Lifespan Regulation by Evolutionarily Conserved Genes Essential for Viability

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. The lifespan of an animal is determined by both environmental and genetic factors, and many of the mechanisms identified to increase lifespan are evolutionarily conserved across organisms. Previous longevity screens in C. elegans have identified over 100 genes, but ∼2,700 essential for normal development were excluded from analysis. Paradoxically, these essential genes are five times more likely to be highly conserved in phylogeny than genes with no obvious developmental phenotypes. We screened these 2,700 essential genes for increased adult lifespan by initiating the gene knockdown once the animal had reached adulthood, thus bypassing earlier developmental roles. We identified 64 genes that can extend lifespan when inactivated postdevelopmentally. More than 90% of the genes we identified are conserved from yeast to humans. Many of the newly identified longevity genes extend lifespan as robustly as the most well-characterized longevity mutants. It is possible that the homologues of these genes may also regulate lifespan in other organisms as well. Genetic analysis places some of these genes in known pathways regulated by insulin-like signaling, although many of these gene inactivations function independently of this mechanism of lifespan extension. Surprisingly, a subset of these gene inactivations that induce potent developmental arrest also facilitate enhanced survival in the arrested state, suggesting that aging at any stage may be subject to regulatory control.