Discovering lifespan extension drugs by screening for stress resistance

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.

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4 comments

  1. Hey, friend… this is anecdotal and non-scientific, but I was struck by a corellation.

    In China, practitioners of the internal martial arts were considered to gain longevity compared to the standard population. A lot of that probably has to do with lifestyle, but one of the things I *have* noticed, when doing lots of standing meditation, etc, is how ridiculously relaxed one is when training intensively. Seriously, I could almost fall asleep in some of those standing postures. That level of relaxation might simply mean you’re not suffering as many stress markers, b/c you’ve got more of a buffer before you go over some “stress line.”

    Again, not scientific at all, but thought I’d toss it out there.

  2. Interesting, but I’d hesitate to call any study of 11 different compounds (which are all known antioxidants) a “screen”. At best it’s an investigation into the mechanisms by which those 11 compounds work. I got all excited about reading this, thinking they’d looked at a few thousand novel chemicals, but the result is rather underwhelming.

    At what point does studying lots of different things officially become a “screen”? 10? 20? 100? 1000?

  3. Good point, Virgil. I think the thing that’s cool is that they automated a lot of the readouts. I forgot to mention it in my analysis, but this is basically a proof-of-principle for a very high-throughput screen: the worms are detected fluorescently, and this could easily be generalized to a larger screen with minimal human intervention. It sounds like they were still measuring death manually here, though I know (read: “think”/”believe”) from conversations and conference talks that this lab has developed an automated way to determine lifespan as well.

    I think something becomes a screen when it can be scaled up to ten times as big with only a minimal increase in effort…

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