A small-molecule Psora-4 acts as a caloric restriction mimetic to promote longevity in C. elegans.

ABSTRACT

In populations around the world, the fraction of humans aged 65 and above is increasing at an unprecedented rate. Aging is the main risk factor for the most important degenerative diseases and this demographic shift poses significant social, economic, and medical challenges. Pharmacological interventions directly targeting mechanisms of aging are an emerging strategy to delay or prevent age-dependent diseases. Successful application of this approach has the potential to yield dramatic health, social, and economic benefits. Psora-4 is an inhibitor of the voltage-gated potassium channel, Kv1.3, that has previously been shown to increase longevity and health span in the nematode Caenorhabditis elegans (C. elegans). Our recent discovery that Psora-4 lifespan benefits in C. elegans are synergistic with those of several other lifespan-extending drugs has motivated us to investigate further the mechanism by which Psora-4 extends lifespan. Here, we report that Psora-4 increases the production of free radicals and modulates genes related to stress response and that its effect intersects closely with the target set of caloric restriction (CR) genes, suggesting that it, in part, acts as CR mimetic. This effect may be related to the role of potassium channels in energy metabolism. Our discovery of a potassium channel blocker as a CR mimetic suggests a novel avenue for mimicking CR and extending a healthy lifespan.