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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36 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.

    • Jezus, TUR, keep yr shirt on.

      TUR wrote:
      “Recommending NSAID is dangerous because you don’t know the people you are recommending it to.”

      A recommendation is not a prescription. Ad hominem is downright rude, unscholarly, and an eye-sore on an otherwise brilliant forum.

    • I agree with TUR. The article contains logical errors. I use against aging only antioxidants, no antiglycating agents, no telomeres “extension”, no calorie restriction (except hunger), and yet I “getting old” 3 times slower.

      I formulated a number of principles, compliance with which is necessary to you get started quench free radicals.
      I’ll give you half of this principles:

      1) Take only a Supplement, which prolong the life of at least 100%.

      2) Half of the chemicals are antioxidants and half are oxidizing agents, choose only quenchers of free oxygen radicals

      3) Do not use natural antioxidants, but artificial. What already exists in the nature, It will no prolong the life (eg. NAC)

      4) Give priority to the mitochondrial antioxidants such as the most famous of them SKQ1

      People are choosing anti aging products which they will use, completely unscientific manner. They’ll find anywhere on the internet promising substances that can prolong life.
      They take the list from the beginning and try to get googled individual substances.
      They will prefer supplements when the salesman smiled at them, and they do not take supplements, which they failed to find it in google. Thus, though they violate my principles formulated and therefore they age as well as others.

      • For arthritic pain in a knee I’ve used Ibu 400mg TID po.
        It’s intriguing effects on the high-affinity tryptophan transporter was an added point of interest.

        http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270464/

        “These findings identify a safe drug that extends the lifespan of divergent organisms and reveal fundamental cellular properties associated with longevity.”

        “We find that ibuprofen extends the replicative lifespan of yeast cells by destabilizing the high-affinity tryptophan transporter. ”

        My doses were high, possibly helpful with arthritic pain but the life extending effects are present in c.elegans at much lower mmolar levels than that dosing regimine provided.

        I still use it occasionally especially on cold rainy days so common here in the Pacific Northwest. I’ve found excellent pain relief with some of our other nifty anti-inflammatory stuffs, nootropics and other substances.

        Ibu is proposed (by me at least) to be useful in hormetic doses.

        • That is interesting. Thanks for the comment. You should try rubbing a little Cortizone 10 cream on your knee before you go to bed at night. You will find the pain is all gone by morning. In fact use it on any joint or muscle that hurts. I don’t know why; but it works. The label says it is an anti-itch cream; but it heals everything that hurts. It is available over the counter at any drug store.

          • I guess it’s worth a try though I’ve never considered topical corticosteriods for joint pain. Orally if it’s rheumatic in nature, but never heard of it being useful for osteoarthritis.

            Pain all gone now with tianeptine TID and occ. senlank BID sq. and other agents too numerous to mention.

            Thanks!

    • Yes, that is a proposed mechanism of action whereby statins benefit life expectancy.

      I’m yet to digest this article that seems to have it both ways…

      PLoS One. 2012; 7(6): e39581.
      Published online 2012 Jun 21. doi: 10.1371/journal.pone.0039581
      PMCID: PMC3380867
      Statin Treatment Increases Lifespan and Improves Cardiac Health in Drosophila by Decreasing Specific Protein Prenylation

      “Statins do not extend lifespan by reducing endogenous CoQ10”

      “…we investigated whether simvastatin extended lifespan by reducing endogenous ubiquinone levels. Diets supplemented with simvastatin and/or ubiquinone were administered to Drosophila. Supplementation with CoQ10 alone significantly shortened lifespan, while simvastatin alone significantly lengthened it (Figure 4; Table 1). CoQ10 and simvastatin together significantly lengthened lifespan, although not by as much as simvastatin alone”

      A bit puzzling, but it is only 2AM here. MORE COFFEE!!!

  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).

    • Well, before you flush all of your antioxidants, mice experiments have shown a 10%-30% increase in mean life expectancy, but no increase in maximum life expectancy when fed the antioxidant BHT (butylated hydroxytoluene), which is a powerful antioxidant. This means that more mice lived to their maximum age; but did not live past the maximum. In other words the survival curve was squared. What might this mean in human terms? If we assumed 100 years was the maximum human lifespan, then more people would live up toward 100; but not past 100. (Although the record human lifespan is 122). BHT is a synthetic molecule, available off the Internet.
      I have used BHT off and on over the last 30 years with no negative reactions.

      • I got such a laugh telling folk I used a tablespoon of BHT in oil a day “to extend my shelf life”.
        Gosh, was it cheap! I got a kilo by mail for about $4 in 1975 or so.
        Later, it didn’t seem worth the effort, antioxidants showing so little clinical evidence of worth for life extension.
        And BHT could mess with my Irish whiskey ration.
        And nothing is permitted that!

  11. Nice concept which deserves of attention. Do you believe that SOD in the form of gliadin complex (gliSODin) might have chance of reaching the mitochondria or other right grounds to act efficiently?
    Also the SKQ substance is only available in eye drops form or other forms also exist i.e. for P.O. administration?
    Thank you for the excellent work and I wish a happy New Year

    • Hi Georgios. Josh does not think much of the free radical theory of aging; but if you study free radicals, you will see that very little good can come from them. There can be very little doubt that most of the cellular damage occurring over time is caused by free radicals. There are a couple of problems with the studies involving antioxidants. First of all as you add antioxidants to the diet, the body down-regulates its own production of antioxidants. Secondly, the inner membrane of the mitochondria is a very tight bacterial type of membrane which restricts the free passage of most compounds, including the body’s natural protein-based antioxidants, as well as probably the common vitamin type antioxidants. On the other hand there is the possibility that C60 and maybe even BHT can penetrate the mitochondria to quench free radicals. Nevertheless, although free radicals probably cause the damage involved in aging, they are not the actual cause of aging. The cause of aging is the fact that the body down-regulates its repair functions as it grows older. This is written into the genetic code. In fact there are at least 3 genes found in animals as well as humans which appear to have no function other than to kill the host. That would include the genes AGE 1 and AGE 2 which produce a kinase which phosphorylates certain signaling proteins which affect such protein complexes as FOXO and FORKHEAD, thereby affecting which genes are turned on or off. As well as the gene for vitellogin, a lipoprotein whose only function appears to be to carry fats around in the body and dump them where they don’t belong, such as in the arteries. As a side note, replacing the AGE 1 gene with a nonsense gene lengthens the lifespan of C. elegans by 10 times. No other intervention in animals even comes close, not even diet restriction. Knocking out the AGE 2 gene adds even more to the lifespan, indicating the 2 genes have different targets. In addition, removing the gene for vitellogenin increases lifespan by 40%.

      • “…if you study free radicals, you will see that very little good can come from them.”

        But that ‘very little good’ is in the crucial matter of redox signalling. Not to be casually screwed with. It is a good illustration of the dose making the poison, the poison that doesn’t kill strengthens, and hormesis in general.

        I’ve stopped using daily microgram doses of Methylene Blue for this reason. The odd superoxide spun from step 3 of the mitochondrial cascade is normal, and stimulating of antioxidant defenses.

  12. PPQ stimulates biogenesis in all mitochondria and works with co-q 10 better than PPQ alone.NAC stimulates glutathione production which is found lacking in all chronic illness.Milk thistle protects the liver and increases glutathione production.Ashwaghanda and rhodiola regulate high cortisol and aid in serotonin production.Resveratrol acts to lengthen life as a similiar effect as mild starvation.Resveratrol is inthe interior of cells as a protective mechanism.Astaxanthin helps destroy free radicals,helps joints and the heart.Hawthorne berry and magnesium protect and aid the heart.You are incorrect in your blanket statement of supplements.

  13. So, for us laymen here who are looking for suggested supplements to improve health, it seems there is no answer but the trusted “diet and exercise” because nobody agrees.

    SQ1 seems to have garnered the most favorable results. I thought taking NAC, PQQ and CoQ10 would be a good start. But now I am more confused than ever.

    I’m wrapping up my PhD so I understand studies and research but my speciation is not physiology. Please help.

    Thank you.

  14. I’ve read many sources saying aspirin is a long term risk for macular degeneration. A very poor trade off. Sigh. Are you “in” with Pharma?

    • Thank you for alerting me to this, Charlie. I’ve read this for the first time. I’ll read more. It is always disconcerting to see that there are tradeoffs and complications. Perhaps we should look at family history of AMD and heart disease before deciding whether to take aspirin. I wonder if ibuprofen has the same issues.

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