Delaying the Degenerative Disease of Aging

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Marisol Corral-Debrinski and Bruce Ames at Aging 2008

Bruce Ames is a professor of Biochemistry and Molecular Biology at the University of California, Berkeley, and a senior scientist at Children’s Hospital Oakland Research Institute (CHORI). He is the inventor of the Ames test, a system for easily and cheaply testing the mutagenicity of compounds. His research focuses on cancer and aging and he has authored over 500 scientific publications. He is among the few hundred most-cited scientists in all fields.

The following transcript of Bruce Ame’s presentation at the free symposium entitled Aging: The Disease, The Cure, The Implications has not been approved by the speaker.  Video is also available.

 Delaying the Degenerative Disease of Aging

I would like to tell you about two areas of research we have been doing on aging and why I think that both are going to lead to delaying aging. The first is mitochondrial decay. My interest is preventative medicine. I worked on DNA damage, its relation to cancer, and how to delay it. I realized that cancer was one of the degenerative diseases of aging, along with heart disease and brain dysfunction, all the things you learn about soon enough.

I got interested in aging, and a postdoc came to by lab who knew about mitochondria. If you read the literature you know that there is a lot of circumstantial evidence suggesting that mitochondria decay, and that is contributing to a lot of aging. There are about 500 mitochondria per cell. It is the most complicated organelle in the cell. Basically they are burning your fuel, fat and carbohydrate. “Burning” means taking electrons from them. If you add four electrons to oxygen, which is the electron-acceptor (all the oxygen you are breathing goes through the mitochondria) and that process creates ATP, which powers your muscles, your brain and your metabolism. You make kilos of ATP everyday. We ran tests on aging in rats and mice. We decided we would work on mitochondrial decay and determine to what extent that is contributing to aging and how we could manipulate it without waiting two years for the rat to get old.

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All of life is trade-offs. You are adding four electrons to oxygen. If you add them one at a time, you are adding all these oxidants. That is an inevitable byproduct of living. Nature is better than most engineers—it is 98 or 99% efficient, but as you get older the mitochondria are putting out more oxidants. It is like an old car engine that has less efficiency and more black smoke.

We set out to compare mitochondria from old rats and young rats and try interventions. We tried lots of things and found two substances that would delay all the assay from mitochondrial decay that we had set up. We had set up four different areas of mitochondrial function that were known to decay with age. Between these two substances, it delayed these.

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This is a blow-up of mitochondria. As I said, there are about 500 per cell. It makes all the energy in the cell. There is an outer-membrane, an inner-membrane, and inside the mitochondria. This membrane potential across this inner-membrane drives Complex V here to make ATP, the chemical energy of the body.

Basically, mitochondria recharge old batteries. What this burning process does is it moves electrons across these complexes. Each of these complexes have hundreds of proteins. A thousand proteins get shipped in from the nucleus and into the mitochondria. The mitochondria have their own piece of DNA and they make a few proteins. It is all very complicated and lots of Nobel Prizes have been awarded for the people who figured all this out. Basically, this process pumps protons across the mitochondrial membrane, and that charge across the membrane drives Complex V.

The two compounds we came up with were acetyl carnitine, which is a normal mitochondrial metabolite, and lipoic acid. We were feeding them much higher levels than you can normally get in food, and they worked. It made old mitochondria look more like young mitochondria. We tested aspects of brain function in rats, mice and dogs, and it worked. The university of California took out a patent on this combination. It is called Juvenon and is sold over the web. I founded a company and put all the stock in a foundation so that I have no financial interest, but the money is all going to go to science. The company is selling lots of these pills, the money goes into clinical trials. I am quite excited about that. Complex IV decay contributes to Alzheimers, Complex I decay contributes to Parkinson’s, and more and more diseases of aging are being traced to mitochondrial decay, though it is not the whole story.

That is all I am going to say about that area because it was published awhile back, but I want to tell you about my new enthusiasm. You are all aging yourself faster, and I would like to tell you how to avoid that. Half the world is aging themselves faster by eating lousy diets. This shows metabolism:

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What do you need to run your metabolism? You need energy, and you get that by burning your fat and carbohydrate, but you need something else. You need about forty micronutrients from food. Metabolism requires fifteen minerals including iron, magnesium, manganese, calcium, and copper. You need about fifteen vitamins, and those become coenzymes or hormones. Then you need two essential fatty acids, omega 3s and omega 6s. Then you need about eight essential amino acids. If you do not get any one of those, you will die, so you need to be eating a balanced diet.

Over the past fifty years nutritionists and biochemists figured out we need niacin, which becomes an important coenzyme used in hundreds of enzymes. British sailors on long ocean voyages, a third of them would die, their teeth would fall out and get scurvy. Then they found out that if they took limes on the voyages and ate lots of limes, then they did not get scurvy, so the British sailors were called “limeys.” Then, vitamin C was isolated.

We have eliminated mostly rickets, scurvy and berriberri, these diseases that come from vitamin deficiency. Yet we are not eating what the committees think we ought to be eating. Recommended dietary allowances (RDA) is what the committees say we should be getting for each of those. Two standard deviations below that is something called the EAR, but nobody gives a damn because there is no pathology associated with it. What I am going to tell you is I think I know what the pathology is. Being low in one of these micronutrients ages you faster.

The argument is that throughout all of evolution, animals were running out of one micronutrient or another—fifteen minerals are not spread evenly in the world. Animals are running out of magnesium or iron. What does nature want to do when you are running out of magnesium? It cuts out any metabolism that is long-term. DNA damage shows up as cancer five years down the road? The hell with it. Your adaptive immunity leads to dying of a more severe infection five years down the road? The hell with it. Your mitochondria put out more oxygen radicals, so you have Parkinson’s or Alzheimer’s? The hell with it. Basically you are paring down to what is vital so you can reproduce a little bit. That’s what nature cares about.

That is the argument: I call it triage.  The first iteration of this was published a couple years ago.  We keep on finding one example after another, and we are in the middle of trying to test it in people.  The pathology is all insidious—it is the very things that happen with aging.  DNA damage goes up with aging, your adaptive immunity goes out with aging, your mitochondria put out more oxygen radicals with aging, and that is what is accelerated by micronutrient deficiency.

That is the argument.  I’m a bit of a visionary, so you don’t have to believe it all, but I am going to try to prove to the scientific community in the years I have left to do science that all this is true.

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This shows what percent of the population is below the EAR.  The EAR is where the committees put a red flag if you are not getting enough.  Menstruating women are losing iron.  16% are below the EAR for iron.  All kinds of nasty things happen when you are anemic.  For magnesium, 56% of the US population is below.  What is going on here?  Where do you get magnesium?  It’s in the center of the chlorophyll molecule.  If you eat anything green, you are getting magnesium.  The main source is green things.  You eat a big plate of spinach, you are getting a healthy dose of magnesium.  The body wants two calciums to one magnesium, but we are dreadfully short of magnesiums because people aren’t eating their greens.  You get a little from whole grains, and people are not eating a lot of whole grains either.

Zinc is very important.  There are hundreds of enzymes with zinc fingers that are turning on and off things.  You make a cell a little zinc-deficient and you knock out all these things.  Practically everyone is low on vitamin E.  Half the population is low on Omega 3 fatty acids.  You start adding all of this up and you wonder whether anyone besides Walter Willett is eating a perfect diet–he is the leading epidemiologist on nutrition.

Now, are we talking about 10% of the population, or are we talking about 80% of the population?  My own guess is it is going to be a sizable percent of the population—all the poor and all the obese.  The obese are eating sugary soft drinks and donuts and they think they are hungry all the time because their body is craving that missing magnesium.

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I first got onto this when a geneticist named Jim MacGregor came to my lab on sabbatical.  He had just stumbled on the fact that folic acid deficiency breaks your chromosomes.  Folia is the latin word for leaf—foliage.  My mentor at Caltech, where I got my PhD back in the early ‘50s, was Herschel Mitchell, and he first isolated folic acid from four tons of spinach.  If you don’t eat your greens, you are not getting folic acid.  If you don’t have enough folic acid, you start putting uracil in your somatic cell DNA and in your sperm, so you are making nicks and breaks in your own DNA, just like getting irradiated.

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MacGregor started looking in people, and this is the baseline for chromosome breaks.  When I looked at what percent of people were at the level of folic acid deficiency where it was breaking chromosomes, it was half the poor.

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Here is a comparison of X-rays and folic acid.  We looked at iron.  Too much iron—that’s men eating too much meat.  Two billion women and children were not getting enough iron.  Too much or too little iron wrecks your mitochondria.  If you want to age yourself faster, just eat low iron.  Mae West said too much of a good thing is wonderful, but I think she was thinking about sex, not micronutrients.  You don’t want to overdo things.

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Mouse pups who are low on iron don’t do well on IQ tests, and the rat pups don’t do well on rat IQ tests, and kids don’t do well in school if they didn’t get enough iron.  The brain is a trillion neurons and a thousand connections each.  You don’t get a good diet and your brain is not functioning well.

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We started looking at many micronutrients, and in every case we found DNA damage.  I thought, why the hell is nature doing that?  It had to do with mitochondria pouring out more oxygen radicals.  This shows a cell that is biotin deficient and it just fills up with oxygen.     The mitochondria pour out oxygen, just like they were old.

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I looked up on the web, and you find all kinds of micronutrient deficiencies that are associated with chromosome breaks or cancer, but epidemiology in people is a very iffy science.  The epidemiology joke is, “Miami is a weird place.  Everybody is born Hispanic and dies Jewish.”

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The first iteration of my paper on triage, I call it, argues that the pathology associated with low micronutrient intake is aging you faster.  This came out two years ago, and now we are working on the second iteration.  It is not just DNA damage and your mitochondria pouring out oxygen radicals, it’s your immune system. If you look at what goes wrong with the immune system with aging, there are six things that go wrong.  If you look up has anyone ever looked at this versus micronutrient deficiency, the literature is out there and we keep on finding more examples.

I think all aspects of your aging are going faster.  Just to finish up, many years ago we published a paper that folate deficiency knocked out your CD8s relative to your CD4s.  I didn’t understand it, but we published it.  Now I understand it, because it is one of the things that goes out with aging in the immune system and when you are short on micronutrients.

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This says, “You’re fifty-seven years old.  I’d like to get that down a bit.”  I think, if all this is true, we are talking about half the world.  Micronutrients are dirt cheap.  It’s what your mom said.  Eat your veggies, eat a good, balanced diet, and take a multivitamin as insurance.  You don’t get all the micronutrients from the multivitamin.  You need Omega 3s, which you get from deep sea fish.  You need magnesium, calcium and potassium, which would make the multivitamin way too big, so you need to be sure you are getting those things.  But don’t overdo it.

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