Lifespan regulation by evolutionarily conserved genes essential for viability.
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.
Curran
Sean P
SP
Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Ruvkun
Gary
G
D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002999:Clone Cells; D017124:Conserved Sequence / Q000235:genetics*; D019143:Evolution, Molecular; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D020043:Genes, Essential; D017238:Genes, Helminth; D007328:Insulin / Q000378:metabolism; D007814:Larva; D008136:Longevity / Q000235:genetics*; D008928:Mitochondria / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D007328:Insulin; D014157:Transcription Factors; C108831:daf-16 protein, C elegans