Inhibition of the gut ceramidase Asah2 decelerates the vertebrate ageing rate

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Abstract The pace of ageing varies markedly among vertebrate species and individuals. However, the mechanisms underlying these differences in ageing rates remain unclear. Here, we show that the activity of the gut ceramidase Asah2 determines species- and strain-specific rates of vertebrate ageing. Comparative genomic analyses of vertebrate species and strains with different ageing rates reveal an association between low Asah2 activity and increased lifespan. Using the ultra-short-lived killifish Nothobranchius furzeri as a model, we demonstrate that knockout of Asah2 ( asah2 KO) extends lifespan and attenuates systemic ageing phenotypes, including declines in locomotor activity, abnormal protein accumulation in the brain, and accumulation of senescent cells in the liver. asah2 KO elevates levels of ceramide species with long-chain fatty acids in the intestine, and supplementation with these ceramide species suppresses ageing phenotypes and extends lifespan in wild-type fish. asah2 KO and ceramide supplementation alter gut microbiota composition, and asah2 KO-derived microbiota transplantation attenuates ageing phenotypes, suggesting that reduced Asah2 activity prevents ageing through intestinal ceramide-mediated modulation of the microbiota. Given the evolutionary conservation of the Asah2 gene and its age-dependent upregulation in fish and humans, Asah2 and ceramides may act as ageing accelerators and decelerators, respectively, across animal species.

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