Exercise Protection of the Aging Nervous System: Defining Exercise Impact on Cell and System

Project Summary Exercise is the most effective anti-disease, pro-health intervention that the medical field can offer to our aging population, with myriad studies documenting substantial protection against disease and even extending lifespan by years. Still, our understanding of the molecular mechanisms that mediate protection against aging, and in particular brain aging, remain surprisingly incomplete. Better knowledge will be fundamental to clinical efforts to directly enhance exercise outcomes and to design exercise mimetics that can confer healthy aging. We found that regular swim exercise in the important aging model C. elegans can induce remarkable benefits that include longevity and enhanced old age functionality of multiple tissues, including protection against natural aging nervous system decline and against neuronal dysfunction in models of Alzheimer's disease. With an eye toward understanding the molecules required for long-term systemic benefits of exercise, we identified the conserved extracellular superoxide dismutase sod-4 as a protein with an unusual superpower-SOD-4 is not needed for the training, or the physical improvements that immediately accompany training, but instead, SOD-4 acts so that the long-term benefits of exercise are maintained late into adult life. The detailed characterization of the C. elegans nervous system is unparalleled in biology-every neuron and its connections are known, and the activity of each neuron can be simultaneously assessed inside the living, animal. We applied state-of-the-art multi-neuron imaging to show that the nervous system activity/connectivity become disorganized with age, featuring hyperactivity similar to that in mammalian brain aging. To elucidate the neuroprotective effects of exercise in aging, our collaborative team will combine our pioneering use of C. elegans as a conserved model of exercise with comprehensive multi-neuron imaging in pursuit of the following scientific aims: Aim 1: We will perform multi-neuron imaging in aging C. elegans +/- exercise to directly measure the impact of exercise on individual neuron activity, network connectivity, and system-wide dynamics--the first description of how exercise impacts neuronal decline in aging at cell and systems levels in whole nervous system context. Aim 2: We will use multi-neuron imaging to define how sod-4 sustains exercise impact across the whole nervous system, and apply molecular genetics approaches to discern the basic rules by which SOD-4 is supplied to promote system-wide maintenance of exercise benefits.