Discovering compounds with robust pro-longevity activities

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DESCRIPTION (provided by applicant): Aging is the single largest risk factor for chronic disease in developed countries and is consequently responsible for an enormous social and economic burden. The development of therapies or preventive measures aimed at reducing or delaying age-related disease must be a priority for the biomedical community. However, the traditional models of drug discovery are failing when it comes to the major chronic diseases of the elderly. Perhaps targeting aging directly would improve our chances of increasing healthspan. Based on the accumulated genetic data on lifespan determination in invertebrates there may be hundreds of potential targets to pharmacologically slow or otherwise alter the course of aging. There may be a more limited set of metabolic or physiological alterations that confer longevity such as enhanced homeostatic mechanisms, optimal bioenergetics, improved stem cell function etc. that could be targeted. Despite the wealth of targets, we do not have a large range of chemical compounds that slow aging in mammals at hand to test the idea that targeting aging could lead to improved clinical trial outcomes for age-related disease. The arguably very successful NIA-funded Interventional Testing Program (ITP) addresses this issue by testing compounds for effects principally on longevity in the lab mouse following a standardized protocol at multiple research facilities. This has led to the important discovery that rapamycin reproducibly extends lifespan. This proposal is a response to RFA-AG-13-010 which sets out to build a testing program in a tractable, short-lived organism (Caenorhabditis strains) to provide a set of high quality robust compounds for testing mouse models of aging and age-related disease. We have discovered a series of chemical compounds that delay the onset of age-related pathology and extend lifespan. These compounds were identified in focused chemical screens and high throughput screens of both synthetic compounds and natural products. Some of these compounds are now being utilized in mouse aging studies. Here we propose to leverage this experience, together with some innovative approaches to studying compounds action to test new, sponsor-suggested compound structures as part of the CITP.