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Genes Dev. 2016 Jun 15;30(12):1409-22. doi: 10.1101/gad.282277.116. Epub 2016 Jun 16.

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

Author information

1
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
2
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA;
3
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; MOE Key Laboratory of Protein Sciences, Department of Pharmacology, School of Medicine, Tsinghua University, Beijing 100084, China;
4
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA;
5
Department of Developmental Neurobiology, Division of Developmental Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

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-adenosyl-methionine (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.

KEYWORDS:

CG8956/Ahcy89E/AhcyL2; CG9977/AhcyL1; S-adenosyl-homocysteine (SAH); aging; life span; methionine restriction

PMID:
27313316
PMCID:
PMC4926864
DOI:
10.1101/gad.282277.116
[Indexed for MEDLINE]
Free PMC Article

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