Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila

Abstract

Methionine restriction (MetR) extends lifespan in various organisms, but its mechanistic understanding remains incomplete. Whether MetR during a specific period of adulthood increases lifespan is not shown. In Drosophila, MetR is reported to extend lifespan only when amino acid levels are low. Here, by using an exome-matched holidic medium, we show that decreasing Met levels to 10% extends Drosophila lifespan with or without decreasing total amino acid levels. MetR during the first four weeks of adult life robustly extends lifespan. MetR induces the expression of Methionine sulfoxide reductase A (MsrA) in young flies, which reduces the oxidatively-damaged Met. MsrA induction is foxo-dependent and persists for two weeks after cessation of the MetR diet. Loss of MsrA attenuates lifespan extension by early-adult MetR. Our study highlights the age-dependency of the organismal response to specific nutrient and suggests that nutrient restriction at a particular period of life is sufficient for healthspan extension.