Delaying Ageing & Optimising Health With Diet & Nutritional Supplementsby Bruce Ames
When you eat fat and carbohydrate, you burn them in the 500 mitochondria that are in each cell.
All the oxygen you breathe in goes through the mitochondria. You’re pulling electrons from fuel and adding them to oxygen. But there’s always a little leakage from this process to make superoxides or hydrogen peroxide and hydroxyl radicals. These are the very substances you get from radiation exposure. So the process of living is similar to being exposed to radiation.
This is behind the free radical theory of ageing for which the evidence continues to grow.
Mitochondrial decay is a key factor in ageing and degenerative diseases. Defences against this within the cells include superoxide dismutase, catalase and other many other enzymes that are designed to destroy these oxidants. But it doesn’t pay nature to be 100% perfect because nature wants you to reproduce and nature selects for genes that benefit early reproduction. Degenerative diseases come too late to be selective factors.
Every time DNA gets damaged you get a lesion in it. Then repair mechanisms come along to fix the damage so the DNA is unblemished. The other repair systems are specific enzymes, half of which are for oxidants. Meanwhile the lesions undergo chemical changes and end up in the urine. Looking at the urine it was discovered that there are around 100,000 damaged DNA bases that are repaired each day for every cell in the body. This was much greater than expected. The repairs are nearly 100% but not quite, and the efficiency of repair lessens with ageing.
Protein also undergoes oxidation and this process accelerates with ageing. Lipids also oxidize similarly. Mitochondrial decay is a key factor in ageing although not the only one. In the mitochondria, proteins are passed across an inner membrane creating an electrical charge across it. Mitochondria are like rechargeable batteries and it’s that charge that allows ATP, the chemical energy of the cell, to be made and to power our bodies. With ageing the membrane potential goes down, a key lipid functions less well making the membrane stiffer and protein function is less efficient. Oxygen utilisation goes down and oxidant leakage goes up, so more damaging oxidants are made. This slow decaying is at the root of a lot of degenerative diseases.
Acetyl Carnitine & Lipoic Acid
Acetyl carnitine is a small molecule that’s used only in mitochondria to transport fatty acids into the mitochondria to be burned. In an experiment with old rats it was found that supplementing acetyl carnitine in their drinking water improved the factors associated with ageing. A key mitochondrial lipid that goes down with age came back up with the supplement.
Membrane potential improved. The only thing that didn’t improve was oxidation. The old rats were still pouring out oxidants at the same rate. So lipoic acid was tried since this is a strong antioxidant and a mitochondrial coenzyme. It was put in their food for a month. It brought down the level of oxidants similar to those of a young animal. Then both were tried together. Glutathione, a key antioxidant, came back up. Aldehydes from lipid oxidation go up strongly with age but came down almost to the levels of a young animal.
The rats were also much more active, had better immune function, and better brain function. Looking directly at the brain it was found that it was RNA and not DNA that was being oxidized. The mechanism is now reasonably well understood. The aldehyde from lipid peroxidation damages key proteins. Acetyl carnitine protects against this and lipoic acid lowers the level of the aldehydes.
It was originally thought that lipoic acid worked by keeping the oxidants in check but it turns out that in part at least it acts as a weak oxidising agent that switches on a signaling system that turns on some of the antioxidant defences of the body. There are around 200 or so enzymes that get turned on when certain chemical groups get damaged. This in turn creates another compound that binds to a DNA sequence called the antioxidant response element that turns on the enzyme defences. Lipoic acid turns on this system. Garlic and broccoli act in the same way.
A meta analysis was carried out on all the clinical trials that had been done with acetyl carnitine for cognitive impairment and mild Alzheimer’s. The overall analysis suggests that it works in humans although the evidence isn’t particularly strong.
For lipoic acid the meta analysis covering a number of clinical trials suggests that it does work. Even if this combination isn’t the whole story, there are so many scientists working in the field of ageing that there is bound to be much progress.
Obesity, Cancer & Life Expectancy
Life expectancy continues to improve. It’s 78.9 for women and 71.4 for men. Single men live 8 years less than married men. Although better infant mortality reflects some of this, for those aged 65, life expectancy is also improving.
What in your diet makes you age faster? Since cancer increases with age we can look at cancer as a marker for ageing. Epidemiologists are in agreement that about 30% of cancers are due to smoking, 35% is caused by unbalanced diets, too many calories and too little fibre and micronutrients, 20% by chronic infections (mostly in poor countries) 20% hormones, 2% occupational and less than 1% by pollution, mostly heavy air pollution. But of course America is spending all its money on pollution.
Obesity is already a huge and growing problem.
With smoking there are 400,000 premature deaths a year in the USA. Obesity will be much worse. It’s a long-term health problem that’s tied to diabetes, cancer, Alzheimer’s, an abundance of health disorders. This will put a huge financial burden on the country. Diet is an area where real advances in disease and ageing can be made, but doctors aren’t interested in diet. What doctor ever asks you about your diet? Yet it is the main determinant of health.
Nutritional Deficiencies Are Common
Vitamins and minerals are kind of old hat because there is little acute deficiency disease any more. But I would argue there’s a lot of ill health that lies between acute deficiency disease and the recommended daily amount. Whatever vitamin or mineral you look at, 10% or more of the population is really low and this is fouling up their biochemistry.
Iron deficiency for example. Worldwide there are 2 billion women and children who are not getting enough. Deficiency knocks out your mitochondria so you age faster and your neurons are the first thing to go. 25% of American women are borderline anaemic. Menstruating women are losing iron and not getting enough in their diets. Iron costs very little. Putting resources where it matters would have a major impact. 10% of the population is very low and deficiency breaks your chromosomes in the same way as being irradiated. It’s probably knocking out your mitochondria as well.
With folate, B12 and B6 deficiencies you get chromosome breaks. Vitamin C deficiency is also common. Poorer members of the population are worse affected because they have poor diets and don’t take multivitamins.
Everything is linked in nutrition. Zinc is in a thousand enzymes turning genes on and off and much else. Without sufficient zinc you are disabling all sorts of defence and other systems, so we have to think of everything in biochemistry as linked together. There are 40 micronutrients we need to be getting in our diet and the optimum is the amount needed for long-term health. We are far from that in the population and yet it costs very little to provide it.
Overweight & Underfed
Why are we obese? Is it just calories in and exercise out? I think it’s more than that. Americans are eating junk. The 10 leading sources of calories in the USA that makes up about a third of all calories (for some it’s a lot more than this) represent poor food choices. The first is sugary soft drinks. This is a nutritional disaster. Each drink contains 40 grams or more of sugar going all at once into the gut. with no vitamins or minerals. It contains lots of calories without filling you up. You don’t see a lot vegetable in the top ten, not a lot of whole grains! Obese people have poor diets. They are deficient in everything. They’re low in calcium, magnesium, iron, folate, B12, B6 etc. Whatever you want to measure they are at the low end of the population intake because they rely too much on refined carbohydrate and sugar.
I believe they are hungry all the time. Their bodies are craving the missing ingredients. If you take a rat and keep it zinc deficient, it keeps on eating to get the missing zinc. Two decades ago experiments were done on rats where one group got a high quality diet and the other group ate a junk diet. Although both groups could eat as much as they wanted, the first group stopped eating when satisfied and remained lean. The other group ballooned up. Satiety involves fibre. If you don’t get fibre you don’t get full. It may also be true for a lot of nutrients too.
Another theory is that the gut holds the key. Obese people have chronic inflammation. They are high in C-reactive protein, a measure of inflammation. A leaky gut allows bacteria to enter the system and to create this inflammation. This stops oxidation of fatty acids, raises blood lipids and makes you lethargic. How does their gut become leaky? Their diet is too low in fibre. Need both soluble and insoluble fibre to keep the gut cells happy. They like to live on the fermentation products of soluble fibre, the butyric acids. If these cells don’t get what they need, the barrier function gets impaired and unwanted substances can penetrate the gut wall. Trans fatty acids don’t help either.
Nutritional Deficiency & Ageing
It was discovered that when mice were put on a diet that lacked folic acid the mice were full of chromosome breaks. These were worse than what’s seen in radiation exposure. The same is true for vitamins B6 and B12. These are also needed to keep homocysteine levels down. We recently published a paper comparing folic acid deficiency with irradiation. They are not even in the same ball park. People are worried about tiny levels of radiation. There’s talk of spending trillions on cleaning up tiny amounts of radiation. You’d be way ahead of the game by giving everyone a folic acid pill. We worry about the wrong things. Huge resources are put where it doesn’t matter and not where it does matter – diet.
A study put a dozen people on defined diets. The only differences were in the levels of B6. Chromosome breaks were then measured. Once you go down to half the RDA for the vitamin you get breaks in the chromosomes. So getting enough vitamins and minerals is essential. We’ve also shown that sperm count and sperm quality goes down with folate deficiency. We’ve also studied iron. This mineral causes all sorts of mitochondrial damage and oxidants to be produced in excess, but too little iron is a disaster because too little wrecks your mitochondria. Iron deficiency interferes with heme synthesis. Heme carries oxygen in your blood. Deficiencies of biotin, pantothenic acid and copper also do this. The effect is to pour oxygen radicals into the cell. This happens even before anaemia sets in. The consequences of heme deficiency look very similar to what happens with ageing and neurodegeneration. A cheap multivitamin and mineral would prevent all this.
I believe everybody should take one as insurance. The whole northern tier of the USA is vitamin D deficient which is a risk factor for cancer and brittle bones etc. You need 20 minutes of sunshine each day to make this vitamin. There isn’t enough sunshine in northern parts. Blacks and Hispanics get even less as well as people who stay indoors. So take a multivitamin. But you need more than this.
There’s not enough magnesium and calcium in a multi. There’s no fibre. Also need omega 3 fatty acids. These are really important. 30% of the fatty acids in your brain neurons are DHA. If you don’t eat oily fish you won’t get enough. The nutrition community doesn’t like pills. Mark Twain was a little skeptical too: “The main distinguishing characteristic between man and the lower animals is the desire to take pills.”
They think if you tell people to take pills they won’t eat proper food. Trouble is they’ve been trying for 20 years to get people to each fruits and vegetables while their diet continues to get worse. So I feel everyone should be told to take a pill and get a good diet besides.
Mega Nutrition & Genes
You can go to a health food store and buy very large quantities of some vitamins. For instance a B100 pill. I thought this was crazy and so did my colleagues. But it might not be. You can raise coenzyme levels with large quantities of B vitamins. If you have mutated genes that deform protein, you can sometimes get over the error with larges doses of vitamins to raise coenzymes. We found 50 different genetic diseases where high dose vitamin therapy had a beneficial effect. For instance there’s a rare genetic disease where children go blind because of a lack of a mitochondrial enzyme. The cause for this was found. It turned out to be a B6 dependent enzyme. When very high doses of B6 were given to children prone to this disease, they didn’t go blind.
The fallout from this won’t be so much in rare genetic diseases as in other areas such as polymorphisms (genetic variations). For instance there are 400,000 people around the Mediterranean that have glucose 6 phosphate dehydrogenase deficiency disease. This lowers glutathione levels in cells. This knocks out the malaria parasite. Malaria was the big killer of kids in Africa and all around the Mediterranean.
This mutation makes kids more resistant to malaria but it makes them more sensitive to oxidation. So if they eat a meal of fava beans - these have oxidants in them - they can get a haemolytic anaemia. Pythagoras, the famous Greek mathematician, told his followers not to eat beans. The classical scholars thought he was a nut, but now it all makes sense.
There are many different mutations but there’s one in an area of India that ought to be curable by feeding them high levels of niacin. Clinical trials will take place to see if high levels of nutrients will help these and other polymorphisms.
In ageing you have the mitochondria decaying. There are all sorts of coenzymes in there. Mitochondrial coenzyme levels can be raised. So theoretically we can do something about ageing. We’ve being doing work in this area and the preliminary results look promising. There are lots of ways to intervene. I think people are going to live a lot longer.
Bruce Ames is professor of biochemistry and molecular biology at the University of California, Berkeley, and senior scientist at Children’s Hospital Oakland Research Institute. His main interest of study is identifying mutagens that damage human DNA, the body's defences against them, and the consequences of DNA damage for cancer and ageing. He has published over 450 papers.
This article is an edited version of a lecture given by Bruce Ames. For further information about the work of this renowned scientist please visit bruceames.org
This article was first published in Enzyme Digest No. 70, Autumn 2005
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