A Conserved Regulatory System for Aging

that move normally, are fully fertile, and have a normal San Francisco, California 94143 metabolic rate. In addition, it has also been possible to obtain long-lived genetic mosaics that do not produce fat. The fact that these long-lived mutants can appear While many processes in biology, such as cell differenti-so normal makes one optimistic that if this system exists ation and development, increase complexity, the aging in humans, then by perturbing it in the right way, it may process increases entropy and culminates in the death be possible to extend normal youthfulness and lifespan. of the animal. Thus, the discovery that single gene muta-So far, the only dauer-like trait that has not been un-tions in many organisms can extend lifespan dramati-coupled from longevity in C. elegans is stress resistance. cally was surprising. These mutations indicated that the Thus, it is possible that the ability to detoxify reactive aging process is subject to regulation; it is not as random oxygen species is what extends lifespan. This is plausi-and haphazard as it seems. Even more surprising are ble, because catalytic antioxidants are known to extend some recent findings suggesting that a conserved sys-the lifespan of C. elegans (Melov et al., 2000) and be-tem regulating lifespan may have arisen early in evolu-cause overexpression of superoxide dismutase (SOD) tion. This regulatory system also controls diapause-like has been shown to extend the lifespan of Drosophila states, which are relatively quiescent states that allow an (Sun and Tower, 1999). animal to postpone reproduction in response to adverse The C. elegans DAF-2 pathway acts non cell autono-environmental conditions. This connection is particu-mously to regulate dauer formation and adult lifespan. larly intriguing because, in at least some cases, lifespan The gene acts in neuroectoderm and, to a lesser extent, extension can be uncoupled from other aspects of dia-in internal organs, to produce one or more downstream pause, allowing active and fertile animals to remain signals or hormones which, in turn, regulate lifespan youthful much longer than normal. and dauer formation. DAF-2 also acts non cell autono-Insulin/IGF-1 Signaling in C. elegans mously to regulate adult fertility and intestinal fat metab-A pathway that regulates both lifespan and diapause olism. One downstream hormone may be a steroid li-was first discovered in C. elegans (reviewed in Guarente gand for DAF-12, a nuclear hormone receptor homolog and Kenyon, 2000). In response to food limitation and that promotes dauer formation. crowding, juvenile worms enter …