Whether lifespan can be influenced by stimuli other than nutrients or stress has not been well studied. We have recently made the exciting discovery that in nematodes, males shorten the lifespan of the opposite sex in a manner that involves secreted compounds, including pheromones. Remarkably, males trigger accelerated demise in the opposite sex in a manner that is similar to the `system failure' characteristic of older individuals in many species. Males appear to elicit this generalized demise in the opposite sex by hijacking many longevity-assurance genes, including nutrient-sensing pathways. Furthermore, we have tantalizing evidence that changes in chromatin regulators can delay male-induced demise. Our hypothesis is that generalized system failure can be counteracted by maintenance of specific chromatin states and modulated by communication via secreted compounds between individuals. To test our idea, we will determine the cellular and molecular underpinning of generalized system failure. We are particularly excited to uncover the conserved epigenomic mechanisms that protect against premature demise. Finally, we plan to discover the secreted compounds and neural circuitry that mediate lifespan regulation between individuals. Understanding the mechanisms involved in male-induced demise will provide new conceptual advances about general system failure and reveal new and conserved ways to maintain organismal homeostasis and youthfulness. Importantly, this work will also set the foundations to study how the lifespan of one individual is influenced by the presence of other individuals, which has been under-studied. Because this work involves the identification of secreted compounds, it has the exciting potential of identifying new small molecules that can modulate the rate of aging.
Aging is associated with increasing frailty and a constellation of diseases and health disorders. How environmental factors are sensed by organisms to mediate pro- or anti- aging effects are not well characterized. Here we propose to use the worm C. elegans as a model system to identify the fundamental circuitry by which environmental inputs translate into integrative aging, which should give key insights into possible mechanisms to delay system failure and frailty.
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