The long-term goal of this project is to identify mechanisms that protect the nervous system from aging and neurodegenerative disorders. Aging precipitates dramatic alterations in the physiology of all organisms, compromising cellular function, reducing resistance to stress, and increasing the likelihood of developing age-related diseases. Characteristic conditions are late-onset neurodegenerative disorders and cognitive decline. Remarkably, while age is known to be a strong determinant of these conditions, the molecular mechanisms leading to natural age-related neural deterioration are virtually unknown. We propose a compelling approach to elucidate the mechanisms by which neurons age, how brain function is affected by aging and how, in turn, this is related to aging of the whole body. Through our research in a powerful genetic model organism we have uncovered, for the first time, the presence of genes that appear exclusively dedicated to protecting neurons and neuronal circuits from the effects of aging. These findings provide us with a unique entry point to elucidate the mechanisms of neuronal aging. We propose to use robust genetic aproaches in C. elegans, a model system with a strong track record of contributions to the field of aging and nervous system development and function, to tease apart the molecular mechanisms underlying normal age-dependent brain decline and neuropathological conditions manifested during senescence. We will achieve this by (1) establishing the progression of age-related changes in the nervous system and elucidating the role of the neuronal protection genes we have indentified during aging, (2) test the role of lifespan-determining pathways in neuronal aging, and (3) identifying new gene products that function to protect the nervous system from aging. Ultimately, we expect that this research will provide a much-needed paradigm-shifting strategy for the design of effective interventions to improve human life at old age and to ameliorate the consequences of neurodegenerative diseases and cognitive decline. 1 PUBLIC HEALTH RELEVANCE: While mental decline and the onset of neurodegenerative diseases are strongly dependent on age, the mechanisms by which aging triggers these conditions is largely unknown. The goal of this project is to understand how brain cells age, how brain function is affected and how in turn this is related to aging of the whole body, with the major goal of uncovering strategies to counteract age-related brain decline. We predict that this research strategy will open up completely novel and powerful advances into our understanding of nervous system aging. Ultimately, these studies are expected to fully direct and speed up future research in mammalian systems, where genetic approaches to identify aging-related genes is still quite complicated. The proposed studies in C. elegans are expected to establish a strong foundation to elucidate the molecular mechanisms of neuronal aging, at the single- neuron, circuit, and circuit output (behavior) levels. We expect that our findings will foster the study of novel molecular mechanisms that control neuronal decline and its relationship to aging, which will dramatically enhance our understanding of the molecular codes used by neurons to actively protect neuronal function despite developmental, mechanical, and environmental challenges. We expect that our research will have fundamental implications for the treatment of neurodegenerative diseases and the development of approaches to ameliorate the consequences of aging for cognition, thus improving the quality of human life at old age.