Anti-oxidants: A Disappointment or Worse

Oxidative damage was the prevailing theory of aging in the 1990s, and anti-oxidants became the preferred prescription for youthfulness. But in lab animals and in human studies, the cure didn’t pan out – anti-oxidants never did fulfill their potential, and this left the theorists scratching their heads. Then, in recent years the situation became curiouser and curiouser, with hints that oxidative damage might be essential for a kind of stress signal that tells the body to “stay young”.

The Theory

The theory of oxidative damage was known as the “free radical theory” of aging, and it dates to physicist Denham Harman in the 1950’s. The main evidence for it was that damaged molecules – proteins, sugars, and DNA – can be found in the cells of old people, much more so than in young people. The theory is that the cell’s energy-generating machinery (in organelles called mitochondria) is designed around forms of oxygen that are highly reactive, precisely because of their high energy content. In the process of energy generation, inevitably some of these reactive oxygen species (ROS) leak into parts of the cell where they can cause trouble by corroding essential molecules.

From the first, some noted that there were some problems with the theory: One was the pace. You might imagine that these damaged molecules would accumulate gradually over a lifetime, but in fact they are found only in modest quantities until cells become very old, when the damage appears suddenly to be quite severe. And there was a paradox: Muscular activity was known to use energy at a rapid rate, and spurts of exercise generate free radicals far faster than the body can “clean them up”. Yet people (and animals) who exercise live longer, on average than those who don’t. And activity is much higher in youth, when damage seems to be accumulating slowly, than they are in old age, when the damage becomes a catastrophe.

Nobody (except maybe Cynthia Kenyon) stopped to ask: Why should we expect a Mayfly to accumulate as much oxidative damage in one day as a Galapagos tortoise does in 100 years?

 

The Remedy

If aging was caused by oxidative damage, then medicines that protect against oxidative damage might be able to retard aging. In the 1990s, the race was on to test anti-oxidants for their life extension potential. The body’s own anti-oxidant system sits on a foundation of three substances: glutathione (GSH), superoxide dismutase (SOD), and ubiquinone (also called Coenzyme Q, sold as a supplement called CoQ10). All of them are problematic for oral dosage. Glutathione is produced in the body as-needed, and only lasts a few minutes. There is a supplement, n-acetyl cysteine or NAC, which is a precursor to glutatione, but, once again, no one has been able to demonstrate life extension with NAC supplemention of lab animals. SOD is even more transient, but there is a cantaloupe extract called glisodin that purports to stimulate the body’s production. No life extension has been demonstrated with glisodin supplementation.

The least difficult is CoQ; still, absorption through the stomach is poor, and very little of it gets through to the mitochondria where it is needed*. There is some evidence that CoQ10 lowers risk of heart disease, especially for people taking statin drugs, which knock out the body’s own CoQ10. In lab animals, too, supplementing with CoQ may improve health, but it has failed to extend life span.

Lab scientists like to study aging in roundworms, C. elegans, because they are easy to grow in a petri dish and they have a fixed, short life span. In the 1980s, one of the first discoveries about aging in worms was that many genes affect life span. The capacity to disable individual genes or to snip them entirely out from the chromosome was developed in the 1980s. It was discovered that removing a particular gene made the animals longer than normal worms that had the gene. The gene was dubbed CLK-1, suggesting that it might be a “clock” for aging. Remove one copy of the gene, and the worms live twice as long. Remove both copies and the worm lives 10 times as long!  What does this gene do, such that removing it has such life extension power? It turned out that CLK-1 was an essential step toward making the worm’s version of CoQ!

This was completely unexpected. Disable the worm’s chief mitochondrial anti-oxidant, and the worm lives ten times longer! But the knock-out blow for anti-oxidant supplements came in 1994, with the Finnish “ATBC study”.  It turns out that vitamins A, C and E are also anti-oxidants. 30 thousand Finnish smokers were enrolled in a trial large enough to see even modest improvements in cancer rates and overall mortality. The study did discern a difference – in the wrong direction. People receiving the supplements were slightly more at risk for cancer, and significanctly more likely to die.

 

Why did anti-oxidant therapy fail to extend life span?

The counter-productive role for anti-oxidants was so unexpected that it was at first dismissed as certainly a statistical fluke. But other studies since ATBC have confirmed the same thing: for extending life span, anti-oxidant vitamins are worse than useless.

Then, ten years later, another line of research offered a possible hint about the meaning of these results – the physiology behind the epidemiology.

Loss of insulin sensitivity is a classic hallmark of aging. As we get older, we poison ourselves with sugar, as I wrote a few weeks ago. Exercise has been known to help preserve insulin sensitivity, but here’s what was found in some lab studies in the mid-2000s: anti-oxidants can block this benefit.

This suggests a hypothesis that is on the edge of geriatric medicine: Free radicals play a vital role in the signaling that controls the rate of aging. It is precisely the chemical damage that is done by vigorous exertion that tells the body to try harder, to dial up the defenses that can slow the aging process.

When the body is stressed, it rises to protect itself. The surprising thing is that frequently the body is able to overcompensate for the stress-induced damage. The body lives longer stressed than un-stressed. This effect is called hormesis, and it has been seen with exercise, with starvation, with many toxins and even with low doses of ionizing radiation.

You may be wondering: if the body is capable of dialing up its defenses even when stressed, why would it not do so all the time? Aren’t we programmed by natural selection to be as strong and as healthy as we are able to be? Isn’t it part of that program to resist the disintegration of old age with whatever resources the body can muster?

This reasoning is right on the money, and it has a profound implication. The body is not doing its best to avoid aging. The body – “willfully” in some genetic sense of the word – allows damage to accumulate. Protective mechanisms are turned off in old age, and aging is permitted to overtake us.

I have promoted a theory that this is done to help stabilize population levels by leveling the death rate. In times of plenty, when stress is minimal, aging provides a measure of population control. But when times are stressful, there are plenty of individuals dying of famine or hardship, and aging steps aside. “Life is tough enough now – slow down the suicide train!”

 

Oxidation and inflammation

There’s no doubt that oxidative damage to the body’s chemistry accompanies aging, and it accelerates at older ages. But this damage is not inevitable. I suspect that the high rates of damage in old age come not from the body’s everyday energy metabolism, but from chronic inflammation, which is known to rise catastrophically with advanced age. Inflammation is the body’s own front-line defense against microbes, turned against the self in old age as a mechanism of programmed death. Oxidative damage may be self-inflicted.

 

Bottom line advice for preserving your health

Skip the anti-oxidants. Bring on the anti-inflammatories. I recommend omega-3 oils, turmeric, ginger, and daily aspirin or ibuprofen.

*A renowned Russian biochemist, Vladimir Skulachev invented a form of CoQ with an extra tail on the end of the molecule that is designed to be sucked up by mitochondria. It is known affectionately as SkQ, and it shows promise for life extension in mice, and has been used as eye drops for treatment of macular degeneration and presbyopia.

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18 thoughts on “Anti-oxidants: A Disappointment or Worse

  1. A group from Denmark tried to replicate the experiment with anti-oxidant vitamins and exercise, but they found no effect on insulin sensitivity. In fact, none of the benefits of exercise were lost or diminished when vitamins were administered. “Our results indicate that administration of antioxidants during strenuous endurance training has no effect on the training-induced increase in insulin sensitivity in healthy individuals.”
    http://www.ncbi.nlm.nih.gov/pubmed/21325105 (2010)

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  3. The 1994 study on antioxidants was done on the cheap. They used synthetic vitamins. What they proved is synthetic vitamins do more harm than good.

    I take 200 mg COq10 from Life Extension daily. My recent blood test showed that my COq10 level was on the high end of the range. I think they have solved the absorbility problem.

    • I take CoQ10 as well. There is good evidence that it protects the heart.
      The form you’re probably talking about is called Ubiquinol, which addresses the issue of absorption through the stomach. But once it gets into the bloodstream, there is still the issue of getting CoQ into the mitochondria, and that process is very inefficient. That’s why the work of Skulachev (see footnote) is so promising. The only anti-oxidant studies that have achieved life extension in mammals involve bringing the anti-oxidant into the mitochondria. In addition to Skulachev, there is a UWashington study where mitochondrial genes were modified to express more of the anti-oxidant catalase. http://www.niehs.nih.gov/research/supported/sep/2005/lifespan/index.cfm

      • The question I’m sure you’re already asking yourself is — Will mitochondrial stress from a lessening of CoQ10 provide more of a hormetic remodeling that makes it actually better to not consume coq10. It would be interesting to see if the lessening of coq10 over time might actually be slightly advantageous to an aging individual, but there is always tradeoffs (with less energy production). It would be nice to just supplement with hormones as we age, but I believe they also decline for exactly the same reason. And while having less testosterone for men might be disconcerting for some (or other hormones for women), it probably has a net positive effect on longevity as long as your have your body in good working condition. I’m convinced that as long as you can keep a minimum about of strength to starve off Sarcopenia and illness, you probably don’t want an excess of muscle because you don’t actually want to maximize mitochondria (at least in my view) (I also understand maintaining muscle at 90+ is going to be really difficult ). Think of the mitochondrial situation of a baby vs that of a middle aged individual (They have less mitochondria per area I would assume).

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  5. Some good reasoning in this article, but. If free radicals contribute to youth, then smokers and sun bathers ought to look youngest no? You could argue that smoking overwhelmes the body as a non natural inhalation of free radicals, but what about sun damage from even averege sun exposure?

  6. I’m really sorry but your conclusions and advice lack scientific and logic reasons. Noone with deep understanding of the human body would present it the way you did. The lack of scientific sources that are discussed shows that you are picking your sources to fit your opinion and needs. Advices can harm people!
    As it is too strenous to pick out every wrong detail, just a bottom line: Populations in wealthy and stress-free enviroments live definitely longer than elsewhere, they just die from other diseases and causes. Low grade inflammation is definitely a topic nowadays, but the connections and implications remain too unclear, especially for you to say that it is the main cause of aging. Recommending NSAID is dangerous because you don’t know the people you are recommending it to; next there are also negative effects of nsaids, enough studies done, like increasing inflammation in athletes, hindering gains, causing hypertension etc.
    The right amount of antiinflammatories, antioxidants, polyphenols etc, their TIMING and relations to health are not clear! Even fish-oil and vitamin d can have very strong negative effects on your health!

    • Thanks for your comments. Data is incomplete and interpretations are subjective and often controversial. The advice and opinions here are my own.
      In response to
      > Populations in wealthy and stress-free environments live definitely longer…
      It is generally true that wealthier countries have longer life spans, and there are many reasons for this: better education, better medical care, better hygiene, etc. I wouldn’t equate wealthy with stress-free. Also: “hormesis” works for moderate stress, and how much stress is considered “moderate” varies with different kinds of stress. Low doses of ionizing radiation increase life span, even as they increase the cancer risk. For slightly higher doses, the cancer risk overwhelms any hormetic benefit.

      > there are also negative effects of nsaids
      Yes, there are risks, and the variation among different people’s metabolisms is wide. I believe that most people over 50 can benefit from daily aspirin or ibuprofen, but of course individuals differ, and there are many people for whom this advice will not be right.

  7. Does PQQ add any help for mitochondrial support?
    I guess that again, as with CoQ10, mitochondrial absorbability is paramount, as with lipoic acid, acetyl carnitine, or anything else used, and as there is no way to know.

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  10. Here is a major review of anti-oxidant trials, (Bjelakovic et al 2008)
    http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007176/abstract

    Sixty-seven randomised trials with 232,550 participants were included. Forty-seven trials including 180,938 participants had low risk of bias. Twenty-one trials included 164,439 healthy participants. Forty-six trials included 68111 participants with various diseases (gastrointestinal, cardiovascular, neurological, ocular, dermatological, rheumatoid, renal, endocrinological, or unspecified). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects meta-analysis (relative risk [RR] 1.02, 95% confidence interval [CI] 0.99 to 1.06), but significantly increased mortality in a fixed-effect model (RR 1.04, 95% CI 1.02 to 1.06). In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial heterogeneity. In the trials with a low risk of bias, the antioxidant supplements significantly increased mortality (RR 1.05, 95% CI 1.02 to 1.08). When the different antioxidants were assessed separately, analyses including trials with a low risk of bias and excluding selenium trials found significantly increased mortality by vitamin A (RR 1.16, 95% CI 1.10 to 1.24), beta-carotene (RR 1.07, 95% CI 1.02 to 1.11), and vitamin E (RR 1.04, 95% CI 1.01 to 1.07), but no significant detrimental effect of vitamin C (RR 1.06, 95% CI 0.94 to 1.20). Low-bias risk trials on selenium found no significant effect on mortality (RR 0.90, 95% CI 0.80 to 1.01).

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