There are good and bad free radicals. Good free radicals like nitric oxide, NO, act as useful signaling molecules, and NO keeps our blood vessels dilated and our blood pressure in range. But when NO or indeed any signaling free radical, is too high, it is bad. Now bad free radicals damage cellular molecules like lipids, proteins, and nucleic acids. However those bad free radicals are good because they induce antioxidant defense enzymes like SOD and catalase (mitohormesis). Now antioxidant vitamins are good because they quench bad free radicals that damage cellular molecules, but they are bad because they reduce the induction of our endogenous antioxidant defense mechanisms, which is our 24/7 protective mechanism. Until we develop sustained release antioxidant vitamins that protect aqueous, non-aqueous, and amphipathic compartments, and targeted to the most vulnerable compartments (such as the antioxidant “MitoQ” is to the highly vulnerable compartments within mitochondria), antioxidant vitamins cannot give us sufficiently broad spectrum and 24/7 protection. Confused? You shouldn’t be if you understand that this is nature – dialectical and contradictory to the core of its core. If you insist on “clear and distinct” concepts of everything, good luck finding it here – or anywhere for that matter.
Anyone wanna bet that antioxidant defense enzymes also have a bad side?
Analogy: our antioxidant defense enzymes are like our oral fluid (including saliva), giving us 24/7 protection against free radicals and cavities/gum disease, respectively. Non-sustained release antioxidant vitamins are like dental hygiene procedures, good while they last, but not offering any 24/7 protection. That is oral fluid’s job, and oral fluid must be well-nourished by a good diet to do that job effectively (see Weston Price’s work for ample proof of that). By analogy, our good antioxidant defense enzymes must be induced by a burst of bad free radicals.
Question: Does dental hygiene actually compromise oral fluid quality? If it does, more dialectic. No easy answers – we need dental hygiene for obvious reasons.
- A complication: antioxidant supplements are not just antioxidants. Like enzymes, cofactors are pleiotropic – they do so many different things in the body. Vitamin C’s most critical role in the body is either its support of immune function or in making the compounds that form a stable and strong connective tissue.
- Antioxidant enzymes have the advantage over antioxidant vitamins in possessing turnover (they can detoxify many free radicals per enzyme per second). Both molecules can be regenerated.
- Antioxidant vitamins have the disadvantage in being able to propagate free radical reactions. Antioxidants are also pro-oxidants; they are more properly termed “redox reagents,” except that term does not capture their pleiotropy.
- Antioxidant vitamins have an advantage in being smaller, in being able to be here and there (greater range of protection, occupying lipophilic, hydrophilic, and amphipathic regions of the cell), and perhaps in being more easily removed and excreted when they are irreversibly damaged.
- To see if antioxidants can replace the cellular antioxidant enzymes, a complete set of antioxidant vitamins still needs to be devised and tested. The set would have good absorbability, good bioavailability, and a gradual gradient of hydrophilicity / hydrophobicity so that the whole cell can be protected, roughly divisible into three categories: hydrophilic (like vitamin C), hydrophobic (like vitamin E and CoQ10), and amphipathic (like lipoic acid).
- Denham Harman’s Free Radical Theory of Aging is too narrowly conceived. Damaging molecules are not all free radicals. Aldehydes like methylglyoxal and glucosone do a lot of damage too. Radiation damage macromolecules, sometimes by formation of free radicals, sometimes not. Etc.
- Michael Ristow contends that contrary to Harman’s theory, ROS are necessary and helpful to induce antioxidant enzyme defenses, that antioxidant supplements interfere with this induction and are thus harmful, and that this induction correlates to longer maximum lifespan. He concludes that Denham Harman’s Free Radical Theory of Aging is called into question. Am I missing something? The definition of a free radical as something wholly bad is called into question for the second time (the first was the discovery of useful free radicals like nitric oxide). The evidence presented is consistent with the Harman theory if the defenses induced actually are responsible for increased lifespan and if there are no other life-extending effects of these enzymes besides antioxidation. By definition, hormesis and mitohormesis are dialectical: a low level of something is actually beneficial while still being very bad at high levels. In this case, free radicals are good and bad and have good and bad effects. In other words, Harman erred by conceiving of free radicals as clearly and distinctly bad, when they are more like a zero, good and bad. Harman missed the dialectic, while Ristow is clearly seeing it.
- Ristow’s results cannot establish that the antioxidant enzymes caused this lifespan extension by virtue of their antioxidant activities. Enzymes are almost always highly pleiotropic. Any benefit actually due to enzymes like SOD and catalase may be due partly or mostly to functions other than quenching free radicals. Pleotropic functions of these enzymes would explain why lifespan extension correlated to higher activities of antioxidant enzymes, but not to one or more antioxidants. A simpler explanation of the failure of antioxidants to extend lifespan is that the antioxidant cocktails we have to date simply do not function as well or as durably as the 24/7 high turnover antioxidant enzymes.
- In addition, other molecules (besides antioxidant enzymes) more relevant to lifespan extension may also have been induced by the free radicals.
- What I will never understand about Ristow’s thesis: if no cocktail of antioxidant vitamins has ever brought about lifespan extension (arguing that antioxidants are not powerful enough, not comprehensive enough, and not optimally located to function as great antioxidant protection), how come these cocktails can interfere with the induction of enzymes that may be responsible for actual lifespan extension? Do antioxidants exert their deleterious effect by altering gene expression patterns, specifically by reducing the induction of antioxidant defense enzymes?
- Another thought: What happens as we age? If antioxidant enzyme activities decline faster than the proper absorption/distribution of antioxidant supplements, then there could be an age at which it is better to supplement than to rely on antioxidant enzymes. In any case, in any individual in which the antioxidant enzymes are not up to par (say a mutant SOD1 or SOD2), it may be wise to see if supplementation improves his situation.
- Besides anti-oxidation, supplements have too many other valuable properties to simply let them go. A possible way around Ristow, a way to have one’s antioxidant supplements and still induce defense enzymes to their maximum safe level: occasional extreme exercise to overwhelm the sum total of all of our antioxidant defenses.
- Another possible way around Ristow: take supplements intermittently. Take occasional vacations from supplements that last long enough and exercise hard enough during these vacations to induce the defense enzymes to healthful levels.
- Oxidative stress also increases the production of antioxidant vitamins – animals who make vitamin C can double production when stressed, and we increase our production of CoQ10 under oxidative stress
- Is free radical stress just one of many hormetic stressors that we would do well to expose ourselves to (always within the hormetic range)? Is this whole field of hormesis an illustration of “What does not kill me makes me stronger” (Friedrich Nietzsche)?