The proposed work explores genetic and physiological factors that determine inter-individual differences in lifespan, using genetically identical C. elegans reared in a novel system that allows individuals to be followed throughout their lives in isolated, identical environments. Preliminary research using this method identified a microRNA regulator of insulin/IGF-1-like signaling that can, early in adult life, predict almost half of later lifespan variability. This "Pathway to Independence" award application includes a mentored career development plan for transition of the candidate, Dr. Zach Pincus, into an independent investigator, as well an accompanying research plan describing the proposed experiments on the determinants of individual lifespan, health, and stress-resistance. The candidate, Dr. Pincus, is a postdoctoral fellow at Yale, in the lab of Dr. Frank Slack in the Department of Molecular, Cellular, and Developmental Biology. The work leading to his graduate degree in Biomedical Informatics at Stanford University was conducted in the lab of Dr. Julie Theriot in the Stanford Biochemistry Department, and focused on algorithms for representing and comparing the shapes of populations of single cells. In the Theriot lab, Dr. Pincus then applied these tools to biophysical studies on the molecular determinants of complex and largescale organization such as cell shape and movement. The mentoring and career development plan will supplement his background, which is evenly split between bench biology and computational methods development, with training and instruction in each, and in the particular areas that this project involves: aging biology, nematode biology, mathematical analysis of dynamical systems, and light microscopy. Dr. Pincus's goal is to become a faculty member in an interdisciplinary bioscience, developmental biology, or similar department at an academic, private, or governmental facility, in which he can research the biology of inter-individual variability and how it relates to lifespan determination. This research on inter-individual variability requires a novel assay system developed by Dr. Pincus that allows individual C. elegans to be examined by light microscopy throughout their lives. The project proposes to measure early-life levels of various fluorescent reporters of relevant physiological processes including insulin signaling, developmental robustness, and stress responses, and to determine which if any of those processes determine later longevity and health. The project further proposes to determine, by several independent avenues of investigation, whether there are distinct long-lived, stress- resistant "robust" cohorts of animals, distinct from more "frail" individuals, as has long been proposed in the literature. This work has clear and significant implications for human health and longevity. The identification of biomarkers that predict or determine future stress-resistance, robustness, and longevity, which are currently extremely rare, will be of great value to an aging society as such markers may lead to the development of appropriate lifespan-prolonging interventions and the ability to target them to at-risk populations.
This project seeks to explore the non-genetic, non-environmental factors that determine a surprisingly large fraction of variability in lifespan. Does random damage accumulation cause certain individuals to die earlier than others, or is lifespan and/or stress-resistance determined earlier in life, perhaps even during development? Understanding the answer to this question will help direct the development of appropriate lifespan-prolonging interventions, and the identification of at-risk populations.