Sirtuins are not conserved longevity genes

Abstract It is central to biology that sequence conservation suggests functional conservation. Animal longevity is an emergent property of selected traits that integrates capacities to perform physical and mental functions after reproductive maturity. Though the yeast SIR2 gene was nominated as a longevity gene based on extended replicative longevity of old mother cells, this is not a selected trait: SIR2 is selected against in chronological aging and the direct targets of SIR2 in replicative lifespan are not conserved. Though it would be difficult to imagine how a gene that advantages 1 in 5 million yeast cells could have anticipated causes of aging in animals, overexpression of SIR2 homologs was tested in invertebrates for longevity. Because artifactual positive results were reported years before they were sorted out and because it was not known that SIR2 functions as a pro-aging gene in yeast chronological aging and in flies subject to amino acid deprivation, a global pursuit of longevity phenotypes was driven by a mixture of framing bias, confirmation bias, and hype. Review articles that propagate these biases are so rampant that few investigators have considered how weak the case ever was for sirtuins as longevity genes. Acknowledging that a few positive associations between sirtuins and longevity have been identified after thousands of person-years and billions of dollars of effort, we review the data and suggest rejection of the notions that sirtuins (i) have any specific connection to lifespan in animals and (ii) are primary mediators of the beneficial effects of NAD repletion.