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?