan [712]. 25

Figure 18. Energy intake, energy expenditure (EE), and WHO-predicted energy 

requirements (WHO) of Space Shuttle crewmembers before 

(checked bars) and during (open bars) space flight. Data are from 

Lane et al., 1997 and Lane et al., 1999 [348, 351]. 26

Figure 19. Plasma total protein (left panel) and albumin (right panel) in Skylab 

crewmembers before and after flight. Data are from Leach and 

Rambaut [361]. 29

Figure 20. Protein synthesis and energy deficit. Stein et al. , Am J Physiol 

Endocrinol Metab 1999 [627], adapted with permission. 30

Figure 21. Urinary amino acid excretion by Apollo crewmembers (n = 12) before 

and after flight. Data are from Leach et al. 1975 [366]. 31

Figure 22. The bone resorption marker n-telopeptide (NTX) was positively 

correlated with the ratio of animal protein to potassium intake 

(APro/K) during week 4 of bed rest (solid line, squares), while no 

relationship was observed in ambulatory subjects (dashed line, 

circles). Adapted from Zwart et al. [756]. 34

Figure 23. Urine pH (mean ± SD) of amino acid-supplemented (■) and placebo (○) 

groups during 4 weeks of bed rest. *Significantly different from 

before bed rest (Pre), P < 0.05. #

Significant difference between 

groups, P < 0.05. Figure is from Zwart et al., J Appl Physiol 2005 

[757]. 35

Figure 24. Urinary n-telopeptide (NTX) excretion (mean ± SD) of amino acidsupplemented (■) and placebo (○) groups during 4 weeks of bed 

rest. *Significantly different from before bed rest, P < 0.05 (no 

significant differences between groups). Figure is from Zwart et al., 

J Appl Physiol 2005 [757]. 35

Figure 25. Urinary calcium excretion (mean ± SD) of amino acid-supplemented 

(AA, ■) and placebo (○) groups during 4 weeks of bed rest. #

AA 

values were significantly different from pre-bed rest values, P <

0.05. Figure is from Zwart et al., J Appl Physiol 2005 [757]. 35

Figure 26. Plasma insulin (n = 22) and glucose (n = 33) in Apollo crewmembers 

before and after flight. Data are from Leach et al., 1975 [366]. 38
182 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

Figure 27. Plasma glucose in Skylab crewmembers (n = 9) before, during, and after 

flight. Data are from Leach and Rambaut, 1977 [361]. 38

Figure 28. Plasma insulin in Skylab crewmembers (n = 9) before, during, and after 

flight. Data are from Leach and Rambaut, 1977 [361]. 38

Figure 29. Plasma triglycerides in Skylab crewmembers (n = 9) before and after 

flight. Data are from Leach and Rambaut, 1977 [361]. 42

Figure 30. Serum high-density lipoproteins (HDL) in ISS crewmembers (n = 12) 

before and after flight. Postflight data are from landing day or 2 to 

12 months after flight. Because HDL is not a routine measurement 

at landing, some data were available only at the next medical exam. 42

Figure 31. Serum low-density lipoprotein (LDL) in ISS crewmembers (n = 12) 

before and after flight. Postflight data are from landing day or 2 to 

12 months after flight. Because LDL is not a routine measurement 

at landing, some data were available only at the next medical exam. 42

Figure 32. Relationship between the loss of body mass observed after landing and 

the change in serum LDL in ISS crewmembers (n = 12). Because 

LDL is not a routine measurement at landing, some data were 

available only at the next medical exam, which ranged from 50 to 

257 days after landing. 43

Figure 33. Serum (n = 33) and urinary (n = 30) sodium from Apollo crewmembers. 

Numbers in bars represent the percent change from preflight values. 

Adapted from Leach et al., 1975 [366]. 48

Figure 34. Serum (n = 33) and urinary (n = 30) chloride from Apollo crewmembers. 

Numbers in bars represent the percent change from preflight values. 

Adapted from Leach et al., 1975 [366]. 48

Figure 35. Plasma sodium of Skylab crewmembers (n = 9) before, during, and after 

flight. Data are from Leach and Rambaut, 1977 [361]. 48

Figure 36. Plasma chloride of Skylab crewmembers (n = 9) before, during, and after 

flight. Data are from Leach and Rambaut, 1977 [361]. 49

Figure 37. Serum sodium (left panel) and chloride (right panel) of Shuttle 

crewmembers (n = 2 to 6) during and after flight, expressed as a 

percent change from preflight values. Data are from Leach-Huntoon 

et al., 1987 [359]. 49

Figure 38. In-flight dietary sodium intake (mg/d) across space programs. Apollo n = 

33, Skylab n = 9, Shuttle n = 32, Mir n = 7, ISS n = 23. Apollo and 

Skylab data are from Bourland et al., 2000 [62]. Figure is adapted 

from Smith and Lane, 2008 [611], with additional data from Smith 

et al., 2005, and Smith and Zwart, 2008 [610, 612]. 49

Figure 39. Fecal sodium excretion in 4 groups with different sodium intake (∆: 50 

mmol NaCl/d; □: 200 mmol NaCl/d; ○: 400 mmol NaCl/d; ■: 550 
List of Figures 183

mmol NaCl/d). Values are mean ± SEM (n = 8). Fecal sodium 

excretion increased significantly with increasing sodium intake. 

**Significantly different from the 50 mmol NaCl/d group. 

++Significantly different from the 200 mmol NaCl/d group (P < 

0.01). Adapted from Heer, 1996 [240]. 50

Figure 40. Serum (n = 33) and urinary (n = 30) potassium of Apollo crewmembers. 

Numbers in bars represent the percent change from preflight values. 

Adapted from Leach et al., 1975 [366]. 53

Figure 41. Exchangeable potassium of Apollo 15, 16, and 17 crewmembers after 

flight, as the percent change from preflight values. Data are from 

Leach et al., 1975 [366]. 53

Figure 42. Plasma potassium of Skylab crewmembers (n = 9) before, during, and 

after flight. Data are from Leach and Rambaut, 1977 [361]. 54

Figure 43. Serum potassium of Shuttle crewmembers (n = 2-6) during and after 

flight, expressed as the percent change from preflight values. Data 

are from Leach-Huntoon et al. 1987 [359]. 54

Figure 44. Serum retinol (n = 23) and retinol-binding protein (n = 18) in ISS 

crewmembers before and after long-duration space flight. Data are 

from Smith et al., 2005 [610]. 58

Figure 45. Vitamin D synthesis, activation, and catabolism. Dusso et al., Am J 

Physiol Renal Physiol 2005 [149], adapted with permission. 60

Figure 46. Plasma 25-hydroxyvitamin D of Skylab crewmembers (n = 9) before and 

after flight. Data are from Leach and Rambaut, 1977 [361]. 61

Figure 47. Serum 25-hydroxyvitamin D concentrations before and after 4- to 6-

month space flights on the International Space Station (n = 23). 

Each line represents 1 crewmember. The “Pre mean” point on each 

line is the average of data collected about 6 months and about 6 

weeks before launch. R+0 = Recovery plus zero days, that is, 

landing day. These samples are typically collected 2 to 8 hours after 

landing. Adapted from Smith and Zwart, Adv Clin Chem 2008 

[612]. 61

Figure 48. Serum 25-hydroxyvitamin D and parathyroid hormone concentrations 

before (average of data from samples collected about 6 months and 

6 weeks before launch) and after (landing day, typically collected 2 

to 8 hours after landing) 4- to 6-month space flights on the 

International Space Station. Each symbol represents 1 crewmember. 

Adapted from Smith and Zwart, Adv Clin Chem 2008 [612]. 62

Figure 49. Serum phylloquinone before and after 4- to 6-month space flights on the 

International Space Station. Each line represents 1 crewmember (n

= 15). The “Pre Mean” point on each line is the average of data 

collected about 6 months and about 6 weeks before launch. R+0 = 
184 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

Recovery plus zero days, that is, landing day. These samples are 

typically collected 2 to 8 hours after landing. Data are from Smith et 

al. [610]. 68

Figure 50. Red blood cell folate concentrations before and after 4- to 6-month space 

flights on the International Space Station (n = 23). Each line 

represents 1 crewmember. The “Pre mean” point is the average of 

data collected about 6 months and 6 weeks before launch. R+0 = 

Recovery plus zero days, that is, landing day. These samples are 

typically collected 2 to 8 hours after landing. Adapted from Smith 

and Zwart, 2008 [612]. 72

Figure 51. Plasma vitamin C in 7 subjects during 21 days of bed rest. Data, from 

Zwart et al. [762], are expressed as percent change from before bed 

rest. 79

Figure 52. Plasma calcium of Skylab crewmembers (n = 9) before and after flight. 

Data are from Leach and Rambaut, 1977 [361]. 88

Figure 53. Serum calcium of Shuttle crewmembers (n = 2-6) during and after flight, 

expressed as a percent change from preflight values. Data are from 

Leach-Huntoon et al., 1987 [359]. 89

Figure 54. Plasma parathyroid hormone (PTH) concentrations of Skylab 

crewmembers (n = 9) before and after flight. Data are from Leach 

and Rambaut, 1977 [361]. 89

Figure 55. Plasma total alkaline phosphatase of Skylab crewmembers (n = 9) before 

and after flight. Data are from Leach and Rambaut, 1977 [361]. 90

Figure 56. Plasma phosphate of Skylab crewmembers (n = 9) before, during, and 

after flight. Data are from Leach and Rambaut, 1977 [361]. 95

Figure 57. Urinary phosphorus of ISS crewmembers (n = 23) before and after longduration space flight. Data are from Smith et al., 2005 [610]. 95

Figure 58. Serum (n = 32) and urinary (n = 23) magnesium from Apollo 

crewmembers. Numbers in bars represent the percent change from 

preflight values. Adapted from Leach et al., 1975 [366]. 97

Figure 59. Serum magnesium of Shuttle crewmembers (n = 2-6) during and after 

flight, expressed as a percent change from preflight values. Data are 

from Leach-Huntoon et al., 1987 [359]. 97

Figure 60. Plasma magnesium of Skylab crewmembers (n = 9) before and 0, 1, 3-4, 

and 14 days after flight. Data from Leach and Rambaut, 1977 [361]. 98

Figure 61. Serum (left panel) and urinary (right panel) magnesium before and after 

4- to 6-month space flights on the International Space Station. Each 

line represents 1 crewmember. The “Pre mean” point on each line is 

the average of data collected about 6 months and about 6 weeks 

before launch. R+0 = Recovery plus zero days, that is, landing day. 
List of Figures 185

These samples are typically collected 2 to 8 hours after landing. 

Data are from Smith et al., 2005 [610]. 98

Figure 62. Red blood cell mass (mL/kg body mass) after space flight. Each point 

represents 1 crewmember. Data are expressed as percent change 

from preflight values. Adapted from Smith, 2002 [605]. 101

Figure 63. Serum iron and ferritin in ISS crewmembers (n = 23) before and after 

long-duration space flight. Data are from Smith et al., 2005 [610]. 102

Figure 64. Serum copper before and after 4- to 6-month missions on the 

International Space Station. Each line represents 1 crewmember. 

The “Pre Mean” point for each line is the average of data collected 

about 6 months and about 6 weeks before launch. R+0 = Recovery 

plus zero days, that is, landing day. These samples are typically 

collected 2 to 8 hours after landing. Data are from Smith et al., 2005 

[610]. 105

Figure 65. Serum ceruloplasmin before and after 4- to 6-month missions on the 

International Space Station. Each line represents 1 crewmember. 

The “Pre Mean” point on each line is the average of data collected 

about 6 months and about 6 weeks before launch. R+0 = Recovery 

plus zero days, that is, landing day. These samples are typically 

collected 2 to 8 hours after landing. Data are from Smith et al., 2005 

[610]. 105

Figure 66. Serum and urinary zinc status from 11 ISS crewmembers before and after 

flight. Data are from Smith et al., 2005 [610]. 110

Figure 67. Urinary iodine excretion of ISS crewmembers before and after longduration space flight (n = 23). Data are from Smith et al., 2005 

[610]. 113

Figure 68. Artist’s image of the next-generation lunar landing. Credit: NASA. 130

Figure 69. Artist’s concept of Martian habitat and exploration vehicles. Credit: 

NASA. 130

XIX. LIST OF TABLES

Table 1. Planned (menu) and required nutrient intake on 

International Space Station missions. 13-14

Table 2. In-flight dietary intake of Apollo, Skylab, and Shuttle crewmembers. 15

XX. ABBREVIATIONS

8OHdG 8-hydroxy-2'-deoxyguanosine 

AI adequate intake 

AMP adenosine monophosphate 

ASTP Apollo-Soyuz Test Project 

BW body weight 

cal calorie 

CoA coenzyme A 

d day 

DFE dietary folate equivalent 

DLR German Aerospace Center 

DNA deoxyribonucleic acid 

DRI dietary reference intake 

EAR estimated average requirement 

EE energy expenditure 

EER estimated energy requirement 

EGR erythrocyte glutathione reductase 

Eq equivalent 

ESA European Space Agency 

EVA extravehicular activity (space walk) 

FAD flavin-adenine dinucleotide 

g gram 

G acceleration, gravity; 1G = Earth gravity 

GLA gamma-carboxyglutamic acid 

GPX glutathione peroxidase 

Gy Gray 

h, hr hour 

HDL high-density lipoprotein 

HRP Human Research Program 

ISS International Space Station 

IU international unit 

IVA intravehicular activity 

J joule 

k kilo 

L liter 
190 Scott M. Smith, Sara R. Zwart, Vickie L. Kloeris and Martina Heer 

LBM lean body mass 

LDL low-density lipoprotein 

μ micro 

m meter, milli 

M mega 

MDA malondialdehyde 

mol mole 

MRI magnetic resonance imaging 

mRNA messenger RNA 

n nano 

n number of subjects 

NAD nicotinamide adenine dinucleotide 

NADP nicotinamide adenine dinucleotide phosphate 

NADPH reduced form of nicotinamide adenine dinucleotide phosphate 

NASA National Aeronautics and Space Administration 

NDS-R Nutrition Data System for Research 

NE niacin equivalent 

NEEMO NASA Extreme Environment Mission Operations 

NLT not less than 

NTE not to exceed 

NTX n-telopeptide 

P probability 

PL pyridoxal 

PLP pyridoxal 5'-phosphate 

PM pyridoxamine 

PMP pyridoxamine 5'-phosphate 

PN pyridoxine 

PNP pyridoxine 5'-phosphate 

PTH parathyroid hormone 

RBC red blood cell 

RDA recommended dietary allowance 

RE retinol equivalent 

RNA ribonucleic acid 

ROS reactive oxygen species 

RSA Russian Space Agency 

SD standard deviation 

SEM standard error of the mean 

SLS Spacelab Life Sciences 

SOD superoxide dismutase 

TEE total energy expenditure 

THF tetrahydrofolate 

U unit 

UV-B ultraviolet B light 

WHO World Health Organization 

y year 
INDEX

#

1G, 189 

5-hydroxytryptophan, 80 

A

abdominal cramps, 110 

abnormalities, 58, 66, 76, 104, 113 

absorption, 33, 36, 41, 50, 51, 60, 65, 73, 76, 84, 87, 

89, 90, 93, 94, 96, 97, 100, 104, 106, 107, 108, 

110, 111, 125, 127, 129, 137, 143, 149, 150, 153, 

156, 163, 165, 170, 174 

acceleration, 144, 189 

accounting, 20, 33 

accuracy, 120 

acetate, 125 

acetylcholine, 82 

acid, 14, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 41, 

44, 51, 52, 67, 68, 71, 73, 75, 77, 78, 80, 81, 82, 

83, 84, 85, 94, 100, 104, 107, 114, 126, 127, 133, 

135, 137, 138, 139, 142, 143, 146, 147, 148, 149, 

156, 157, 159, 160, 162, 163, 164, 165, 170, 171, 

172, 174, 181, 189, 190 

acidic, 21, 127 

acidity, 82 

acidosis, 34, 50, 53, 143 

activation, 60, 76, 80, 87, 111, 125, 183 

acute, 47, 87, 111, 119, 133, 150, 156, 160, 161, 164, 

172 

adaptation, 1, 8, 28, 45, 93, 100, 102, 133, 136, 141, 

157, 162, 167 

additives, 117 

adenine, 73, 74, 76, 77, 189, 190 

adenosine, 50, 73, 189 

adenosine triphosphate, 73 

ADH, 139 

adipose, 41, 59, 66 

adipose tissue, 41, 59, 66 

administration, 31, 32, 92, 149, 160, 173 

ADP, 74 

adrenal glands, 78 

adult, 41, 47, 87, 100, 107, 138, 146, 151, 171 

adults, 52, 57, 60, 64, 69, 78, 81, 84, 85, 107, 114, 

136, 145, 147, 171 

aerobic exercise, 32 

aerospace, 146 

affective disorder, 144 

African-American, 171 

age, 26, 36, 51, 78, 81, 87, 96, 143, 151, 173 

agent, 66, 77, 79, 104, 113, 114 

agents, 77, 84, 92, 127 

aging, 136, 143, 144, 152, 158, 166, 168 

agricultural, 143 

aid, 32, 129 

air, 28, 39, 103, 112, 129 

albumin, 29, 45, 46, 138, 181 

alcohol, 19, 109 

alkali, 137, 164 

alkaline, 78, 90, 107, 109, 150, 184 

alkaline phosphatase, 90, 107, 109, 150, 184 

alpha, 133, 147, 151, 158, 163, 168 

alpha-tocopherol, 151, 158 

alternatives, 117 

alters, 174 

aluminum, 94, 116 

amelioration, 169 

amino acid, 20, 29, 30, 31, 32, 33, 34, 35, 36, 37, 71, 

73, 75, 80, 83, 114, 125, 137, 142, 148, 149, 159, 

167, 170, 181 

ammonia, 33 

Amsterdam, 162 

anabolism, 134 

anaemia, 141 

analgesics, 127 

analog, 1, 17, 31, 46, 62, 90, 92, 103, 120, 153, 175 

androgen, 167 
192 Index 

androgens, 172 

anemia, 66, 71, 76, 80, 81, 82, 100, 101, 102, 104, 

106, 140, 142, 161, 171 

aneuploidy, 135 

angiography, 160 

anhydrase, 109 

animal models, 22, 32, 44, 77, 92, 125 

animal studies, 28, 51, 66, 83, 89, 92, 120, 125 

animal tissues, 107 

animals, 32, 37, 108, 125, 150 

anorexia, 74, 94, 169 

antacids, 125 

antagonists, 68, 85, 143, 163 

Antarctic, 62, 63, 148, 157, 159, 160, 164, 166, 173 

antibody, 85 

anti-cancer, 126 

anticoagulant, 67 

anticoagulants, 138 

anticoagulation, 68 

antidepressants, 127 

antigen-presenting cell, 59 

antioxidant, 59, 65, 66, 67, 77, 79, 80, 112, 119, 120, 

121, 127, 138, 141, 147, 149, 163, 171 

apathy, 74 

apatite, 109 

apoptosis, 120, 147, 163, 168 

appetite, 21, 28, 57 

apples, 11 

arachidonic acid, 41 

argument, 34 

army, 27 

arrest, 53 

arsenic, 142 

arteriosclerosis, 65 

artery, 152 

articular cartilage, 141 

ascorbic acid, 14, 77, 78, 100, 104, 127, 148 

ash, 33, 142 

aspartate, 126, 145 

assessment, ix, 17, 62, 81, 91, 142, 145, 156, 158, 

163, 165, 166, 172, 173, 174 

assumptions, 27, 91 

asthma, 126 

atherosclerotic plaque, 44 

Atlantis, 8, 179 

atmospheric pressure, 72, 76 

ATP, 73 

atrophy, 30, 33, 44, 53, 66, 83, 120, 135, 136, 162, 

164, 167 

autopsy, 98, 105, 107 

availability, 27, 41, 63, 89, 92, 100, 103, 148, 154 

aviation, 149 

B

B vitamins, 143, 171 

background information, 17 

bacteria, 67, 71, 82, 84 

barrier, 147 

basal metabolic rate, 20, 171 

beef, 4, 127, 179 

behavior, 62, 63, 72, 100, 149 

beneficial effect, 44 

benefits, 25, 44, 66, 140, 155 

beriberi, 74 

beta-carotene, 144, 151, 154 

beverages, 7, 8, 10, 39, 46, 117 

bicarbonate, 152 

bile, 71 

bilirubin, 163 

binding, 58, 87, 100, 107, 183 

bioavailability, 40, 73, 100, 123, 126, 127 

biochemistry, 92, 139, 164, 166, 167, 168 

biological activity, 57, 74 

biological markers, 137 

biological systems, 65 

biopsies, 91, 139, 169 

biopsy, 30, 91 

biosynthesis, 77, 162 

biotin, 83, 84, 136, 139, 142, 148, 154, 157, 161 

biotransformation, 125, 126 

birth, 150 

bisphosphonate treatment, 154 

bleeding, 78 

blocks, 29 

blood, 37, 39, 40, 47, 49, 52, 58, 59, 65, 67, 71, 72, 

80, 83, 87, 100, 101, 102, 103, 104, 106, 112, 

133, 136, 140, 142, 150, 151, 152, 155, 157, 163, 

164, 165, 166, 170, 174, 184, 185, 190 

blood clot, 67 

blood glucose, 37, 39, 40 

blood lead levels, 150 

blood plasma, 80, 170 

blood pressure, 52, 136 

body composition, 26, 152, 159 

body fat, 24, 173, 180 

body fluid, 102, 109, 141, 143, 152, 153, 160, 165 

body mass, 1, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 

30, 31, 43, 44, 45, 46, 54, 87, 101, 136, 141, 151, 

180, 182, 185, 190 

body weight, 4, 14, 21, 23, 26, 47, 52, 137, 151, 180, 

189 

bonding, 145 

bonds, 41 

bone density, 36, 140, 144, 149 

bone growth, 33, 172 
Index 193

bone loss, 17, 32, 37, 44, 51, 52, 64, 69, 78, 88, 89, 

90, 91, 92, 93, 94, 95, 108, 135, 143, 146, 147, 

148, 153, 155, 156, 162, 163, 164, 165, 166, 171, 

173, 174, 175 

bone marrow, 59, 100, 141, 168 

bone mass, 32, 51, 78, 88, 90, 91, 139, 154, 156, 

158, 171 

bone mineral content, 87 

bone remodeling, 108, 145 

bone resorption, 34, 35, 51, 59, 60, 89, 90, 91, 92, 

94, 110, 137, 143, 145, 162, 164, 170, 174, 181 

bonus, 11 

boron, 158 

bowel, 40 

brain, 37, 59, 74, 78, 82, 104, 107, 109, 127, 136, 

151 

breakdown, 27, 29, 30, 36, 127 

breast cancer, 157 

breast carcinoma, 144 

breast milk, 84, 135 

breathing, 119 

broad spectrum, 144 

broccoli, 149 

building blocks, 29 

bulbs, 78 

burning, 85 

burns, 44 

bypass, 134 

bystander effect, 120 

C

Ca2+, 120 

cachexia, 169, 172 

calcification, 65, 94, 96 

calcitonin, 92, 134, 145, 149, 156 

calcium, 14, 33, 34, 35, 36, 50, 51, 52, 59, 60, 63, 

64, 65, 67, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 

97, 100, 107, 108, 133, 134, 136, 137, 138, 139, 

140, 141, 142, 144, 145, 146, 147, 148, 149, 150, 

155, 156, 158, 160, 161, 163, 164, 166, 169, 173, 

174, 175, 181, 184 

calcium oxalate, 33, 51, 164 

calf, 135, 169, 173 

caloric restriction, 166 

calorie, 137, 189 

calorimetry, 24 

cAMP, 50 

campaigns, 173 

Canada, 147 

cancer, 40, 41, 44, 57, 59, 64, 67, 78, 100, 103, 112, 

113, 123, 126, 133, 137, 138, 139, 140, 144, 145, 

150, 155, 157, 165, 169, 170, 172 

cancer cells, 59 

carbohydrate, 13, 19, 34, 37, 39, 40, 43, 83, 84, 94, 

99, 109, 114, 117, 126, 137, 141, 148, 159, 165 

carbohydrate metabolism, 40, 109 

carbohydrates, 19, 37, 39, 73, 126 

carbon, 41, 71, 73 

carcinogenesis, 149, 154 

carcinogenic, 127 

carcinogenicity, 154 

carcinoma, 144 

cardiac arrest, 53 

cardiac function, 52, 155, 166 

cardiomyopathy, 94, 111 

cardiopulmonary, 112, 134, 155 

cardiopulmonary bypass, 134 

cardiovascular disease, 40, 64, 103, 144, 147, 148, 

150, 156, 171 

cardiovascular function, 28, 47 

cardiovascular system, 104, 175 

carotene, 57, 58, 144, 151, 154, 170 

carotenoids, 57, 123, 148, 150, 159 

carrier, 84 

cartilage, 59, 141 

catabolic, 30, 160 

catabolism, 23, 24, 27, 60, 80, 84, 111, 136, 172, 

180, 183 

catalysis, 138 

catalyst, 100 

catalytic activity, 109 

cataracts, 77, 78, 139, 173 

catecholamines, 81, 139 

cation, 47, 52, 96 

cats, 87, 159 

CDR, 141, 149 

cecum, 21, 40 

cell, 1, 47, 59, 65, 71, 72, 73, 78, 80, 87, 94, 96, 100, 

101, 103, 106, 109, 126, 133, 134, 142, 144, 151, 

162, 166, 171, 175, 184, 185, 190 

cell culture, 175 

cell death, 66, 151 

cell division, 71, 87 

cell growth, 109 

cell line, 144 

cell membranes, 47, 65, 87, 94 

cell metabolism, 133 

cell surface, 100 

cellulose, 40 

central nervous system, 82, 104 

ceruloplasmin, 104, 105, 185 

cheese, 6, 179 

chemotherapeutic drugs, 127 

chicken, 4, 140, 143, 179 

childbearing, 151 
194 Index 

children, 33, 64, 87, 134, 135 

chloride, 47, 48, 49, 51, 143, 148, 156, 161, 164, 

175, 182 

cholecalciferol, 163 

cholesterol, 40, 43, 44, 75, 107, 110, 148 

chromium, 14, 114, 115, 134, 137, 142, 167 

chromosomal instability, 135 

chromosome, 73, 121, 135 

chronic disease, 43, 59, 142 

chronic renal failure, 87, 115 

cigarette smoke, 126 

cigarette smoking, 124 

circadian, 138 

circulation, 101 

cirrhosis, 57 

cleanup, 27 

cleavage, 80 

clinical approach, 138 

clinical assessment, ix 

clinical trial, 163 

clinically significant, 52, 61 

clone, 144 

coagulation, 67, 87 

cobalamin, 14, 170 

cocoa, 4, 179 

coefficient of variation, 79 

coenzyme, 73, 74, 76, 81, 84, 189 

cofactors, 76 

coffee, 100 

cognitive deficits, 100 

cognitive function, 27, 63 

cohort, 155, 170 

collaboration, 13 

collagen, 77, 90, 91, 104, 106, 109 

colon, 41, 84, 138, 139, 144, 145, 147 

colon cancer, 138, 139, 145 

colorectal cancer, 104 

Columbia, 7, 9, 179 

combination therapy, 95 

combustion, 19 

commodity, 47 

common symptoms, 83 

communication, 24 

competition, 31 

complex carbohydrates, 39 

compliance, 8, 163 

complications, 68, 97 

components, 25, 36, 40, 41, 106, 161 

composition, 26, 27, 28, 143, 144, 152, 159, 160 

compounds, 57, 65, 71, 76, 77, 80, 92, 99, 111, 125, 

127 

computed tomography, 87 

concentration, 60, 61, 65, 71, 90, 100, 102, 133, 150, 

161 

configuration, 9 

confinement, 133 

congenital heart disease, 134 

conjugation, 125 

connective tissue, 104, 106 

consensus, 60, 84, 93 

constipation, 40, 41, 53 

constraints, 9, 45 

consumption, 4, 8, 11, 19, 24, 26, 27, 32, 37, 71, 83, 

117, 123, 129, 143, 158, 161, 171 

consumption rates, 11 

contaminants, 21 

contingency, 28 

contractors, 5 

control, 21, 41, 47, 63, 87, 91, 97, 101, 133, 139, 

153, 159, 162 

control group, 63 

controlled studies, 67 

conversion, 75, 81, 107, 126 

cooling, 27 

copper, 79, 104, 105, 106, 110, 137, 142, 147, 151, 

156, 161, 185 

coronary artery disease, 152 

coronary heart disease, 44, 57, 103, 114, 134, 164 

correlation, 34, 44, 59, 103, 107, 150, 163 

cortisol, 25, 30, 31, 115 

cost saving, 7 

costs, 94 

countermeasures, 1, 17, 27, 32, 37, 91, 92, 93, 94, 

118, 123, 131, 135, 139, 146, 161, 163, 169, 173, 

174, 175 

CRC, 133, 136, 143, 152, 160, 161, 163, 167, 171, 

172 

creatinine, 29, 31 

credit, 4, 5, 6, 7, 8, 10, 179, 180 

cretinism, 113 

Crohn’s disease, 87 

crops, 129 

cross-linking, 141 

cross-sectional, 30, 81, 143, 158, 160 

cross-sectional study, 158, 160 

crystallites, 108 

crystallization, 51, 164 

culture, 175 

cyclic AMP, 139 

cysteine, 80 

cytochrome, 99, 111, 125, 126, 138, 143, 145, 162 

cytochrome oxidase, 99 

cytokine, 162 

cytokines, 120 

cytosolic, 71 
Index 195

D

database, 14, 163 

death, 1, 27, 29, 36, 44, 46, 52, 53, 57, 64, 65, 66, 

71, 74, 75, 78, 80, 82, 88, 94, 97, 100, 104, 110, 

111, 112, 113, 114, 115, 151, 160, 168 

decompression, 118, 119 

defects, 104 

defense, 65, 109, 121, 147 

defenses, 119, 163 

deficiency, 1, 36, 44, 47, 52, 57, 58, 60, 62, 63, 64, 

65, 66, 67, 71, 72, 73, 75, 76, 78, 81, 82, 83, 84, 

85, 87, 95, 96, 100, 103, 104, 106, 107, 108, 110, 

111, 113, 114, 125, 126, 127, 129, 135, 137, 139, 

141, 142, 143, 145, 146, 147, 154, 155, 157, 160, 

161, 165, 168, 171, 174 

deficit, 24, 30, 88, 123, 137, 180, 181 

deficits, 100 

definition, 118, 175 

degradation, 27, 74, 165 

dehydration, 23, 44, 45, 46, 163 

dehydrogenase, 74, 76, 109 

delivery, 100, 102 

dementia, 75 

demyelination, 76, 82 

Denmark, 63 

densitometry, 91 

density, 36, 42, 43, 47, 58, 60, 110, 136, 140, 144, 

149, 156, 158, 161, 165, 168, 182, 189, 190 

dental caries, 108 

deoxyribonucleic acid, 189 

Department of Agriculture, 140 

Department of Health and Human Services, 140 

deposition, 89 

depressed, 78, 101 

depression, 81, 147 

deprivation, 148, 173 

derivatives, 65, 71, 74 

dermatitis, 41, 75, 80, 83, 85, 115 

destruction, 74 

detoxification, 111 

deviation, 79, 190 

dexamethasone, 126 

diabetes, 47, 59, 64, 87, 145, 147 

diagnostic criteria, 145 

diaphragm, 120, 152 

diaphysis, 98 

diarrhea, 44, 47, 75, 85, 110 

diet, 20, 22, 24, 27, 29, 32, 33, 34, 36, 37, 39, 51, 52, 

53, 55, 57, 73, 75, 83, 85, 89, 93, 94, 95, 96, 104, 

106, 107, 110, 114, 115, 126, 137, 141, 142, 143, 

145, 147, 149, 151, 164, 169, 180 

dietary, 13, 14, 15, 20, 21, 22, 27, 28, 31, 33, 34, 36, 

37, 39, 40, 41, 42, 43, 47, 49, 50, 51, 52, 53, 58, 

64, 65, 66, 67, 69, 71, 72, 74, 75, 77, 78, 79, 81, 

82, 84, 85, 88, 89, 93, 94, 96, 99, 100, 103, 104, 

106, 107, 109, 111, 112, 113, 114, 115, 125, 126, 

127, 136, 137, 138, 139, 140, 141, 142, 144, 145, 

146, 147, 149, 150, 154, 156, 158, 160, 161, 163, 

168, 173, 175, 180, 182, 187, 189, 190 

dietary fat, 41, 42, 43, 168 

dietary fiber, 14, 40, 41, 100 

dietary intake, 15, 20, 21, 22, 27, 28, 31, 33, 34, 43, 

47, 64, 66, 69, 74, 75, 77, 78, 79, 81, 82, 84, 85, 

93, 96, 99, 103, 106, 107, 109, 111, 112, 113, 

115, 147, 156, 180, 187 

dietary iodine, 114 

dietary supplementation, 142, 160 

diets, 8, 33, 34, 36, 40, 41, 45, 83, 85, 126, 134, 136, 

143 

differentiation, 82 

diffusion, 47 

disability, 166 

Discovery, 10, 180 

diseases, 59, 60 

disinfection, 163 

disorder, 144, 168 

displacement, 50 

distress, 75, 78, 97, 100, 104, 113 

distribution, 39, 41, 43, 47, 52, 125 

disulfide, 114 

diuretic, 47, 160 

diving, 72, 76 

division, 71, 87 

DNA, 71, 75, 79, 103, 111, 120, 121, 137, 139, 140, 

144, 147, 151, 161, 169, 171, 189 

DNA damage, 79, 103, 120, 137, 144, 147, 151, 171 

DNA repair, 111, 121 

dogs, 87, 155 

donor, 75 

dosimetry, 162 

drainage, 44 

drinking, 46, 114, 140 

drinking water, 46, 114 

drug interaction, 125, 143, 170 

drug metabolism, 125, 126 

drug-induced, 160 

drugs, 92, 125, 126, 127, 151, 155 

drying, 57 

duration, 1, 7, 8, 9, 13, 21, 22, 28, 30, 31, 43, 44, 45, 

54, 58, 61, 64, 65, 69, 72, 73, 77, 78, 79, 81, 82, 

84, 88, 90, 91, 92, 93, 95, 96, 98, 102, 103, 105, 

110, 111, 113, 118, 119, 120, 124, 125, 127, 129, 

131, 139, 152, 153, 158, 164, 165, 166, 167, 172, 

174, 175, 183, 184, 185 
196 Index 

dysregulation, 139 

E

earth, 162 

eating, 11, 123, 168 

edema, 47 

egg, 83, 100 

eicosanoids, 41 

eicosapentaenoic acid, 44, 135, 165, 172 

elderly, 60, 65, 87, 138, 161, 163, 166 

electricity, 8 

electrolyte, 44, 45, 52, 152, 153, 165 

electrolytes, 44, 150 

electron, 75, 99 

embryonic development, 57 

emotional, 77 

endocrine, 24, 43, 47, 93, 134, 153, 155, 167, 170 

endocrine system, 134, 155 

endocrinology, 152 

endurance, 27 

energy, 4, 17, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 

30, 31, 32, 36, 37, 39, 41, 43, 50, 52, 66, 67, 68, 

80, 85, 87, 91, 104, 119, 123, 125, 135, 136, 137, 

141, 148, 149, 152, 153, 161, 164, 168, 171, 173, 

180, 181, 189, 190 

energy consumption, 4 

energy density, 168 

energy transfer, 41, 67, 80, 85, 119 

enlargement, 113 

environment, 3, 28, 62, 71, 81, 93, 103, 117, 119, 

123, 124, 127, 129, 140, 156 

environmental conditions, 1 

environmental factors, 33 

enzymatic, 81 

enzyme-linked immunoassay, 162 

enzymes, 29, 50, 57, 74, 77, 83, 94, 104, 106, 109, 

110, 112, 125, 126, 145 

epiphysis, 98, 105 

epithelial cells, 59 

erythrocyte, 74, 76, 136, 189 

erythropoietin, 101, 102, 103, 140, 141, 150 

essential fatty acids, 41 

estimating, 20 

ethanol, 57, 134 

etiology, 146 

Euro, 68, 137 

Europe, 129 

European Space Agency, 13, 23, 176, 189 

evolution, 143 

examinations, 42, 137 

excretion, 29, 30, 31, 33, 34, 35, 36, 39, 47, 50, 51, 

73, 75, 81, 82, 83, 88, 89, 90, 91, 93, 94, 96, 99, 

108, 110, 113, 125, 129, 134, 136, 137, 138, 139, 

142, 144, 146, 147, 150, 153, 154, 157, 159, 164, 

165, 168, 170, 181, 182, 185 

exercise, 24, 25, 27, 30, 32, 91, 92, 98, 119, 120, 

133, 135, 136, 139, 140, 142, 144, 148, 155, 159, 

161, 162, 163, 164, 166, 168, 169, 171, 173, 174 

exercise performance, 161, 163 

expenditures, 25, 181 

exposure, 1, 19, 29, 59, 60, 62, 63, 64, 71, 72, 73, 74, 

75, 76, 78, 80, 85, 92, 119, 120, 126, 131, 144, 

148, 157, 159, 164, 171 

extensor, 133 

extracellular matrix, 104 

eye, 78, 119, 147 

F

FAD, 76, 189 

failure, 45, 155, 160 

family, 57 

FAO, 173 

fasting, 27, 37, 39, 87, 135, 139, 143, 144, 148, 153, 

157 

fat, 7, 9, 13, 23, 24, 28, 37, 39, 41, 42, 43, 44, 57, 66, 

67, 148, 151, 153, 160, 168, 173, 180 

fatigue, 9, 53, 78, 85, 100, 112, 118, 120, 141, 162 

fats, 19 

fatty acid, 41, 43, 44, 65, 75, 83, 84, 93, 126, 138, 

139, 147, 148, 160, 172 

February, 3, 9, 136 

feces, 44, 50, 71, 87, 94 

feeding, 32, 135, 146, 157, 160 

feet, 85, 92, 175 

females, 79, 156 

femoral bone, 171 

femur, 164 

ferritin, 76, 99, 100, 101, 102, 103, 106, 136, 154, 

161, 185 

fever, 44 

fiber, 14, 30, 40, 41, 100, 117, 123, 148 

fibers, 30, 81, 111, 140, 142 

fibrosis, 57 

film, 3 

Finland, 133 

fish, 44, 100, 126, 163 

fish oil, 44, 126, 163 

flavonoids, 123 

flavor, 8, 162 

flexor, 133, 156 

flood, 127 

flow, 46, 53 

flow rate, 46 

fluctuations, 37, 160 
Index 197

fluid, 21, 41, 44, 45, 46, 47, 50, 52, 102, 117, 141, 

143, 148, 149, 152, 153, 155, 159, 165 

fluoride, 14, 108, 109, 148, 151, 155, 158 

flushing, 75 

folate, 14, 71, 72, 73, 75, 76, 81, 82, 127, 135, 139, 

141, 142, 146, 147, 148, 164, 184, 189 

folic acid, 71, 73, 127, 149, 163, 164 

food, ix, 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 17, 19, 20, 21, 

22, 27, 28, 33, 36, 37, 39, 40, 46, 49, 52, 58, 59, 

62, 63, 64, 65, 69, 71, 73, 74, 75, 76, 77, 78, 80, 

81, 82, 83, 84, 85, 94, 96, 99, 100, 103, 106, 108, 

109, 111, 112, 115, 117, 123, 125, 129, 136, 137, 

146, 160, 164, 165, 168, 175, 179 

food intake, 1, 11, 36, 37, 49, 62, 168 

food products, 3, 71, 137 

food safety, 3 

Ford, 169 

forgetfulness, 72 

fortification, 134 

Fox, 143, 151 

fracture, 33, 59, 60, 68, 138, 148, 156 

fractures, 64, 138 

Framingham study, 104 

free radical, 65, 66, 67, 79, 103, 137, 138 

free radicals, 103, 137 

freeze-dried, 3, 7, 8, 9 

fructose, 37 

fruits, 62, 63 

fuel, 8, 25, 28, 43, 44, 46, 74 

fuel cell, 8 

funding, 9 

G

gait, 64 

gamma, 141 

gamma radiation, 137, 151, 163 

gamma rays, 78 

gamma-ray, 151 

gastric, 44, 82, 108, 113, 127 

gastric glands, 113 

gastritis, 82 

gastrointestinal, 21, 40, 44, 75, 78, 84, 85, 89, 97, 

100, 104, 112, 113, 127 

gastrointestinal tract, 44, 89, 104, 127 

gauge, 83, 100 

gender, 43, 74, 103, 145 

gender differences, 43, 74 

gene, 57, 151 

gene expression, 57 

generation, 9, 127, 130, 185 

genes, 141 

genetic abnormalities, 66 

Geneva, 173 

genotype, 145 

Germany, vii, 51, 141, 146, 155, 167, 175 

gland, 78, 113 

glossitis, 75 

glucagon, 115, 134 

gluconeogenesis, 106 

glucose, 37, 38, 39, 40, 75, 110, 114, 115, 125, 133, 

134, 140, 154, 155, 168, 170, 181, 182 

glucose metabolism, 115 

glucose tolerance, 39, 110, 114, 133, 155 

glucose tolerance test, 39, 133 

glutamate, 80, 126 

glutathione, 75, 76, 77, 111, 125, 136, 168, 189 

glutathione peroxidase, 75, 111, 189 

glycerol, 41 

glycine, 71 

glycogen, 19, 23, 37, 46, 80 

glycosaminoglycans, 50 

goiter, 113 

gold, 59 

Gore, 147 

government, 15 

grain, 148 

grapefruit, 4, 125, 126, 138, 149, 154, 179 

gravitational stress, 119 

gravity, 92, 99, 129, 133, 138, 139, 141, 146, 148, 

157, 166, 168, 170, 173, 174, 189 

ground-based, 1, 17, 19, 22, 25, 28, 30, 31, 40, 44, 

46, 50, 62, 91, 92, 98, 99, 103, 118, 119, 120, 

124, 133, 152, 165, 175 

groups, 35, 50, 60, 63, 65, 71, 87, 108, 181, 182 

growth, 24, 33, 41, 75, 82, 85, 109, 110, 113, 170, 

172 

growth hormone, 24, 170 

guidelines, 8, 60, 96, 117, 140 

gums, 40, 78 

gut, 40, 139 

H

H2, 143, 163 

habitat, 103, 129, 130, 185 

habitation, 9 

half-life, 74, 82 

handicapped, 147 

hands, 85 

harm, 36 

hazards, 114 

HDL, 42, 110, 182, 189 

headache, 57, 85 

healing, 133, 148 
198 Index 

health, 1, 3, 8, 17, 18, 28, 31, 33, 37, 44, 49, 51, 55, 

59, 64, 66, 69, 82, 84, 88, 93, 94, 104, 131, 136, 

140, 141, 143, 144, 146, 150, 152, 158, 159, 160, 

161, 162, 164, 169, 170, 171 

Health and Human Services, 140 

health status, 8 

hearing loss, 83 

heart, 44, 57, 74, 76, 78, 82, 84, 92, 100, 103, 109, 

111, 114, 134, 136, 145, 147, 155, 160, 164, 168 

heart disease, 44, 57, 103, 114, 134, 145, 147, 164, 

168 

heart failure, 155, 160 

heat, 3, 19, 44, 77, 78, 163, 171 

heating, 8, 27 

heavy metals, 111 

height, 26 

Helicobacter pylori, 127 

helmets, 117 

hematocrit, 101, 102 

hematologic, 153 

hematological, 85, 102 

hematopoiesis, 102 

heme, 100 

hemochromatosis, 115 

hemodynamic, 44, 134 

hemodynamic effect, 134 

hemoglobin, 99, 101, 102 

hemolytic anemia, 66 

hepatotoxicity, 75, 154 

herbs, 126, 138 

high-density lipoprotein, 42, 110, 182, 189 

high-frequency, 163 

high-risk, 60, 62, 64 

hip, 138, 152, 156 

hip fracture, 138, 156 

histamine, 143 

histidine, 71 

histological, 156 

histology, 173 

homeostasis, 28, 43, 44, 45, 49, 50, 52, 90, 94, 101, 

108, 115, 136, 138, 143, 150, 152, 158, 160, 163, 

167, 173 

homocysteine, 71, 72, 81, 82, 83 

Hong Kong, 147 

hormonal control, 47 

hormone, 24, 31, 36, 50, 60, 62, 65, 80, 89, 90, 93, 

97, 109, 114, 134, 136, 145, 149, 154, 170, 183, 

184, 190 

hormones, 29, 44, 77, 113, 115, 171 

hospitalized, 161 

host, 84, 109 

HRP, ix, 189 

human, ix, 1, 3, 19, 28, 37, 41, 45, 51, 65, 66, 73, 74, 

79, 83, 92, 94, 100, 104, 109, 113, 114, 116, 119, 

120, 129, 134, 137, 138, 139, 140, 141, 142, 143, 

144, 145, 146, 147, 150, 151, 155, 157, 159, 160, 

161, 166, 167, 168, 170, 173, 174, 175 

human subjects, 1, 170 

humans, 1, 22, 32, 41, 52, 66, 71, 82, 87, 90, 96, 100, 

107, 108, 119, 123, 125, 129, 134, 138, 139, 140, 

143, 149, 150, 154, 157, 159, 163, 165, 166, 167, 

168, 171, 174 

hydration, 45, 46, 108, 168 

hydride, 74 

hydrogen, 41, 50, 76, 111 

hydrogen bonds, 41 

hydrogen peroxide, 76, 111 

hydrolases, 106 

hydrolysis, 125 

hydrolyzed, 76 

hydroxide, 94 

hydroxyapatite, 87 

hydroxyl, 159 

hydroxylation, 163 

hydroxyproline, 51, 88, 90, 91, 144, 150 

hyperaldosteronism, 47 

hyperbaric oxygen therapy, 134 

hypercalcemia, 65, 88, 95, 156 

hypercalciuria, 33, 51, 93, 95, 136, 167 

hyperglycemia, 115 

hyperhomocysteinemia, 80 

hyperinsulinemia, 114 

hyperkalemia, 53, 160 

hypernatremia, 52 

hyperparathyroidism, 141 

hyperphosphatemia, 94, 96 

hypertension, 52, 127, 140 

hypertrophy, 168 

hypokalemia, 53 

hypokinesia, 24, 137, 144, 145, 170, 174 

hyponatremia, 52 

hypophosphatemia, 94 

hypotension, 52, 170 

hypothesis, 21, 33, 45, 91, 101, 102, 136, 142, 159 

hypothyroidism, 113 

hypoxia, 151 

I

ice, 133 

identical twins, 34, 166, 174 

identification, 89, 141, 145 

idiopathic, 136, 164, 169 

imaging, 32, 190 

immersion, 144 
Index 199

immigrants, 141 

immobilization, 140, 156, 167 

immune function, 78, 100, 104, 106, 110, 112 

immune response, 28, 62, 110, 139 

immune system, 23, 47, 100, 106, 111, 168, 169 

immunity, 57, 109, 157, 164 

immunoassays, 89 

immunological, 85 

impaired glucose tolerance, 114 

impaired immune function, 112 

in situ, 51, 58, 100, 124 

in vitro, 151 

in vivo, 155 

inactivation, 126, 138 

inactive, 126 

incidence, 40, 77, 78, 103, 144, 146 

inclusion, 11 

incubators, 119 

Indian, 144 

indicators, 120, 157 

indices, 91, 156 

induction, 111, 141, 170 

industry, 163 

infants, 84, 104, 119, 150, 160 

infarction, 103, 127, 163 

infection, 57, 100 

infections, 64 

inflammation, 100, 136, 138, 161 

inflammatory, 28, 100, 103 

inflammatory response, 100 

ingestion, 22, 126, 134 

inhibition, 51, 94, 112 

inhibitor, 33 

inhibitors, 125, 126, 127, 163 

inhibitory, 157 

initiation, 127, 139 

injection, 32 

injury, 91, 92, 103, 119, 149, 153, 157, 164, 169 

insight, 88 

insomnia, 85 

instability, 135 

insulin, 24, 37, 38, 39, 40, 43, 68, 85, 109, 110, 114, 

115, 134, 136, 155, 167, 168, 170, 173, 181, 182 

insulin resistance, 39, 40, 68, 114, 115, 167, 168, 

173 

insulin sensitivity, 68, 168 

integrity, 96, 108, 109 

interaction, 24, 27, 52, 58, 84, 100, 124, 145, 175, 

180 

interactions, 51, 84, 96, 109, 120, 124, 125, 127, 

143, 149, 154, 164, 170 

interference, 112 

internalization, 114 

International Space Station, 1, 5, 8, 9, 10, 13, 26, 61, 

62, 63, 68, 72, 76, 98, 105, 157, 166, 169, 175, 

176, 179, 180, 183, 184, 185, 187, 189 

interstitial, 45 

intervention, 125 

intestine, 59, 84, 109, 110 

intoxication, 46 

intravascular, 45 

intravenous, 136, 160 

invasive, 110 

inversion, 143 

iodine, 14, 111, 113, 114, 142, 157, 163, 174, 185 

ionic, 113 

ionizing radiation, 73, 79, 103, 120, 139, 170 

ions, 74, 103, 108 

Irish Republican Army, 27 

iron, 8, 13, 15, 73, 76, 79, 99, 100, 101, 102, 103, 

104, 106, 107, 114, 115, 125, 134, 136, 139, 142, 

150, 151, 154, 156, 161, 163, 164, 165, 166, 168, 

169, 175, 185 

iron deficiency, 100, 103, 142, 154, 165 

irradiated foods, 78 

irradiation, 64, 77, 78, 138, 141, 143, 151, 161 

irritability, 72 

irritation, 108 

ischemic heart disease, 168 

isoforms, 83 

isolation, 63 

isomerization, 81, 126 

isoniazid, 126 

isotope, 173 

isotopes, 30 

isozymes, 162 

ISS, 8, 9, 10, 11, 13, 14, 17, 20, 21, 22, 23, 28, 42, 

43, 49, 52, 54, 58, 61, 62, 64, 66, 68, 69, 72, 73, 

74, 75, 77, 78, 81, 82, 85, 93, 95, 96, 99, 102, 

105, 106, 110, 113, 117, 118, 119, 120, 123, 129, 

157, 175, 179, 180, 182, 183, 184, 185, 189 

J

JAMA, 142, 151, 153 

Japan, 63 

Japanese, 11, 13, 63, 173 

joints, 111 

Jun, 133, 136, 137, 140, 141, 144, 145, 148, 149, 

152, 154, 155, 157, 158, 159, 160, 161, 162, 164, 

165, 166, 170, 171, 172, 173 

justification, 173 
200 Index 

K

K+, 33 

ketones, 28, 39 

kidney, 46, 50, 59, 60, 74, 88, 94, 96, 104, 114, 133, 

137, 140, 143, 146, 163 

kidney stones, 88 

kidneys, 76, 78, 82, 107, 109 

kinase, 114 

kinases, 106 

kinetic studies, 90 

kinetics, 32, 90, 100, 166, 167 

King, 150, 171 

Krebs cycle, 75 

L

lactose, 37 

latency, 60 

LDL, 42, 43, 182, 190 

lean body mass, 24, 27, 54, 136, 151, 180, 190 

learning, 67 

left ventricle, 52 

leg, 29, 30, 32, 173 

leptin, 24, 43, 134, 167 

lesions, 41 

leucine, 32, 81, 157 

leukocytes, 78, 104, 139 

life sciences, 15, 152 

life-threatening, 64, 68 

likelihood, 40, 44, 65, 119, 127 

limitations, 7 

linear, 41, 67, 80, 85, 119 

linkage, 40 

links, 144, 164 

linoleic acid, 41 

linolenic acid, 41 

lipid, 42, 65, 66, 77, 84, 99, 104, 106, 107, 114, 119, 

120, 126, 147, 149, 150, 151, 162, 174 

lipid metabolism, 99, 104, 114 

lipid oxidation, 77 

lipid peroxidation, 65, 66, 106, 107, 119, 120, 126, 

150, 151 

lipids, 103, 104, 126, 155 

lipoprotein, 42, 43, 110, 149, 182, 189, 190 

liver, 19, 37, 57, 58, 59, 67, 71, 74, 75, 76, 78, 80, 

82, 84, 104, 107, 109, 114, 127, 139, 147, 153, 

154, 155, 161, 163, 167, 170, 174 

liver damage, 104 

liver disease, 107, 161 

loading, 45, 50, 156 

logistics, 11, 58 

long period, 9, 75 

longitudinal study, 140 

loss of appetite, 57 

losses, 22, 29, 32, 44, 88, 109, 134, 148, 172 

low-density lipoprotein, 42, 43, 182, 190 

low-level, 170 

lumbar spine, 135 

lumen, 50 

lung, 59, 109, 144, 169, 172 

lung cancer, 144 

lungs, 78 

lymphocytes, 66, 139, 151, 170 

lysine, 80 

M

macromolecules, 29 

macronutrients, 14, 19, 126, 148 

magnesium, 15, 94, 96, 97, 98, 99, 148, 158, 161, 

164, 173, 184 

magnetic resonance imaging, 32, 190 

maintenance, 20, 22, 32, 44, 47, 100, 111 

malabsorption, 66, 82, 87, 127 

males, 63, 79, 151 

malignancy, 135 

malnutrition, 66, 104, 123, 143 

malondialdehyde (MDA), 119, 120, 141, 154, 190 

mammals, 159 

management, ix, 142 

manganese, 14, 106, 107, 108, 142, 143, 158, 161 

manipulation, 168 

marrow, 59, 71, 100, 141, 168 

Mars, 1, 63, 79, 129 

Martian, 130, 185 

mass loss, 20, 22, 23 

matrix, 67, 104 

maturation, 104 

meals, 8, 73, 131 

measurement, 22, 42, 43, 59, 91, 142, 147, 165, 180, 

182 

measures, 32, 150 

meat, 33, 100 

mechanical properties, 161 

mechanical stress, 30 

medical care, 125 

medications, 125, 127 

medicine, 141, 151, 158, 165, 166 

membranes, 47, 57, 66, 87, 94, 109 

memory loss, 100 

men, 14, 26, 33, 36, 40, 43, 46, 52, 54, 58, 66, 69, 

74, 75, 77, 79, 82, 84, 85, 88, 93, 96, 99, 103, 

106, 107, 109, 111, 112, 114, 115, 134, 137, 138, 

140, 154, 155, 156, 163, 168, 171, 173 
Index 201

menopause, 51 

menstruation, 109 

mental retardation, 113 

Mercury, 3, 4, 111, 157, 179 

messengers, 94 

meta-analysis, 36, 158 

metabolic, 4, 20, 23, 25, 27, 30, 31, 34, 40, 44, 53, 

74, 75, 76, 81, 83, 84, 85, 87, 110, 117, 135, 140, 

143, 153, 170, 171, 172, 173 

metabolic acidosis, 34, 53, 143 

metabolic changes, 153, 173 

metabolic pathways, 76 

metabolic rate, 20, 25, 27, 44, 110, 171 

metabolism, 1, 23, 25, 30, 31, 34, 37, 40, 44, 46, 51, 

52, 59, 62, 63, 64, 65, 68, 71, 72, 73, 75, 77, 81, 

82, 83, 84, 89, 91, 93, 94, 98, 99, 100, 102, 104, 

106, 108, 109, 111, 112, 114, 115, 123, 125, 126, 

129, 133, 134, 136, 137, 139, 140, 141, 142, 143, 

144, 145, 146, 151, 153, 154, 155, 157, 158, 159, 

162, 163, 164, 165, 166, 167, 172, 173, 174, 175 

metabolite, 30, 166 

metabolites, 31, 82, 83, 163 

metabolizing, 127 

metallic taste, 110 

metals, 17, 79, 109, 110, 111, 137 

methionine, 34, 71, 80, 81, 164 

mice, 120, 141, 148 

microbial, 84 

microflora, 41, 69 

microgravity, 19, 21, 29, 37, 47, 67, 104, 129, 131, 

134, 138, 139, 140, 141, 142, 143, 144, 146, 150, 

155, 159, 161, 162, 163, 167, 168, 170, 171, 173 

micronutrients, 136 

middle-aged, 152, 170, 173 

military, 27, 39, 160 

milk, 84, 104, 135 

mineral water, 137 

mineralization, 94 

mineralized, 108 

minerals, 14, 17, 27, 107, 126, 168 

Minnesota, 14, 47, 150 

missions, 1, 5, 6, 7, 8, 9, 11, 13, 15, 17, 19, 21, 22, 

26, 27, 28, 29, 31, 36, 39, 40, 43, 45, 46, 49, 60, 

61, 62, 65, 67, 68, 69, 73, 75, 79, 81, 82, 88, 91, 

93, 94, 101, 103, 105, 111, 113, 114, 116, 117, 

120, 123, 125, 128, 129, 131, 138, 146, 153, 157, 

164, 165, 175, 179, 185, 187 

mitochondria, 84, 107 

mitochondrial, 126 

mitral valve, 53 

mobility, 151 

models, 22, 32, 44, 62, 63, 73, 77, 92, 102, 103, 124, 

125, 133, 136, 146, 152, 160, 162, 167, 171, 172, 

175 

modulation, 165 

mole, 190 

molecules, 29, 74, 120 

molybdenum, 143, 158 

monkeys, 168 

monoamine oxidase inhibitors, 125, 127 

monocytes, 59 

monosaccharides, 37 

monosodium glutamate, 126 

moon, 1, 3, 129, 157 

morbidity, 145, 165 

mortality, 140, 144, 145, 152, 165 

mortality rate, 144 

Moscow, 135 

motion, 21, 140, 146, 151 

motion sickness, 21, 146, 151 

mouth, 21, 40 

MRI, 107, 172, 190 

mRNA, 50, 101, 136, 155 

mucosa, 127 

multi-ethnic, 136 

multiple factors, 21 

multiple sclerosis, 59, 64, 166 

muscle, 1, 17, 19, 23, 28, 29, 30, 31, 32, 34, 36, 37, 

39, 44, 52, 53, 59, 64, 66, 74, 78, 80, 81, 87, 91, 

94, 96, 109, 111, 114, 115, 120, 133, 135, 136, 

137, 139, 140, 142, 153, 159, 160, 164, 167, 168, 

169, 172, 173, 174 

muscle atrophy, 33, 44, 66, 120, 135, 136 

muscle contraction, 87 

muscle mass, 29, 31, 32, 39, 137 

muscle performance, 173 

muscle strength, 31, 32, 173 

muscle tissue, 20, 30, 80, 81 

muscle weakness, 53, 74, 94, 96 

muscles, 30, 82, 145, 151 

musculoskeletal, 32, 51, 54, 87, 92, 99, 163, 172, 

175 

musculoskeletal system, 87 

Muslim, 63, 64 

myoblasts, 165 

myocardial infarction, 103, 127, 163 

myoglobin, 99 

N

NaCl, 50, 144, 182 

NAD, 74, 75, 190 

NADH, 75, 77 

naringin, 125 
202 Index 

NASA, vii, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14, 17, 103, 

114, 118, 123, 129, 130, 145, 148, 149, 152, 153, 

156, 157, 158, 160, 161, 165, 166, 169, 171, 172, 

175, 179, 180, 185, 190 

National Academy of Sciences, 114 

National Aeronautics and Space Administration, ix, 

3, 148, 149, 152, 153, 157, 158, 161, 165, 169, 

172, 190 

National Research Council, 158 

natural, 123, 152 

natural food, 123 

nausea, 57, 110 

necrosis, 111 

negative consequences, 36, 52 

nephrocalcinosis, 65 

nerve, 52, 66, 74, 76 

nervous system, 82, 104, 136 

Netherlands, 140 

neural function, 73 

neurodegenerative, 72 

neuroendocrine, 104 

neurological disorder, 66, 81 

neuropathy, 80, 81, 143 

neuropeptides, 104 

neurotoxicity, 72 

neurotransmitter, 82 

neurotransmitters, 72, 77 

neutrophils, 104 

New York, 133, 136, 138, 145, 146, 147, 149, 155, 

157, 161, 166 

niacin, 14, 74, 75, 76, 142, 148, 168, 190 

nickel, 143 

nicotinamide, 73, 74, 75, 77, 190 

nicotinic acid, 74, 75, 114 

Nielsen, 156 

nitric oxide, 127 

nitrogen, 29, 32, 77, 151, 167, 172 

nitroso compounds, 127 

non-uniform, 105 

norepinephrine, 127 

normal, 11, 43, 44, 47, 57, 59, 60, 62, 88, 98, 100, 

102, 104, 106, 137, 138, 140, 150, 154, 164, 173 

normal conditions, 88 

NTE, 13, 14, 190 

nuclear receptors, 64 

nuclei, 59 

nucleic acid, 29 

nutrient, 1, 13, 15, 17, 23, 27, 31, 72, 77, 84, 85, 96, 

107, 109, 123, 125, 126, 127, 129, 131, 143, 163, 

187 

nutrients, 1, 15, 17, 18, 19, 28, 33, 39, 40, 41, 44, 57, 

71, 73, 80, 93, 106, 111, 117, 123, 125, 126, 127, 

129, 131, 136, 142, 145, 160, 171, 172, 175 

nutrition, ix, 1, 17, 18, 23, 24, 31, 41, 52, 92, 93, 

104, 106, 116, 117, 118, 129, 131, 133, 134, 135, 

136, 137, 138, 139, 141, 142, 144, 145, 146, 147, 

148, 149, 150, 152, 156, 158, 159, 161, 162, 163, 

164, 166, 167, 168, 169, 170, 171, 172, 173, 174, 

175, 180 

nutritional supplements, 123, 134 

nuts, 7 

O

obese, 148 

obesity, 44 

observations, 53, 137, 138, 143, 152, 164, 172 

oil, 147, 163 

oils, 44, 126 

older adults, 136, 145 

olfaction, 21 

oligosaccharides, 37 

omega-3, 41, 93 

omeprazole, 126 

onion, 78 

online, 166, 174 

optimal health, 31, 37 

oral, 123, 138, 147, 154, 172 

orbit, 5, 6, 8, 21, 32, 40, 92, 179 

organ, 119 

organic, 83, 111 

organic peroxides, 111 

ornithine, 83, 155 

orthostatic hypotension, 170 

orthostatic intolerance, 45, 148 

os calcis, 88 

osmolality, 44 

osmotic, 47, 50 

osmotic pressure, 47 

osteoarthropathy, 111 

osteoblasts, 108 

osteocalcin, 67, 68, 90, 137 

osteomalacia, 60, 64, 96, 126, 144, 160, 164 

osteoporosis, 64, 88, 92, 108, 139, 141, 145, 147, 

148, 149, 152, 154, 156, 158, 162, 163, 172 

ovaries, 113 

ovary, 59 

overload, 73, 100, 101, 103, 144, 161 

oxalate, 33, 51, 164 

oxidants, 162 

oxidation, 24, 41, 43, 74, 77, 109, 125, 138, 145, 180 

oxidation products, 77 

oxidative, 17, 28, 75, 76, 79, 99, 100, 103, 104, 107, 

112, 118, 119, 120, 121, 123, 133, 134, 144, 147, 

164, 167, 168, 169, 171, 175 
Index 203

oxidative damage, 17, 76, 79, 100, 103, 104, 118, 

119, 120, 121, 123, 133, 169, 175 

oxidative stress, 75, 79, 107, 112, 119, 121, 134, 

164, 167, 168 

oxide, 127, 169 

oxygen, 18, 24, 73, 76, 77, 78, 80, 99, 102, 103, 104, 

118, 119, 120, 134, 138, 139, 141, 150, 154, 157, 

160, 163, 190 

oxygen consumption, 24 

oxygenation, 162 

P

packaging, 3, 5, 9, 129, 175 

packets, 4, 179 

pain, 64, 94, 108, 110, 141 

palpitations, 100 

pamidronate, 162, 171 

pancreas, 78, 107, 114 

pancreatic, 111, 114, 172 

pancreatic cancer, 172 

pantothenic acid, 84, 85, 142, 143, 148 

paralysis, 53, 172 

parathyroid, 36, 50, 60, 62, 65, 90, 93, 97, 134, 136, 

144, 149, 164, 183, 184, 190 

parathyroid glands, 164 

parathyroid hormone, 36, 50, 60, 62, 65, 90, 93, 97, 

134, 136, 149, 183, 184, 190 

parenteral, 41, 104, 137, 139 

Paris, 158 

parsley, 78 

particles, 120 

pathology, 147 

pathophysiology, 133, 150 

pathways, 59, 76, 101, 107, 151, 169 

patients, 1, 30, 50, 92, 100, 104, 107, 134, 136, 139, 

141, 147, 155, 156, 160, 161, 164, 166, 170, 172 

PC12 cells, 120, 168 

pears, 4, 179 

pectin, 44, 163 

pectins, 40 

pellagra, 75 

pentane, 119, 137, 150, 154, 157 

peptide, 39 

perception, 21 

pericardial, 155 

periodic, 19 

peripheral nerve, 76 

pernicious anemia, 82 

peroxidation, 65, 66, 104, 106, 107, 119, 121, 126, 

150, 151, 162, 174 

peroxide, 76, 111 

personal communication, 24 

phagocytic, 94 

pharmaceuticals, 124 

pharmacodynamics, 154 

pharmacokinetics, 154 

pharmacological, 84, 91, 94, 127, 131, 142, 145, 155 

Philadelphia, 151, 156, 158, 160, 169 

phlebotomy, 100, 156 

phosphate, 33, 51, 73, 74, 77, 80, 93, 94, 95, 96, 100, 

127, 145, 147, 148, 184, 190 

phosphoenolpyruvate, 83, 139 

phospholipids, 41, 66 

phosphorus, 59, 93, 94, 95, 96, 107, 148, 154, 158, 

161, 184 

phosphorylation, 99 

photodegradation, 135 

physical exercise, 92 

physicians, 172 

physiological, 1, 17, 28, 29, 30, 52, 67, 100, 110, 

119, 133, 134, 142, 145, 146, 151, 160, 170, 172, 

175 

physiological factors, 110 

physiology, 24, 129, 133, 147, 151, 152, 157, 158, 

160, 175, 180 

phytates, 111 

pilots, 158 

pituitary, 78, 167, 168 

placebo, 35, 65, 181 

placenta, 59, 113 

planetary, 19, 28, 93, 117, 136 

planning, 94, 129, 175 

plantar, 133 

plants, 37, 67, 129 

plaques, 44 

plasma, 30, 31, 39, 40, 41, 42, 45, 47, 48, 65, 66, 75, 

78, 80, 84, 87, 93, 97, 98, 100, 101, 102, 109, 

110, 119, 121, 139, 141, 142, 149, 157, 170 

plasma levels, 93 

plasma membrane, 109 

plasma proteins, 31 

plastic, 7 

platelets, 66 

platforms, 175 

play, 37, 45, 59, 71, 76, 107, 111, 114, 116 

PLP, 80, 190 

polymers, 155 

polyphenols, 100, 111 

polysaccharides, 37, 40 

polyunsaturated fatty acid, 41, 65, 126, 139, 172 

polyuria, 47 

pools, 78, 82, 111, 139 

population, 34, 36, 77, 79, 87, 92, 136, 138, 143, 

159, 173 

population group, 87 
204 Index 

pork, 143 

positive correlation, 34 

postmenopausal, 51, 140, 141, 145, 149, 154, 155, 

162, 163 

postmenopausal women, 51, 140, 141, 145, 154, 155 

potassium, 33, 34, 52, 53, 54, 55, 78, 93, 96, 99, 138, 

143, 145, 148, 149, 152, 155, 161, 166, 173, 174, 

181, 183 

poultry, 100 

power, 7, 8, 9, 134 

precipitation, 111 

prediction, 20 

predictors, 51 

preference, 8, 11 

pregnant women, 157 

premature infant, 119 

premenopausal, 51, 141, 158 

premenopausal women, 51, 158 

pressure, 45, 47, 52, 72, 76, 103, 118, 136, 148, 166, 

174 

prevention, 43, 44, 106, 136, 138, 145, 147, 150, 

152, 158, 169, 170 

probability, 190 

production, 5, 39, 41, 60, 69, 85, 104, 170, 173 

productivity, 39 

program, 3, 7, 8, 9, 11, 13, 19, 20, 64, 137, 149 

pro-oxidant, 79, 109 

propranolol, 141 

propulsion, 129 

prostaglandin, 30, 120, 155 

prostate, 59, 133, 137, 138, 145, 157, 170 

prostate cancer, 133, 137, 138, 157, 170 

protection, 76, 77, 143, 165 

protein, 13, 14, 23, 24, 29, 30, 31, 32, 33, 34, 36, 37, 

39, 45, 55, 58, 66, 67, 75, 83, 84, 93, 94, 104, 

109, 112, 125, 126, 127, 134, 135, 137, 140, 141, 

142, 145, 146, 148, 149, 150, 151, 153, 154, 157, 

159, 160, 165, 166, 167, 168, 170, 171, 172, 173, 

174, 180, 181, 183 

protein synthesis, 23, 30, 109, 112, 142, 160, 165, 

167, 168 

proteins, 19, 31, 67, 75, 83, 87, 100, 103, 120, 127 

proteolysis, 27, 32, 66, 142, 164, 172 

prothrombin, 67 

protocol, 117, 119, 156 

protocols, ix, 32, 144 

proton pump inhibitors, 125, 127 

proxy, 39 

psychological well-being, 123 

psychophysiology, 123 

public health, 146 

purines, 33 

pyridoxal, 80, 190 

pyridoxamine, 80, 190 

pyridoxine, 80, 190 

pyrimidine, 71 

pyrophosphate, 73 

pyruvate, 73, 80, 83, 107 

Q

quantum, 160 

quartz, 60 

quinine, 65 

quinone, 78 

R

race, 107 

racemization, 80 

radiation, 1, 18, 21, 41, 44, 60, 62, 63, 64, 67, 71, 73, 

74, 76, 79, 80, 81, 85, 103, 104, 106, 119, 120, 

123, 129, 135, 137, 139, 140, 141, 144, 148, 149, 

150, 151, 154, 157, 160, 162, 163, 169, 170 

radiation damage, 67 

radical formation, 79 

radius, 92 

range, 25, 27, 36, 39, 43, 57, 60, 63, 74, 76, 83, 87, 

106, 107, 125 

rash, 107 

rat, 120, 139, 147, 148, 151, 152, 154, 155, 157, 163, 

168 

rats, 110, 111, 113, 134, 138, 139, 144, 157, 161, 

165, 167, 171 

RDA, 15, 43, 72, 75, 78, 79, 82, 84, 85, 96, 99, 103, 

190 

reactive nitrogen, 77 

reactive oxygen species, 73, 77, 119, 120, 139, 141, 

163, 190 

ready to eat, 4, 179 

receptors, 47, 59, 64, 100, 147, 151 

recovery, 31, 91, 93, 94, 102, 153, 164 

recycling, 66, 129 

red blood cell, 37, 71, 72, 80, 100, 101, 103, 106, 

133, 151, 170, 190 

red wine, 126, 138, 161 

redox, 74, 76, 79, 100 

redox-active, 79 

regenerate, 77 

regeneration, 66 

regional, 107, 140 

regulation, 37, 52, 66, 93, 104, 107, 109, 114, 133, 

139, 141, 149, 151, 153, 162 

rehydration, 8, 27 

relapse, 166 
Index 205

relationship, 34, 43, 50, 55, 59, 62, 68, 82, 94, 100, 

104, 112, 126, 144, 158, 181 

relationships, 34, 40, 148, 164, 167, 175 

relaxation, 52 

relaxation time, 53 

relevance, 141 

reliability, 69, 110 

remodeling, 108, 145 

remodelling, 160 

renal, 17, 33, 36, 37, 39, 46, 47, 49, 50, 51, 52, 65, 

87, 88, 90, 99, 112, 115, 137, 140, 141, 146, 147, 

159, 160, 169, 171, 172, 173 

renal disease, 160 

renal failure, 87, 115 

renal function, 46 

repair, 111, 121, 134, 161 

replication, 109 

reproduction, 57 

Republican, 27 

research and development, 175 

reserves, 29, 173 

reservoir, 33 

resistance, 39, 40, 68, 97, 114, 115, 133, 149, 167, 

168, 173 

resistive, 30, 32, 159, 161, 162 

resolution, 89 

resources, 27, 94 

respiration, 74 

respiratory, 115 

responsiveness, 136 

retardation, 75, 85, 113 

reticulum, 120 

retinoic acid, 126, 138, 162 

retinoids, 159, 162 

retinol, 14, 57, 58, 126, 138, 144, 156, 162, 183, 190 

retinol-binding protein, 58, 183 

retinopathy, 66 

returns, 101 

rhabdomyolysis, 115 

riboflavin, 76, 77, 135, 142, 147, 148, 151 

ribonucleic acid, 190 

ribose, 75 

rickets, 60, 64, 94 

risk, 1, 3, 17, 22, 33, 36, 37, 39, 41, 43, 44, 46, 51, 

52, 57, 58, 59, 60, 62, 64, 68, 84, 85, 88, 90, 99, 

103, 112, 113, 114, 118, 119, 123, 131, 133, 134, 

138, 139, 140, 141, 142, 145, 146, 148, 149, 150, 

155, 156, 157, 160, 163, 164, 169, 170, 171, 172, 

173 

risk assessment, 142, 172 

risk factors, 139, 140, 141, 169, 172 

risks, 17, 18, 36, 44, 66, 67, 75, 131, 157 

RNA, 109, 190 

rodent, 32 

ROS, 120, 190 

Russia, 5, 6, 58, 98, 179 

Russian, 1, 9, 10, 11, 13, 21, 22, 39, 58, 61, 64, 98, 

105, 107, 121, 190 

S

safety, 3, 67, 92, 93, 163, 171 

saline, 148, 170 

saliva, 78 

salt, 21, 33, 45, 50, 51, 134, 139, 140, 143, 144, 145, 

155, 163 

sample, 10, 34, 58 

saturation, 51, 72, 76, 100, 118, 120, 140, 166 

savings, 7 

scaling, 107 

scientific knowledge, ix 

sclerosis, 59, 64, 166 

scores, 10 

scurvy, 1, 77, 78 

search, 76 

seasonal affective disorder, 144 

secondary radiation, 120 

secrete, 120 

secretion, 30, 36, 40, 87, 89, 114, 167 

seizures, 97 

selenium, 14, 104, 111, 112, 148, 170 

self, 164 

SEM, 50, 183, 190 

senile, 162 

sensitivity, 21, 39, 68, 73, 85, 113, 114, 135, 137, 

162, 168 

sepsis, 44 

series, ix, 45, 50 

serine, 71 

serotonin, 80, 81 

serum, 43, 44, 50, 58, 60, 61, 62, 63, 68, 71, 81, 83, 

87, 90, 94, 97, 100, 103, 104, 105, 106, 107, 110, 

112, 133, 134, 136, 140, 142, 150, 151, 154, 155, 

158, 159, 161, 173, 182 

serum ferritin, 100, 103, 106, 136, 154 

serum transferrin, 100, 142, 151 

shipping, 175 

short-term, 30, 134, 152, 153, 154 

side effects, 108, 113, 175 

sign, 68 

signaling, 104 

signals, 107 

signs, 63, 83, 95, 97, 108 

silicon, 143 

simulation, 135, 146, 162 

sites, 32, 58, 88, 107, 109 
206 Index 

skeletal muscle, 31, 37, 74, 109, 115, 120, 135, 140, 

142, 159, 169, 172 

skeleton, 88, 108, 157, 161 

skin, 41, 44, 50, 59, 60, 63, 109, 113, 115, 147 

sleep, 25, 107 

sleep disorders, 107 

smoke, 126 

smoking, 124 

SOD, 120, 159, 190 

sodium, 7, 8, 9, 13, 45, 47, 48, 49, 50, 51, 52, 53, 54, 

93, 94, 136, 137, 138, 140, 141, 143, 144, 145, 

146, 148, 150, 154, 155, 156, 158, 161, 164, 175, 

182 

solar, 8, 144 

soleus, 164 

solvent, 44, 50 

sounds, 28 

soy, 33, 149 

Soyuz, 5, 6, 22, 39, 133, 179, 189 

space environment, 3, 119, 129 

space exploration, 5, 147, 158 

space shuttle, 137, 167 

space station, 1, 4, 5, 9, 13, 19, 20, 61, 93, 98, 133, 

166, 173, 179 

species, 73, 77, 119, 120, 139, 141, 163, 190 

spectroscopy, 120 

spectrum, 144, 170 

speculation, 112 

speed, 27 

spices, 78, 138 

spin, 120 

spinal cord, 91, 92, 157, 164 

spinal cord injury, 91, 92, 157, 164 

spine, 135, 152, 158 

spleen, 78, 82, 114 

St. Louis, 150, 163 

stability, 59, 65, 67, 69, 73, 74, 75, 76, 77, 78, 80, 

81, 83, 85, 124, 129 

stabilize, 91 

stages, 65 

standard deviation, 79, 190 

standard error, 190 

Standards, 117, 158 

starch, 37 

starvation, 20, 27, 29, 47, 87, 111, 150, 172 

sternum, 98, 105 

steroid, 75, 77, 80 

Steroid, 143 

steroid hormone, 77, 80 

steroid hormones, 77 

steroids, 80 

stomach, 22, 59, 73, 127 

storage, 27, 37, 46, 67, 71, 73, 74, 77, 78, 79, 85, 99, 

100, 101, 103, 104, 127, 163 

strain, 102 

strains, 31 

strategies, 139, 149 

strawberries, 4, 179 

strength, 27, 31, 32, 133, 137, 145, 173 

stress, 21, 25, 27, 28, 30, 31, 44, 58, 59, 67, 75, 77, 

79, 80, 106, 107, 112, 115, 119, 121, 134, 141, 

155, 160, 164, 166, 167, 168 

stress level, 31 

stressors, 79, 124 

stroke, 127 

strontium, 174 

subgroups, 87 

submarines, 62 

substances, 41, 123 

substrates, 19, 57, 125, 145 

sucrose, 34, 37 

sugar, 37, 39 

sugars, 39, 73 

sulfate, 148 

sulfur, 33, 34, 37, 76, 112, 125, 149 

sulfuric acid, 33, 34 

summer, 6, 62, 63, 157, 179 

Sun, 143, 144 

sunlight, 59, 60, 62, 63, 64, 126, 144, 148, 173 

superoxide, 106, 120, 190 

superoxide dismutase, 120, 190 

supplemental, 53, 64, 65, 66, 67, 110, 147 

supplements, 13, 61, 64, 65, 67, 71, 97, 112, 123, 

126, 134, 144, 155, 168, 174 

supply, 1, 37, 39, 59, 74, 76, 77, 80, 81, 83, 84, 100, 

109, 110, 146 

suppression, 60, 110 

surface area, 109 

surgical, 134, 170 

survivability, 27, 28 

survival, 20, 27, 159, 160 

sweat, 44, 47 

Switzerland, 173 

symptoms, 41, 47, 74, 75, 78, 83, 85, 104, 107, 111, 

113, 115, 147 

synapses, 127 

syndrome, 8, 154, 161, 168 

synthesis, 23, 30, 32, 37, 41, 60, 67, 71, 73, 80, 81, 

84, 100, 101, 104, 106, 109, 112, 142, 160, 165, 

167, 168, 181, 183 

T

target organs, 59 

target population, 92 
Index 207

taste, 21, 110, 137, 151 

tea, 100 140 

team members, 173 

television, 25, 181 

tendon, 161 

tension, 120 

term plans, 129 

testis, 59 

testosterone, 32, 92, 168, 171, 173 

testosterone production, 173 

Texas, vii, 175, 177 

therapeutics, 145, 155 

therapy, 47, 93, 94, 95, 127, 134, 137, 138, 142, 145, 

157, 160 

thiamin, 73, 74, 127, 142, 148 

threatening, 64, 68 

threshold, 21, 149 

thymus, 59 

thyroid, 31, 113, 156, 157, 171 

thyroid cancer, 113 

thyroid gland, 113 

thyroiditis, 113 

tiger, ix 

timing, 36 

tissue, 19, 22, 23, 27, 28, 30, 36, 41, 59, 65, 66, 74, 

78, 79, 80, 81, 88, 96, 99, 100, 103, 104, 106, 

108, 109, 111, 153, 154, 159, 165 

tocopherols, 65, 168 

Tokyo, 135, 143, 149 

tolerance, 24, 39, 110, 114, 115, 133, 142, 155 

torque, 156 

total body irradiation, 141 

total energy, 24, 25, 26, 29, 36, 39, 43, 181, 190 

total parenteral nutrition, 41, 104, 137 

toxic, 75, 100, 107, 113, 115, 119, 124, 149 

toxic effect, 75 

toxic side effect, 113 

toxicity, 53, 57, 73, 74, 75, 82, 83, 97, 100, 103, 107, 

110, 112, 113, 114, 126, 137, 142, 154, 169, 171 

trabecular bone, 67, 147, 152 

trace elements, 158, 171 

training, 133, 137, 144, 158, 168, 171, 173 

transcriptional, 151 

transfer, 11, 41, 67, 80, 84, 85, 96, 119 

transferrin, 99, 100, 101, 103, 114, 135, 139, 142, 

147, 150, 151, 161, 165, 169 

transmission, 52, 74, 87 

transport, 50, 52, 75, 99, 100, 104, 114, 149 

transportation, 44 

traps, 113 

trauma, 111, 115, 151 

travel, 1, 17, 63, 115, 123, 131, 136 

triacylglycerols, 41 

trial, 63, 65, 155, 163 

tricarboxylic acid cycle, 107 

triglycerides, 42, 182 

triiodothyronine, 25, 113, 161 

trout, 147 

tryptophan, 75 

tuberculosis, 158 

tubular, 47, 139 

turnover, 30, 50, 78, 101, 136, 144, 146, 148, 150, 

152, 164, 166, 173 

twins, 34, 166, 174 

type 1 diabetes, 145, 147 

tyramine, 127 

U

U.S. Department of Agriculture, 140 

ubiquitin, 172 

ultraviolet, 59, 60, 62, 144, 157, 160, 190 

ultraviolet B, 60, 62, 157, 190 

ultraviolet light, 62 

uncertainty, 69 

undernutrition, 23, 24, 28, 47 

uniform, 105 

United States, 5, 6, 63, 179 

urea, 106 

uric acid, 33 

urinary, 29, 30, 31, 33, 34, 35, 39, 47, 48, 50, 51, 53, 

68, 75, 80, 82, 83, 87, 88, 89, 90, 92, 95, 97, 98, 

99, 108, 110, 111, 113, 119, 120, 134, 138, 144, 

147, 150, 154, 155, 157, 158, 162, 164, 168, 169, 

182, 183, 184, 185 

urine, 34, 44, 46, 50, 71, 74, 76, 84, 88, 164 

uterus, 59 

UV light, 65 

UV radiation, 162 

V

validation, 92, 99, 163 

values, 22, 23, 35, 41, 47, 48, 49, 53, 54, 60, 76, 88, 

89, 97, 101, 173, 180, 181, 182, 183, 184, 185 

vanadium, 116, 143 

variability, 31, 34, 88, 164 

variables, 31, 34, 80 

variation, 79, 100, 138, 152 

vasoconstriction, 120 

vegetables, 4, 7, 11, 62, 63, 127, 152, 179 

vehicles, 46, 129, 130, 185 

velocity, 145 

ventricle, 52 

vertebrae, 68 
208 Index 

vesicles, 127 

vibration, 92, 135, 173 

virus, 62 

visible, 10, 180 

vision, 57, 75 

vitamin A, 57, 58, 59, 104, 126, 127, 135, 142, 148, 

153, 154, 156, 166 

vitamin B1, 76, 82, 83, 127, 142, 143, 148, 164 

vitamin B12, 76, 82, 83, 127, 142, 143, 148, 164 

vitamin B12 deficiency, 82 

vitamin B6, 30, 76, 80, 81, 135, 142, 143, 148, 149, 

164 

vitamin C, 1, 14, 66, 77, 78, 79, 80, 127, 134, 137, 

148, 149, 157, 163, 168, 173, 184 

vitamin C deficiency, 1 

vitamin D, 13, 14, 59, 60, 61, 62, 63, 64, 65, 93, 94, 

97, 123, 126, 133, 135, 136, 137, 138, 140, 141, 

143, 144, 145, 146,147, 148, 156, 158, 159, 160, 

162, 163, 166, 168, 169, 171, 173, 175, 183 

vitamin D deficiency, 62, 63, 64, 137, 141, 160 

vitamin D receptor, 145 

vitamin E, 65, 66, 67, 121, 148, 149, 164 

vitamin K, 41, 67, 68, 69, 93, 142, 159, 168, 170, 

173 

vitamins, 14, 27, 41, 57, 67, 71, 76, 82, 111, 126, 

143, 147, 151, 171 

vomiting, 44, 47, 57, 110, 112 

W

walking, 92, 170 

warfarin, 67, 149 

warrants, 81, 99 

water, 4, 8, 9, 15, 23, 24, 27, 44, 45, 46, 47, 57, 76, 

82, 109, 113, 114, 117, 125, 129, 137, 144, 146, 

148, 150, 152, 156, 159, 163, 171, 179 

water-soluble, 57, 76, 82, 125 

weakness, 36, 53, 74, 94, 96 

weight loss, 22, 43, 135, 172 

well-being, 123 

Western countries, 67 

wheat, 129 

windows, 60 

wine, 126, 138, 161 

winter, 62, 63, 164, 166 

Wistar rats, 110 

women, 14, 26, 36, 40, 43, 46, 51, 52, 54, 58, 63, 66, 

69, 74, 75, 77, 79, 82, 84, 85, 93, 96, 99, 103, 

106, 107, 109, 111, 112, 114, 115, 138, 140, 141, 

143, 144, 145, 146, 148, 149, 150, 151, 154, 155, 

156, 157, 158, 169, 173 

World Health Organization (WHO), 4, 13, 14, 15, 

20, 26, 173, 180, 181, 190 

wound healing, 133, 148 

X

xerophthalmia, 57 

Y

yield, 68, 74, 84, 90, 115 

yolk, 100 

young men, 134 

young women, 51, 144, 149 

Z

zinc, 14, 15, 109, 110, 111, 139, 143, 150, 151, 171, 

185