Genetic cartography of longevity in humans and mice: Current landscape and horizons

Michael Hook, Suheeta Roy, Evan G Williams, Maroun Bou Sleiman, Khyobeni Mozhui, James F Nelson, Lu Lu, Johan Auwerx, Robert W Williams

Aging is a complex and highly variable process. Heritability of longevity among humans and other species is low, and this has given rise to the idea that it may be futile to search for gene variants that control rates of aging. We argue that the problem is mainly due to low power and the genetic and environmental complexity of longevity. In this review we highlight progress made in mapping genes and molecular networks associated with longevity, paying special attention to work in mice and humans. We summarize 40 years of linkage studies using murine cohorts and 15 years of studies in human populations that have exploited candidate gene and genome-wide association methods. A small but growing number of gene variants contribute to known longevity mechanisms, but a much larger set have unknown functions. We outline these and other challenges and suggest some possible solutions, including more intense collaboration between research communities that use model organisms and human cohorts. Once hundreds of gene variants have been linked to differences in longevity in mammals, it will become feasible to systematically explore gene-by-environmental interactions, dissect mechanisms with more assurance, and evaluate the roles of epistasis and epigenetics in aging. A deeper understanding of complex networks-genetic, cellular, physiological, and social-should position us well to improve healthspan.