biostudies-literatureHernandez-Arciga UNIA NIH HHSNIDDK NIH HHSNHLBI NIH HHSNIH HHSNIGMS NIH HHSeads1532https://www.ebi.ac.uk/biostudies/studies/S-EPMC12002124biostudies-literatureUnknown11(16)Aging is associated with dysregulated methionine metabolism and increased levels of enzymes in the tyrosine degradation pathway (TDP). To investigate the efficacy of targeting either methionine metabolism or the TDP for healthspan improvement in advanced age, we initiated dietary MetR or TDP inhibition in 18-month-old C57BL/6J mice. MetR significantly improved neuromuscular function, metabolic health, lung function, and frailty. In addition, we confirmed improved neuromuscular function from dietary MetR in 5XFAD mice, whose weight was not affected by MetR. We did not observe benefits with TDP inhibition. Single-nucleus RNA and ATAC sequencing of muscle revealed cell type-specific responses to MetR, although MetR did not significantly affect mouse aging epigenetic clock markers. Similarly, Science advancesDietary methionine restriction started late in life promotes healthy aging in a sex-specific manner.PMC12002124P30 AG013319R35 GM146869U54 AG075931R01 AG070034P30 AG024827K01 DK115543R01 HL135062R03 AG075651S10 OD023684P30 AG068635R01 DK138967U54 AG054345R00 AG057792R01 AG082696R21 DK121266Vinknes KJBrooke RTElshorbagy AMolina EWeisz OAStamenkovic CBueno MChuan BAlbalawy WNOvrebo BAlder JKSacco AAl Hammood FPinto AFMPascal LEGonzalez TFFlores LCTan RJGraham ACooke DParkhitko AASukoff Rizzo SJYadav SWilliams SGSipula IJHartman HLStolt EEickelberg OIkeno YHernandez-Arciga USteinhauser MLMcMahon BTroensegaard HSmarz COlsen TNaikwadi MUDiedrich JKAbles GPJurczak MJFinkel TVandevender AMNicoletti CFrahm KALittle GJfalseDietary methionine restriction started late in life promotes healthy aging in a sex-specific manner.Aging is associated with dysregulated methionine metabolism and increased levels of enzymes in the tyrosine degradation pathway (TDP). To investigate the efficacy of targeting either methionine metabolism or the TDP for healthspan improvement in advanced age, we initiated dietary MetR or TDP inhibition in 18-month-old C57BL/6J mice. MetR significantly improved neuromuscular function, metabolic health, lung function, and frailty. In addition, we confirmed improved neuromuscular function from dietary MetR in 5XFAD mice, whose weight was not affected by MetR. We did not observe benefits with TDP inhibition. Single-nucleus RNA and ATAC sequencing of muscle revealed cell type-specific responses to MetR, although MetR did not significantly affect mouse aging epigenetic clock markers. Similarly, 2025-01-01T00:00:00Z2025 Apr2026-06-01T10:20:26.857Z2026-04-08T11:18:57.388ZS-EPMC120021244023887110.1126/sciadv.ads1532