Why Don’t Antioxidant Supplements Extend Lifespan?

Out of all the theories of aging, only one can account for this spread of lifespans in different animals from days to centuries, the Mitochondrial Free Radical Theory of aging, in which lifespan is thought to be determined by the rate at which your mitochondria—the power plants within our cells—spew out free radicals.

When longevity researchers measured the antioxidant defenses of long-lived species, they found them to have lower, rather than higher, levels of antioxidant capacity. This was misinterpreted as a strike against the Mitochondria Theory of Aging, but it makes perfect sense. Long-lived species have no need to invest resources in mitigation, since they have such low baseline levels of free radical formation in the first place. We can learn from the wisdom of this strategy by treating the cause by reducing mitochondrial free radical formation in the first place, in one of only two known ways: regular aerobic exercise and controlling one’s intake of the amino acid methionine.

But why not just take a daily antioxidant pill and slouch on the couch and eat whatever you want? Because it doesn’t work. Antioxidant supplements make up a multi-billion dollar industry and are frequently touted for supposed anti-aging benefits, despite the findings of hundreds of studies finding no clear effect. Those taking antioxidant supplements don’t appear to live any longer, and when put to the test in randomized controlled trials, if anything, beta carotene, vitamin A, and vitamin E supplements seemed to increase mortality. Supplement users may, in effect, be paying to live a shorter life.

It all started with cohorts like the Western Electric study published in 1981. More than a thousand men had been followed for nearly 20 years, and there seemed to be a stepwise drop in risk of lung cancer among long-time smokers who got more and more beta carotene in their diet. This carotene index was basically just adding up how much fruits, vegetables, and soup the men ate. So, did they start treating smokers with fruits, veggies, and soup? No, tried giving them beta carotene pills instead. However, those randomized to beta carotene got more lung cancer than those who got sugar pills, and there were more deaths from lung cancer, heart disease, and stroke, and a shorter average lifespan overall. This didn’t stop researchers from repeating the same mistake over and over again. A half dozen other beta carotene trials continued to show increased mortality.

One explanation for the debacle is the unnaturally high doses they used, up to 20 times the average daily intake. In a petri dish, you can demonstrate that dietary levels of beta carotene (which you may achieve in your bloodstream eating lots of sweet potatoes, for example) have a very different effect than the levels reached through supplementation. Dietary doses protected against oxidative damage to DNA and cell membranes, whereas supplement doses increased cellular injury. The same was found for the red pigment lycopene. At eat-lots-of-tomatoes levels, lycopene was protective, but at supplemental doses, lycopene made things worse.

Even if we used the right dose, beta carotene and lycopene are but two of thousands of phytonutrients found in plant foods. Yes, those with higher circulating levels of beta carotene in the bloodstream tend to live longer, but where is beta carotene found? Healthy foods like sweet potatoes and collard greens. Beta carotene levels may be just a proxy for fruit and vegetable consumption. The same is true for other antioxidants. Those with more vitamin C in their bloodstream, or vitamin E, or lycopene, or selenium tend to live longer, but that doesn’t mean these vitamins or minerals had anything to do with it. They just may be markers of healthy eating in general, which can lead to a longer life for the array of other reasons—more potassium, more fiber, fewer unhealthy foods.

Antioxidants may also work in concert. Supplements contain only a select few antioxidants, whereas your body relies on hundreds of them, all working together to create a network to help the body dispose of free radicals. High doses of a single antioxidant may disturb this delicate balance. Rather than working in isolation, antioxidant compounds can act synergistically. In essence, the whole (food) may be greater than the sum of its parts.

Defenders of the Mitochondrial Theory have blamed the lack longevity benefit on the use of antioxidants that may not be able to cross into the mitochondria. Oxidative damage to mitochondrial DNA is correlated to longevity, but damage to the rest of the cell’s DNA is not. But mitochondria-targeted antioxidants, like alpha-lipoic acid or coenzyme Q10, also failed to impact longevity. Antioxidants can intercept free radicals spewing from mitochondria before they affect the rest of our DNA, but mitochondrial DNA is right in the heart of the storm, explaining the 15-fold to hundred-fold higher estimated mutation rate. Antioxidants might not have time to intercede inside the mitochondria before the damage is done.

Some free radicals are so reactive that they only exist for billionths of a second, traveling a distance of no more than a few molecular diameters, making it nearly impossible for antioxidants to intercede before mitochondrial DNA takes a hit. The close proximity or even physical contact between the mitochondrial DNA and the source of free radical formation likely explains why antioxidants can’t seem to slow the rate of aging, but that doesn’t mean antioxidant-rich foods can’t help prevent age-related diseases linked to oxidative damage to the 99.999995 percent of our DNA outside of the mitochondria.