Two sides of lifespan regulating genes: pro-longevity or anti-longevity?

Traditionally, ageing has been considered a passive and entropic process, in which damages accumulate on biological macromolecules over time and the accumulated damages lead to a decline in overall physiological functions. However, the discovery of a longevity mutant in the nematode Caenorhabditis elegans has challenged this view. A longevity mutant is a mutant organism, in which a reduction-of-function of a certain gene prolongs the lifespan. Thus, the discovery of longevity mutants has shown the existence of genes, which function to shorten lifespan in wild-type organisms, promoting extensive hunting for longevity-regulating genes in short-lived model organisms, such as yeast, worms and flies. These studies have revealed remarkable conservation of longevity-regulating genes and their networks among species. Decreased insulin/IGF-like signalling and decreased target of rapamycin (TOR) signalling are both shown to extend lifespan in evolutionarily divergent species, from unicellular organisms to mammals. Intriguingly, most of these longevity-regulating pathways reveal pro-longevity and anti-longevity effects on lifespan, depending on biological and environmental contexts. This review summarizes pleiotropic functions of the conserved longevity-regulating genes or pathways, focusing on studies in C. elegans.