Genetic variation underlying the response to longevity interventions

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DESCRIPTION (provided by applicant): Nearly all multicellular organisms undergo progressive degradation of physiological function as they get older-that is, they age. Over the last two decades remarkable insights into the molecular regulation of conserved genetic pathways underlying stress resistance and other age-related phenotypes raises the prospect that specific pharmacological interventions can be identified that will enhance human health throughout the entirety of their lifespan. A major concern here, however, is that the response of any particular individual to a drug treatment may be highly dependent on their specific genetic background; something that has been observed in a number of studies. The hope, therefore, is to identify drug interventions that maintain their desired effects even in the face of substantial genetic variation within a population. The nematode genus Caenorhabditis provides an ideal context for addressing this issue because (1) much of the fundamental biology of the critical target pathways has been conducted using a member of this group (C. elegans) and (2) very similar experimental approaches can be used to test drug-intervention responses of a set of related species that span a broad range of potential genetic backgrounds, equivalent to the distance between mice and humans. The goal of the Caenorhabditis Intervention Testing Program (CITP) is to examine a variety of pharmacological agents for consistent effects across these species (and natural isolates within species). Here, we aim to (1) measure the effect of pharmacological interventions on the lifespan of multiple nematode species, (2) evaluate the impact of pharmacological interventions on physiological and biochemical measures of health, and (3) analyze the specific molecular and physiological functions hypothesized to underlie intervention-induced increases in lifespan and health measures. These experiments will be carried out using a variety of innovative assays that allow high throughput, high precision estimates of individual longevity, physiology, behavior and health. Project goals will be achieved via a joint management structure that is overseen by a Steering Committee of program participants and selected outside members, with drug candidates selected by an appointed Access Panel. All experimental outcomes will be made available to the broader scientific community, as well as being published in the scientific literature. Identifying drug treatments tha enhance health and physiological performance, particularly in regard to holding back the regular degradation of function usually associated with aging, has the potential to revolutionize the manner which people age-prolonging healthy states much later into life-thereby decreasing costs of healthcare delivery in an increasingly aging society.