Long-lived organisms tend to be resistant to many types of stress, whereas short-lived organisms tend to be stress sensitive. This happy coincidence allows us to screen for longevity mutants by looking for stress resistance rather than long life (advantage: it takes a lot less time to do the primary screen).

The same logic ought to apply to small-molecule drugs: Any compound that increases stress resistance has an improved change of extending lifespan. That hypothesis has been operationally tested by the Lithgow lab, who performed a small-scale screen of antioxidant compounds and looked for molecules that increased thermotolerance in the worm C. elegans. Several of these drugs also increased lifespan. From Benedetti et al.:

Compounds that confer thermal stress resistance and extended lifespan The observation that long-lived and relatively healthy animals can be obtained by simple genetic manipulation prompts the search for chemical compounds that have similar effects. Since aging is the most important risk factor for many socially and economically important diseases, the discovery of a wide range of chemical modulators of aging in model organisms could prompt new strategies for attacking age-related disease such as diabetes, cancer and neurodegenerative disorders … . Resistance to multiple types of stress is a common trait in long-lived genetic variants of a number of species; therefore, we have tested compounds that act as stress response mimetics. We have focused on compounds with antioxidant properties and identified those that confer thermal stress resistance in the nematode Caenorhabditis elegans. Some of these compounds (lipoic acid, propyl gallate, trolox and taxifolin) also extend the normal lifespan of this simple invertebrate, consistent with the general model that enhanced stress resistance slows aging.

Note that the authors tested resistance to thermal, rather than oxidative stress — given their choice to screen only antioxidant compounds, to do the latter would have been a bit circular. Still, given the history of antioxidant compounds as candidate anti-aging compounds, and the widespread belief that reactive oxygen species per se are a causative force in aging, the decision to screen only antioxidants does raise the possibility that the lifespan extension is due to the antioxidant activity of these compounds and that the stress resistance is merely an epiphenomenon.

Then again, it’s quite impressive that so many different antioxidants of so many different types can confer thermotolerance and increased longevity, and suggests that perhaps the association between antioxidants and longevity may have never had much to do with oxidation as such, but rather with some as-yet-uncovered connection between antioxidants and the activation of stress response pathways.