SPRING/SUMMER 2011 Oregon State University The

Not All Fats AreCreated Equal

Linus PaulingInstitute

The

From theDirectorBalz Frei, Ph.D.LPI Director and Endowed ChairOSU Distinguished Professor ofBiochemistry and Biophysics

R E S E A R C H N E W S L E T T E R

continued on page 2continued on page 2

Center of Excellence for Research on Complementary and Alternative Medicine— DESIGNATED BY THE NATIONAL INSTITUTES OF HEALTH AS A —

Oregon State University

F

S P R I N G / S U M M E R 2 0 1 1

An Interview with Donald B. Jump, Ph.D.Professor of NutritionLPI Principal Investigator

or three reasons, 2011 is a banner year for the LinusPauling Institute. First, the new Linus Pauling Science

Center is nearing completion and will open its doors inAugust. The architects, general contractor, and projectmanager have done an outstanding job keeping constructionof the new building near-flawless, on schedule, and onbudget. The $62.5 million, 105,000-square-foot sciencecenter is the most expensive academic building project inthe history of Oregon State University and will be a workingmemorial to our founder and OSU alumnus, Dr. LinusPauling. The top two floors of the four-story building willbe dedicated to the Institute and provide state-of-the-artlaboratory space for our faculty, students, and researchstaff in the Institute’s three major research programs:the Cancer Chemoprotection Program, the Healthy AgingProgram, and the Cardiovascular and Metabolic DiseasesProgram. The new building will represent a leap forwardfor 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 laboratoryand office space for two new Principal Investigators inthe Healthy Aging Program. This program, directed bylong-time LPI faculty member and Jamieson EndowedChair in Healthspan Research, Dr. Tory Hagen, has twoprincipal 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

Q. You’re from the East Coast, but you spent a fewyears at Oregon State University in the 1970s.What were you doing here then?

A. I was working with George Beaudreau in theDepartment of Agricultural Chemistry. I had completedmy master’s degree at Rutgers and wanted a change.I grew up in Delaware, where the highest point is 400feet above sea level, and I had seen pictures of the Westand thought that would be a great place to go. Whiledoing my master’s work, I worked for the Institute ofCancer Research and learned how to culture cells,mainly mammary cancer cells. I worked with Georgefor 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 professorat Michigan State University and then joined theLinus Pauling Institute in 2007. What attractedyou to LPI?

A. LPI is an internationally recognized center fornutrition research with a strong focus in the area ofmicronutrients, antioxidants, and supplements. Myarea of research is omega-3 fatty acids as regulators oflipid metabolism. Omega-3 fatty acids, also called n-3fatty acids, are often taken as supplements. N-3 fattyacids are generally beneficial to human health. I wasattracted to the LPI because of its capacity to carry outsophisticated analyses of lipids using chromatographicand 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 in

Continued from cover — Interview with Dr. Donald JumpContinued from cover — From the Director

2 Spring/Summer 2011

dietary supplements, to postpone age-related diseasesand 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 healthyaging. I am looking forward to introducing our newfaculty member to you in the next Research Newsletter.The final position in the Healthy Aging Program, whichwe hope to fill in the next two years, will focus on thecausation and prevention of age-related neurodegenerativediseases, such as Alzheimer’s or Parkinson’s disease.

Third, in 2011, we will hold our Diet and OptimumHealth 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 sessionson the role of diet and micronutrients in immunefunction, cardiovascular diseases, and healthy aging,as well as two sessions focusing on vitamin E andprobiotics. The detailed program with all the speakersand 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 anti-inflammatory factors in promoting health and preventingdisease. The awardee will join our illustrious list ofprevious winners, Drs. Bruce N. Ames from theUniversity of California, Berkeley, and Children’sHospital Oakland Research Institute; Walter Willettfrom Harvard; Paul Talalay from Johns Hopkins;Mark Levine from the National Institutes of Health;and Michael Holick from Boston University School ofMedicine. The fall edition of the Newsletter willprovide a summary of the conference and a detailedprofile of this year’s LPI Prize winner, along with aglimpse of the new Linus Pauling Science Center. LPI

2007; we have renovated some parts of the house andmade some improvements to the property. We alsohave a boat and like to sail off South Beach nearNewport. We really like the coast. I grew up on theEast 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 thyroidhormones on liver function. What did you find?

A. Thyroid hormones are hydrophobic hormones thatregulate nuclear receptors; these receptors regulate geneexpression. When I was a post-doctoral fellow at theUniversity 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 atthe 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 carbohydratesand thyroid hormone—a synergy in the control ofgenes involved in lipid metabolism. Glucose, insulin,and thyroid hormones were found to regulate multiplegenes involved in liver fat metabolism. At MSU, wehad established mechanisms to measure gene expressionin the liver; we carried out time-course studies toexamine the effects of thyroid hormone action andsucrose (a simple carbohydrate) on liver gene expression.We applied this same approach to examine the effect ofdietary fat and carbohydrate on liver gene expression.Rats were fed high-sucrose diets or diets supplementedwith n-3 and n-6 fatty acids to examine their effectson liver gene transcription. Sucrose stimulated theexpression of genes that make fat, while polyunsaturatedfatty acids attenuated the expression of these genes.This discovery was the first to document effects ofdietary 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 regulatescertain genes involved in lipid metabolism.What impact does that have on health?

A. That’s an interesting question. It turns out that thethyroid hormone receptor interacts with a form of theretinoic acid receptor in cells. Both receptors functionto 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 connectivetissue—to adipocytes or fat cells. We found that noneof the cells responded to thyroid hormone, whichprompted us to look at retinoic acid regulation ofadipocyte function. That’s when we found a retinoicacid regulatory scheme. While interesting, theimplications of this finding to human health remain unclear.

LPI is grateful for the bequests

we have received from the

following friends this pastyear:

Dorothy B. Alcocer

Audrey M. Carlan

(pledged intent)

Frances Reilly Cunningham

Arthur Kahn

Sidney Licht

Victoria J. Mastrobuono

Janet P. Roberts

Francis B. Rosevear

Earl Winston Schulz

Christen J. Wegener

George B. Whatley

continued on page 4

The Linus Pauling Institute 3

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 howdietary fats affect liver genes that regulateendogenous 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. Humandiets typically contain more saturated and mono-unsaturated fats than polyunsaturated fats.

Q. What are the differences between saturated,monounsaturated, and polyunsaturated fats?

A. The term saturation refers to the absence of chemicaldouble 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 fattyacids have one double bond; polyunsaturated fattyacids have two or more double bonds. The bulk offatty acids are found in cell membranes and storagelipids, like triglycerides. Fatty acids in membranesaffect the structure and function of the membrane.A bulky lipid—an unsaturated fat—or a non-bulkylipid like a saturated fat will influence the structure ofthe membrane and the function of proteins imbeddedin membranes differently. There are many receptors inplasma membranes that communicate environmentalsignals 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 optimumconcentration of the various types of fats in thebody to maintain proper membrane fluidityand function.

A. Yes, but that optimum concentration is likely to beinfluenced by gender, age, genetic background, andhealth status.

Q. What about trans fat?A. Trans fat is unsaturated fat, but the double bond is in

a different configuration. There are two fundamentalconfigurations for double bonds, either trans or cis.Natural double bonds in corn oil are in the cisconfiguration, whereas the hydrogenation of corn oilproduces fatty acids with the trans configuration.Unsaturated fats with the trans configuration behavemore 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.

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. Inn-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 of

the saturated and unsaturated fatty acids of the variousclasses that we just discussed. The predominant n-3fatty acid in plants is alpha-linolenic acid. It’s found insoybean oil, canola oil, and walnuts. Olive oil containsn-9 fatty acids like oleic acid. Linolenic and alpha-linolenic acids are essential fatty acids that we have toget from our diet in order to make longer chain poly-unsaturated fatty acids that are very important inbiological functions—the long chain, highly unsaturatedn-3 fatty acids are found in salmon, other cold waterfish, and in fish oil supplements (anchovy oil). These areknown 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 arenot efficiently converted to n-3 forms in ourbodies, does this suggest that early humansconsumed lots of fish?

A. This is an interesting question. There is some evidencesuggesting that humans in the plains of Africa migratedto the coast. Once there, they would have had moreaccess to fish that are enriched in very long chain n-3fatty 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 acidsdon’t have unusual health problems. Also, certain tissuesmaintain their lipids despite significant variation in diet.

OMEGA-3 (n-3) AND OMEGA-6 (n-6) FATTY ACIDS

Carboxyl end n-3 Methyl end

HO

O

HO

O

3rd carbon

6th carbon

Carboxyl end 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 bondsare indicated by parallel lines.


Continued from page 3 — Interview with Dr. Donald Jump

Q. Are sufficient amounts maintained because ofthe slow turnover and slow loss in the brainand nervous tissue?

A. That is one interpretation, but more study is requiredto 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 asregulators 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 makingstorage lipids like triglycerides. An early step inmaking triglycerides is adding oleic acid to glycerol-phosphate. Triglycerides are the main storage formfor lipids in adipose tissue in our bodies. Elevatedtriglycerides in the blood are an independent riskfactor for cardiovascular disease.

Q. Why do elevated triglyceride levels contributeto heart disease?

A. Good question! High blood triglyceride levels may bea marker for abnormal or ectopic storage of lipids intissues. Accumulating triglycerides in muscle, liver,and other tissues induces inflammation and insulinresistance, resulting in type-2 diabetes. Type-2 diabetesis 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 the

synthesis of triglycerides by lowering the cellular levelof substrates for triglyceride synthesis. This is achievedby inhibiting fatty acid synthesis and enhancing fattyacid 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 causehealth problems. Our modern diets provide too muchn-6 and not enough n-3 fatty acids. The n-6 fattyacids are precursors to inflammatory lipids. Andinflammatory lipids play an important protective rolein many biological functions that are very important.When n-6 fatty acids are in excess, they tip the balanceto 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, calciumflux, hormone regulation, cell growth, metabolism,vasodilation, bronchodilation, and other functions.Isoprostanes are eicosanoids made from the free-radical

mediated peroxidation of the n-6 fatty acid, arachidonicacid, 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 thatcan 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 lipidsand 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 fattyacids promote the progression of colon cancer, while n-3fatty 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 ofdietary fat on cancer. In contrast, excess body fat is arisk factor for numerous cancers.

Q. Is there much evidence that fish oilsupplementation 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 fatsand their impact on health and disease. Many scientistsare trying to find out if studies carried out in cell cultureand animals are applicable to humans. N-3 fatty acidsare clearly beneficial in the control of blood triglyceridelevels and in cardioprotection. These clinical trials mayreveal beneficial effects of n-3 fatty acids on otherprocesses, like inflammation and cognitive function.

Q. Are the doses used in these animal studiesgreater 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 fattyliver disease, we look at the effect of EPA, DHA, and acombination of EPA and DHA. Most fish oil capsulescontain 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, whichis a key event in blood coagulation. If you take thesecompounds and use fish oil, you may significantlyincrease the time it takes to stop bleeding. If someoneis 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 acidshas changed dramatically over the past fewgenerations as our diets have changed. Do weknow anything about the optimal ratio?


A. In general, a high n-6 to n-3 ratio is consideredpro-inflammatory. More studies are required to definethe optimal ratio.

Q. Do you think that consuming fatty fish a coupletimes a week is equivalent to taking a fish oilsupplement or is it better to take a fish oilsupplement 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 bottleand make sure that it has a level of DHA and EPA thatis consistent with cardiovascular protection—about500 mg of combined DHA and EPA per day—as anabsolute minimum.

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 triglyc-erides but may elevate cholesterol in some individuals.Consumption of fish oil changes the characteristics ofthe polyunsaturated fatty acids within the arterial wallso 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 membranephospholipid metabolism by phospholipases generatesn-6 fatty acids that enter the prostaglandin synthesispathway and produce inflammatory eicosanoids.Membrane-associated n-3 fatty acids are less likely tobe 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 ofinflammatory 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, alpha-linolenic acid is not as efficacious in cardioprotectionas DHA and EPA. Thus, supplementing the diet withDHA 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 epidemicamong children and adults in America. Howwould 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 the

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 carbohydrateintake will contribute to increased fat deposition. Thebody has only so much capacity to store carbohydrates,and it does so in the form of glycogen. If you fill upthe glycogen pool, the rest becomes fat. Dietary fat, onthe other hand, is also very important because of thenature of the fat that we eat, which tends to be morebiased toward saturated and monounsaturated fatsand less polyunsaturated fats, resulting inimbalances in the distribution of fat in tissues.

Q. Last summer the mediareported your discovery thatdiabetic 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 workmay have promise for an alternative method to treatsome diabetic complications. Humans with metabolicsyndrome and obese mice that have characteristics ofmetabolic syndrome have a polyunsaturated fat profilein blood that is different from normal, healthy humansor mice. A large number of enzymes in the liverparticipate in the production of polyunsaturated fattyacids. We examined the effect of obesity and diabeteson these enzymes and found that one enzyme, calledelongase-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 anadenovirus to contain the gene expressing fatty acidelongase-5. Infection of mice with the adenovirus leadsto the expression of the enzyme in the liver and noother tissue. The liver starts making more of theenzyme 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 increasethe expression of this enzyme. Fibrates are used to

continued on page 7


Robert Tanguay, Ph.D., OSU Distinguished Professor of Molecular ToxicologyDepartment of Environmental and Molecular Toxicology

Summary:MicroRNAs—non-coding RNAs that affectgene regulation—have emerged in recent years as importantregulators of many cellular and physiological processes.In zebrafish, microRNAs prevent excess vitamin A fromcausing spine defects during development. Exposure toalcohol during early development in zebrafish interfereswith microRNA activity, resulting in abnormalities in thedevelopment of the nervous system.

t is well established that dietary constituents can eitherpositively or adversely affect fetal development, but we

don’t have a good understanding of the relevant mechanisms.As you may remember from biology class, there are severalforms 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 fundamentalphysiological and cellular processes and has been increasinglyimplicated in cancer, immune disorders, and cardiovascular,neurodegenerative, and metabolic diseases. MicroRNAs(miRNAs) are a class of ncRNA molecules that arepredicted to post-transcriptionally regulate the expressionof 30-60% of all human protein-coding genes, and as such,microRNAs play key roles in cellular and developmentalprocesses. MicroRNAs have emerged as targets ofdevelopmental, hepatic, neurological, and carcinogenictoxicological agents and have increasingly been identified asregulators of xenobiotic-metabolizing enzymes. The goal ofour pilot study funded by LPI was to determine whethermisregulation of miRNA expression during developmentconstitutes a specific mechanism by which developmentaltoxicants exert their effects.

Vitamin A is necessary for normalvertebrate growth and development.Jill Franzosa, a graduate student inmy laboratory, investigated thedevelopmental role of miRNAs usingan active form of vitamin A, all-transretinoic acid (RA). We know thatexcesses or deficiencies of RA adverselyaffect development. In this study, we

demonstrated that treating zebrafish in early developmentalstages with RA results in a distinct curved body axis similarto the axis and spine defects observed in other vertebrates,including humans. To determine whether specific miRNAsare misexpressed after RA exposure, gene analyses wereconducted at several critical developmental stages.Strikingly, the expression of three miRNA family members

MicroRNAs Play Critical Roles in DevelopmentResponses to Dietary Constituents

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 alsoshowed that repression of the implicated miRNA by geneticalterations resulted in similar embryonic defects. Whenspecific miRNA mimics were injected into embryos, axisdefects induced by developmental exposure to RA wereprevented. Together, these results indicate that the axisdefects elicited by exposure to RA during developmentresult partly from repression of specific miRNAs andsubsequent misregulation of cyp26a1. This study sheds lighton the role of miRNAs in mediating the teratogenic effectsof 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 fellowTamara Tal used alcohol as a neuro-toxicant in zebrafish to examine therole of miRNAs in the development ofa functional nervous system. WhilemiRNAs are critical to nervous systemdevelopment, the neurobehavioralfunction of miRNAs is unknown.Prenatal alcohol exposure produces a

range of conditions in offspring, collectively referred to asfetal alcohol syndrome disorder (FASD). Epidemiologicalstudies suggest that the majority of children with FASDhave deficits in neurobehavioral function, even in theabsence of clinically discernable physical abnormalities.We assessed larval zebrafish neurobehavior by measuringthe 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 thathad been developmentally exposed to alcohol.

At developmental stages inzebrafish coincident withalcohol-induced neuro-behavioral abnormalities,expressions of multiplemiRNAs in the centralnervous system weresignificantly altered.Subsequent computationalanalyses revealed thatalcohol disrupts expressionof miRNAs that directneurogenesis.

I

Jill Franzosa

Dr. Tamara Tal

Zebrafish embryo


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

Our research resulted in numerous awards andrecognitions. Jill Franzosa’s research was honored with theElsevier best platform presentation award in toxicogenomicsat the 2010 Society of Environmental Toxicology andChemistry annual meeting, first place poster award at the2010 Pacific Northwest Association of ToxicologistsConference, poster award winner at the 2010 AquaticAnimal Model for Human Disease Annual Meeting, firstplace in the Molecular Biology graduate student award atthe 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 microRNAswas recognized at the 2010 Pacific Northwest Associationof Toxicologists Regional Conference, won a first-placeposter award at the 2010 International NeurotoxicologyConference, won a first-place postdoctoral research awardfrom the Molecular Biology specialty session, and won asecond-place poster award from the Neurotoxicologyspecialty section at the 2010 Society of Toxicology annualmeeting. Both Dr. Tal and Jill Franzosa recently presentedtheir research in the symposium session titled “Uncoveringthe role of microRNAs in toxicology” at the 2011 Societyof Toxicology annual meeting.

Based upon the success of this project, Jill was alsoawarded a prestigious predoctoral National Institutes ofHealth Ruth L. Kirschstein NRSA Fellowship to investigatethe role of microRNAs in aging. Together, these findingswill generate new fundamental knowledge about the role ofmicroRNAs in mediating basic biological responses tochemical or dietary toxicological insult.

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 developdiabetes and metabolic syndrome as you grow older.I think dietary supplements of n-3 fatty acids areprudent for just about everybody as long as they arenot on an anticoagulant therapy.

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

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 therapyapproach” described above. We are defining themechanism used by polyunsaturated fatty acids tocontrol diabetic complications.

LPI

LPI

Continued from page 5 — Interview with Dr. Donald Jump

Zebrafish

Bill Town’s Story of Inspirations a dedicated high school science teacher, Bill Townwas creative in his efforts to inspire his students.

He decided the class needed a scientific hero whoworked in a lab. Bill’s choice was Linus Pauling, atwo-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 Februarytradition 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 inspirationfor him and his students, Bill felt remembering theLinus Pauling Institute in his will was a fitting way ofthanking 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 giftwill 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 LinusPauling Institute Legacy Circle. Contact Michele Ericksonat 541-737-3744 or [email protected].

A

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

september 13-16, 2011 • corvallis, ORegon • USA

Tuesday, September 13, 2011

2:OOpm Registration begins

3:00 Welcome and Opening RemarksBalz Frei, Linus Pauling Institute,Oregon State University, Corvallis, OR

SESSION 1 - 3:15 TO 5:15 PM

VITAMIN E: BIOLOGICAL FUNCTIONSAND CONTROVERSIES

Chair: Maret Traber, Linus Pauling Institute,Oregon State University, Corvallis, OR

3:15 The α-tocopherol transfer protein:Biochemical mechanisms and healthimplicationsDanny ManorCaseWestern Reserve University, Cleveland, OH

3:45 Anti-inflammatory effects of vitamin Eforms and their metabolitesQing JiangPurdue University,West Lafayette, IN

4:15 The effect of vitamin E supplementation oncardiovascular risk in diabetic individualswith different haptoglobin phenotypesAndrew P. LevyTechnion Faculty of Medicine,Technion-IsraelInstitute of Technology, Haifa, Israel

4:45 Does vitamin E decrease chronic diseaserisk by protecting against free radicals?Etsuo NikiNational Institute of Advanced IndustrialScience andTechnology, Osaka, Japan

6:30 Welcome Reception and Tour of theLinus Pauling Science Center

6th international conference on


Wednesday, September 14, 2011

6:00am Organized Walk/Run

7:30 Breakfast provided

SESSION 2 – 8:30 AM to Noon

MICRONUTRIENTS, DIET,AND IMMUNE FUNCTION

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

Corvallis, OR

8:30 Nicotinamide (vitamin B3) and innate immuneresponse to microbial infectionGeorge LiuCedars-Sinai Medical Center and UCLASchool of Medicine, Los Angeles, CA

9:00 Vitamin D and infectious diseasesCarlos A. Camargo, Jr.Harvard Medical School, Boston, MA

9:30 The impact of nutrition on the immuneresponse against influenzaElizabeth M. GardnerMichigan State University, East Lansing, MI

10:00 Coffee/Tea Break

10:30 Zinc, inflammation, and susceptibility to sepsisDaren KnoellThe Ohio State University, Columbus, OH

11:00 Inflammation, neutrophil function, and traceelement status in the morbidly obesePam J. FrakerMichigan State University, East Lansing, MI

11:30 Polyunsaturated fatty acids and their impacton the immune systemRobert S. ChapkinTexas A&M University, College Station,TX

12:00 Lunch provided

DIET and OPTIMUM HEALTH

8:30 Protective effect of resveratrol in miceand monkeysJulie MattisonAging, Metabolism, and Nutrition Unit,National Institute on Aging, Baltimore, MD

9:00 How to help your mouse live longer: Diets,drugs, MIF-KO, and sibsRichard MillerUniversity of Michigan, East Lansing, MI

9:30 Lipoic acid and healthspan: Mechanismsof actionTory HagenLinus Pauling Institute, Oregon State University,Corvallis, OR


10:30 Protein and metabolic homeostasis in agingand longevityGordon J. LithgowThe Buck Institute for Research on Aging, Novato, CA

11:00 Mitochondrial decay in human aging:A translational approachChrisitaan LeeuwenburghUniversity of Florida, Gainesville, FL

11:30 Rapamycin and dietary restriction: Do they sharea common mechanism in lifespan extension?Viviana PerezUniversity of Texas Health Science Center atSan Antonio, San Antonio,TX

12:00 Lunch provided

SESSION 6 – 1:20 to 4:00 PM

ORAL ABSTRACTS AND YOUNGINVESTIGATOR AWARD FINALISTS

Eight 20-minute talks;TBA



LPI PRIZE CEREMONY AND PLENARYLECTURE BY AWARDEE

Chair: Balz Frei, Linus Pauling Institute,Oregon State University, Corvallis, OR

6:30 Reception

7:00 Banquet Dinner

Friday, September 16, 2011

Travel Day



DIET AND CARDIOVASCULAR DISEASEChair: Balz Frei, Linus Pauling Institute,Oregon State University, Corvallis, OR

1:30 A diet based on high-heat-treated foods promotesrisk factors for diabetes mellitus andcardiovascular diseasesVeronika SomozaUniversity of Vienna,Vienna,Austria

2:00 Dietary patterns and risk of mortality fromcardiovascular diseaseTeresa FungSimmons College and Harvard School of Public Health,Boston, MA

2:30 New evidence on the effects of aMediterranean-style diet on cardiovascular diseaseRoman EstruchHospital Clinic, University of Barcelona, Barcelona, Spain



GUT MICROBES AND PROBIOTICS –ROLE IN HEALTH AND DISEASEChair: Sharon Krueger, Linus Pauling Institute,

Oregon State University, Corvallis, OR

3:30 The human microbiome and cancerCindy DavisDivision of Cancer Prevention, National Cancer Institute,Bethesda, MD

4:00 Evolutionary glycomics: Breast milkoligosaccharides and bifidobacteria infantisJ. Bruce GermanUniversity of California, Davis, CA

4:30 Pre and probiotics: Food fad or bacterial therapy?Robert G. MartindaleOregon Health & Science University, Portland, OR

5:00 - 7:00pmPoster Session, hors d'oeuvres and drinks provided

Thursday, September 15, 2011

6:00am Organized Walk/Run

7:30 Breakfast provided

SESSION 5 – 8:30 AM to Noon

CALORIC 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 Centerat San Antonio, San Antonio,TX

For more information about the Conference,please visit the LPI Web site at

http://lpi.oregonstate.edu/conf2011 or phonethe Institute at 541-737-5075.

The New Dietary Reference Intakes for Vitamin DAdrian Gombart, Ph.D., Associate Professor of Biochemistry and Biophysics

LPI Principal Investigator


he Institute of Medicine (IOM) released new dietaryreference intakes (DRIs) for calcium and vitamin D on

November 30, 2010. The IOM concluded that vitamin Dplays a key role in bone health and that current evidencedoes not support other health benefits from vitamin Dsupplementation, although the IOM called for additionalresearch 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 IOMraised the RDA in children (1-18 years) and adults (19-70years) from 200 IU to 600 IU per day and raised thetolerable upper intake level (UL) for adults from 2,000 IUto 4,000 IU per day. For the elderly (>70 years), the RDAwas increased to 800 IU per day. The majority of vitamin Dexperts 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 hasbeen used extensively by physicians. During the pressconference, they said that it was warranted by the availablescientific 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 changewill likely cause significant confusion for both physiciansand their patients, but it should be noted that it is onlyrelevant to bone health and may not be optimal for otherhealth benefits that have been attributed to vitamin D.

While the new RDA may bring many people into the newsufficient 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 decisionson a lack of randomized controlled trials (RCTs) thatdemonstrate a clear benefit from taking vitamin Dsupplements beyond bone health, but there is overwhelmingevidence 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 clearwhen applied to micronutrients. For example, subjects inthe placebo group in an RCT will still have some of themicronutrient under evaluation in their bodies—unlike anRCT testing drugs; otherwise, they would get deficiencydiseases. While anecdotal reports or single studies seem tobe good enough for the IOM to determine the UL, multipleRCTs demonstrating similar outcomes are required for theRDA. 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 bythe IOM and should ensure that individuals, particularlyin 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 LPIMicronutrient Information Center section on vitamin D(http://lpi.oregonstate.edu/infocenter/vitamins/vitaminD).

ll of us at the Linus Pauling Institute believe that anactive lifestyle and regular exercise are critical for

achieving a healthy body weight and optimum health.But, talking the talk isn’t enough—we also need to walkthe 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 racetogether with several LPI graduate students, my family,and our team captain, Scott Leonard, a senior research

assistant in the Institute. Our 12-member team, aptlynamed “Linus Pauling Institute—Powered by Oranges,”will have to cover 216 miles in the beautiful OregonCascade Mountains, running day and night. I’m sure itwill be a very exciting—and exhausting—event! Followthe 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

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Powered by Oranges!

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Previously, our lab utilized a transplacental mouse modelto look specifically at the ability of maternal diet to altercancer risk in offspring exposed to chemicals in uteroand/or through lactation. Women are unavoidably exposedto 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 fuelsand released into the air we breathe and the soil in whichour food grows. If pregnant mice are exposed only onceto the PAH dibenzo[def,p]chrysene (DBC), their offspringsuccumb to T-cell lymphoblastic lymphomas during earlyadulthood and lung tumors later in life. We have usedthis model to demonstrate significant protection againstDBC-induced lung tumors and T-cell lymphomas inoffspring when the maternal diet is supplemented with2,000 parts per million (ppm) I3C.

Multiple mechanisms exist for the anti-carcinogenicactions of indoles and isothiocyanates. These mechanismsare 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 modulatemetabolism and detoxication of foreign substances in thebody had been identified. Indoles and isothiocyanates areconsidered blocking agents, as they are capable of alteringthe 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 cancersurvival pathways. Normal cells have intrinsic sensorsthat are encoded by our DNA and prevent them fromdividing when an error in the replication machinery occurs.When a cell is exposed to certain carcinogens, resultantmutations in its DNA may change the code so that thesesensors are damaged or deleted, resulting in uncontrolled

regulation of cell growth and activation of the survivalpathways, 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 moreI3C molecules readily link together to form what is knownas an acid condensation product. The primary productof this reaction is the dimer diindolylmethane (DIM). Inrodents 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.

Protecting the Fetusfrom CarcinogensLyndsey ShoreyLPI Graduate Fellow

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

n 1997 a panel of scientists from the World Cancer ResearchFund 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 yearslater, the panel reported only a “probable” protective effectof fruits and vegetables on cancer risk. While vegetables aregenerally known to be healthful, as they are high in fiber,vitamins, and minerals, and low in fat and cholesterol, it hasbeen difficult to demonstrate a direct association betweenoverall vegetable consumption and cancer prevention in humansdue to the heterogeneity of exposures, genetics, and, ultimately,the diseases collectively referred to as cancer. However, certaintypes of vegetables produce phytochemicals that are notessential nutrients but may have beneficial health properties.

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

glucosinolates to become biologically active, they must bemetabolized by myrosinase—a plant enzyme released from theplant tissue when it’s chopped or chewed—into two classesof chemicals known as indoles and isothiocyanates, whichare 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 allcruciferous 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 inisothiocyanates 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.

continued on page 12

I

Glucobrassicin Indole-3-carbinol Diindolylmethane

myrosinase released acid condensation reaction

Conversionof glucobrassicinin food todiindolylmethanein the stomach.

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 potentthan I3C. Our studies are the first to use DIM in leukemiacells, and our results are consistent with reports in othercancer cells that DIMand/or I3C block thedivision and proliferationof cancer cells and induceprogrammed cell deathby modulating specificcellular proteins thatregulate these processes.Dietary supplementationwith DIM also reducedthe growth of thesehuman leukemia cellstransplanted into mice.Therefore, our datasupport the currenttheory that DIM may mediate the physiological effects of I3C.

Cruciferous vegetables have great potential to reduce therisk of certain cancers. Epidemiological studies havesuggested an inverse relationship between cruciferousvegetable consumption and gastric, endometrial, andcolorectal cancer and cancers of the lung, prostate, breast,and bladder. One explanation as to why these studieshave been more suggestive than definitive may be geneticdifferences in how individuals metabolize these compounds—some of us need to consume more cruciferous vegetablesin order to receive the same level of protection. Cookingand storage processes, such as chopping, pickling, freezing,

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

The concept that thefetal and early postnatalenvironment mayprogram the developingindividual to havealtered susceptibility todisease in adulthood isan exciting and growingfield of research termed“fetal origins.” Currently,we are using the trans-placental model to studywhether the whole foodsfrom which I3C, DIM,and SFN are derived

can also reduce the cancer risk of offspring exposed tocarcinogens in utero. We are supplementing the diet ofpregnant mice with broccoli sprouts, Brussels sprouts, I3C,SFN, or the combination of I3C and SFN, and we willmonitor the offspring for up to 10 months of age (middleage in a mouse). This study will assess the molecular changesthat occur during the development of the lymphomas andlung tumors and the amelioration of these changes by eitherthe active phytochemicals or the whole foods. We willspecifically explore epigenetic mechanisms—processes thatresult in heritable changes in regulation of genes notinvolving modification of the DNA sequence—as they relateto the fetal origins of cancer.


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

Basic Needs for Cognitive PerformanceMicronutrients are directly or indirectly involved in a

number of cognitive processes that are dependent on energymetabolism in brain cells, blood supply to the brain, synthesisof neurotransmitters (chemicals that are released from a nervecell and result in the transmission of an impulse to othercells), neurotransmitter binding to its receptors, nerve impulsepropagation, 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 glucoseto carbon dioxide and water. Certain minerals, such asmagnesium, iron, and manganese, are also needed tocomplete the metabolism of glucose.

Proper blood supply to the brain is necessary to deliveroxygen, glucose, and macronutrients, as well as micro-nutrients, for normal cognitive function. Good nutrition canhelp maintain optimal blood supply to the brain and lowerthe risk of stroke—a pathological condition that results fromimpaired blood supply to the brain.

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 micro-nutrient supplementation improves cognitive abilities inhealthy people, attenuates age-related cognitive decline, orimproves mental function in patients with Alzheimer’s disease.

ood nutritional status is imperative for normal cognition.Several micronutrients (vitamins and nutritionally

essential minerals) have important biochemical roles in thebrain and are needed for proper cognitive function. Thisarticle summarizes the basic needs of the brain for cognition,the cognitive effects of select micronutrient deficiencies, andthe present knowledge regarding the cognitive effects ofmicronutrient supplementation.

Continued from page 11 — Protecting the Fetus

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FoodSource

Servingsize (vol)

Brussels sproutsGarden cressMustard greensHorseradishKaleWatercressTurnipCabbage (savoy)Cabbage (red)BroccoliCauliflowerBok choi (pak choi)Kohlrabi

Servingsize (g)

Glucosinolates(mg/serving)

To achieve 2,000 ppm I3CGrams Servings

1/2 cup1/2 cup1/2 cup1 tbsp1 cup1 cup1/2 cup1/2 cup1/2 cup1/2 cup1/2 cup1/2 cup1/2 cup

44252815673465454544503567

104987924673260352927221931

20.512.417.230.348.651.652.662.475.379.1110.389.4104.9

0.50.50.62.00.71.50.81.41.71.82.22.61.6


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 neurotransmitternorepinephrine, and the mineral zinc is needed for functioningof the neurotransmitters norepinephrine, aspartate, andgamma-aminobutyric acid (GABA). Vitamins could possiblyaffect neurotransmitter binding to receptors on neurons,thereby altering neurotransmission.

Micronutrients may indirectly influence nerve impulsepropagation 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 neuro-transmission. 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.

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

Consequences of Select MicronutrientDeficienciesThiaminPhosphorylated 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 hasbeen implicated in membrane functions of neurons and inthe generation of nerve impulses. Thus, inadequate intakeof thiamin can negatively affect cognition. Severe thiamindeficiency causes beriberi; the dry and wet types of beriberiinvolve 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. Severeniacin deficiency, known as pellagra, has been historicallyassociated with poverty and consumption of a dietpredominantly based on corn, which is low in bioavailableniacin. Today, the condition is uncommon but can occurin cases of chronic alcoholism and in individuals withmalabsorption syndromes. Neurologic symptoms of pellagrainclude headache, fatigue, apathy, depression, ataxia, poorconcentration, delusions, and hallucinations, which can leadto confusion, memory loss, psychosis, dementia, and death.

Pantothenic AcidPantothenic acid (vitamin B5) is needed for the oxidative

metabolism of glucose and fats and also for synthesis offats, cholesterol, steroid hormones, the hormone melatonin,

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

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

Vitamin B6Pyridoxal, 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 vitaminB6 is uncommon, but alcoholics are thought to be most atrisk due to inadequate dietary intakes and impairedmetabolism of the vitamin. Neurologic symptoms ofsevere vitamin B6 deficiency include irritability, depression,confusion, and seizures.

BiotinBiotin (vitamin B7) is required for carboxylase enzymes that

are 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 prolongedintravenous feeding (parenteral nutrition) without biotinsupplementation, in individuals consuming high amounts ofraw egg white containing a protein that binds biotin andprevents its absorption, and in those with inherited disordersof biotin metabolism. Neurologic symptoms of biotindeficiency 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 deficiencyin the absence of vitamin B12 deficiency does not causeneurologic symptoms. However, individuals with geneticdisorders of folate metabolism have experienced seizuresand progressive neurologic deterioration.

Vitamin B12In humans, vitamin B12 is a required cofactor for two

enzymes: methionine synthase, which is needed for theproduction of methionine from homocysteine, andL-methylmalonyl-CoA mutase, which is involved in crucialmetabolic pathways. Vitamin B12 deficiency affects 10-15%of adults over the age of 60 years. It damages the myelinsheath of nerves and is frequently associated with neuro-logical problems. Neurologic symptoms are the only clinicalindicator of vitamin B12 deficiency in about 25% of cases.

continued on page 14

Such symptoms include numbness and tingling of theextremities, difficulty walking, problems with concentration,memory loss, disorientation, and dementia. Severe B12deficiency is associated with pernicious anemia and, if untreated,can lead to “megaloblastic madness,” characterized bydelusions and hallucinations. Atrophic gastritis, an age-relatedcondition resulting in diminished digestive factors, is oftenassociated with decreased absorption of vitamin B12 from food.

Vitamin CVitamin C accumulates in the central nervous system, with

neurons of the brain having especially high levels. Vitamin Cis 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 damageto 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.

Vitamin DVitamin D is important for normal brain development and

function, and vitamin D deficiency may impair cognitiveabilities. Some studies in older adults have either linkedlower 25-hydroxyvitamin D levels—the clinical indicatorin the blood of vitamin D status—with measures of poorcognitive performance or higher 25-hydroxyvitamin D levelswith measures of better cognitive performance. However, theassociation between 25-hydroxyvitamin D concentrationsand cognitive performance is not yet clear.

Vitamin EIn the brain and other tissues, the alpha-tocopherol form of

vitamin E is a key fat-soluble antioxidant that prevents lipidperoxidation and helps to maintain the integrity of cellmembranes. Thus, vitamin E deficiency causes lipid peroxi-dation in brain tissues. Severe vitamin E deficiency resultsmainly 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).

CalciumCalcium ions are important intracellular signals that regulate

a number of physiological processes, including neuronal geneexpression and neuronal secretion of neurotransmitters.Normal blood levels of calcium are maintained even whendietary intake of calcium is inadequate because the skeletonprovides a large reserve of the mineral. Thus, dietary calciuminadequacy primarily affects bone health.

IodineIodine is required for the synthesis of thyroid hormones,

which are important for myelination of the central nervoussystem. Iodine is critical for normal development of the brain;therefore, deficiency of this mineral during critical periods offetal development or childhood can have deleterious effectson cognition. The most extreme cognitive effect of develop-mental iodine deficiency is irreversible mental retardation;milder cognitive effects include various neurodevelopmentaldeficits, including intellectual impairment.

IronIron is an essential component of hundreds of proteins and

enzymes involved in various aspects of cellular metabolism.The mineral is needed for proper development of oligoden-drocytes (the brain cells that produce myelin) and for severalenzymes that synthesize neurotransmitters. Accordingly, irondeficiency during various stages of brain development hasnegative consequences. Maternal iron deficiency duringpregnancy has serious consequences for the woman and thefetus, including permanent learning and memory deficits inthe offspring. Iron deficiency during childhood may beassociated with impaired cognitive development.

MagnesiumMagnesium is required for more than 300 metabolic reactions,

many of which are important for normal brain function. Overtmagnesium deficiency has been induced experimentally andresults in neurologic and muscular symptoms that includetremor, muscle spasms, and tetany (involuntary musclecontractions). According to recent surveys, many Americansdo not have an adequate intake of magnesium.

SeleniumSelenium is required for glutathione peroxidases (GPx),

important antioxidant enzymes in the brain and other tissues.Selenium deficiency has been associated with decreasedGPx activity in the brains of laboratory animals and maybe linked to a reduced antioxidant capacity in the brain.

ZincZinc 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 neurologicfunction. However, deficiency of the mineral during criticalperiods of cognitive development can be more devastating,causing congenital malformations or deficits in attention,learning, memory, and neuropsychological behavior.


Continued from page 13 — Micronutrients andCognitive Function

mental illness. He discussed the exquisite chemicalsensitivity of the brain to vitamin deficiencies and addressedthe theoretical basis for micronutrient supplementationto help treat mental illness in his seminal paper,Orthomolecular Psychiatry, published in 1968 in Science.

To date, many of the RCTs of micronutrientsupplementation have employed elderly subjects orindividuals with pathological conditions like Alzheimer’sdisease. Thus, there is a need for well-designed, large-scale, long-term RCTs in healthy adults and in children.In addition, the available RCTs have used a number ofdifferent cognitive assessments; therefore, more standardizedapproaches would be useful to interpret evidence acrossstudies. Studies that measure micronutrient status in bloodand correlate that with cognitive function are also neededto 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 InformationCenter: http://lpi.oregonstate.edu/infocenter/cognition.html.This article was underwritten, in part, by a grant fromBayer Consumer Care AG, Basel, Switzerland.

DevelopmentsMichele EricksonLPI Director of Development

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Rates are subject to change. This information should not be consideredor relied upon as legal advice. Before entering into a planned givingarrangement 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 adviceabout 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 otherwiseguaranteed by the California Life Insurance Guaranty Association.

The charitable gift annuity:It’s a win-win. For you and for LPI.inus Pauling left an enduring legacy with hiscontributions to science, peace, and healthy

living. And you can continue that legacy—withfinancial benefits for you today—through acharitable gift annuity (CGA).

It’s simple: For a donation of cash or securitiesvalued at $25,000 or more, the OSU Foundationinvests your gift and pays you an annuity for life.After your lifetime, the remaining assets aredistributed to the Linus Pauling Institute at OSU.

The annuity rate—locked in for life—depends onyour 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 largeportion of your annual payment is tax free. You’llreceive a tax deduction for your initial gift, and itmay reduce taxes on your estate.

Sample rates based on $25,000 CGA:

Age ofannuitant

Annuityrate*

Annualpayment

Charitablededuction**

65

5.5%

$1,375

$7,004

70

5.8%

$1,450

$9,014

75

6.4%

$1,600

$10,630

80

7.2%

$1,800

$12,244

85

8.1%

$2,025

$14,023

90

9.5%

$2,375

$15,420

*These rates represent the rate schedule put into effect 7/1/2010 by the American Councilon Gift Annuities (ACGA) and are subject to change.**Assumes an IRS discount rate of 3.0%.

Call or e-mail to learn more:

Julie IrmerOSU FOUNDATION | OFFICE OF GIFT PLANNING800-336-8217 • [email protected]/giftplanning


CholineAlthough not considered a vitamin, choline is an essential

nutrient needed for myelination of nerves, synthesis of theneurotransmitter acetylcholine, and synthesis of variousstructural and cell-signaling molecules, including phospho-lipids (phosphatidylcholine and sphingomyelin) that areimportant components of cell membranes. Choline deficiencyduring the perinatal period in laboratory animals results inpersistent memory and other cognitive deficits in offspring.

Effects of Micronutrient SupplementationCompared to the consequences of micronutrient

deficiencies, considerably less is known about the cognitiveeffects of micronutrient supplementation. Overall, there iscurrently little evidence that micronutrient supplementationprovides cognitive benefits related to attention, memory, orexecutive functions (higher-order cognitive processes thatinclude reasoning, planning, strategic thinking, problemsolving, and multitasking). Some studies, however, havereported that multivitamin/mineral supplementation maybenefit subjective measures of mood and psychological well-being. Additionally, evidence that supplementation with Bvitamins or antioxidant vitamins prevents age-associatedcognitive decline is largely lacking, although randomizedcontrolled trials (RCTs) of longer duration are needed.

Linus Pauling was interested in the relationship of criticalmicronutrients and enzymes with mental function, including

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

Linus Pauling InstituteStephen Lawson, Research Newsletter EditorOregon State University571 Weniger HallCorvallis, Oregon 97331-6512

phone: 541-737-5075fax: 541-737-5077email: [email protected] Web site: http://lpi.oregonstate.edu

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Page 1 .....From the Director

Page 1 .....Not All Fats Are Created Equal

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

Page 8 .... 6th International Conferenceon Diet and Optimum Health

MicronutrientResearch forOptimum Health

Page 10 .....The New Dietary ReferenceIntakes for Vitamin D

Page 11 .... Protecting the Fetusfrom Carcinogens

Page 12 .... Micronutrients andCognitive Function

Page 15 ..... Developments

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