Reprogramming organismal lifespan through modulation of neuropeptides

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Aging is the primary risk factor for debilitating diseases such as Alzheimer’s disease. Can manipulation of neurons in the brain alter the body’s physiological state to extend lifespan and prevent neurodegenerative disease? Neuropeptides are signaling molecules released by neurons that act through modulatory receptors expressed throughout the brain and body to regulate homeostasis. Whether neuropeptides could control long-term phenotypes such as the rate of aging, neurodegeneration and cognitive decline remains largely unknown. Neuropeptides have been implicated in Alzheimer’s disease in humans. For example, the neuropeptide Galanin (GAL) is overexpressed in degenerating brain regions in Alzheimer’s disease, low levels of the neuropeptide Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) are correlated with higher amyloid burden and memory decline, and the number of neurons expressing the neuropeptide Hypocretin are significantly reduced in postmortem hypothalamus of Alzheimer's disease patients. However, a systematic characterization of the role and mode of action of neuropeptides in regulating vertebrate lifespan and their impact on neurodegeneration and cognitive decline is missing. This is largely because aging and lifespan experiments in transgenic vertebrates are slow (3+ years in mice) and low throughput. I will take advantage of a short-lived vertebrate model the African killifish to (1) determine if deletion of key neuropeptides can alter lifespan, healthspan, and cognitive decline, (2) investigate the mode of action of one neuropeptide that I have already found to extend lifespan when knocked out, and (3) test if neuropeptides can act as pro-longevity factors when delivered later in life to counter age-associated cognitive decline. To achieve this, I will use interdisciplinary technologies at the nexus of genetics, aging, and neuroscience. I already have exciting tools and data that support my goal. I built a library of neuropeptide knockout killifish targeting 22 human-conserved neuropeptides using CRISPR/Cas9 and I optimized the protocol for lifespan and healthspan assessment in the killifish. In tantalizing preliminary data, I found that knockout of the AD-associated neuropeptide GAL in killifish results in progressive cognitive decline suggesting that neuropeptides could be key modulators of neurodegeneration in disease such as Alzheimer’s disease. By focusing on diverse neuropeptides that interact with specific druggable receptors, I hope the long-term impact of this work will translate to clinical solutions to age-associated Alzheimer’s disease and others. For the mentored part of my training at Stanford University, I will receive training from my mentor Dr. Karl Deisseroth, co-mentor Dr. Anne Brunet, and an exceptional scientific advisory team with expertise in neuroscience, neuropeptides, aging, neurodegeneration, genetic screening, and CRISPR methods. This work, my technical training, and my career development at Stanford University will provide me with the skills and foundations required to be a leader of a laboratory at a top academic institution, discovering genes critical for longevity and for countering cognitive decline in Alzheimer’s disease.