Lifespan Regulation by Evolutionarily Conserved Genes Essential for Viability

TLDR

Evolutionarily conserved mechanisms that control aging are predicted to have prereproductive functions, yet the role of essential growth and development genes in longevity has not been previously assessed. The authors screened 2,700 essential Caenorhabditis elegans genes and identified 64 whose postdevelopmental inactivation extends lifespan. These 64 genes are highly conserved from yeast to humans, cluster into insulin, metabolic, translation, RNA, and chromatin pathways, and many extend lifespan as strongly as the best known regulators, with some causing larval growth arrest yet surviving longer, suggesting insulin signaling regulates aging at all life stages.

Abstract

Evolutionarily conserved mechanisms that control aging are predicted to have prereproductive functions in order to be subject to natural selection. Genes that are essential for growth and development are highly conserved in evolution, but their role in longevity has not previously been assessed. We screened 2,700 genes essential for Caenorhabditis elegans development and identified 64 genes that extend lifespan when inactivated postdevelopmentally. These candidate lifespan regulators are highly conserved from yeast to humans. Classification of the candidate lifespan regulators into functional groups identified the expected insulin and metabolic pathways but also revealed enrichment for translation, RNA, and chromatin factors. Many of these essential gene inactivations extend lifespan as much as the strongest known regulators of aging. Early gene inactivations of these essential genes caused growth arrest at larval stages, and some of these arrested animals live much longer than wild-type adults. daf-16 is required for the enhanced survival of arrested larvae, suggesting that the increased longevity is a physiological response to the essential gene inactivation. These results suggest that insulin-signaling pathways play a role in regulation of aging at any stage in life.