32 Mechanisms of Ageing and Longevity

Abstract

Aging, long thought to be solely the byproduct of wear and tear, is actually a highly controlled process, regulated by a combination of genetic and environmental factors. Our overarching goals are: (1) to understand the molecular mechanisms by which known ‘longevity genes’ regulate aging in mammals; and (2) to discover novel genes and processes that control lifespan using two genetic models for aging: the nematode C. elegans and the extremely short-lived African fish N. furzeri. We are particularly interested in the aging of the nervous system. My presentation will be focused on the importance of stem cells in the brain during aging in mammals. In the nervous system, neural stem cells (NSCs) are thought to be important for learning, memory, and mood regulation. During aging, both the pool of NSCs and their ability to give rise to new neurons decline, raising the possibility that NSC depletion may underlie part of the cognitive dysfunctions during aging. However, the molecular mechanisms that regulate the maintenance of the NSC pool throughout lifespan are largely unknown. We have found that FoxO3, a member of a transcription factor family known to extend lifespan in invertebrates, maintains the NSC pool in adult mice. Analysis of the program of genes regulated by FoxO3 in NSCs suggests that FoxO3 maintains the adult NSC pool by inducing a program of genes that preserves cellular quiescence and regulates oxygen metabolism. Because NSCs are thought to be important for cognitive function and mood regulation, the ability of FoxO3 to maintain the NSC pool in adult organisms might have important implications for counteracting brain aging in long-lived species, including humans.