The brain as a control center for other organs during aging - SUMMARY The goal of this multi-investigator proposal is to determine how the brain can act as ‘neural pacemaker’ to regulate the tempo of aging of the whole organism. Aging is a multifaceted process that alters the function of every organ and is associated with devastating diseases. An inherent limitation to understand and target aging has been the ability to perform systems level studies to identify central drivers of organismal aging. All vertebrate studies have remained limited because of the low throughput nature of studies in mice, and we miss an integrative understanding of aging. The recent pioneering of the killifish, a vertebrate with a naturally compressed lifespan, has made previously intractable challenges possible. The killifish is one of the shortest-lived vertebrates, with a compressed lifespan of only ~6 months. The conserved aging characteristics of the killifish and the availability of genomic, proteomic, and genetic tools make it an ideal model for conducting longitudinal, high-throughput studies of aging and longevity. We have recently generated transformative technologies to interrogate aging in a scalable manner in the killifish. We have performed video-tracking continuously throughout the killifish lifespan. Using artificial intelligence, we have parsed these extraordinary complex datasets and made the tantalizing observation that behavior acts as a predictive biomarker of aging. We also conducted a genetic screen for killifish lifespan, which uncovered new neuropeptides that impact organismal lifespan. Moreover, we generated ‘multi-omics’ datasets reporting molecular phenotypes in response to aging and longevity interventions. Finally, we have built new tools to test neural systems throughout lifespan to gain unbiased understanding of control centers for aging. In this multi-investigator proposal, we are combining our unprecedented ability to study high level aging markers in the killifish, uncover molecular phenotypes of aging, and identify and manipulate genetic and neural networks to test the hypothesis that the brain affects the tempo of aging. We propose to conduct the following experiments: 1: Leverage continuous behavioral recording to identify behaviors that accurately predict the tempo of aging. 2: Uncover secreted factors that connect the brain to the rest of the body for the regulation of aging. 3. Determine how molecular changes in the brain dictate organismal fitness during aging. 4: Identify new neuronal activity networks during aging and longevity. Knowledge resulting from these studies should be transformative to understand the fundamental mechanisms that control and synchronize aging and longevity, a finding that will likely have therapeutic value for extending healthy lifespan. As the median age of the human population continues to rise on all continents, these issues are directly pertinent to major medical and societal problems faced in the United States and worldwide.
