Longevity in response to lowered insulin signaling requires glycine N-methyltransferase-dependent spermidine production.

Luke S Tain,Linda Partridge,Tobias Nespital,Yvonne Hinze,Chirag Jain,Jenny Froehlich,Sebastian Grönke

doi:10.1111/acel.13043

Luke S Tain, Linda Partridge + Show 5 more

Open Access

https://doi.org/10.1111/acel.13043

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Journal: Aging cell	Publication Date: Nov 13, 2019
Citations: 35	License type: CC BY 4.0

Affiliation: Max Planck Institute for Biology of Ageing

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 N‐methyltransferase (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 Gnmt‐dependent 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 evolutionarily 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 aging and prevent disease.

Highlights

Aging is the primary risk factor for human cardiovascular disease, dia‐ betes, cancer, and neurodegenerative disorders including Alzheimer's disease (Johnson, Dong, Vijg, & Suh, 2015; Partridge, Deelen, & Slagboom 2018)
The IIS‐mediated increase in spermidine levels required glycine N‐methyl‐ transferase (Gnmt) (Figure 4b). These findings suggest that reduced IIS activity can modulate methionine metabolism and polyamine syn‐ thesis, but not the transsulfuration pathway (TSP) or glutathione, through Gnmt (Figure 4b)
In response to reduced IIS, Met metabolism is altered, through the tissue‐specific transcriptional up‐regulation of the glycine N‐methyl transferase, Gnmt

Summary

| INTRODUCTION

Aging is the primary risk factor for human cardiovascular disease, dia‐ betes, cancer, and neurodegenerative disorders including Alzheimer's disease (Johnson, Dong, Vijg, & Suh, 2015; Partridge, Deelen, & Slagboom 2018). To determine whether polyamine synthesis enzyme activity un‐ derlies Gnmt‐mediated dilp mutant longevity, we quantified key metabolites of the methionine cycle (Met, SAM, and SAH) and of poly‐ amine synthesis (spermidine, ornithine, and putrescine) (Figure 4a) in wild‐type and dilp mutant flies in the presence and absence of Gnmt (GnmtMi and GnmtMi,dilp double mutants). P62 levels are reduced in the fat body of GnmtMi flies and GnmtMi,dilp double mutant flies This suggests that Gnmt may play a role in autophagy activation in response to spermidine treatment. To determine whether the responses to reduced IIS and sper‐ midine treatment led to functional changes in autophagy, we quantified the level of autophagy using LysoTracker Red (LTR) in the fat bodies of control and dilp mutant flies in the presence and absence of Gnmt and with and without spermidine treatment. These results suggest that the response of increasing Gnmt expression is a conserved response to reduced IIS activity and that this response may be mechanistically similar, acting through spermidine

| DISCUSSION

Findings

| EXPERIMENTAL PROCEDURES