Reprogramming organismal lifespan through modulation of neuropeptidergic circuits

Aging is the number one risk factor for debilitating diseases such as neurodegeneration. Can manipulation of neurons in the brain alter the body’s physiological state to extend lifespan? Neuropeptides are key modulators of short-term homeostasis such as feeding, temperature, and sleep. But whether neuropeptidergic circuits could also control long-term phenotypes such as the rate of aging remains largely unknown. Mounting evidence suggests that neuropeptides can influence lifespan. However, there has not been a systematic characterization of the role of neuropeptides or the neuronal circuits that produce them in regulating vertebrate lifespan. This is largely because lifespan experiments in vertebrates are prohibitively slow (3+ years in mice) and the implicated genes are tested using only a candidate-based approach. I propose to take advantage of the promising new model organism the African killifish with a naturally compressed lifespan to (1) identify neuropeptidergic cell types and neuropeptides that change with old age and in response to longevity interventions, (2) determine if deletion of key neuropeptides can alter lifespan, and (3) examine if chronic stimulation of age-dependent neuropeptidergic cell types extends lifespan and promotes rejuvenation. With these experiments, I will determine if manipulation of circuits in the brain can reprogram organismal lifespan.