(previous session)

At the end of the meeting, Martin Brand and Stuart Kim led a group discussion about the free radical theory of aging. Martin began the discussion by pointing out that “after 50 years, you would expect a theory to accumulate enough evidence to convince us that it’s true or false – but the fact that we’re still discussing it today means that hasn’t happened.” I’m paraphrasing slightly, but that’s the general idea.

Martin Brand (who doesn’t, by the way, adhere to this theory) started by summarizing the evidence in favor of FRTA:

  • “50 million Frenchmen can’t be wrong” (i.e., there are lots of correlative experiments)
  • SOD2 knockout is bad
  • catalase overexpression is good

Stuart rejoined with some contradicting evidence:

  • Superoxide dismutase protects against oxidative stress but has little effect on lifespan in mice
  • Deletion of mitochondrial SOD extends lifespan in C. elegans
  • High oxidative damage levels in the longest-living rodent, the naked mole-rat.

To the last of which, others answered:

  • The naked mole rat isn’t suffering from a global increase in oxidative damage – rather, there are a small number of proteins with increased damage, which may represent antioxidant proteins protecting the rest of the cell
  • There’s no evidence that naked mole rats increase damage with age, which is a more relevant metric

The first two pieces of Stuart’s contradicting evidence were more difficult to challenge. Some ideas:

  • Overexpressing an antioxidant enzyme in the wrong subcellular compartment wouldn’t be predicted to have any effect on lifespan

Martin also asked questions about whether FRTA is even falsifiable, and lamented the absence of an alternative clear, single-sentence “singular” theory of aging.

No final resolution but on the balance it seems like the theory is on the ropes, as we’ve discussed here before.


Mitochondria produce reactive oxygen species (ROS) as a byproduct of metabolism. These ROS are implicated in the mitochondrial free radical theory of aging (MFRTA) as the major cause of aging phenotypes. If the MFRTA is true, one could delay aging by removing these mitochondrially-produced ROS with enzymes or antioxidants. Although many antioxidant therapies for cancer and other age-related diseases have proved fruitless, these studies did not specifically target antioxidants to the mitochondria. One group recently did just that in mice with catalase, an antioxidant enzyme normally found in peroxisomes. By translocating catalase to the mitochondria, the scientists expanded the lifespan of the animals by five months.

Such genetic manipulations such as these are not in the cards when it comes to preventing human aging. Therefore, other mitochondrial targeting strategies must be employed. Accordingly, Vladamir Skulachev’s group synthesized an antioxidant attached to a positively charged ion, which they call SkQ1. This compound can readily pass through the cell membrane and travel to the mitochondrial intermembrane space, the only negatively charged region in the cell. There, SkQ1 will soak up any ROS formed by the electron transport chain. SkQ1 works similarly to the popular MitoQ, but does not have the pro-oxidant properties MitoQ is known to have at higher concentrations. SkQ1 is also better than MitoQ at inhibiting apoptosis induced by hydrogen peroxide. Studies by the group also showed that SkQ1 proved beneficial for heart and cardiovascular disease , tumor growth, and cataracts .

Anisimov et al found that SkQ1 increases the lifespan of several species of animals. The median and maximum lifespan of the fungus P. anserina was significantly increased with treatment of SkQ1. In the crustacean C. affins, the mean lifespan of SkQ1-treated animals was doubled compared to controls. In Drosophila, SkQ1 treatment significantly increased median lifespan in both males and females. Additionally, the researchers investigated the timing of SkQ1 treatment using Drosophila. Flies treated with SkQ1 during only their first week of life had the same survival curve as flies treated throughout their lives. There was no effect on survival in flies treated with SkQ1 for one week starting at 30 days of age, but, for flies treated constantly from 30 days of age, there was a reversion to the lifespan curve of flies treated constantly from day one. These results are reminiscent of Michael Rose’s experiments on the timing of calorie restriction in Drosophila.

In mice, the optimal dose of SkQ1 increased median lifespan by about 90%, with a maximum lifespan for both control and treated mice between 800- 850 days. It would be interesting to see if the mouse strain they used or husbandry conditions had any effect on the results, as a 800 days is an entire year shorter than the reported maximum lifespan for mice.

SkQ1 treatment had its largest effect on preventing death from non-cancerous diseases, with SkQ1-treated mice actually having a higher incidence of a certain kind of cancer, mammary gland adenocarcinoma. This might have to do with the fact that SkQ1 prevents the disappearance of estrus in female mice. Finally, fibroblasts treated with SkQ1 were more resistant than controls to hydrogen peroxide treatment, and expressed almost no β-galactosidase activity, a marker of senescence.

Notably, SkQ1 treatment is the only anti-aging treatment other than calorie restriction that has been shown to be effective across such a wide range of species. These results suggest that SkQ1 or other methods of chemical targeting of antioxidants to mitochondria hold promise as a novel means of intervening in the aging process.

(For more on SkQ1, see the coverage at Longevity Meme.)

How might hormesis — the protective effect of low-dose or acute stress against higher-dose or chronic stress — work at the molecular level? One possibility is that the mild “priming” stress tones up the protective actions of stress responses: a hit of peroxide, for example, might accelerate expression of antioxidant enzymes like superoxide dismutase, protecting the cell against a future oxidative wallop. To the extent that chronic stresses can be risk factors for age-related decline in cellular function, hormetic stress might protect the cell against such long-term grinding damage, and ultimately against aging itself.

Compounds that protect against stress and aging might therefore function in a hormetic manner — either by literally stressing cells or by “simulating” stress, i.e., inducing protective stress responses without actually causing even short-term acute damage. Consistent with this idea are some recent findings on resveratrol, a compound found in red wine grapes that has been implicated in extending lifespan, improving exercise tolerance, and as an antioxidant.

Putics et al. have demonstrated that resveratrol induces the heat shock response (HSR), a well-studied and canonical stress response that results in higher expression of protein chaperones. The effect is not due to the compound’s antioxidant activity, and is distinct from endoplasmic reticulum folding stress pathways such as the unfolded protein response. For reasons that escape me, the authors did not attempt to determine whether the known resveratrol target proteins, the sirtuins, play a role in the induction of the HSR.

Furthermore, treatment with resveratrol protect cells against severe heat shock, a hallmark of hormesis. The authors suggest in the final sentence of the abstract that

Our results reveal resveratrol as a chaperone inducer that may contribute to its pleiotropic effects in ameliorating stress and promoting longevity.

This is a long way from having been proven — future work will need to uncover the mechanism by which resveratrol induces the HSR, and manipulate the genetics of both the resveratrol-heat shock connection and the heat shock response itself in a system suitable for the study of longevity — but it’s a promising start.

One wonders whether heating the resveratrol might have a synergistic effect. Glögg, anyone?