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

Abstract

Aging is a risk factor for many human pathologies and is characterized by extensive metabolic changes. Using targeted high-throughput metabolite profiling in Drosophila melanogaster at different ages, we demonstrate that methionine metabolism changes strikingly during aging. Methionine generates the methyl donor S-adenosylmethionine (SAM), which is converted via methylation to S-adenosyl-homocysteine (SAH), which accumulates during aging. A targeted RNAi screen against methionine pathway components revealed significant life span extension in response to down-regulation of two noncanonical Drosophila homologs of the SAH hydrolase Ahcy (S-adenosyl-L-homocysteine hydrolase [SAHH[), CG9977/dAhcyL1 and Ahcy89E/CG8956/dAhcyL2, which act as dominant-negative regulators of canonical AHCY. Importantly, tissue-specific down-regulation of dAhcyL1/L2 in the brain and intestine extends health and life span. Furthermore, metabolomic analysis of dAhcyL1-deficient flies revealed its effect on age-dependent metabolic reprogramming and H3K4 methylation. Altogether, reprogramming of methionine metabolism in young flies and suppression of age-dependent SAH accumulation lead to increased life span. These studies highlight the role of noncanonical Ahcy enzymes as determinants of healthy aging and longevity.

Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species

“…They found that downregulation of Sams led to decreased levels of H3K4me3 and H3K9me2 in Drosophila S2 cells (Liu, Barnes, & Pile, ) . Consistent with this, we found that activation of flux in methionine metabolism via downregulation of dAhcyL1 significantly suppressed the level of H3K4me3 (Parkhitko et al, ). The corepressor SIN3, which controls histone acetylation through association with the histone deacetylase RPD3, binds to the promoter regions of genes involved in methionine metabolism and regulates levels of SAM and H3K4me3 (Liu & Pile, ).…”

“…Downregulation of dAhcyL1/dAhcyL2 at the whole‐organism and tissue‐specific level extends lifespan and healthspan. In our model, downregulation of dAhcyL1/dAhcyL2 activates Ahcy13, which in turn promotes SAH and homocysteine processing, resulting in an increase in methionine flux and an effect reminiscent of methionine restriction (Parkhitko et al, ).…”

Novel roles for GATAe in growth, maintenance and proliferation of cell populations in the Drosophila renal tubule

“…Additionally, these MTs also exhibited a strong upregulation of Adenosylhomocysteinase like 1 (AhcyL1) (∼5-fold increase, Fig. 5I), a gene involved with methionine metabolism and recently shown to be involved in the control of Drosophila lifespan (Parkhitko et al, 2016).…”

Emerging Insights into the Metabolic Alterations in Aging Using Metabolomics

“…Methionine metabolism was also reported to be significantly altered with age, as demonstrated by a high-throughput targeted metabolomics study in flies revealing that S-adenosyl-homocysteine (SAH) metabolite accumulates with age, and that suppressing the age-dependent SAH accumulation in turn suppresses the H3K4 trimethylation (H3K4me3), thus mimicking methionine restriction and leading to the health span and lifespan extension in flies [86,87]. The effects of dietary restriction (DR) and age were also investigated in different tissues from flies, demonstrating that DR significantly alters the metabolome and impedes the age-related changes in the metabolome [88]. This study identified a network structure of metabolites that were altered by DR in flies, including the amino acids, nicotinamide adenine dinucleotide (NAD), and novel metabolic pathways, which shed mechanistic insights on the DR mediated protective effects on health span and lifespan in flies [88].…”

“…The effects of dietary restriction (DR) and age were also investigated in different tissues from flies, demonstrating that DR significantly alters the metabolome and impedes the age-related changes in the metabolome [88]. This study identified a network structure of metabolites that were altered by DR in flies, including the amino acids, nicotinamide adenine dinucleotide (NAD), and novel metabolic pathways, which shed mechanistic insights on the DR mediated protective effects on health span and lifespan in flies [88]. Interestingly, the fecal metabolomics approach recently examined the age-related differences in the metabolome of long-lived brown bats (i.e., a non-model mammalian organism), which demonstrated that 41 metabolites were altered between young and elderly bats with significant differences in metabolites that were associated with the tryptophan metabolism and incomplete protein digestion, indicating the importance of protein homeostasis and tryptophan metabolism pathways in longevity [89].…”