Dietary methionine restriction started late in life promotes healthy aging in a sex-specific manner.

Ulalume Hernández-Arciga, Ceda Stamenkovic, Shweta Yadav, Chiara Nicoletti, Wafaa N Albalawy, Farazdaq Al Hammood, Tiffany Fuentes Gonzalez, Maitreyi U Naikwadi, Aidan Graham, Christian Smarz, Gabriela J Little, Sean-Paul G Williams, Brenda McMahon, Ian J Sipula, Amber M Vandevender, Byron Chuan, Diana Cooke, Antonio F M Pinto, Lisa C Flores, Hannah L Hartman, Jolene K Diedrich, Robert T Brooke, Jonathan K Alder, Krystle A Frahm, Laura E Pascal, Emma Stolt, Hannibal Troensegaard, Bente Øvrebø, Amany Elshorbagy, Elsa Molina, Kathrine J Vinknes, Roderick J Tan, Ora A Weisz, Marta Bueno, Oliver Eickelberg, Matthew L Steinhauser, Toren Finkel, Gene P Ables, Yuji Ikeno, Thomas Olsen, Alessandra Sacco, Michael J Jurczak, Stacey J Sukoff Rizzo, Andrey A Parkhitko

Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, PA, USA.Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, PA, USA. · pubmed

Paper

Abstract

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, an 8-week MetR intervention in a human trial (NCT04701346) showed no significant impact on epigenetic clocks. The observed benefits from late-life MetR provide translational rationale to develop MetR mimetics as an antiaging intervention.

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Research summary

Dietary methionine restriction in late life improves various health parameters in mice. The study addresses the potential of dietary interventions to promote healthy aging, targeting metabolic pathways associated with aging rather than merely treating age-related diseases.

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