UCSF

Understanding the evolutionary links between an animal’s reproductive state and its rate of aging has been of interest to scientists since the field of aging research first began. Contrary to the “Disposable Soma Theory” on the evolution of aging, which proposes that the greedy germline poses an unavoidable cost to the rest of the body, studies exploring germline-less C. elegans have revealed that the longevity afforded these animals is due to complex and highly regulated molecular mechanisms, rather than just a change in resource allocation from progeny production to somatic tissue maintenance. The fact that lifespan benefits are seen when the germline tissues are disrupted in worms, flies, grasshoppers, rats and humans excitingly suggests an evolutionarily conserved pathway linking reproductive tissues to aging. This study aimed to uncover the upstream effectors of this longevity pathway, in order to determine how the germline functions to prevent life extension in normal intact C. elegans. Unbiased genetic and biochemical screens were performed to find genes and proteins involved in the KRI-1-mediated activation of DAF-16, which occurs upon germline-ablation and is integral to the resulting longevity. Many overlapping factors were found using these complimentary techniques, validating the combined genetic/biochemical approach. One particular gene of interest found to promote DAF-16 activity in germline-less worms was itr-1, a gene encoding the worm’s only IP3-responsive Ca2+ channel. However, RNAi knockdown of itr-1 not only decreased the lifespan of germline(-) worms, but did so in germline(+) worms as well, suggesting ITR-1 plays more broad role in lifespan regulation. Consistent with this, itr-1(RNAi) was found to impair DAF-16 activity in the intestine of two daf-2 mutants (e1370 and e1368), and also greatly inhibit the lifespan of these long-lived strains. Thus, ITR-1 appears to act as a more general longevity promoting factor in C. elegans, possibly working through regulation of intestinal DAF-16. Interestingly though, ITR-1 was also shown to regulate activity of several other components of germline-less longevity, specifically SKN-1, DAF-12 and the MitoUPR. Thus, ITR-1 may actually control lifespan through regulation of multiple downstream pathways. Understanding these pathways will be of great interest for future research.