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Oregon State University

The

Linus Pauling
Institute

R E S E A R C H

N E W S L E T T E R

From theDirector

Not All Fats Are
Created Equal

Balz Frei, Ph.D.
LPI Director and Endowed ChairOSU Distinguished Professor of
Biochemistry and Biophysics

An Interview with Donald B. Jump, Ph.D.
Professor of Nutrition
LPI Principal InvestigatorFor three reasons, 2011 is a banner year for the Linus
Pauling Institute. First, the new Linus Pauling Science
Center is nearing completion and will open its doors inAugust. The architects, general contractor, and project
manager have done an outstanding job keeping constructionof the new building near-flawless, on schedule, and on
budget. The $62.5 million, 105,000-square-foot science
center is the most expensive academic building project in
the history of Oregon State University and will be a working
memorial to our founder and OSU alumnus, Dr. Linus
Pauling. The top two floors of the four-story building will
be dedicated to the Institute and provide state-of-the-art
laboratory space for our faculty, students, and researchstaff in the Institute’s three major research programs:
the Cancer Chemoprotection Program, the Healthy Aging
Program, and the Cardiovascular and Metabolic Diseases
Program. The new building will represent a leap forward
for the Institute, bringing together our scientists, students,
and administrative staff under a single roof for the firsttime, promoting increased interactions and newcollaborations, and generating scientific discoveries indisease prevention and health promotion through researchin nutrition, micronutrients, and dietary supplements.

Second, the new building will also provide laboratory
and office space for two new Principal Investigators inthe Healthy Aging Program. This program, directed bylong-time LPI faculty member and Jamieson Endowed
Chair in Healthspan Research, Dr. Tory Hagen, has two
principal goals: to better understand the cellular andmolecular processes underlying the biology of aging, suchas declining energy metabolism and immune function andincreased chronic inflammation and oxidative stress;
and to identify dietary and lifestyle regimens, including

continued on page 2

Q. You’re from the East Coast, but you spent a few
years at Oregon State University in the 1970s.
What were you doing here then?
A. I was working with George Beaudreau in the
Department of Agricultural Chemistry. I had completed
my master’s degree at Rutgers and wanted a change.
I grew up in Delaware, where the highest point is 400
feet above sea level, and I had seen pictures of the Westand thought that would be a great place to go. While
doing my master’s work, I worked for the Institute ofCancer Research and learned how to culture cells,
mainly mammary cancer cells. I worked with George
for about three years on cell culture and retroviruses anddecided to go back to graduate school for a doctorate inbiochemistry from Georgetown University.

Q. You rose through the ranks to become a professor
at Michigan State University and then joined theLinus Pauling Institute in 2007. What attracted
you to LPI?
A. LPI is an internationally recognized center for
nutrition research with a strong focus in the area of
micronutrients, antioxidants, and supplements. My
area of research is omega-3 fatty acids as regulators oflipid metabolism. Omega-3 fatty acids, also called n-3
fatty acids, are often taken as supplements. N-3 fatty
acids are generally beneficial to human health. I was
attracted to the LPI because of its capacity to carry out
sophisticated analyses of lipids using chromatographic
and mass spectrometric methods.

Q. What do you like to do in your free time?
A. My wife and I work on our old house and property.
The property was neglected when we purchased it incontinued on page 2— DESIGNATED BY THE NATIONAL INSTITUTES OF HEALTH AS A —Center of Excellence for Research on Complementary and Alternative Medicine

Continued from cover — From the Director
dietary supplements, to postpone age-related diseases
and deficits of daily living, thereby extending healthspan.
We are currently conducting a national search for afaculty position in “Biochemistry of Aging” and haveidentified an outstanding candidate with expertise in therole of protein stability and oxidative stress in healthy
aging. I am looking forward to introducing our new
faculty member to you in the next Research Newsletter.
The final position in the Healthy Aging Program, which
we hope to fill in the next two years, will focus on thecausation and prevention of age-related neurodegenerative
diseases, such as Alzheimer’s or Parkinson’s disease.
Third, in 2011, we will hold our Diet and Optimum
Health conference in Corvallis for the first time, whichallows us to showcase the beautiful campus of OSU andthe new Linus Pauling Science Center. This will be oursixth Diet and Optimum Health conference, and it willfeature some of the most prominent scientists in thefields of nutrition, aging research, and preventive andorthomolecular medicine. The program includes sessions
on the role of diet and micronutrients in immune
function, cardiovascular diseases, and healthy aging,as well as two sessions focusing on vitamin E andprobiotics. The detailed program with all the speakers
and topics appears on pages 8-9. In addition, we willaward the sixth Linus Pauling Institute Prize for HealthResearch, which recognizes innovation and excellencein research relating to the roles of micronutrients,
phytochemicals, and dietary antioxidant and antiinflammatory factors in promoting health and preventing
disease. The awardee will join our illustrious list ofprevious winners, Drs. Bruce N. Ames from the
University of California, Berkeley, and Children’s
Hospital Oakland Research Institute; Walter Willett
from Harvard; Paul Talalay from Johns Hopkins;
Mark Levine from the National Institutes of Health;and Michael Holick from Boston University School of
Medicine. The fall edition of the Newsletter will
provide a summary of the conference and a detailed
profile of this year’s LPI Prize winner, along with aglimpse of the new Linus Pauling Science Center. LPI

bequests
LPI is grateful for thethe
we have received from
year:
st
pa
is
following friends thVictoria J. Mastrobuono
Janet P. Roberts
Francis B. Rosevear(pledged intent)
Earl Winston Schulz
Frances Reilly Cunningham
Christen J. Wegener
Arthur Kahn
George B. Whatley
Sidney Licht
Dorothy B. Alcocer
Audrey M. Carlan

2

Spring/Summer 2011

Continued from cover — Interview with Dr. Donald Jump
2007; we have renovated some parts of the house andmade some improvements to the property. We also
have a boat and like to sail off South Beach near
Newport. We really like the coast. I grew up on the
East Coast, and my wife is from Oregon, so we bothhave an affinity for the ocean.

Q. In the early 1980s, you studied the effect of thyroid
hormones on liver function. What did you find?
A. Thyroid hormones are hydrophobic hormones that
regulate nuclear receptors; these receptors regulate gene
expression. When I was a post-doctoral fellow at the
University of Minnesota with Jack Oppenheimer, weestablished that thyroid hormone receptors are foundin or bound to active regions on DNA (chromatin).
I learned a lot about endocrinology during my time at
the University of Minnesota; that knowledge had asignificant influence on my first academic position atMichigan State University (MSU).

Q. Are there interactions between thyroid hormonesand dietary factors that affect liver function?
A. There is significant interaction between carbohydrates
and thyroid hormone—a synergy in the control ofgenes involved in lipid metabolism. Glucose, insulin,
and thyroid hormones were found to regulate multiple
genes involved in liver fat metabolism. At MSU, we
had established mechanisms to measure gene expression
in the liver; we carried out time-course studies to
examine the effects of thyroid hormone action andsucrose (a simple carbohydrate) on liver gene expression.
We applied this same approach to examine the effect of
dietary fat and carbohydrate on liver gene expression.
Rats were fed high-sucrose diets or diets supplemented
with n-3 and n-6 fatty acids to examine their effects
on liver gene transcription. Sucrose stimulated theexpression of genes that make fat, while polyunsaturated
fatty acids attenuated the expression of these genes.
This discovery was the first to document effects of
dietary fatty acids on gene expression, and it set thestage for much of our future research.

Q. Your cell culture studies with fat cells showed thata form of vitamin A called retinoic acid regulates
certain genes involved in lipid metabolism.
What impact does that have on health?
A. That’s an interesting question. It turns out that the
thyroid hormone receptor interacts with a form of theretinoic acid receptor in cells. Both receptors function
to control lipid metabolism.

Q. Would that explain why some people withhypo- or hyperthyroid activity are thin or fat?
A. Perhaps. We first used cells that had the capacity todifferentiate from fibroblasts—cells in connective
tissue—to adipocytes or fat cells. We found that noneof the cells responded to thyroid hormone, which
prompted us to look at retinoic acid regulation of
adipocyte function. That’s when we found a retinoic
acid regulatory scheme. While interesting, theimplications of this finding to human health remain unclear.

Q. Could deficiencies in vitamin A in certain areasof the world affect lipid metabolism?
A. Possibly.
Q. You’ve published a long series of papers on how
dietary fats affect liver genes that regulate
endogenous fatty acid synthesis and oxidation.
Which dietary fats are important in these effects?
A. All types of dietary fats affect liver metabolism andgene expression. Saturated fats promote fatty acidsynthesis, while polyunsaturated fats inhibit fatty acidsynthesis and promote fatty acid oxidation. Human
diets typically contain more saturated and monounsaturated fats than polyunsaturated fats.

Q. What are the differences between saturated,monounsaturated, and polyunsaturated fats?
A. The term saturation refers to the absence of chemical
double bonds between carbon atoms in the fatty acidchain. The fatty acid is “saturated” with hydrogen atoms.
Saturated fatty acids tend to have a more rigid structure.
Unsaturated fatty acids have at least one double bond.
The flexibility of that fatty acid increases as the numberof double bonds increases. Monounsaturated fatty
acids have one double bond; polyunsaturated fatty
acids have two or more double bonds. The bulk of
fatty acids are found in cell membranes and storage
lipids, like triglycerides. Fatty acids in membranes
affect the structure and function of the membrane.
A bulky lipid—an unsaturated fat—or a non-bulky
lipid like a saturated fat will influence the structure of
the membrane and the function of proteins imbedded
in membranes differently. There are many receptors inplasma membranes that communicate environmental
signals to the inside of the cell. As the nature of thelipids in membranes changes, the function of thesereceptors and the control of cell function also change.

Q. That suggests that there is an optimum
concentration of the various types of fats in the
body to maintain proper membrane fluidityand function.
A. Yes, but that optimum concentration is likely to be
influenced by gender, age, genetic background, andhealth status.

Q. What about trans fat?
A. Trans fat is unsaturated fat, but the double bond is ina different configuration. There are two fundamental
configurations for double bonds, either trans or cis.
Natural double bonds in corn oil are in the cis
configuration, whereas the hydrogenation of corn oil
produces fatty acids with the trans configuration.
Unsaturated fats with the trans configuration behave
more like saturated fats.

Q. Do trans fats occur naturally in our diet or dothey come mostly from processed products?
A. Ruminants generate trans fats during the process offood digestion. Ingesting dairy products or meat fromruminants will increase the dietary intake of trans fats.

OMEGA-3 (n-3) AND OMEGA-6 (n-6) FATTY ACIDSHO
O
Carboxyl end

3rd carbon

n-3

Methyl end

HOO
Carboxyl end

6th carbon

n-6

Methyl end

A vertex between two lines indicates a carbon atom, which canmake four bonds. Carbon atoms bind each other and oxygenor hydrogen (not shown) atoms in this diagram. Double bonds
are indicated by parallel lines.

Processed foods containing “hydrogenated vegetableoil” or “partially hydrogenated vegetable oil” areanother source of dietary trans fats.

Q. What is the difference between n-3, n-6, andn-9 fatty acids?
A. The number refers to the location of the double bondin the molecule. Fatty acids have a carboxyl end and amethyl end—the alpha and the omega, respectively. In
n-3 fatty acids, the double bond is three carbons fromthe methyl end. An n-6 fatty acid has the double bondsix carbons away, and in an n-9 fatty acid, the doublebond is nine carbons away from the methyl end.

Q. What foods contain n-3, n-6, and n-9 fatty acids?
A. All of the plants in our diet have varying amounts ofthe saturated and unsaturated fatty acids of the various
classes that we just discussed. The predominant n-3
fatty acid in plants is alpha-linolenic acid. It’s found insoybean oil, canola oil, and walnuts. Olive oil contains
n-9 fatty acids like oleic acid. Linolenic and alphalinolenic acids are essential fatty acids that we have toget from our diet in order to make longer chain polyunsaturated fatty acids that are very important inbiological functions—the long chain, highly unsaturated
n-3 fatty acids are found in salmon, other cold water
fish, and in fish oil supplements (anchovy oil). These are
known to be cardioprotective and control blood lipids.

Q. The brain contains a lot of n-3 fatty acids,
which also affect cognition, mood, and learning.
Since the fats found in most dietary plants are
not efficiently converted to n-3 forms in ourbodies, does this suggest that early humans
consumed lots of fish?
A. This is an interesting question. There is some evidence
suggesting that humans in the plains of Africa migrated
to the coast. Once there, they would have had moreaccess to fish that are enriched in very long chain n-3
fatty acids. Dietary conversion of alpha-linolenic acidto n-3 fatty acids like eicosapentaenoic (EPA) anddocosahexaenoic (DHA) fatty acids is slow but effective.
Vegetarians who consume plants with n-3 fatty acids
don’t have unusual health problems. Also, certain tissues
maintain their lipids despite significant variation in diet.

continued on page 4

The Linus Pauling Institute3

Continued from page 3 — Interview with Dr. Donald Jump

Q. Are sufficient amounts maintained because of
the slow turnover and slow loss in the brain
and nervous tissue?
A. That is one interpretation, but more study is required
to assess mechanisms controlling tissue-specificsynthesis and turnover of polyunsaturated fatty acids,
for example, in the central nervous system.

Q. Polyunsaturated fats, or PUFAs, are importantin energy metabolism, for cell structure, and as
regulators of gene expression, especially thosethat control n-9 fatty acid synthesis. What don-9 fatty acids do in the body?
A. N-9 fatty acids are monounsaturated fats found inolive oil, for example, and also synthesized in the bodyfrom glucose. They are very important for making
storage lipids like triglycerides. An early step inmaking triglycerides is adding oleic acid to glycerolphosphate. Triglycerides are the main storage form
for lipids in adipose tissue in our bodies. Elevatedtriglycerides in the blood are an independent risk
factor for cardiovascular disease.

Q. Why do elevated triglyceride levels contributeto heart disease?
A. Good question! High blood triglyceride levels may be
a marker for abnormal or ectopic storage of lipids intissues. Accumulating triglycerides in muscle, liver,and other tissues induces inflammation and insulin
resistance, resulting in type-2 diabetes. Type-2 diabetes
is a risk factor for cardiovascular disease.

Q. How do n-3 fatty acids suppress triglycerides?
A. N-3 fatty acids like the ones in fish oil inhibit thesynthesis of triglycerides by lowering the cellular levelof substrates for triglyceride synthesis. This is achievedby inhibiting fatty acid synthesis and enhancing fatty
acid oxidation.

Q. Do n-6 fatty acids promote insulin resistance?
A. The short answer is no. In general, the n-3 and n-6
polyunsaturated fatty acids are beneficial in theprevention of chronic disease. However, too much,or an imbalance of n-6 versus n-3 fatty acids may cause
health problems. Our modern diets provide too muchn-6 and not enough n-3 fatty acids. The n-6 fatty
acids are precursors to inflammatory lipids. And
inflammatory lipids play an important protective rolein many biological functions that are very important.
When n-6 fatty acids are in excess, they tip the balance
to a point of enhanced inflammation within the tissue.

Q. Is that mediated by prostaglandins?
A. Yes, mainly eicosanoids. Prostaglandins, leukotrienes,
and thromboxanes are all made from these fats andhave a wide variety of functions. For example,
prostaglandins are synthesized in almost all cells.
These eicosanoids control platelet aggregation, calcium
flux, hormone regulation, cell growth, metabolism,
vasodilation, bronchodilation, and other functions.
Isoprostanes are eicosanoids made from the free-radical

4

Spring/Summer 2011

mediated peroxidation of the n-6 fatty acid, arachidonic
acid, and have been used as biomarkers of oxidative stress.

Q. Which fatty acids are anti-inflammatory?
A. N-3 fatty acids—the fish oils.
Q. How do dietary fats affect the retinopathy that
can accompany diabetes?
A. Diabetic retinopathy is a problem with the vascularsystem of the retina; it is similar to atherosclerosis.
Diabetic retinopathy involves enhanced storage of lipids
and a loss of vascularity within the retina.

Q. Do dietary fats influence tumorigenesis and,if so, how?
A. The impact of dietary fat on tumorigenesis is controversial.
There are studies in animals suggesting that n-6 fatty
acids promote the progression of colon cancer, while n-3
fatty acids attenuate the development of colon cancer.

Q. Is there any evidence that dietary fats affecttumor growth in people?
A. At this time, the evidence is not compelling. There arenearly 90 clinical trials investigating the impact of
dietary fat on cancer. In contrast, excess body fat is arisk factor for numerous cancers.

Q. Is there much evidence that fish oil
supplementation is beneficial?
A. There are over 470 clinical trials—ongoing or completed—investigating the impact of n-3 fatty acids on humanhealth. There is certainly a lot of interest in these fats
and their impact on health and disease. Many scientists
are trying to find out if studies carried out in cell culture
and animals are applicable to humans. N-3 fatty acids
are clearly beneficial in the control of blood triglyceride
levels and in cardioprotection. These clinical trials may
reveal beneficial effects of n-3 fatty acids on otherprocesses, like inflammation and cognitive function.

Q. Are the doses used in these animal studies
greater than what people would consume ina diet that includes fish?
A. Typically, yes. And in some cases they are biased towarda particular kind of n-3 fatty acid. In our studies on fatty
liver disease, we look at the effect of EPA, DHA, and a
combination of EPA and DHA. Most fish oil capsules
contain a combination of EPA and DHA, and the ratioof these two is highly variable depending on the source.

Q. Do you recommend supplementation with fish oil?
A. Yes. Before taking fish oil, consult with your physician
to be sure that there is not some underlying problem,
such as increased bleeding time. Aspirin, vitamin E, anda drug called Plavix inhibit platelet aggregation, which
is a key event in blood coagulation. If you take thesecompounds and use fish oil, you may significantly
increase the time it takes to stop bleeding. If someone
is taking an anticoagulant or planning surgery, theyshould discontinue use of fish oil supplements.

Q. The ratio of the intake of n-6 to n-3 fatty acids
has changed dramatically over the past few
generations as our diets have changed. Do weknow anything about the optimal ratio?

A. In general, a high n-6 to n-3 ratio is considered
pro-inflammatory. More studies are required to define
the optimal ratio.

Q. Do you think that consuming fatty fish a couple
times a week is equivalent to taking a fish oil
supplement or is it better to take a fish oil
supplement regularly?
A. I think a supplement is probably better for healthbecause it’s more uniform and continuous.

Q. If one chooses to take a fish oil supplement, whatcriteria are important in making the selection?
A. Look at the composition of the fatty acids on the bottle
and make sure that it has a level of DHA and EPA thatis consistent with cardiovascular protection—about
500 mg of combined DHA and EPA per day—as an
absolute minimum.

relative importance of simple carbohydrates and dietaryfats in obesity. For a long time, we thought thatcarbohydrates like simple sugar (glucose, fructose, andsucrose) were not well converted to fat in humans.
We now know that’s not true. There is a reasonableamount of scientific evidence that elevated carbohydrate
intake will contribute to increased fat deposition. The
body has only so much capacity to store carbohydrates,
and it does so in the form of glycogen. If you fill up
the glycogen pool, the rest becomes fat. Dietary fat, on
the other hand, is also very important because of thenature of the fat that we eat, which tends to be morebiased toward saturated and monounsaturated fats
and less polyunsaturated fats, resulting in
imbalances in the distribution of fat in tissues.

Q. How does EPA or DHA influence the risk forstrokes and heart attacks?
A. That is complicated and related, in part, to the controlof blood lipid levels. Generally, fish oils lower triglycerides but may elevate cholesterol in some individuals.
Consumption of fish oil changes the characteristics ofthe polyunsaturated fatty acids within the arterial wall
so that they may be less prone to cause inflammation.
Membrane lipids contain both n-6 and n-3 fatty acids.
If those are predominately n-6 fatty acids, which aresubstrates for making eicosanoids, then membrane
phospholipid metabolism by phospholipases generates
n-6 fatty acids that enter the prostaglandin synthesis
pathway and produce inflammatory eicosanoids.
Membrane-associated n-3 fatty acids are less likely to
be cleaved out of membrane phospholipids. Moreover,n-3 fatty acids are poor substrates for enzymes thatgenerate prostaglandins. So fish oil has the potential toreduce inflammation by lowering the production of
inflammatory eicosanoids.

Q. How does alpha-linolenic acid from walnuts,
for example, benefit cardiovascular health?
A. The benefit gained from alpha-linolenic acid is that it isa precursor to DHA and EPA. However, alphalinolenic acid is not as efficacious in cardioprotection
as DHA and EPA. Thus, supplementing the diet with
DHA and EPA provides better cardioprotection.

Q. Some large-scale epidemiological studies foundthat walnut consumption, which is rich inalpha-linolenic acid, was associated withdecreased risk for atrial and ventricularfibrillation (cardiac arrhythmia).
A. Again, that probably relates to the conversion ofalpha-linolenic acid to EPA and DHA, which areanti-arrhythmic.

Q. There is a lot of interest in the obesity epidemic
among children and adults in America. How
would you gauge the contribution of dietaryfats or carbohydrates to this?
A. Simple carbohydrates like sugar and calorically dense,
high-fat foods contribute to the problem, as well as alack of exercise. There’s ongoing debate about theQ. Last summer the media
reported your discovery that
diabetic mice could be cured by manipulatinga gene that makes a fat-metabolizing enzyme.
How does that work? Is there any way toincrease that enzymatic activity in humans?
A. First of all, the term “cure” was media hype. Our work
may have promise for an alternative method to treat
some diabetic complications. Humans with metabolic
syndrome and obese mice that have characteristics ofmetabolic syndrome have a polyunsaturated fat profilein blood that is different from normal, healthy humans
or mice. A large number of enzymes in the liver
participate in the production of polyunsaturated fatty
acids. We examined the effect of obesity and diabetes
on these enzymes and found that one enzyme, called
elongase-5, had decreased levels of activity in liversof fat mice. We then restored fatty acid elongase tonormal levels in livers of obese, diabetic mice; thistreatment corrected the hyperglycemia and fatty liver,
but did not correct the obesity. In other words, themice were obese, but no longer diabetic.

Q. How did you raise the enzyme levels in thelivers of the mice?
A. We used an adenovirus-mediated gene therapy approachto elevate expression of the enzyme. We engineered an
adenovirus to contain the gene expressing fatty acidelongase-5. Infection of mice with the adenovirus leads
to the expression of the enzyme in the liver and noother tissue. The liver starts making more of the
enzyme within 24 hours after infection.

Q. Are there compounds that raise the enzyme levelin the liver?
A. Our studies in mice have shown that fibrates increase
the expression of this enzyme. Fibrates are used tocontinued on page 7

The Linus Pauling Institute5MicroRNAs Play Critical Roles in Development
Responses to Dietary Constituents
Robert Tanguay, Ph.D., OSU Distinguished Professor of Molecular Toxicology
Department of Environmental and Molecular Toxicology
Summary: MicroRNAs—non-coding RNAs that affectgene regulation—have emerged in recent years as important
regulators of many cellular and physiological processes.
In zebrafish, microRNAs prevent excess vitamin A from
causing spine defects during development. Exposure toalcohol during early development in zebrafish interfereswith microRNA activity, resulting in abnormalities in thedevelopment of the nervous system.

It is well established that dietary constituents can either
positively or adversely affect fetal development, but wedon’t have a good understanding of the relevant mechanisms.
As you may remember from biology class, there are several
forms of RNA. During a process called transcription,
enzymes produce complementary RNA from DNA.
Messenger RNA transfers information from DNA to thecell’s ribosome, where proteins are made. Over the pastten years, another kind of RNA—non-coding RNA(ncRNA)—has emerged as a pivotal player in fundamental
physiological and cellular processes and has been increasingly
implicated in cancer, immune disorders, and cardiovascular,
neurodegenerative, and metabolic diseases. MicroRNAs(miRNAs) are a class of ncRNA molecules that are
predicted to post-transcriptionally regulate the expressionof 30-60% of all human protein-coding genes, and as such,microRNAs play key roles in cellular and developmental
processes. MicroRNAs have emerged as targets ofdevelopmental, hepatic, neurological, and carcinogenic
toxicological agents and have increasingly been identified as
regulators of xenobiotic-metabolizing enzymes. The goal of
our pilot study funded by LPI was to determine whether
misregulation of miRNA expression during development
constitutes a specific mechanism by which developmental
toxicants exert their effects.

Vitamin A is necessary for normalvertebrate growth and development.
Jill Franzosa, a graduate student in
my laboratory, investigated thedevelopmental role of miRNAs using
an active form of vitamin A, all-transretinoic acid (RA). We know that
excesses or deficiencies of RA adversely
Jill Franzosa
affect development. In this study, wedemonstrated that treating zebrafish in early developmental
stages with RA results in a distinct curved body axis similar
to the axis and spine defects observed in other vertebrates,
including humans. To determine whether specific miRNAs
are misexpressed after RA exposure, gene analyses wereconducted at several critical developmental stages.
Strikingly, the expression of three miRNA family members

6

Spring/Summer 2011

was significantly repressed by RA treatment during theearly stages of somitogenesis (development of skin andskeletal muscle and bones). Based on a prediction thatmiRNAs target the key RA-inactivating enzyme, cyp26a1,
we then confirmed, for the first time, that cyp26a1 is abona fide target of the specific miRNA family. We also
showed that repression of the implicated miRNA by genetic
alterations resulted in similar embryonic defects. Whenspecific miRNA mimics were injected into embryos, axis
defects induced by developmental exposure to RA wereprevented. Together, these results indicate that the axis
defects elicited by exposure to RA during development
result partly from repression of specific miRNAs andsubsequent misregulation of cyp26a1. This study sheds lighton the role of miRNAs in mediating the teratogenic effects
of retinoic acid and provides a more in-depth view of thegenetic regulatory mechanisms that control the action ofvitamin A during normal development.
In other studies, postdoctoral fellow
Tamara Tal used alcohol as a neurotoxicant in zebrafish to examine therole of miRNAs in the development ofa functional nervous system. While
miRNAs are critical to nervous systemdevelopment, the neurobehavioral
function of miRNAs is unknown.
Dr. Tamara Tal
Prenatal alcohol exposure produces arange of conditions in offspring, collectively referred to as
fetal alcohol syndrome disorder (FASD). Epidemiologicalstudies suggest that the majority of children with FASD
have deficits in neurobehavioral function, even in theabsence of clinically discernable physical abnormalities.
We assessed larval zebrafish neurobehavior by measuring
the distance moved during alternating periods of light anddark. Transient exposure to alcohol during early neuraldevelopment resulted in increased physical activity.
These alterations in behavior persisted in juveniles that
had been developmentally exposed to alcohol.
At developmental stages inzebrafish coincident withalcohol-induced neurobehavioral abnormalities,
expressions of multiple
miRNAs in the central
nervous system weresignificantly altered.
Subsequent computational
analyses revealed that
alcohol disrupts expressionof miRNAs that direct
neurogenesis.

Zebrafish embryo

We then used genetically altered zebrafish to examine thefunctional role of alcohol-sensitive miRNAs. Decreasing
the activity of miRNAs in the central nervous systemproduced behavioral hyperactivity in larval and juvenile fish
similar to that observed with alcohol. These data indicatethat ethanol exposure causes errors in the expression of
miRNAs that may collectively choreograph nervous systemdevelopment and function and support the concept thatmiRNA signaling pathways are targets of developmental
neurotoxicants like alcohol.

Continued from page 5 — Interview with Dr. Donald Jump
manage dyslipidemia in humans; fibrates lower bloodlevels of cholesterol and triglycerides.

Q. Do you have any dietary recommendations forthe prevention or treatment of diabetes withrespect to fatty acids?
A. The American Diabetes Association (www.diabetes.org)
has an excellent Web site for this information. If yourbody mass index (BMI) exceeds 30, you may develop
diabetes and metabolic syndrome as you grow older.
I think dietary supplements of n-3 fatty acids are
prudent for just about everybody as long as they are
not on an anticoagulant therapy.

Q. What are your plans for future research?
A. We have two major projects under way in the lab. In

Zebrafish

Our research resulted in numerous awards andrecognitions. Jill Franzosa’s research was honored with the
Elsevier best platform presentation award in toxicogenomics
at the 2010 Society of Environmental Toxicology andChemistry annual meeting, first place poster award at the2010 Pacific Northwest Association of Toxicologists
Conference, poster award winner at the 2010 Aquatic
Animal Model for Human Disease Annual Meeting, firstplace in the Molecular Biology graduate student award at
the 2010 Society of Toxicology annual meeting, and a firstplace platform presentation award at the 2009 PacificNorthwest Association of Toxicologist Conference.
Dr. Tamara Tal’s research in alcohol-sensitive microRNAs
was recognized at the 2010 Pacific Northwest Associationof Toxicologists Regional Conference, won a first-placeposter award at the 2010 International Neurotoxicology
Conference, won a first-place postdoctoral research award
from the Molecular Biology specialty session, and won asecond-place poster award from the Neurotoxicology
specialty section at the 2010 Society of Toxicology annual
meeting. Both Dr. Tal and Jill Franzosa recently presented
their research in the symposium session titled “Uncovering
the role of microRNAs in toxicology” at the 2011 Societyof Toxicology annual meeting.
Based upon the success of this project, Jill was also
awarded a prestigious predoctoral National Institutes of
Health Ruth L. Kirschstein NRSA Fellowship to investigate
the role of microRNAs in aging. Together, these findings
will generate new fundamental knowledge about the role ofmicroRNAs in mediating basic biological responses tochemical or dietary toxicological insult. LPI

one, we are investigating the use of n-3 fatty acids asa way to prevent the development of fatty liverassociated with diet-induced obesity. The second lineof investigation is a continuation of the “gene therapy
approach” described above. We are defining themechanism used by polyunsaturated fatty acids tocontrol diabetic complications. LPI

Bill Town’s Story of InspirationAs a dedicated high school science teacher, Bill Town
was creative in his efforts to inspire his students.
He decided the class needed a scientific hero who
worked in a lab. Bill’s choice was Linus Pauling, a
two-time Nobel Prize-winner and charismatic chemist.
So, for Dr. Pauling’s birthday on February 28th, Billbought a birthday card, had all his students sign it, andmailed it to Dr. Pauling. It was a wonderful surprise foreveryone when the class received a thank-you notefrom Dr. Pauling himself! The following year, whenBill pulled out a birthday card, the students organizeda birthday party for Dr. Pauling. It became a February
tradition that lasted for most of Bill’s teaching career.
When it was time to plan his will, Bill knew that hewanted his estate to support science education andscience teaching. Since Linus Pauling was an inspiration
for him and his students, Bill felt remembering theLinus Pauling Institute in his will was a fitting way of
thanking Dr. Pauling for showing students the fun ofchemistry and the love of science.
All of us at the Linus Pauling Institute deeply appreciateBill’s act of inspiration in remembering LPI in his estate.
As part of the LPI Legacy Endowment Fund, Bill’s gift
will continue the legacy of a truly great scientist andhumanitarian, while generating new discoveries thatcreate a better future for everyone.
Have you remembered LPI in your estate plans? We'dbe honored to recognize you as a member of the Linus
Pauling Institute Legacy Circle. Contact Michele Erickson
at 541-737-3744 or Michele.Erickson@oregonstate.edu.

The Linus Pauling Institute7

6th international conference on

DIET and OPTIMUM HEALTH
Organized and sponsored by the Linus Pauling Institute•Co-sponsored by the Oxygen Club of California

september 13-16, 2011 • corvallis, ORegon • USA
Wednesday, September 14, 2011

Tuesday, September 13, 2011
2:OOpm Registration begins
3:00

Welcome and Opening Remarks
Balz Frei, Linus Pauling Institute,Oregon State University, Corvallis, OR

6:00am Organized Walk/Run
7:30

SESSION 2 – 8:30 AM to Noon

MICRONUTRIENTS, DIET,
AND IMMUNE FUNCTIONSESSION 1 - 3:15 TO 5:15 PM

Chairs: Adrian Gombart and Emily Ho,
Linus Pauling Institute, Oregon State University,
Corvallis, OR

VITAMIN E: BIOLOGICAL FUNCTIONSAND CONTROVERSIESChair: Maret Traber, Linus Pauling Institute,Oregon State University, Corvallis, OR
3:15

3:45

4:15

8

The α-tocopherol transfer protein:
Biochemical mechanisms and health
implications
Danny Manor
Case Western Reserve University, Cleveland, OH

Anti-inflammatory effects of vitamin E
forms and their metabolites
Qing Jiang
Purdue University,West Lafayette, IN
The effect of vitamin E supplementation on
cardiovascular risk in diabetic individuals
with different haptoglobin phenotypes
Andrew P. Levy
Technion Faculty of Medicine,Technion-Israel
Institute of Technology, Haifa, Israel

4:45

Does vitamin E decrease chronic diseaserisk by protecting against free radicals?
Etsuo Niki
National Institute of Advanced Industrial
Science and Technology, Osaka, Japan

6:30

Welcome Reception and Tour of theLinus Pauling Science Center

Spring/Summer 2011

Breakfast provided

8:30

Nicotinamide (vitamin B3) and innate immune
response to microbial infection
George Liu
Cedars-Sinai Medical Center and UCLA
School of Medicine, Los Angeles, CA

9:00

Vitamin D and infectious diseases
Carlos A. Camargo, Jr.
Harvard Medical School, Boston, MA

9:30

The impact of nutrition on the immune
response against influenza
Elizabeth M. Gardner
Michigan State University, East Lansing, MI

10:00

Coffee/Tea Break

10:30

Zinc, inflammation, and susceptibility to sepsis
Daren Knoell
The Ohio State University, Columbus, OH

11:00

Inflammation, neutrophil function, and traceelement status in the morbidly obese
Pam J. Fraker
Michigan State University, East Lansing, MI

11:30

Polyunsaturated fatty acids and their impact
on the immune system
Robert S. Chapkin
Texas A&M University, College Station,TX

12:00

Lunch provided

SESSION 3 – 1:30 to 3:00 PM

8:30

Protective effect of resveratrol in miceand monkeys
Julie Mattison
Aging, Metabolism, and Nutrition Unit,
National Institute on Aging, Baltimore, MD

9:00

How to help your mouse live longer: Diets,
drugs, MIF-KO, and sibs
Richard Miller
University of Michigan, East Lansing, MI

9:30

Lipoic acid and healthspan: Mechanismsof action
Tory Hagen
Linus Pauling Institute, Oregon State University,
Corvallis, OR

10:00

Coffee/Tea Break

10:30

Protein and metabolic homeostasis in aging
and longevity
Gordon J. Lithgow
The Buck Institute for Research on Aging, Novato, CA

11:00

Mitochondrial decay in human aging:A translational approach
Chrisitaan Leeuwenburgh
University of Florida, Gainesville, FL

11:30

Rapamycin and dietary restriction: Do they share
a common mechanism in lifespan extension?
Viviana Perez
University of Texas Health Science Center at
San Antonio, San Antonio,TX

12:00

Lunch provided

DIET AND CARDIOVASCULAR DISEASE
Chair: Balz Frei, Linus Pauling Institute,Oregon State University, Corvallis, OR
1:30

A diet based on high-heat-treated foods promotes
risk factors for diabetes mellitus andcardiovascular diseases
Veronika Somoza
University of Vienna,Vienna, Austria

2:00

Dietary patterns and risk of mortality fromcardiovascular disease
Teresa Fung
Simmons College and Harvard School of Public Health,Boston, MA

2:30

New evidence on the effects of aMediterranean-style diet on cardiovascular disease
Roman Estruch
Hospital Clinic, University of Barcelona, Barcelona, Spain

3:00

Coffee/Tea BreakSESSION 4 – 3:30 to 5:00 PM

GUT MICROBES AND PROBIOTICS –ROLE IN HEALTH AND DISEASE
Chair: Sharon Krueger, Linus Pauling Institute,Oregon State University, Corvallis, OR
3:30

4:00

4:30

The human microbiome and cancer
Cindy Davis
Division of Cancer Prevention, National Cancer Institute,
Bethesda, MD
Evolutionary glycomics: Breast milkoligosaccharides and bifidobacteria infantis
J. Bruce German
University of California, Davis, CA
Pre and probiotics: Food fad or bacterial therapy?
Robert G. Martindale
Oregon Health & Science University, Portland, OR

SESSION 6 – 1:20 to 4:00 PM

ORAL ABSTRACTS AND YOUNGINVESTIGATOR AWARD FINALISTS
Eight 20-minute talks;TBA
4:00

Coffee/Tea Break

5:00 - 7:00pm

SESSION 7 – 4:15 to 5:30 PM

Poster Session, hors d'oeuvres and drinks provided

Thursday, September 15, 2011

LPI PRIZE CEREMONY AND PLENARY
LECTURE BY AWARDEE
Chair: Balz Frei, Linus Pauling Institute,Oregon State University, Corvallis, OR

6:00am Organized Walk/Run
7:30

Breakfast provided

SESSION 5 – 8:30 AM to NoonCALORIC RESTRICTION MIMETICS,
DIET, AND HEALTHY AGING
Chairs: Tory Hagen, Linus Pauling Institute,Oregon State University, Corvallis, OR and
Viviana Perez, University of Texas Health Science Center
at San Antonio, San Antonio,TX

6:30

Reception

7:00

Banquet Dinner

Friday, September 16, 2011
Travel Day

For more information about the Conference,
please visit the LPI Web site at
http://lpi.oregonstate.edu/conf2011 or phone
the Institute at 541-737-5075.

The Linus Pauling Institute9The New Dietary Reference Intakes for Vitamin D
Adrian Gombart, Ph.D., Associate Professor of Biochemistry and Biophysics
LPI Principal Investigator

The Institute of Medicine (IOM) released new dietaryreference intakes (DRIs) for calcium and vitamin D on
November 30, 2010. The IOM concluded that vitamin D
plays a key role in bone health and that current evidence
does not support other health benefits from vitamin D
supplementation, although the IOM called for additional
research targeted at other health outcomes to continue.
The changes in the recommended dietary allowance (RDA)
for vitamin D were based solely on bone health. The IOM
raised the RDA in children (1-18 years) and adults (19-70
years) from 200 IU to 600 IU per day and raised thetolerable upper intake level (UL) for adults from 2,000 IU
to 4,000 IU per day. For the elderly (>70 years), the RDA
was increased to 800 IU per day. The majority of vitamin D
experts were disappointed by these conservative increases,
but they should be considered steps in the right direction.
The IOM also made another very important change.
After reviewing the published literature, they concluded thatthe serum level of vitamin D sufficient for bone health isabove 20 ng/ml rather than 30-32 ng/ml, a value that has
been used extensively by physicians. During the press
conference, they said that it was warranted by the available
scientific evidence even though it had not been one of theirtasks. By lowering the sufficient level, they, in effect,
reduced the number of people that would be considered tohave inadequate serum levels of vitamin D. This change
will likely cause significant confusion for both physicians
and their patients, but it should be noted that it is only
relevant to bone health and may not be optimal for other
health benefits that have been attributed to vitamin D.
While the new RDA may bring many people into the new
sufficient range, a cut-off of 20 ng/ml is controversial in thevitamin D research community because it does not consider

other areas of health that the IOM has concluded are notsupported by the currently published data.
The IOM is very conservative and based their decisions
on a lack of randomized controlled trials (RCTs) that
demonstrate a clear benefit from taking vitamin D
supplements beyond bone health, but there is overwhelming
evidence that supports biological plausibility for a role ofvitamin D in numerous other health outcomes. For example,
most non-bone cells have receptors for vitamin D, and weknow that the function of immune cells is affected byvitamin D. The IOM narrowly focused on RCTs as the“gold standard”—an almost impossible hurdle to clear
when applied to micronutrients. For example, subjects inthe placebo group in an RCT will still have some of the
micronutrient under evaluation in their bodies—unlike an
RCT testing drugs; otherwise, they would get deficiency
diseases. While anecdotal reports or single studies seem tobe good enough for the IOM to determine the UL, multiple
RCTs demonstrating similar outcomes are required for the
RDA. Clearly, this is a double standard. DRIs need totake into account the totality of evidence, not just RCTs.
LPI continues to recommend a daily intake of 2,000 IU ofvitamin D. This is well below the UL of 4,000 IU set by
the IOM and should ensure that individuals, particularly
in areas of the world where sun exposure is limited forextended periods of the year, get enough vitamin D. Also,
to adjust for individual differences and ensure adequatebody vitamin D status, LPI recommends aiming for aserum 25-hydroxyvitamin D level of at least 80 nmol/l(32 ng/ml). You can find this information and therecommendations for infants and children in the LPI
Micronutrient Information Center section on vitamin D(http://lpi.oregonstate.edu/infocenter/vitamins/vitaminD).
LPI

Powered by Oranges!

A

ll of us at the Linus Pauling Institute believe that an
active lifestyle and regular exercise are critical forachieving a healthy body weight and optimum health.
But, talking the talk isn’t enough—we also need to walk
the walk! That’s why I’m taking LPI’s message about ahealthy lifestyle to the streets. I am training hard toparticipate in the August 5-6 Cascade Lakes Relay race
together with several LPI graduate students, my family,
and our team captain, Scott Leonard, a senior research

10

Spring/Summer 2011

assistant in the Institute. Our 12-member team, aptly
named “Linus Pauling Institute—Powered by Oranges,”
will have to cover 216 miles in the beautiful Oregon
Cascade Mountains, running day and night. I’m sure it
will be a very exciting—and exhausting—event! Follow
the team, read tips on staying healthy, and join us withyour support by going to http://lpi.oregonstate.edu andclicking on “Powered by Oranges.”
Balz Frei, Director, Linus Pauling InstitutePreviously, our lab utilized a transplacental mouse model
to look specifically at the ability of maternal diet to alter
cancer risk in offspring exposed to chemicals in utero
and/or through lactation. Women are unavoidably exposed
to environmental pollutants during pregnancy, and thefetus is especially sensitive to these chemicals. One classof chemicals known as polycyclic aromatic hydrocarbons(PAHs) are produced from the combustion of fossil fuels
and released into the air we breathe and the soil in which
our food grows. If pregnant mice are exposed only once
to the PAH dibenzo[def,p]chrysene (DBC), their offspring
succumb to T-cell lymphoblastic lymphomas during early
adulthood and lung tumors later in life. We have used
this model to demonstrate significant protection against
DBC-induced lung tumors and T-cell lymphomas inoffspring when the maternal diet is supplemented with2,000 parts per million (ppm) I3C.

Protecting the Fetus
from Carcinogens
Lyndsey Shorey
LPI Graduate Fellow
Summary: Feeding indole-3-carbinol (I3C), a phytochemicalfound in cruciferous vegetables, to pregnant mice can protect
against cancer in the offspring from in utero exposure tochemical carcinogens. In the body, I3C reacts to form anothercompound, diindolylmethane (DIM). Human leukemia cells
in culture treated with DIM exhibited depressed growth andincreased apoptosis (programmed cell death), which isbeneficial for cancer protection.

In 1997 a panel of scientists from the World Cancer Research
Fund and the American Institute for Cancer Research
estimated that 30-40% of all cancers could be prevented bymodifying lifestyle factors like diet and exercise. Ten years
later, the panel reported only a “probable” protective effectof fruits and vegetables on cancer risk. While vegetables are
generally known to be healthful, as they are high in fiber,
vitamins, and minerals, and low in fat and cholesterol, it has
been difficult to demonstrate a direct association between
overall vegetable consumption and cancer prevention in humans
due to the heterogeneity of exposures, genetics, and, ultimately,
the diseases collectively referred to as cancer. However, certain
types of vegetables produce phytochemicals that are notessential nutrients but may have beneficial health properties.

Multiple mechanisms exist for the anti-carcinogenic
actions of indoles and isothiocyanates. These mechanisms
are broadly classified as either blocking or suppressive,
based on the respective phases, known as initiation andprogression, of cancer development during which thesemechanisms are effective. Before the anticancer effects ofthese phytochemicals were known, their ability to modulate
metabolism and detoxication of foreign substances in the
body had been identified. Indoles and isothiocyanates are
considered blocking agents, as they are capable of altering
the rate and extent to which a person, tissue, or cell caneliminate certain carcinogens. Furthermore, thesecompounds can be effective in reducing the progressionof cancer cells by targeting what are known as cancer
survival pathways. Normal cells have intrinsic sensors
that are encoded by our DNA and prevent them from
dividing when an error in the replication machinery occurs.
When a cell is exposed to certain carcinogens, resultant
mutations in its DNA may change the code so that thesesensors are damaged or deleted, resulting in uncontrolled

Broccoli, Brussels sprouts, mustard, kale, cabbage,horseradish, and arugula are in the Cruciferae plant family
and are a rich source of a class of phytochemicals known
as glucosinolates. Glucosinolates are sulfur-containing
compounds that contribute to the sometimes bitter orpungent aroma and flavor of these vegetables. In order for
Glucobrassicin

Indole-3-carbinol

Diindolylmethane

Conversionof glucobrassicinin food todiindolylmethane
in the stomach.

myrosinase released

glucosinolates to become biologically active, they must be
metabolized by myrosinase—a plant enzyme released from theplant tissue when it’s chopped or chewed—into two classesof chemicals known as indoles and isothiocyanates, which
are widely accepted as responsible for the beneficial healthproperties of crucifers. Over 100 different glucosinolates havebeen identified, and when acted upon by myrosinase, theyyield unique products. Some glucosinolates are found in all
cruciferous vegetables, and others may be especially enrichedin particular vegetables. For example, indole-3-carbinol (I3C)
is derived from the glucosinolate glucobrassicin, abundant inbroccoli, Brussels sprouts, kale, and cabbage. Interest in
isothiocyanates as anticancer agents has been growing sincethe 1960s, and sulforaphane (SFN), derived from anotherglucosinolate (glucoraphanin), abundant in broccoli andbroccoli sprouts, has become the most studied isothiocyanate.

acid condensation reaction

regulation of cell growth and activation of the survival
pathways, leading to cancer.
My work has primarily focused on the suppressive
mechanisms of I3C on human cancer cells from a patientwith T-cell leukemia. I3C is highly unstable; when it entersan acidic environment, such as the stomach, two or more
I3C molecules readily link together to form what is known
as an acid condensation product. The primary productof this reaction is the dimer diindolylmethane (DIM). In
rodents and humans consuming I3C, very little I3C ismeasurable in plasma or urine. Therefore, DIM, which isdetectable in plasma, is thought to contribute greatly tosome of the effects attributed to I3C.

continued on page 12

The Linus Pauling Institute11

Continued from page 11 — Protecting the Fetus

stir-frying, or microwave cooking, also variably influence
the amount of glucosinolates in the edible portion of thesevegetables. Therefore, it is often difficult to demonstrate
the potential health benefits of a particular food whenlooking at highly heterogeneous human data compared tocontrolled laboratory studies.

We treated leukemia cells with I3C or DIM and foundthat many of the same molecular targets were altered byeither of the treatments, but DIM was 8-9 times more potent
than I3C. Our studies are the first to use DIM in leukemia
cells, and our results are consistent with reports in other
The concept that thecancer cells that DIM
FoodServing Serving Glucosinolates To achieve 2,000 ppm I3C
fetal and early postnatal
and/or I3C block the
Sourcesize (vol) size (g) (mg/serving)
Grams
Servings
environment may
division and proliferation
0.5
program the developing
104
Brussels sprouts 1/2 cup
44
of cancer cells and induce
20.5
0.5
98
Garden cress
1/2 cup25
12.4
individual to haveprogrammed cell death
0.6
79
Mustardgreens
1/2
cup
28
17.2
altered susceptibility toby modulating specific2.0
24
Horseradish
1 tbsp15
30.3
disease in adulthood is
cellular proteins that
0.7
67
Kale
1 cup
67
48.6
an exciting and growing
regulate these processes.
1.5
32
Watercress
1 cup
34
51.6
field of research termed
Dietary supplementation
0.8
60
Turnip1/2 cup65
52.6“fetal origins.” Currently,
1.4
with DIM also reduced
35
Cabbage (savoy)
1/2 cup
45
62.4
1.7
29
1/2 cup45
Cabbage (red)75.3
we are using the transthe growth of these
1.8
27
1/2 cup
44
Broccoli
79.1
placental model to study
human leukemia cells
2.2
22
1/2 cup
50
Cauliflower
110.3
whether the whole foods
transplanted into mice.
2.6
19
35
Bok choi (pak choi) 1/2 cup
89.4
from
which I3C, DIM,
Therefore, our data
1.6
31
Kohlrabi
1/2 cup67
104.9
and SFN are derived
support the current
can also reduce the cancer risk of offspring exposed totheory that DIM may mediate the physiological effects of I3C.
carcinogens in utero. We are supplementing the diet of
Cruciferous vegetables have great potential to reduce thepregnant mice with broccoli sprouts, Brussels sprouts, I3C,
risk of certain cancers. Epidemiological studies have
SFN, or the combination of I3C and SFN, and we will
suggested an inverse relationship between cruciferous
monitor the offspring for up to 10 months of age (middle
vegetable consumption and gastric, endometrial, andage in a mouse). This study will assess the molecular changes
colorectal cancer and cancers of the lung, prostate, breast,that occur during the development of the lymphomas andand bladder. One explanation as to why these studies
lung tumors and the amelioration of these changes by either
have been more suggestive than definitive may be genetic
the active phytochemicals or the whole foods. We will
differences in how individuals metabolize these compounds
specifically explore epigenetic mechanisms—processes that—some of us need to consume more cruciferous vegetables
result in heritable changes in regulation of genes notin order to receive the same level of protection. Cooking
involving modification of the DNA sequence—as they relate
and storage processes, such as chopping, pickling, freezing,
to the fetal origins of cancer. LPI

Micronutrients andCognitive Function
Victoria J. Drake, Ph.D.
LPI Research AssociateManager, Micronutrient Information Center

Summary: Deficiencies of vitamins (B vitamins, vitamins C,
D, and E) or minerals (calcium, iodine, iron, magnesium,
selenium, and zinc) impair cognitive function. More research,
including clinical trials, is necessary to determine if micronutrient supplementation improves cognitive abilities inhealthy people, attenuates age-related cognitive decline, or
improves mental function in patients with Alzheimer’s disease.

G

ood nutritional status is imperative for normal cognition.
Several micronutrients (vitamins and nutritionallyessential minerals) have important biochemical roles in thebrain and are needed for proper cognitive function. This
article summarizes the basic needs of the brain for cognition,
the cognitive effects of select micronutrient deficiencies, andthe present knowledge regarding the cognitive effects of
micronutrient supplementation.

12

Spring/Summer 2011

Basic Needs for Cognitive Performance
Micronutrients are directly or indirectly involved in a
number of cognitive processes that are dependent on energy
metabolism in brain cells, blood supply to the brain, synthesisof neurotransmitters (chemicals that are released from a nerve
cell and result in the transmission of an impulse to othercells), neurotransmitter binding to its receptors, nerve impulse
propagation, and homocysteine metabolism.
The brain is a highly metabolically active tissue that needs aconstant supply of glucose (sugar) to meet energy needs.
Glucose metabolism in the brain requires several vitamins,
including thiamin, riboflavin, niacin, and pantothenic acid,that function as enzyme cofactors in the oxidation of glucose
to carbon dioxide and water. Certain minerals, such as
magnesium, iron, and manganese, are also needed tocomplete the metabolism of glucose.
Proper blood supply to the brain is necessary to deliver
oxygen, glucose, and macronutrients, as well as micronutrients, for normal cognitive function. Good nutrition canhelp maintain optimal blood supply to the brain and lower
the risk of stroke—a pathological condition that results from
impaired blood supply to the brain.

Amino acids and many of the B vitamins are needed tosynthesize various neurotransmitters in the brain. In addition,
vitamin C is required for the synthesis of the neurotransmitter
norepinephrine, and the mineral zinc is needed for functioningof the neurotransmitters norepinephrine, aspartate, andgamma-aminobutyric acid (GABA). Vitamins could possibly
affect neurotransmitter binding to receptors on neurons,
thereby altering neurotransmission.

and the neurotransmitter acetylcholine. Pantothenic aciddeficiency is very rare and has been observed only in cases ofsevere malnutrition. However, deficiency of this vitamin has
been induced experimentally in humans by co-administeringa pantothenic acid antagonist and a pantothenic aciddeficient diet. Participants in this experiment complained ofheadache, fatigue, insomnia, intestinal disturbances, andnumbness and tingling of their hands and feet.

Micronutrients may indirectly influence nerve impulse
propagation by affecting the integrity of the myelin sheath ofnerves. The myelin sheath, composed of lipids and proteins,surrounds and insulates nerve fibers and functions as a conduitin an electrical system, allowing for rapid and efficient neurotransmission. Two B vitamins, folate and vitamin B12, areneeded to maintain the integrity of the myelin sheath; therefore,
these vitamins are important in nerve impulse propagation.
Additionally, the B vitamin thiamin is required for maintenanceof membrane potential and proper conductance of nerves.
Furthermore, iron is required for the development ofoligodendrocytes—myelin-producing cells of the brain.

Experimentally induced pantothenic acid deficiency inlaboratory animals has been shown to cause loss of the
myelin sheath and peripheral nerve damage.

Vitamin B6, folate, and vitamin B12, as well as the nutrientcholine, are involved in the metabolism and reduction ofhomocysteine, a sulfur-containing compound produced in
the metabolism of the amino acid methionine. Some studies
have linked elevated levels of homocysteine with cognitive
dysfunction found in dementia and Alzheimer’s disease.

Consequences of Select Micronutrient
Deficiencies
ThiaminPhosphorylated forms of thiamin (vitamin B1) are required
for reactions involved in the metabolism of carbohydrates,amino acids, and lipids, and one form of the vitamin has
been implicated in membrane functions of neurons and in
the generation of nerve impulses. Thus, inadequate intakeof thiamin can negatively affect cognition. Severe thiamindeficiency causes beriberi; the dry and wet types of beriberi
involve peripheral neuropathy, whereas cerebral beriberi canlead to cell death of neurons and the clinical conditions ofWernicke's encephalopathy and Korsakoff's psychosis,
especially in those who abuse alcohol.

NiacinNiacin (vitamin B3) is needed for a number of redox
reactions (reduction—“electron gain”, oxidation—“electron loss”) and other reactions in the body. Severe
niacin deficiency, known as pellagra, has been historicallyassociated with poverty and consumption of a dietpredominantly based on corn, which is low in bioavailable
niacin. Today, the condition is uncommon but can occur
in cases of chronic alcoholism and in individuals withmalabsorption syndromes. Neurologic symptoms of pellagra
include headache, fatigue, apathy, depression, ataxia, poor
concentration, delusions, and hallucinations, which can leadto confusion, memory loss, psychosis, dementia, and death.

Pantothenic Acid
Pantothenic acid (vitamin B5) is needed for the oxidative
metabolism of glucose and fats and also for synthesis offats, cholesterol, steroid hormones, the hormone melatonin,

Vitamin B6
Pyridoxal, pyridoxine, and pyridoxamine are collectively
called vitamin B6, which is required for the biosynthesis ofseveral neurotransmitters, including GABA, dopamine,
norepinephrine, and serotonin. Severe deficiency of vitamin
B6 is uncommon, but alcoholics are thought to be most at
risk due to inadequate dietary intakes and impaired
metabolism of the vitamin. Neurologic symptoms ofsevere vitamin B6 deficiency include irritability, depression,
confusion, and seizures.

BiotinBiotin (vitamin B7) is required for carboxylase enzymes thatare important in the metabolism of fatty acids and aminoacids. While overt biotin deficiency is quite rare, deficiencyof the vitamin has been observed in patients on prolonged
intravenous feeding (parenteral nutrition) without biotin
supplementation, in individuals consuming high amounts of
raw egg white containing a protein that binds biotin andprevents its absorption, and in those with inherited disordersof biotin metabolism. Neurologic symptoms of biotin
deficiency include depression, lethargy, hallucinations, andnumbness and tingling of the extremities.

FolateFolate (vitamin B9) is required for the metabolism of nucleic
acids (DNA and RNA) and amino acids. The vitamin isalso needed for the synthesis of several neurotransmitters,
including norepinephrine, dopamine, and serotonin, and,along with vitamin B12, folate is required in the breakdownof norepinephrine and dopamine. Dietary folate deficiency
in the absence of vitamin B12 deficiency does not cause
neurologic symptoms. However, individuals with genetic
disorders of folate metabolism have experienced seizures
and progressive neurologic deterioration.

Vitamin B12
In humans, vitamin B12 is a required cofactor for two
enzymes: methionine synthase, which is needed for the
production of methionine from homocysteine, andL-methylmalonyl-CoA mutase, which is involved in crucial
metabolic pathways. Vitamin B12 deficiency affects 10-15%
of adults over the age of 60 years. It damages the myelin
sheath of nerves and is frequently associated with neurological problems. Neurologic symptoms are the only clinicalindicator of vitamin B12 deficiency in about 25% of cases.

continued on page 14

The Linus Pauling Institute13

Continued from page 13 — Micronutrients andCognitive Function
Such symptoms include numbness and tingling of theextremities, difficulty walking, problems with concentration,
memory loss, disorientation, and dementia. Severe B12
deficiency is associated with pernicious anemia and, if untreated,
can lead to “megaloblastic madness,” characterized bydelusions and hallucinations. Atrophic gastritis, an age-related
condition resulting in diminished digestive factors, is often
associated with decreased absorption of vitamin B12 from food.

Vitamin C
Vitamin C accumulates in the central nervous system, withneurons of the brain having especially high levels. Vitamin C
is an important antioxidant that is required for the synthesisof the neurotransmitter norepinephrine, the reduction of metal(e.g., iron, copper) ions in the brain, and for the regenerationof vitamin E. Vitamin C deficiency causes oxidative damage
to lipids and proteins in the brain. Severe vitamin C deficiency,
called scurvy, is potentially fatal. In scurvy, vitamin C is retainedby the brain for neuronal function, and eventual death fromthe disease is more likely due to lack of vitamin C for thesynthesis of collagen—an important structural component ofblood vessels, tendons, ligaments, and bone. Vitamin C isalso required for the conversion of dietary lysine to carnitine,
a compound essential for energy production in the cells’
mitochondria. Hence, scurvy is characterized by fatigue anddepression in addition to physical manifestations.

Calcium
Calcium ions are important intracellular signals that regulate
a number of physiological processes, including neuronal gene
expression and neuronal secretion of neurotransmitters.
Normal blood levels of calcium are maintained even when
dietary intake of calcium is inadequate because the skeleton
provides a large reserve of the mineral. Thus, dietary calcium
inadequacy primarily affects bone health.

IodineIodine is required for the synthesis of thyroid hormones,
which are important for myelination of the central nervous
system. Iodine is critical for normal development of the brain;
therefore, deficiency of this mineral during critical periods offetal development or childhood can have deleterious effects
on cognition. The most extreme cognitive effect of developmental iodine deficiency is irreversible mental retardation;
milder cognitive effects include various neurodevelopmental
deficits, including intellectual impairment.

Iron
Iron is an essential component of hundreds of proteins andenzymes involved in various aspects of cellular metabolism.
The mineral is needed for proper development of oligodendrocytes (the brain cells that produce myelin) and for several
enzymes that synthesize neurotransmitters. Accordingly, irondeficiency during various stages of brain development has
negative consequences. Maternal iron deficiency during
pregnancy has serious consequences for the woman and thefetus, including permanent learning and memory deficits inthe offspring. Iron deficiency during childhood may be
associated with impaired cognitive development.

Magnesium

Vitamin D
Vitamin D is important for normal brain development andfunction, and vitamin D deficiency may impair cognitive
abilities. Some studies in older adults have either linked
lower 25-hydroxyvitamin D levels—the clinical indicatorin the blood of vitamin D status—with measures of poorcognitive performance or higher 25-hydroxyvitamin D levels
with measures of better cognitive performance. However, theassociation between 25-hydroxyvitamin D concentrations
and cognitive performance is not yet clear.

Vitamin E
In the brain and other tissues, the alpha-tocopherol form ofvitamin E is a key fat-soluble antioxidant that prevents lipid
peroxidation and helps to maintain the integrity of cell
membranes. Thus, vitamin E deficiency causes lipid peroxidation in brain tissues. Severe vitamin E deficiency results
mainly in neurological symptoms, including impaired balanceand coordination (ataxia), injury to the sensory nerves(peripheral neuropathy), muscle weakness (myopathy), anddamage to the retina of the eye (pigmented retinopathy).

14

Spring/Summer 2011

Magnesium is required for more than 300 metabolic reactions,many of which are important for normal brain function. Overt
magnesium deficiency has been induced experimentally andresults in neurologic and muscular symptoms that include
tremor, muscle spasms, and tetany (involuntary muscle
contractions). According to recent surveys, many Americans
do not have an adequate intake of magnesium.

Selenium
Selenium is required for glutathione peroxidases (GPx),
important antioxidant enzymes in the brain and other tissues.
Selenium deficiency has been associated with decreased
GPx activity in the brains of laboratory animals and may
be linked to a reduced antioxidant capacity in the brain.

Zinc
Zinc is present at high levels in the brain, where it has
catalytic, structural, and regulatory roles in cellular metabolism.
In the brain, most of the zinc ion is tightly bound to proteins,but free zinc is present in synaptic vesicles and has a role inneurotransmission mediated by glutamate and GABA.
Experimentally induced zinc deficiency in humans has beenshown to impair measures of mental and neurologic
function. However, deficiency of the mineral during critical
periods of cognitive development can be more devastating,causing congenital malformations or deficits in attention,
learning, memory, and neuropsychological behavior.

Developments
Michele Erickson
LPI Director of Development

The charitable gift annuity:
It’s a win-win. For you and for LPI.

L

inus Pauling left an enduring legacy with his
contributions to science, peace, and healthyliving. And you can continue that legacy—with
financial benefits for you today—through acharitable gift annuity (CGA).

It’s simple: For a donation of cash or securities
valued at $25,000 or more, the OSU Foundation
invests your gift and pays you an annuity for life.
After your lifetime, the remaining assets are
distributed to the Linus Pauling Institute at OSU.
The annuity rate—locked in for life—depends on
your age at the time of your gift. It’s also higher thancurrent rates for CDs and money market accounts—
making a charitable gift annuity both a good way tosupport LPI and strengthen your retirement plans.
You’ll also see tax benefits. In many cases, a large
portion of your annual payment is tax free. You’ll
receive a tax deduction for your initial gift, and it
may reduce taxes on your estate.

Choline
Although not considered a vitamin, choline is an essential
nutrient needed for myelination of nerves, synthesis of theneurotransmitter acetylcholine, and synthesis of various
structural and cell-signaling molecules, including phospholipids (phosphatidylcholine and sphingomyelin) that areimportant components of cell membranes. Choline deficiency
during the perinatal period in laboratory animals results inpersistent memory and other cognitive deficits in offspring.

Effects of Micronutrient Supplementation
Compared to the consequences of micronutrient
deficiencies, considerably less is known about the cognitiveeffects of micronutrient supplementation. Overall, there iscurrently little evidence that micronutrient supplementation
provides cognitive benefits related to attention, memory, or
executive functions (higher-order cognitive processes that
include reasoning, planning, strategic thinking, problem
solving, and multitasking). Some studies, however, havereported that multivitamin/mineral supplementation may
benefit subjective measures of mood and psychological wellbeing. Additionally, evidence that supplementation with B
vitamins or antioxidant vitamins prevents age-associatedcognitive decline is largely lacking, although randomized
controlled trials (RCTs) of longer duration are needed.
Linus Pauling was interested in the relationship of critical
micronutrients and enzymes with mental function, including

Sample rates based on $25,000 CGA:Age ofannuitant

65

70

75

80

85

90

Annuity
rate*

5.5%

5.8%

6.4%

7.2%

8.1%

9.5%

Annualpayment$1,375 $1,450 $1,600 $1,800 $2,025 $2,375

Charitable $7,004 $9,014 $10,630 $12,244 $14,023 $15,420
deduction***These rates represent the rate schedule put into effect 7/1/2010 by the American Council
on Gift Annuities (ACGA) and are subject to change.
**Assumes an IRS discount rate of 3.0%.

Call or e-mail to learn more:
Julie Irmer
OSU FOUNDATION | OFFICE OF GIFT PLANNING
800-336-8217 • Gift.Planning@oregonstate.edu
campaignforosu.org/giftplanning
Rates are subject to change. This information should not be consideredor relied upon as legal advice. Before entering into a planned giving
arrangement with any charitable organization, donors should seek theirown professional legal and tax advice. The OSU Foundation does notengage in the marketing of services pertaining to individualized advice
about estate distribution documents. Attention California residents:
Payments made under a charitable gift annuity are subject to regulationby the California Insurance Department but are not insured or otherwise
guaranteed by the California Life Insurance Guaranty Association.
LPI

mental illness. He discussed the exquisite chemicalsensitivity of the brain to vitamin deficiencies and addressed
the theoretical basis for micronutrient supplementation
to help treat mental illness in his seminal paper,
Orthomolecular Psychiatry, published in 1968 in Science.
To date, many of the RCTs of micronutrient
supplementation have employed elderly subjects orindividuals with pathological conditions like Alzheimer’s
disease. Thus, there is a need for well-designed, largescale, long-term RCTs in healthy adults and in children.
In addition, the available RCTs have used a number ofdifferent cognitive assessments; therefore, more standardized
approaches would be useful to interpret evidence acrossstudies. Studies that measure micronutrient status in bloodand correlate that with cognitive function are also needed
to better assess the role of micronutrients in cognition.
Furthermore, intervention trials in individuals withmicronutrient deficiencies are required to fully assess therole of micronutrient supplementation in populations withinadequate or marginal micronutrient status.
For more detailed information on micronutrients andcognition, see the article in the Micronutrient Information
Center: http://lpi.oregonstate.edu/infocenter/cognition.html.
This article was underwritten, in part, by a grant fromBayer Consumer Care AG, Basel, Switzerland. LPI

The Linus Pauling Institute15

Linus Pauling Institute

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Checks should be payable to
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Information on giving isavailable through the
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Micronutrient
Research for
Optimum Health
Printed on recyclable paperusing soy inks

Save the Date! October 14, 2011
Construction isnearing completionon the new
Linus Pauling
Science Center.
SAVE THE DATE
to join us for the
Building Dedication
Ceremony on
October 14, 2011.

Look for these informative articles inside!
Page 1 ..... From the Director
Page 1 ..... Not All Fats Are Created Equal

Page 10 ..... The New Dietary Reference
Intakes for Vitamin D

Page 6 .... MicroRNAs Play Critical Rolesin Development Responses toDietary Constituents

Page 11 .... Protecting the Fetus

Page 8 .... 6th International Conference
on Diet and Optimum Health

Cognitive Function

from Carcinogens

Page 12 .... Micronutrients andPage 15 ..... Developments

Special thanks to Barbara McVicar for editorial assistance and photographs,
authors of signed articles, and Dick Willoughby for the logo photograph of Linus Pauling.