In worms, the fountain of youth is not some magical elixir, but instead springs from the activity of the transcription factor DAF-16. Activating DAF-16 by dialing down the insulin/IGF-1 pathway turns on a life-prolonging genetic program, via a set of signaling molecules that is largely conserved in humans. But there’s a rub—in worms, the insulin/IGF-1 pathway and DAF-16 regulate not just life span, but development, reproductive timing, and immunity. Messing with the human equivalent of DAF-16 (Foxo3a) might help us live longer, but the philosophical question—at what cost?—turns out to be a sticky biological problem, as well.
Two papers in the March 9 Cell aim to untangle the complicated web of DAF-16 signaling. One study, from Andrew Dillin and colleagues at the Salk Institute in La Jolla, California, suggests a way to separate the life-prolonging effects of DAF-16 from its other functions in the roundworm Caenorhabditis elegans. The researchers report the identification of SMK-1, a nuclear protein essential for DAF-16 to regulate aging, but not development or reproduction in worms. SMK-1 works to help DAF-16 turn on a subset of its target genes, and promotes longer life by boosting immunity and the response to oxidative stress. The work raises the enticing possibility that manipulation of the human counterpart of SMK-1 (SMEK3) could selectively slow aging, which remains the single biggest risk factor for neurodegenerative disease. The results are also pertinent to understanding the links between insulin signaling and healthy aging (see ARF related news story).
Led by co-first authors Suzanne Wolff and Hui Ma, the study begins to show how DAF-16 activation in worms triggers divergent downstream pathways to balance survival and reproduction. Presumably, other as-yet unknown proteins like SMK-1 allow DAF-16 to coordinate the multiple genetic programs that not only slow aging, but also delay reproduction, and promote entry into the Dauer dormancy phase.
DAF-16 coordinates signaling inputs coming from upstream, as well, to regulate aging. The second paper, from Jennifer Berman and Cynthia Kenyon at the University of California, San Francisco, sheds light on how this happens. In worms, life can be extended by blocking the insulin/IGF-1 pathway, but also by internal signals from reproductive tissues. Removing germ cells, by laser ablation or genetic modification, prolongs a worm’s life in a pathway that, like insulin/IGF-1, requires DAF-16 activity in intestinal cells. The San Francisco researchers found a pathway independent of the insulin/IGF-1 signaling that involves the action of a lipophilic hormone to regulate DAF-16 and promote longevity.
Berman and Kenyon provide new information about how the reproductive system can regulate aging, a phenomenon that also occurs in mammals. Just as studies of the link between starvation and long life in worms have led to a better understanding of how calorie restriction prolongs life in higher animals, it is hoped that revealing this new pathway will shed light on the links between reproduction and aging in humans, too.—Pat McCaffrey