Bruce Ames, 7th Graham Lecture (1 Of 4)

KEITH WEST: Good afternoon. And welcome to the seventh George G. Graham Lectureship, which occasionally morphs into a symposium. We’re very pleased to have all of you here today. It’s a special event to celebrate the 100th anniversary of the discovery of, not just vitamin A, but vitamins.

It has been a remarkable century of advance in nutritional science in terms of what we know about what nutrition does to our bodies and how they help maintain health. We’ve learned a lot about prevention. And in that process, the vitamins, and the minerals, the micronutrients have become such an important part of the nutrition landscape in terms of what we understand as being needed for good population health. They were invisible a century ago.

Today, they are not invisible. But they remain largely hidden in terms of the public health landscape. And so we have a long way to go to understand what these micronutrients do, and how to develop programs, policies, diets that can optimize health through what they have to contribute. I’d like to say just a few words about George Graham.

George was our founding director of the program in human nutrition. He was the first professor of nutrition in our school– in our program. EV McCollum was our first professor in the School on Nutrition. George was the founding director of the Institute of Nutrition in Lima, Peru, which today stands as one of the leading nutrition institutes in all of Latin America.

He was a prominent member of the academic community, the policy community. He won many awards. And he was a prolific scientist. He was a physician, a clinician, a scientist, who had a curiosity for many aspects of nutrition and how nutrition affects children– how to promote child growth.

This is just a selection of his papers. The topics I’ve highlighted to show that he was also a leader in the micronutrients. One of his early papers dealt with copper deficiency in infancy. His greatest contributions were in evaluating the protein quality and energy levels of the diet that can promote early child growth looking at the quality and nutritional value of cereals.

So many different topics that were addressed by George in his career that formed the basis of many things that we know in these areas of nutrition today. So we’re very grateful for his contributions over the years. And many of us were mentored by George and carry the lessons that we learned from him with us. There was a George Graham Professorship installed in 2005, which puts him clearly– puts his name into the legacy of the school and our nutrition program.

And then we were able to launch the George Graham Lectureship in 2007 through the generous donations of the Middendorf Foundation, the International Fund for Infant Nutrition, and Dr. TC and Mrs. Lee Wu, who have all made this lectureship possible. We’ve had several wonderful previous lectures– Ken Brown; Bill MacLean; a wonderful first symposium with Nevin Scrimshaw, and Carl Taylor, and Charles Stephensen, Claudio Lanata, and Bob Black in 2009 dealing with nutrition and infection; Ricardo Uauy in 2010, Andrew Prentice, and finally Michael Golden was our last one. We’ve had very dynamic lectures. And this one is going to be no different.

So we appreciate you coming. We appreciate our speakers. We have a wonderful keynote speaker followed by dynamic leaders in the field who are going to share their thoughts across the spectrum of micronutrient nutrition. I would like to turn over the microphone to Professor Pierre Coulombe, who’s going to offer us a few reflections on EV McCollum.

Pierre. [APPLAUSE] PIERRE COULOMBE: Thank you Keith. Good afternoon, everyone. There cannot be a gathering celebrating the discovery of vitamins without a few words about Dr. Elmer McCollum– a true pioneer in the field of vitamins, micronutrients, nutrition, and wellness.

Elmer Werner McCollum was born in 1879 in rural Kansas where he grew up on the family farm. And thanks to his mother’s leadership, he was able to attend the University of Kansas where he graduated with a master’s degree in Organic Chemistry in 1904. McCollum had done very well at the University of Kansas and received a scholarship to attend Yale University where he secured a PhD degree under two years while working multiple jobs to sustain himself. In 1907, McCollum was recruited to the faculty in Agricultural Chemistry at the University of Wisconsin.

And there initially, he joined the famous heifer nutritional study that was guided by Professor EB Hart. By then, McCollum had developed a passion and a knack for the study of nutrition from a biochemical perspective, and decided against the will and the advice of his own dean to begin using rats as a model system for such studies. He was the first one to use rats as a model system in this setting. While in Wisconsin, where he stayed for about 11 years, McCollum harnessed the power of the rat model in order to make seminal contributions that led to the discovery of vitamin A, and to the discovery of trace elements in the diet such as manganese and magnesium.

He also devised the letter nomenclature for vitamins, starting with A. And through his outstanding research and advocacy, became a nationally prominent figure. In 1917, McCollum was recruited to the faculty here at our school by our founding dean– William Welch. And he was tasked with being the inaugurating Professor and Chair of the Department of Chemical Hygiene at the School of Hygiene of Johns Hopkins University. That Dean Welch had the foresight of instituting a basic science department grounded in chemistry is a topic for another day.

Anecdotally and ironically, when Welch first met McCollum, he thought that at 6 feet but only 127 pounds, he would be too frail to get the job done. But McCollum, as it turns out, lasted on the job for 30 years and really led this department with poise. McCollum’s research continued to be vibrant. While at Hopkins, he continued his seminal studies on the biochemical determinants of nutrition.

And this body of work, among other successes, led to the discovery of vitamin D. So during those years, McCollum’s advocacy and his prominence continued to rise. And he played key leadership roles in a number of national bodies and organizations that had to do with nutrition and wellness. And he was a special advisor to the military for nutrition during the Second World War, as well as a special advisor to a body created by President Hoover.

McCollum’s advocacy also changed the way bread and milk are manufactured for mass consumption, which is a remarkable feat. He was a sought-after speaker– internationally, as well as nationally. And he wrote regularly for the lead media, notably the McCall magazine, which was targeted for women, for which he wrote for over two decades. McCollum retired in 1946, but remained very active almost until the time of his death in 1967 here in Baltimore.

I have had the good fortune of being closely associated with many great people and remarkable scientists during my career. But staring at the list of awards and recognitions that McCollum received as a result of his efforts throughout his career is really impressive. So I look forward to enjoying this symposium with all of you. And in particular I look forward to the lecture from Doctor Ames, another prominent figure in American science.

And at this time, I would like to invite Dean Klag to introduce our special speaker– Doctor Ames. MICHAEL KLAG: Thank you, Pierre. One of the things I’ve observed in the time I’ve been dean– and I’m sure that Dean Emeritus Sommer will agree– is that there’s something about biochemists that they love to needle deans. Right? So it’s interesting the story that you fit in there that McCollum’s dean suggested he– almost forbid him to work with rats.

But he did so anyway. A few years ago we were celebrating Sharon Krag, who is a faculty member in biochemistry, who is Associate Dean. And her mentor– John [? Skoko, ?] who was in the Department of Biochemistry– spoke about her. And he spoke about the day that she came to him and said, I’ve been asked to be Associate Dean.

And John’s reaction was– he had two reactions. One, he said, it was as if my son told me he was going to go to medical school. It was that bad. And the second thing he said was, in his view, an associate dean is a mouse in training to be a rat.

OK? So it all works around– working on the rat thing. But thank you for those great comments, Pierre. So it is my happy privilege to introduce Dr. Bruce Ames, our speaker today. And to many of us in this room, and those who are connected via the internet, he really needs no introductions.

It was in the 1970s that he invented the Ames test– a simple and inexpensive assay to assess the mutagenicity of compounds. And since then, he’s dedicated his research to the interface between metabolism and prevention; developing a better understanding of the biochemistry of aging; and determining how micronutrients may prevent disease, malnutrition, and obesity. In 1950, a bachelor’s degree graduate from Cornell University in Chemistry and Biochemistry, he followed that directly with a PhD in Biochemistry and Genetics from the California Institute of Technology in 1953. That was 60 years ago today.

And he continues to be productive and provocative. Since then, Bruce has worked in multiple areas of the NIH. Ultimately, he was drawn back to California in 1968 as a professor, and then Chair of Biochemistry at UC Berkeley. He still teaches at Berkeley today, and also serves as senior scientist at the Children’s Hospital of Oakland Research Institute.

As one of this country’s most cited authors across all fields of science, with over 500 publications, we’re really fortunate to have someone of Dr. Ames’ stature as the keynote speaker at today’s seventh George G. Graham Lecture and Symposium. And he’s going to be focusing on an area in which he has made numerous contributions– the roles of micro-nutrients in maintaining health across the lifecycle. We’re also delighted that he’s here for the 100th anniversary celebration of the discovery of vitamins.

At 85 years young, Bruce’s continued enthusiasm for his work, his consistent contributions to the field of nutritional sciences, and his sheer energy level, inspire and challenge the brightest of minds and the youngest of hearts. Please join me in welcoming Dr. Bruce Ames. [APPLAUSE] BRUCE AMES: Thank you. I’ll start off with a dean joke.

I was in the Midwest giving a seminar and went into the men’s room. And instead of paper, which is really good to dry your hands, it was one of those machines where you push a big button. And someone had put a graffiti there saying, to listen to the dean, push the button. [LAUGHTER] AUDIENCE: That’s good.

BRUCE AMES: OK. Let’s see. TECHNICIAN: You can just hit right on that arrow to– BRUCE AMES: Yeah. What’s the pointer? TECHNICIAN: You can hit that right there.

Oh, the pointer’s at the top over there. BRUCE AMES: OK. Thank you. So I seem to change my field every decade or so.

In the last 10 years or maybe a little more, I’ve been in nutrition. And I’d like to tell you why I think nutrition is the key field for aging, and that it’s poor nutrition that’s causing all our accelerated aging, or most of it. So this is your metabolism. And what do you need to run your metabolism? You need about eight or so essential amino acids.

You need about 15 minerals and about 15 vitamins. So I’m going to concentrate on the vitamins and minerals. So if you don’t get these 30 substances in the right amount, what I’m going to argue is it ages you faster– that nature has built in a rationing system when you’re short of any vitamin or mineral. So these are the micronutrients– roughly 50.

And I won’t argue about the number. There’s always a few people who are arguing about it. And I’m going to tell you later I think there’s a whole new class of vitamins nobody’s discovered yet. So are we getting enough? And I think the answer is a clear no.

We’re doing it in the wrong way. Dangit. So these are– the committee set up two numbers– the EAR and the RDA. Now the RDA is what you all know about.

It’s on the potato chip packages. Though I’m sure none of you eat potato chips. [LAUGHTER] And that is the amount the population should be getting. But they determine the EAR first, which is some distribution.

And if you’re below the EAR, you’re officially deficient. And they set the RDA at two standard deviations above the EAR. So even by those criteria, that criteria, iron– 16% of menstruating women are deficient in iron. These women are losing iron all the time.

And they’re not getting enough. And magnesium is a disaster– 56 percent of the US population is officially below the EAR. And nobody cares because there’s no pathology. And I’ll tell you what I think the pathology is going to be.

And where do you get magnesium? Well, you get it from your greens. Nature has color-coded it for you. It’s green because it’s in the center of the chlorophyll molecule. Just the way heme is a porphyrin cage with an iron in it– it’s red– and chlorophyll is a porphyrin cage with a magnesium in it.

It’s green. OK. Not because of the metals. But so eat a big plate of kale and/or spinach, as you prefer.

Zinc is in 2000 enzymes with zinc fingers. It’s really important. And yet 12% of the population is low. And then B6– half of elderly women are below the EAR.

Folate– 16%, and they fortify flour with folate. And E, practically everybody. C– a third of the population. And then they hadn’t set the RDAs and EARs when I made this slide.

But vitamin K, and vitamin D, and calcium, potassium, Omega-3 are all very low in the American population. So we’re not doing very well. We’re eating too much refined food and not enough greens. So I’d like to tell you about an experiment that got me into nutrition with both feet.

And a fellow named Jim MacGregor came to my lab on sabbatical. And he worked at the local USDA lab in Albany, California. And he was doing a test called a micronucleus test. So if you take red blood cells, you all know that’s the one cell in the body that doesn’t have any DNA.

Well, if you stain red blood cells– you put them on a microscope slide and stain them from DNA– in a mouse, one in 2,000 lights up. It has a little bit of chromosome in it. And that’s called the micronucleus test, which if you irradiate the mice, you get more. You get a nice dose-response curve.

And so everybody realized it was somehow a double-strand break. And when the precursor cell– you extrude the nucleus. If there was a chromosome break– a little bit of chromosome gets left behind and it’s easy to assay. So everybody started using this assay because it was so simple.

And MacGregor was doing it and studying whether caffeine interfered with repair enzymes and things like that. I won’t go into it. I drink my espresso in the morning. And I won’t hear anything about it.

[LAUGHTER] And MacGregor– one day all his control mice were full of chromosome breaks. And he yelled at this technician, did you irradiate them by mistake? She said, no. And so he’s a very good scientist. He called up the company that sells the vitamin mix and said, is anything wrong with the vitamin mix? And the person on the other end said, oh.

Dr. MacGregor, we were going to call you. Somebody left folic acid out of the vitamin mix. He said, aha. And so he did dose-response with folic acid.

And folic acid deficiency breaks chromosomes just like radiation. So he thought that was interesting. And he wanted to do this in people. But it doesn’t work in people.

The reason it works is, in humans, the spleen– wherever the spleen is– the blood goes through the spleen a couple of times. And it weeds out any cell that’s a little stiff. That’s the function of the spleen. You don’t want to clog up a capillary somewhere and get a thrombosis.

So MacGregor went to Kaiser– our local health maintenance organization– and said, do you have any people who’ve lost a spleen an accident? And they have 6 million people in the database. They said, yeah, we have hundreds of them. He said, could I call up 20 of them and get a little blood from them? And they said, sure. So that started MacGregor on, what I think, is the most beautiful experiment in nutrition.

And nobody knows about it. It’s buried from 1988 in a journal. And I’d just like to walk this through with you. So he got a baseline of people without spleens.

And he could get a very nice baseline. It was something like rats, except for one guy who is up here. These are the reticular sites– 1% of the newly synthesized ones. And these are the red blood cells.

So here this guy is bouncing up and down for a year when MacGregor was following him. And when he stumbled on this folic acid business in mice, he said, mice don’t have any splenic function. You see, inbred mice have lost it somehow. So he said, gee, maybe this guy’s a little low on folate.

They asked him what he ate. And it wasn’t a very good diet. And it could well be somewhat folate deficient. So he tested him.

And he was low, but not wildly low. But anyway he gave him folinic acid, which is a reduced folate. And the retics in a few days came right down to baseline. Beautiful experiment– you see causality.

The trouble with epidemiology– it’s fiendishly difficult. And they get the wrong answer half the time because they don’t understand mechanism. The epidemiologist joke is, Miami is a weird place. Everybody’s born Hispanic and dies Jewish. [LAUGHTER] So anyway– but the beauty about this experiment is you establish causality.

And MacGregor measured serum folate. And he measured RBC folate. The red blood cells aren’t only delivering oxygen to the tissue. They’re the FedEx trucks of the body.

They’re delivering everything. So red blood cells have much higher levels of vitamins, minerals, you name it. Because they’re dumping it in the tissues along with the oxygen. Anyway, so if retics go down– the newly synthesized ones– and then red blood cells turn over more slowly.

And they go down more slowly. And then, since he only gave folate for a limited period, they both started shooting up again. And MacGregor said, gee, it’d be unethical to do any more experiments on this guy. So he said, hey, he followed him for a while.

But then he thought, well, he’s breaking their chromosomes. And that isn’t such a good thing. So he said, look, you’re very low in folic acid. Either take a pill, or eat some greens in your diet.

Foli is the Latin word for leaf– foliage. And my mentor at Cal Tech when I got there in 1950 is a very young, very green graduate student. First isolated– HK Mitchell first isolated folic acid from four tons of spinach. So they named it after leaf.

Anyway so the guy said, well, give me a pill. So he gave him a bottle of folic acid pills, and said you could buy this at the local health food store. Goodbye. And the guy disappeared.

But it’s a gorgeous experiment. Because he has the levels that do this. And the level that breaks your chromosomes was in 10% of the US population, and half of the poor if you look up numbers of the amount of folic acid. And he came to my lab on sabbatical.

And he showed me this experiment. And I was completely blown away by it. And I said, I’m going to work in nutrition. It can’t be only folic acid.

And I was interested in cancer prevention and things like that. And some years later, both Fenech in Australia and ourselves did an experiment comparing radiation to folic acid. This is Fenech’s experiment. But they were similar.

So these are chromosome breaks. And the more x-rays, the more chromosome breaks– those are the white bars. And the less folic acid, the more chromosome breaks. So you just go down by half in the amount of folic acid, and you already have a significant increase in chromosome breaks.

And people worry about incredibly tiny levels of radiation. The Fukushima– in Japan, in California, they were all going wild that all this radiation was going to wash across the Pacific into California. I mean it was– there are a lot more interesting things to worry about. And the first is smoking and diet.

The first two are smoking and dying. I think bad diet’s going to be worse than smoking. And we helped MacGregor– we were biochemists and mechanism people– so we helped MacGregor work out the mechanism, or at least a plausible one. So methylenetetrahydrofolate methylates uracil to make thymine.

And uracil is in RNA. And thymine’s in DNA. That methyl group doesn’t interfere with base pairing. But it’s a tag that tells the body which is which.

And if you don’t have enough folate, there are four or five types of cancer that have been associated by epidemiology with folate deficiency. And what we show is you get double-strand break. You’re putting uracil in the DNA and getting double-strand break. And then the other form of folate– methyltetrahydrofolate in B12– convert homocysteine to methionine.

And you’re always making more homocysteine. This methionine goes to S-adenosyl methionine, which is the main methylating agent in the cell you’re making, choline, and acetylcholine in neurotransmitters, and all sorts of things. And homocysteine, when it accumulates, shrinks the brain and causes all sorts of cognitive problems. There’s a group in England looking at that.

And it’s associated with heart disease. So again, it’s epi. You have to take it with a bit of a grain of salt. But it’s all plausible.

And the mechanism– the radiation biologists have worked out the mechanism. Radiation gives you clusters of electrons, which oxidizes a base on both strands. So you get two lesions. And that’s the dangerous part of radiation.

Because then repair enzymes are always cruising along the DNA looking for trouble. They see some base that doesn’t look normal. And it gets clipped out. And then the right base pair gets put in and sealed up.

But if you have two nearby ones, you get a double-strand break. And that’s much harder to repair. At least that’s the going theory among the radiation biologists. And you do the same thing when you’re low in folate.

Because you get a uracil in the DNA, and it’s also repaired by a uracil glycosylate. So then Fernando Viteri, who’s a professor of nutrition, knocked on my door one day and said, hey. You guys are expert in mitochondria. If you have too little iron, you foul up your mitochondria.

Would you do an experiment with us looking at the whole range of folate in mice? And we’ll see what happens. Because I think too much– a whole range of iron in mice– too much iron is bad for you, just as too little iron is bad for you. But too little iron is 2 billion women and children over here. And too much iron is a lot of American men who are not menstruating, who are eating too much red meat.

Anyway. And so we looked at all kinds of function in mitochondria, oxidizing the mitochondria, mitochondrial function, DNA damage, and all of that, and put it on the same plot. The red is the sum of all this. So as with most metals, there’s a window.

Metals are tricky, because you get too much. So you have to be really careful. You tell people selenium is good for them, and 5% of the population are going to go out and poison themselves by taking too much selenium So when you talk about metals, you always have to have a warning not to take too much. Because iron– Fe plus plus– looks a lot like zinc plus plus or copper plus plus.

So one metal can exclude another and interfere with another. Calcium magnesium in the body cause– looks at the ratio. So you shouldn’t take a calcium pill. You should take a calcium magnesium pill– roughly two to one.

Or sodium and potassium– everybody says we’re getting too much sodium. But the reason is we’re get too little potassium. Anyway, that’s all I’ll say about that right now. So we did this with a graduate student in Fernando Viteri’s lab and a post-doc in mine.

Did this study– we published several papers on the range of iron in mice. And then Emily Ho came to the lab. And she was interested in zinc. And she was expert on human cells and culture.

So we looked at human cells and culture and made them a little zinc deficient. The cell fills up with oxidants, we think coming out of the mitochondria. And you could show DNA damage by the comet assay. Again I won’t go into detail.

And then one of the other students in the lab was working on biotin– Hani Atamna– and he made human cells in culture biotin deficient. They fill up with oxidants. And you get DNA damage. And we think the signaling is in mitochondria.

I won’t go into the mechanism. But we think we at least have a possible plausible mechanism. But we’re collaborating right now with Janet King– who’s the queen of zinc and who’s in the group– and working with people to see which protein you lose first when you’re zinc deficient. So magnesium deficiency gives you DNA– mitochondrial DNA protein cross links.

And we don’t know whether that’s specific for magnesium or due to other– all sorts of micronutrient deficiencies. But anyway, David [? Kililane ?] in our lab is looking at that. These are in human cells in culture. So then I put into Google the 30 vitamins and minerals– essential vitamins and minerals.

And I also put in chromosome breaks, mutation, DNA damage, cancer, and all this popped up. So you’d have to spend a year in the library in the old days. But Google is wonderful. So Fenech had shown calcium deficiency.

Fenech had shown chromosome breaks in lipid colon cancer. Folate deficiency– MacGregor– our lab, Fenech– had shown chromosome breaks in mice and in humans. Willett had shown cancer in humans. Vitamin D deficiency– Holick showed many types of cancer.

Magnesium deficiency– Bell had shown chromosome breaks. And Larson– cancer– et cetera, et cetera. So there’s a lot of work out there. But nobody had been paying much attention to this.

And people outside nutrition tend to distrust epidemiology with some huge amount– they say it’s such a muddy field, you don’t want to go in there. And I think that’s being unfair to epidemiology and unfair to nutrition. But there is some germ of truth in it. Yeah.

So I kept on thinking about why nature is doing this. Why is it giving us cancer when we’re low in a vitamin or mineral? And one day I had this epiphany. And so we published a paper in 2006 saying, hey. That’s what nature wants.

When you’re running out of a vitamin or mineral– let’s say there are 16 proteins that need that particular vitamin, like vitamin K. Well, the proteins that get it first are the ones essential for survival. Nature does a rationing. So you’re trading short-term survival and reproduction for long-term health.

And in fact all the proteins that are long-term– repairing DNA– all the DNA repair enzymes have magnesium in it. That’s what my guess is what’s going to show up. And we looked at vitamin K. And we looked at selenium. And then I’ll go into those in a little more detail.

And the ones that are long-term– preventing calcification of the arteries or preventing strong bones– those are the ones that get disabled. So a quarter of your metabolism isn’t working. But it’s all a long-term metabolism that isn’t working. So we don’t want to measure just short-term things with vitamins.

We want to measure long-term things. Because we all want to live a long life. So one day, Joyce McCann came into my lab. And she was a former post-doc– 35 years ago or something like that.

She’s a very smart woman. And she was looking for a job in the Bay Area. And I wrote her a rave letter. She didn’t get it.

But I said, Joyce, I’ll hire you. Work on whatever you want. So she wrote four big reviews about the fetus– the developing fetus; and the developing brain; and iron deficiency in mice, in rats, in humans. The brain doesn’t develop well.

And we’re talking about a lot of women. And she did one on Omega-3s. She did one on vitamin D. And then one day she came into my office and said, Bruce, I’m a little skeptical of your triage theory.

I think there’s a better way to tackle it. I said, Joyce, go to it. What do you want to do? So she picked those vitamins and minerals that have been really well studied. And they’re not too complicated.

Zinc is in 2000 enzymes. Magnesium’s in 500. And you’d spend the rest of your life in the library. So she researched one vitamin and one mineral– vitamin K and selenium.

And they’re both beautiful. And they fit beautifully with triage theory. And they have lots of medical implications. So I’ll just go through those briefly.

So vitamin K was discovered by Dam in Denmark. And it was involved with blood clotting. And all the vitamin K proteins are calcium-binding proteins. So vitamin K is a compound called phylloquinone that’s used in plants in photosynthesis.

So again. It’s color-coded. Anything green has vitamin K. And if you eat the vitamin K, it goes– what it is, it’s a co-factor for an enzyme that takes a glutamic acid with one carboxyl group and puts another carboxyl group.

So it has two negative charges that combine to calcium. So they’re all calcium-binding proteins. Blood clotting’s a network of calcium and protein. So blood clotting is clearly essential.

Because you knock them out in mice, and they’re all embryonic lethals. So that’s a relatively crude measure of essentiality. But that’s what was easy to do. And the ones we’re in– so we don’t really care about those.

The ones we’re interested in are all these proteins that get disabled. And, in fact, they do get disabled. Because the body puts that vitamin K into the liver. And you do all the coagulation proteins in the liver.

And then it’s converted to an MK– menaquinone– a form of vitamin K. And that goes to all the tissues equally. And you do all these other proteins in the peripheral tissues. That’s not the liver.

So that’s the way the body prioritizes for vitamin– the essential ones. And so each of these is very interesting and has lots of medical implications. Osteocalcin– you can tell from the name– is in the bone. It moves calcium around in the bone.

You knock it out in mice, the pups are born. They look OK. But you stress them a bit, the bones break. So you can make a bone without osteocalcin.

But it’s not a strong bone. So it’s something more long-term. And that’s what you trade off when you’re short of vitamin K. And Gas6 is a tyrosine kinase receptor– very interesting– involved with acute coronary syndrome, and involved with diabetes and other things.

But I’d just like to talk about matrix Gla protein– which is involved with protecting you against calcification of the arteries– and TGFBI, which is TGF beta-inducible, which is involved with mitosis in cancer. So here’s osteocalcin– the function, mouse knockout, human mutants, anti-coagulant, modest VitK This all comes out of Joyce’s review in the American Journal of Clinical Nutrition. But matrix Gla is really quite interesting. Because you knock the gene out in mice, and the pups are born.

And then at about three months of age, they all drop dead. And you do an autopsy, it’s calcification of the arteries. It looks like an old man with severe calcification of the arteries and heart disease. OK.

So this protein protects you from getting atherosclerotic plaques. And atherosclerotic plaque starts with a calcium phosphate crystal– hydroxyapatite– and calcium phosphate’s very insoluble. You look at it and the crystals form. And the body is full of calcium and phosphate.

So the idea’s that starts the atherosclerotic plaque. But this protein will bind the calcium and prevent the atherosclerotic plaque. So docs get lots of people with calcification of the arteries. But they don’t know all this– that it’s all in the literature.

Because medicine has abdicated. They don’t know any nutrition. They never ask you about– I’ve been going to docs for 60-some years. And nobody’s ever asked me about my nutrition.

So it’s not something medicine is interested in. You get a disease. They try to give you a drug to cure it. But a lot of the disease is caused by lack of micronutrients.

And medicine doesn’t care or doesn’t know about it. Most– I shouldn’t say all medicine. There are obviously people in medicine who are interested in nutrition. TGFBI is TGF beta-inducible.

They knew TGF beta-inducible protein was– people had studied that for years. But they didn’t know there was this funny amino acid Gla. And then someone found that. And it’s vitamin K dependent.

And what does it do? Well, a Japanese knocked it out in mice. And the animals live OK, except their mitosis doesn’t work well. You lose a chromosome here or you lose a chromosome there. So it’s in the matrix.

It interacts with integrin on the surface, which interacts with the microtubules. So you at least can understand the mechanism. To get an accurate mitosis, you need this protein. And the end result is more cancer.

The animals die of cancer. Anyway what’s beautiful about this is you can understand mechanism. And there is this trade off between essential ones and non-essential ones. And this is what we should be measuring.

AUDIENCE: Is there a doctor in this room of [INAUDIBLE] here? I’m sorry to interrupt. BRUCE AMES: That’s all right. AUDIENCE: [INAUDIBLE] a physician in the house. BRUCE AMES: OK.

Oh. I’ll continue. And so the next vitamin we looked at, or mineral, was selenium. And, oh, this is natto.

Natto is a health food in Japan. It’s B. sutilis fermented soybeans. You get it for breakfast in Japan. You look at it, it looks a little yucky.

Taste, smell it– it smells a little yucky. You taste– it tastes a little yucky. So Westerners really don’t like it. But it’s like eating limburger cheese for the first time.

You sort of recoil. But in the end, you can get to like it. And so my wife serves me natto every once in a while. So natto is– all the epidemiology says people who eat natto get less heart disease.

People get less bone fractures. And it’s full of one of these MK derivatives that has a lot of Mk7 in it, which then is the form of vitamin K that works the peripheral tissues and can protect you against those. Now selenium, as you can see, when you don’t have enough, you get cancer, DNA damage, heart disease, hypertension, reduced resistance to infection. The whole immune system is involved– muscle weakness, poor cognitive function, diabetes.

So all these long-term things. And again, Joyce figured out which ones get it first. And it all makes sense. But this selenium uses a completely different method for favoring the essential proteins.

It’s a transfer RNA-modified basis. And I used to work on transfer RNA-modified basis. This is all leftover from the RNA world. There are about 20 modified bases in transforming.

And we have shown one of them was all involved in regulation of amino acid metabolism and pseudouridine. But this methyl group is all involved with which transfer RNA makes the essential ones, and which transfer RNA makes the other non-essential ones. And it’s inhibited by selenium deficiency. So we came up with a mechanism that makes sense.

And again it’s long-term things that suffer. So the immune system– I looked into Google– what proteins in the immune system go down with age? And we came up with six– the CD4 CD8 ratio, increase in anergic factors, low lymphoproliferatives response, decline in antigen-presenting cells, decreased expression of co-stimulatory molecules, decline in IL-12 production. And then I plugged in the 30 vitamins and minerals. A post-doc– Swapna Shenvi from India– worked on this project.

And we didn’t know what was in the literature. But all this popped up. So people have looked at these kinds of things. So deficiency mimics aging.

And in fact, I got a bit of a shock. This folate was our own paper that I’d completely forgotten about. [LAUGHTER] I had this French-Canadian post-doc in the lab– Chantal Courtemanche– and she had shown that the CD4 CD8 ratio changes with aging, and changes on folate deficiency. We thought that was interesting.

But we didn’t understand it at all. But we published in Journal of immunology. And I completely forgot about it. And then it popped up in this Google search.

So anyway. So there’s a fair amount of evidence out there. This is all adaptive immunity. So when you get a shortage of a vitamin or mineral, one of the things you trash is your immune system.

Because that’s long-term. So those cells don’t remember the virus that hit you five years ago. That’s long-term compared to surviving now and reproducing. So you vaccinate people.

Since everybody is eating pretty poor diets, a lot of the vaccination doesn’t take well. But nobody ever thinks of giving them vitamins and minerals along with it. And people know that in poor countries, their immune system works much more poorly in the natives than in the Westerners coming in who are eating a relatively good diet. Anyway.

So in Joyce’s review on vitamin D, we just have four landmark papers coming out. I’m a modest guy. But these are the best papers to come out of my lab ever on vitamin D controlling your brain. It controls serotonin.

It controls oxytocin– all these important hormones and brain morphogen. And it explains autism, and ADHD, and bipolar, and schizophrenia, and antisocial behavior. There are all these experiments in the literature. You lower the level of tryptophan in the brain, you lower the serotonin, and ordinary people become angry. They hate everybody.

And they lose all their inhibitions. All these shooters who shot up the schools who were on these SSRIs, and they stop for a day or two, and they’re in trouble. Anyway that’s– I don’t know whether that’s true or not. But people have written papers saying they think it’s suspicious.

So these are the neurons that activate vitamin D in the brain. And these are some of the few enzymes that are controlled by vitamin D. Vitamin D goes to a steroid hormone that’s controlling 900 genes. You can look up in our database, and look at the 12 bases. That’s the signature for vitamin D receptor binding– vitamin D response element.

And some are turning off genes. And some turning on genes. Well, the one in the brain that makes serotonin is turned on by vitamin D. And the one in the gut in the pineal gland that makes serotonin– and it’s a much stronger enzyme in the gut– is inhibited by vitamin D. Anyway we stumbled on a gold mine. And we’ve been digging out gold.

This is all done by a wonderful scholar in my lab– Rhonda Patrick, a new post-doc. And she’s just cutting across all these fields– psychiatry, and human behavior, and all these things. Anyway, hopefully they’ll come out soon. To finish off, this is one of Fenech’s slides looking at the range of chromosome breaks in people.

Now, women live longer than men and have less DNA chromosome breaks. But the variability is huge. And what’s that due to? I’ll bet most of it is dietary. I mean, nobody– people always think about a part per million in some pesticide.

But that’s all irrelevant compared to our bad diets. And we wrote lots of papers saying pesticides really aren’t anything to worry about. If you want to spend 50% more and buy organic food, fine. But it makes no sense.

Because every plant has 100 toxic chemicals to kill off insects and to kill off you. Because that’s how plants defend themselves. And humans have bred plants so they’re less toxic. And they can eat a little bit of a lot of things.

Anyway the world is much more complicated than just Monsanto is killing us all. Anyway, so the triage analysis provides a mechanism for how moderate vitamin and mineral deficiency increase risk of a disease of aging and suggests a prevention strategy. Half of proteins we analyze are what I call longevity proteins– that they were involved in something long-term. And in 60 million years of evolution, we’ve gone from rats and mice who live two or three years, to humans who live 80 years.

So there are a lot of longevity genes out there. And that means there are going to be a lot of new vitamins if you’d redefine vitamin as to include the maximum lifespan. And we don’t want vitamins to just be short-term. But they don’t discover it as a vitamin if it doesn’t affect the animal short-term.

And so we’re turning up a whole bucket of these. And I’m writing a review saying we should rethink vitamins and minerals. So also it tells us which protein to assay. And the future of preventive medicine is you’re going to stick your finger in a machine.

It’s going to take a finger prick of blood. And already, an entrepreneur friend of mine– Larry Gold– can assay 1,500 proteins in one shot in a finger prick of human blood. And in two years, he’s going to have all 3,500 proteins in human blood. It’s a discovery system for finding– and we’re collaborating with him, with Janet King on zinc.

So she did a human experiment on zinc. We’re sending all the blood to them. And we’ll see what protein– which of the many zinc proteins will change. And I have another entrepreneur friend– Bill Rutter– who’s put a machine in 2,000 hospitals in China.

The Chinese are subsidizing to put these machines in every hospital in China. You put your finger prick– get the finger prick of blood. And he analyzes 20 proteins by monoclonal antibody to see of medical importance. So all this is coming.

And it cuts out expensive doctors. Because the machine sends the results to your iPhone. It’ll say, hey. You’re low in magnesium.

Your DNA repair isn’t working well. Eat a big plate of kale or spinach because it’s in the chlorophyll molecule. Otherwise, you’re going to increase your risk of cancer or something like that. So you cut out expensive phlebotomists, and expensive doctors.

And you’ll take charge of preventing disease, just the way you measure cholesterol. And you know to keep your cholesterol there. So just a word about obesity. [LAUGHTER] So the conventional wisdom is obesity is calories in and exercise out.

So this is calories in. And this is exercise out. [LAUGHTER] I should tell a little story. My wife is Italian.

I get this wonderful Mediterranean diet. But she keeps on nagging me to get more exercise. And one day I told her, when I feel like exercise, I run my experiments. I skip controls.

And I jump to conclusions. [LAUGHTER] And I like that joke so much, I told it about 50 times. And my wife said, I’ve heard enough of that damn joke. I’m getting you a personal trainer.

[LAUGHTER] So now I go twice a week and row, and lift weights, and do all those things. I’m sure it’s good for me. But anyway. So if you look at obesity, the obese are eating the worst diet in the country.

If you define worst as ratio of essential vitamins and minerals to calories, they’re eating all this refined food. So their diet is horrible. It’s really the worst diet in the country. And they get fat because I think nature makes them hungry.

Because it’s craving for that magnesium, and calcium, and Omega3, and all the other things they’re short of. And their diet doesn’t have it. So they just get fat. So give up the refined food, eat your veggies.

It’s all the things your mom told you– a little more fish and a little less red meat. And you’ll be fine. This is top sources of nutrition for 20- to 30-year-olds. I got it off some government– Wakimoto and Block got it off some government website.

And the main item in a 25-year-old diet is sugary soft drinks in terms of calories. And it goes down– pizza, beer, hamburgers, white bread, Coke, cake, french fries, potato chips, rice, cheese or cheese spread. 40% of calories and nothing green in there. Remember, from green things you get your vitamin K, you get your folate, and you get your magnesium– not all things.

So you have to eat a good balanced diet. Nuts are healthy. Berries are healthy. But people around here know all those things.

So obesity is a complete disaster. In every possible disease of aging that’s been looked at, in obese people is much higher. More cognition problems, cognitive dysfunction, more cancer, more heart disease, more diabetes. And it’s a huge cost.

It’s going to be worse than smoking. Anyway, so about 10 years ago, Mark Shigenaga– who’s an independent scientist in our group– and I decided, hey. We have to get vitamins into the poor. And pills don’t work very well because you have to remember and do it.

And the poor aren’t very good at that. So what we decided to do is make a little bar. The local Department of Agriculture USDA lab in Albany, California– which is right next to Berkeley– was making a fruit bar. Just a small bar made of excess California fruit, which there was lots of at the time.

And it was tasty. We knocked on the door and said, could you add some vitamins to the fruit? And they said, sure. So we started a 10-year collaboration. So they’re adding vitamins, soluble fiber, insoluble fiber.

We tried to mimic the Mediterranean diet– all the things we thought were important– and put it in this bar. And it really does wonderful things to people. We’ve done, I think, 18 clinical trials by now, all on a shoestring. And this is what we call our arrow plot.

So what we do– these are ordinary people. People at CHORI– mainly scientists or other reasonably-educated people. And what we’re measuring here is HDL. And we have 25 people.

And we measure– the bottom of the arrow is where we started. And the top of the arrow is two weeks later, eating two bars a day. It’s fish oil, vitamins, and minerals, whatever we could think of that was important in nutrition. And it took us a couple of years before anybody would eat our bar.

But we got it tasty in the end. And it has some blueberries in there, and chocolate. And it tastes pretty good now. So you can see, even the worst person– who’s one of the people in my group who looks like Buddha– and the best person– who is the M.D. In charge of our group who runs marathons, and eats a terrific diet, and everything– and she’s up here.

And you don’t need a statistical analysis. You just look at this and you can see it’s working. And so you see the same sort of thing with HOMA IR. So we started doing all these bioassays.

And we developed some bioassays for DNA damage, which we’re just doing at the moment. And so I think these are cheap. You can’t make a placebo for a bar very easily. We’re trying to.

But it’s– so these wouldn’t meet FDA standards at all. In fact, we’re desperately afraid of getting entangled in FDA’s clutches because that’ll kill the whole project. But the minute you say it improved the asthma of obesity, which there’s no cure for– and the doc from the hospital who works on asthma is working with us. And he made the mistake of calling up FDA.

And we were desperate for a while because we knew they would kill the whole project. But we managed to extricate ourselves. But FDA considers everything a drug. Anyway so to finish off, just a Mark Twain quote.

And life expectancy gets longer every year. This is women. And the top one is women. The bottom one is men.

Women live a little longer than men. But it keeps on going up. Now obesity is going to make a dent in this. Because obesity– cigarette smoking is about 10 years off your life depending on exactly how much you smoke and how long.

And obesity is going to be, I think, even worse than that. And so when they set up Social Security in the ’60s, they thought everybody would be dead by 65. So they set a retirement age to 65. And every projection of the government has been wrong since then.

Because life expectancy keeps on increasing. And they say America has terrible life expectancy compared to Europe. But if you correct for car accidents– it’s a big country– and you’re correct for shooting in the inner cities, then we’re doing better than Europe. And when you look at any specific thing– cancer, whatever– we’re doing better.

So anyway, I shouldn’t get into all that. So this says, you’re 57 years old. I’d like to get that down a bit. [LAUGHTER] And this is our group.

Jung Suh is Korean ethnically, but was brought up in Thailand by a Korean businessman. And he’s wonderful, and is working on ergothioneine, which we think is going to be a new longevity vitamin. And he’s figured out the mechanism. And Joyce McCann, who’s done all these wonderful reviews.

And Swapna, who’s an Indian post-doc. And David, who’s an American post-doc. Then I have a few physicians. Ash Lal is a pediatric hematologist.

And Michele Mietus-Snyder who led a number of our clinical trials, is a pediatric cardiologist. And Hal Helbock is a neonatologist. They all work part-time in the lab. And then Mark Shigenaga’s our guru on the gut.

And Sandy is an independent scientist who’s an expert on mitochondrial DNA sequencing and all of that. So anyway, right now that’s it. [APPLAUSE] Do we have a question period? KEITH WEST: We have several minutes for questions and answers. AUDIENCE: How [INAUDIBLE] you pay for [INAUDIBLE]?? MICHAEL KLAG: You have to use the mic so that they hear it on the web.

AUDIENCE: You have to use the mic, please. AUDIENCE: Thank you for that wonderful presentation. I’m a rheumatologist and very interested in nutrition and it’s impact on chronic diseases. And when my patients ask me whether they should take any supplements, I always hesitate.

Because I’m not sure whether diet converted into a pill is of equal efficacy. So would you comment on that? BRUCE AMES: Well, it all mixes. The vitamin pill mixes in your stomach with all the food. And if you give pyridoxine, it’ll raise pyridoxal phosphate levels in the blood.

Or you give niacin, it raises NAD level. So people don’t– except there are a couple of cases where there’s something different. Vitamin E is a mixture of eight isomers. But they fortify it only with alpha.

And we published some papers that gamma-tocopherol was doing something slightly different. And so there may be two vitamins in there. And then folate, they’re giving you oxidized folate. Because when Mitchell isolated folic acid from four tons of spinach, he oxidized it.

And what’s in the body is reduced folate– tetrahydrofolate. So it’s not quite the same thing. But there are a few little cases like that. But other than that, I think it’s the same as what’s in food.

MICHAEL KLAG: So, Bruce, I think like everybody else, I’m amazed at your ability to synthesize information across disciplines– like the vitamin D and behavior, and all that. And I’m just– I think a lot of us worry about the way that science is now. It drives you towards narrower and narrower reviews. Right? So it’s– and I’m just wondering how you fund this research.

Do you, or is it? BRUCE AMES: Nobody can get funding anymore. And if you’re innovative, my experience is that when I had a really good idea, I never could get it funded. So you bootleg it out of other grants. [LAUGHTER] So when I was doing DNA damage and thought– and all the carcinogens were showing up as mutagens, I was trying to sell the idea, hey, this is really important in cancer.

And, oh, no. It’s viruses. Or, oh, no. It’s the immune system.

And I couldn’t get any money. The Cancer Institute said, bacteria have nothing to teach us about cancer. I got turned down flat. But eventually, I got some money from the Atomic Energy Commission, who is interested in it.

But if you’re innovative in today’s climate, you can not get funded. I can’t get funded for any of this. And after a while, you get tired of just putting in grants and people misunderstanding it. So I’d fund it out of my own pocket.

But I’m running out of money. So it’s– [LAUGHTER] AUDIENCE: I had a question here– two questions briefly. A wonderful talk. Thank you so much.

Electromagnetic fields– the studies of cell phone use and how it changes our glucose metabolism in the brain. Can you comment on electromagnetic fields and how they might change our nutrient needs or our metabolism? Second question– the microbiome is an exciting field of research. Could you merge that with your vitamins for longevity? BRUCE AMES: Well, they’re fashions. And I know very little about magnetic fields.

But I tend to be skeptical of these things unless someone can come up with a plausible mechanism. And the microbiome does seem important. But there are lots of important things. Right now, I think vitamins and minerals are something we can get our hands on.

We think we understand it. And you can measure it in people, which is where we want to go for prevention. AUDIENCE: Dr. Ames, thank you very much. Very interesting talk.

I’m wondering, with the general enthusiasm in the United States for taking supplements– I think 50% of people over the age of 60. Is there a range of supplements that you recommend? Is it the RDA? Or is it– or are super physiological doses of supplements– Should they be avoided? Or do you have any general comment since many people take supplements in terms of recommendations for how much? BRUCE AMES: This is my– I have an Italian wife who feeds me a wonderful Mediterranean diet. But I take my vitamin D pill because I’m in the dark all the time in the lab, or at least– and we eat fish a couple of times a week. But I take a fish oil pill.

So I do take– but minerals you have to be really careful about. You shouldn’t take a calcium pill. You shouldn’t take a magnesium pill. You take a calcium magnesium pill, or a sodium potassium.

Anyway, you have to have a warning on minerals because they look a lot alike. And I think if you give a lot of calcium to somebody, you can trash some of the magnesium [INAUDIBLE].. But other than that warning, I think it’s good insurance. And it’s the poor who don’t take pills who need them, and the rich who are eating relatively good diets– but most of them not perfect– are taking them as insurance.

AUDIENCE: I have a question. Professor Ames, you are artistic. You are an artist in how to blend cell to society perspectives. In public health nutrition, we are constantly challenged and see ourselves as wanting to have students be aware of molecular mechanisms, but take those all the way out to society and prevention.

Can you offer some words of advice on how to capture that literature? It’s so broad. Mike mentioned the complexity of it all. BRUCE AMES: Yeah, it iscomplex. I mean, we– at the beginning of July, we stumbled on– we knew that vitamin D was associated with autism.

It’s higher in northern latitudes. And Somalis move to Sweden. They get five times the rate of autistic kids and things like that. And I stumbled on the fact that serotonin was all involved in tryptophan making serotonin, which I didn’t know before.

And I read that literature. It was really convincing. I went to my post-doc and said, is there some linkage between the vitamin D and the serotonin? And she looked up the VDREs and the gene maps. And so we found somebody who knew about that stuff.

And he explained to her how to do it. And so you need drive. And she was terrific. She did all the scholarship.

And so you have to not be afraid of going into a new field. You can talk to people and learn it. And I seem to have been doing that all my life. But I was always half a geneticist, half a biochemist.

And so it’s useful. It’s so competitive now. If you know two fields where there’s an interface, you have a big advantage over everybody. You don’t have to be as smart.

[LAUGHTER] AUDIENCE: I just have one more question. KEITH WEST: One more question? Is that a problem? AUDIENCE: Yes, I have one more question. AUDIENCE: Basic question kind of like. Do you think that we have discovered all vitamins there are? Or do you think there are some which we have missed, particularly if their effect is not very prominent? BRUCE AMES: We’re just writing a review about longevity vitamins and minerals.

So, for example, lutein and zeaxanthin are in the macular of the eye. And the epidemiology seems to suggest that it protects you against macular degeneration. And you look at the colors– it’s blue light. And blue light is the most toxic light.

And carotenoids have those conjugated string of double bonds, which can take singlet oxygen– which has extra energy– and dissipate its heat. That’s why all plants are full of carotenoids. And it made sense. They’re vitamins.

They’re just longevity vitamins. And Jung has discovered that ergothioneine– he knows exactly what it does. It stops a particular kind of oxidative damage. And he’s just writing a paper on that.

He’s in the group. And we’re going to write this general review saying, hey. You have to broaden what you call a vitamin. And we found many other substances that seem to fit that category.

We don’t– more work will have to be done. But I just want people to rethink things. I should put in a caveat. I’m going to be 85 in two weeks.

And my neurons are decaying. And my mitochondria are decaying ever more rapidly. But I finally figured out what the mitochondria decay into– hypochondria. [LAUGHTER] [APPLAUSE] KEITH WEST: Well, one of the goals of the Graham Lectureship is to have role models.

And we certainly have heard from a role model just now. And Professor Ames, we’d like to give you a token of our appreciation. This is the first Graham award that has not been made in Bangladesh, but been handmade in Baltimore. And so the dean would like to give this to you.

A [INAUDIBLE]. MICHAEL KLAG: Congratulations. [APPLAUSE] BRUCE AMES: Your dean said I’m only allowed to put graham crackers into this. [LAUGHTER] Will this go through airline security? KEITH WEST: I don’t know.

MICHAEL KLAG: We can check it. BRUCE AMES: OK. That’s a [INAUDIBLE]. Thank you.

KEITH WEST: We’ll leave it there. Thank you. OK. So.

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Source: International Health – JHSPH