Partridge, L; (2020) Longevity in response to lowered insulin signalling requires glycine N- methyltransferase-dependent spermidine production. Aging Cell , 19 (1) , Article e13043. 10.1111/acel.13043.

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Abstract

Reduced insulin/IGF signaling (IIS) extends lifespan in multiple organisms. Different processes in different tissues mediate this lifespan extension, with a set of interplays that remain unclear. We here show that, in Drosophila, reduced IIS activity modulates methionine metabolism, through tissue-specific regulation of glycine Nmethyltransferase (Gnmt), and that this regulation is required for full IIS-mediated longevity. Furthermore, fat-body-specific expression of Gnmt was sufficient to extend lifespan. Targeted metabolomics showed that reducing IIS activity led to a Gnmtdependent increase in spermidine levels. We also show that both spermidine treatment and reduced IIS activity are sufficient to extend the lifespan of Drosophila, but only in the presence of Gnmt. This extension of lifespan was associated with increased levels of autophagy. Finally, we found that increased expression of Gnmt occurs in the liver of liver-specific IRS1 KO mice, and is thus an evolutionary conserved response to reduced IIS. The discovery of Gnmt and spermidine as tissue-specific modulators of IIS-mediated longevity may aid in developing future therapeutic treatments to ameliorate ageing and prevent disease.

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