Methionine restriction slows down senescence in human diploid fibroblasts

Abstract

Methionine restriction (MetR) extends lifespan in animal models including rodents. Using human diploid fibroblasts (HDF), we report here that MetR significantly extends their replicative lifespan, thereby postponing cellular senescence. MetR significantly decreased activity of mitochondrial complex IV and diminished the accumulation of reactive oxygen species. Lifespan extension was accompanied by a significant decrease in the levels of subunits of mitochondrial complex IV, but also complex I, which was due to a decreased translation rate of several mtDNA-encoded subunits. Together, these findings indicate that MetR slows down aging in human cells by modulating mitochondrial protein synthesis and respiratory chain assembly.

Cysteine dietary supplementation reverses the decrease in mitochondrial ROS production at complex I induced by methionine restriction

“…Methionine restriction slows down senescence in yeast (Koziek et al 2014) and human cells (Johnson and Johnson 2014) and extends lifespan in invertebrate animal models (Lee et al 2014). Most importantly, MetR (80 %) also increases both mean and maximum life span in mammals (Richie et al 1994;Miller et al 2005;Sun et al 2009).…”

Tissue-specific down-regulation of S-adenosyl-homocysteine via suppression of dAhcyL1/dAhcyL2 extends health span and life span in Drosophila

“…Altogether, our data support the model that reprogramming of methionine metabolism in young flies and suppression of age-dependent SAH accumulation is associated with increased life span. dAhcyL1 and dAhcyL2 regulate both life span and health span Because methionine restriction extends life span in different organisms (Orentreich et al 1993;Koziel et al 2014;Lee et al 2014), multiple components of methionine metabolism change with age, and methionine levels are significantly different in short-and long-lived flies, we systematically evaluated the effect of methionine metabolism enzymes on life span using RNAi. To avoid lethality during development and differences in genetic background, we used the Actin GeneSwitch (ActinGS)- inducible Gal4/UAS expression system (Osterwalder et al 2001;Roman et al 2001), by which UAS-RNAi expression is driven by Gal4 when flies are fed mifepristone (RU486).…”

“…In addition, methionine restriction extends life span in yeast, flies, rodents, and human diploid fibroblasts (Orentreich et al 1993;Koziel et al 2014;Lee et al 2014). Methionine metabolism consists of three branches: salvage, de novo, and transsulfuration pathways.…”

Carnosine and the processes of ageing

“…The rate at which proteins are synthesised can affect the onset of ageing, as methionine restriction [67] and decreased availability of translation initiation factor [68] have been shown to delay ageing onset and extend lifespan. The resulting lowered protein synthesis rate will also decrease error-protein generation; protein biosynthesis is not perfect (the error frequency has been estimated at 3 codons in every 10,000 translated [69]), thus any method which decreases protein synthesis may decrease the generation of errorprotein, thereby decreasing the error-protein load (of any origin) which the homeostatic proteolytic apparatus is required to deal with [70].…”