Squirmy lab subjects’ surprising longevity despite loss of antioxidant defenses may mean that conventional anti-aging wisdom needs a makeover
by Craig Weatherby
The so-called “free radical theory of aging” is more than a half-century old, but it should be called the “free radical theory of lifespan.”
Arguments over the theory have more to do with lifespan than with valuable targeted effects.
For example, topical antioxidants with anti-inflammatory properties can smooth wrinkles and refresh skin tone, for straightforward physiological reasons.
And animal studies suggest that antioxidant-rich extracts of foods like turmeric can dampen inflammation just as effectively as synthetic non-prescription drugs like Aleve.
Regardless, the theory that we age and die because of decay caused by free radicals has become increasingly accepted, despite mixed evidence… most of it rather indirect.
In fact, calling it the “free radical hypothesis of aging,” would better describe the state of the science surrounding the idea that dietary antioxidants can slow aging.
A hypothesis is an idea proposed to explain natural phenomena, and it becomes a theory once it provides accurate predictions and gets accepted by most experts in the field.
Many once-accepted theories have been overturned by new evidence… but none of these had strong, unmatched predictive power.
So far, the free radical theory of aging lacks proven predictive power with regard to the length of lifespan in people or animals.
Now, a series of studies in worms seem to undermine the idea that individual lifespan depends on each person’s innate and/or diet-assisted ability to out-wrestle free radicals.
Free radicals and aging: The story up to this point
In 1956, biologist Denham Harman, PhD, suggested that aging might be caused by “oxidative stress”, which occurs when an organism’s innate antioxidant defenses face an unusually heavy burden of free radicals due to environmental or dietary factors… or have been weakened by illness or poor diet.
The process of turning food into cellular energy generates unstable molecules that steal oxygen atoms from nearby chemical compounds in our cells, such as fatty acids.
Scientists call free radicals “reactive oxygen species” (ROS) for their tendency to react with other chemicals in order to steal oxygen atoms.
These chemical thefts initiate chain reactions in which compounds stripped of oxygen atoms by free radicals in turn snatch oxygen atoms from nearby chemicals, and so on.
Oxidative stress damages cells directly, and switches on pro-inflammatory genes called nuclear transcription factors. And because the body’s inflammation processes produce free radicals, oxidative stress can become a self-perpetuating process.
This is especially true if your diet is high in pro-inflammatory agents - such as sugars, refined starches, and the omega-6 fats that dominate most vegetable oils except olive, macadamia, and hi-oleic sunflower oils - and low in anti-inflammatory antioxidants and omega-3s (from fruits, vegetables, and wild salmon).
Inflammation can also persist if your own internal antioxidant network is weak due to stress, illness, or malnutrition… including lack of omega-3s.
The free radical theory of aging suggests that when free radicals and their products (e.g., oxygen ions and peroxides) build up in cells, they damage cell membranes, genetic material (DNA), and the key energy producing engines called mitochondria, and overwhelm the body’s ability to repair the damage.
In theory, this unrepaired damage causes the cells to age prematurely, and sometimes to turn cancerous.
Free radicals abound in certain air and water pollutants. But under normal circumstances, most of the free radicals in our bodies are produced in the normal course of metabolism, as we transform food into usable cellular energy.
The body’s own “antioxidant network” neutralizes excess free radicals, to prevent collateral metabolic damage to our cells.
Our internal antioxidant network consists largely of specialized enzymes but includes antioxidants such as alpha lipoic acid and vitamins C and E, plus the mineral selenium, which forms part of a key antioxidant enzyme called glutathione peroxidase.
By the way, most of the chemicals we call antioxidants can also act like free radicals, exerting the very same pro-oxidant effects, depending on their own state and surroundings... a fact that underscores the fluid identities of free radicals (pro-oxidants) and antioxidants.
Food-borne antioxidants: What we know about them and why we don’t know more
Plant-rich diets are associated strongly with reduced rates of major diseases, all of which have an inflammatory component made worse by oxidative stress.
And it’s been presumed, logically, that the antioxidant effects of phenolic compounds in plant foods are largely responsible for their apparent preventive-health benefits.
So research has focused on the potent antioxidant potential of phenolic compounds—primarily flavonoids—that abound in tea, cocoa, berries, and other colorful fruits and vegetables.
In test tube experiments, phenols appear to reduce oxidative stress and they often reduce the ill effects of oxidative stress in animals.
Some phenolic supplements—such as turmeric, ginger, and grape seed extracts—appear to significantly reduce oxidative stress, cell damage, and inflammation in lab and clinical tests.
However, phenols are not absorbed from foods in substantial quantities, and eating phenol-rich foods does not yield consistently significant drops in blood markers of oxidative stress.
Still, food and herb extracts high in antioxidant phenols have become popular among people seeking to slow aging and reduce the risk of cancer, as both have been associated with oxidative stress.
(Ironically, the body’s immune cells emit free radicals to kill disease bacteria and cancer cells, which is why the decision to use antioxidants to treat cancer depends on the specific tumor and patient circumstances.)
The most promising natural agents warrant publicly funded clinical tests designed to gain approval as generic drugs bearing approved therapeutic/preventive health claims.
This process requires public funding, because drug companies must hold patents to squeeze enormous profits out of health care consumers until the patent expires.
Natural compounds or extracts are hard to patent and lack allure for the big drug firms.
The problem is that natural products companies don’t have the $300 million needed to mount the multiple, large, well-designed clinical trials needed to possibly gain approval of a disease-treatment claim for any substance, whether synthetic or natural.
But overall, the preliminary clinical tests performed to date using vitamins C and E and various phenols have produced mixed, ambiguous results.
And the results of recent studies in worms suggest that the free radical theory of aging may be incorrect… or at least represent a misleading oversimplification of reality.
Did the antioxidant effects of plant foods blind us to more important ones?
As holistic doctors like Nick Perricone and Andrew Weil agree, it’s looking like the “antioxidants” in foods make a much bigger splash in our bodies through their influence on immunity and inflammation-related genes… not primarily through their role as free radical squelchers.
Some of the same groups of genetic factors—such as PPARs, NfKappaB, and AP-1—play roles in promoting or sustaining diabetic tendencies and inflammation… and influencing these genetic “switches” is the way that major diabetes and anti-inflammatory drugs work.
Even a cursory search of the medical literature reveals hundreds of studies showing seemingly positive effects of plant-borne phenols on key inflammation-related genes and myriad others related to cellular energy, the major degenerative and immune diseases, and general aging.
At the risk of sounding reductionist, it seems likely that the genetic influences that plant “antioxidants” exert in our cells underlay the mountains of epidemiological evidence linking diets high in whole plant foods to reduced disease risks.
What the worms say
Much of modern research in genetics flows from studies in simple creatures like the roundworm called Caenorhabditis elegans (C. elegans)… whose humble DNA overlaps that of allegedly superior humans to a disturbing degree, given our species’ notable superiority complex.
Earlier this month, researchers at Montreal’s McGill University published lab results showing that these worms actually lived longer when their innate ability to “scavenge” free radicals was partially disabled.
According to McGill's Dr. Siegfried Hekimi, most of the evidence for the free radical theory of aging is circumstantial, and instead of causing aging, oxidative stress could be one of its results.
As he said in a press release, “The problem with the theory is that it’s been based purely on correlative data, on the weight of evidence. It is true that the more an organism appears aged, whether in terms of disease, or appearance or anything you care to measure, the more it seems to be suffering from oxidative stress. This has really entrenched the theory, because people think correlation is causation. But now this theory really is in the way of progress.”(MU 2009)
Hekimi and postdoctoral fellow Jeremy Van Raamsdonk progressively disabled five genes responsible for producing a group of antioxidant enzymes called superoxide dismutases (SODs), which detoxify one of the main free radicals.
SODs also constitute a key part of human’s antioxidant network, and earlier studies seemed to show that decreased SOD production shortened an organism’s lifespan… but Hekimi and Van Raamsdonk found the opposite.
None of their mutant worms showed decreased lifespans compared to normal worms, even though oxidative stress was clearly raised. In fact, one variety of mutant worms with disabled SODs actually lived longer than the normal worms.
“The mutation that increases longevity affects the main SOD found in mitochondria inside the animals’ cells,” said Hekimi. “This is consistent with earlier findings that mitochondria are crucial to the aging process. It seems that reducing mitochondrial activity by damaging it with ROS will actually make worms live longer” (MU 2009).
We’d be skeptical of this finding, were it not for the fact that Japanese and British teams published similar results last year (Honda Y et al. 2008; Doonan R et al. 2008).
Regardless of these indications, the McGill researchers agree that in general, oxidative stress is bad for the body.
Excess free radicals may be less responsible for accelerated aging than thought… though no less responsible for disease-promoting genetic influences opposite those usually exerted by the phenols and other “antioxidants” in fruits, vegetables, beans, whole grains, nuts, seeds... and salmon.
Perhaps, instead of “antioxidants”—a misleadingly narrow functional description that reduces a rich mix of complex compounds to an oversimplified stereotype—we could refer to these healthful plant-food factors as “gene adjusters.”
Or call on your Greek for the easier-to-enunciate “phyto-friends.”
- Doonan R et al. Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev. 2008 Dec 1;22(23):3236-41.
- Honda Y, Tanaka M, Honda S. Modulation of longevity and diapause by redox regulation mechanisms under the insulin-like signaling control in Caenorhabditis elegans. Exp Gerontol. 2008 Jun;43(6):520-9. Epub 2008 Mar 18.
- McGill University (MU). Forget the antioxidants? McGill researchers cast doubt on role of free radicals in aging. Feb. 17, 2009. Accessed online Feb. 19, 2009 at http://www.mcgill.ca/newsroom/news/item/?item_id=104612
- Van Raamsdonk JM, Hekimi S. Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet. 2009 Feb;5(2):e1000361. Epub 2009 Feb 6. e1000361 DOI: 10.1371/journal.pgen.1000361
- Yang W, Li J, Hekimi S. A Measurable increase in oxidative damage due to reduction in superoxide detoxification fails to shorten the life span of long-lived mitochondrial mutants of Caenorhabditis elegans. Genetics. 2007 Dec;177(4):2063-74.