Tissue-specific down-regulation of S-adenosyl-homocysteine via suppression of dAhcyL1/dAhcyL2 extends health span and life span in Drosophila.
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.
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
Andrey A
AA
Parkhitko
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA;
Richard
R
Binari
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;
Nannan
N
Zhang
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;
John M
JM
Asara
Department of Developmental Neurobiology, Division of Developmental Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Fabio
F
Demontis
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA;
Norbert
N
Perrimon
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D005260:Female; D006570:Heterochromatin / Q000235:genetics; D007422:Intestines / Q000201:enzymology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008136:Longevity / Q000235:genetics*; D008297:Male; D008715:Methionine / Q000378:metabolism; D008745:Methylation; D012435:S-Adenosylhomocysteine
D029721:Drosophila Proteins; D006570:Heterochromatin; D047908:Intracellular Signaling Peptides and Proteins; C000618371:adenosylhomocysteine hydrolase-like protein 1, Drosophila; C000618372:adenosylhomocysteine hydrolase-like protein 2, Drosophila; D012435:S-Adenosylhomocysteine; D008715:Methionine
CG8956/Ahcy89E/AhcyL2; CG9977/AhcyL1; S-adenosyl-homocysteine (SAH); aging; life span; methionine restriction