Dietary 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, 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.
Authors
- Thomas Olsén (ORCID: https://orcid.org/0000-0003-1805-5221)
- Gabriela Little
- Sean-Paul G. Williams (ORCID: https://orcid.org/0000-0002-5680-7730)
- Oliver Eickelberg (ORCID: https://orcid.org/0000-0001-7170-0360)
- Ian Sipula
- Toren Finkel (ORCID: https://orcid.org/0000-0002-0726-3546)
- K. Frahm (ORCID: https://orcid.org/0000-0002-9269-4294)
- Michael J. Jurczak (ORCID: https://orcid.org/0000-0002-6335-6915)
- Roderick J. Tan (ORCID: https://orcid.org/0000-0003-1012-1722)
- Marta Bueno (ORCID: https://orcid.org/0000-0001-7140-9899)
- Emma Stolt (ORCID: https://orcid.org/0000-0002-4481-225X)
- Ora A. Weisz (ORCID: https://orcid.org/0000-0003-2985-4870)
- Jolene K. Diedrich (ORCID: https://orcid.org/0000-0001-6489-4558)
- Kathrine J. Vinknes (ORCID: https://orcid.org/0000-0002-0756-5042)
- Bente Øvrebø
- Laura E. Pascal (ORCID: https://orcid.org/0000-0003-3840-1662)
- Hannah L. Hartman (ORCID: https://orcid.org/0000-0002-9347-4621)
- Jonathan K. Alder (ORCID: https://orcid.org/0000-0003-3741-6512)
- Elsa Molina (ORCID: https://orcid.org/0000-0003-1603-5438)
- Alessandra Sacco (ORCID: https://orcid.org/0000-0003-1669-0221)
- Wafaa N. Albalawy (ORCID: https://orcid.org/0009-0000-9279-2671)
- Andrey A. Parkhitko (ORCID: https://orcid.org/0000-0001-9852-8329)
- Stacey J. Sukoff Rizzo (ORCID: https://orcid.org/0000-0002-1460-8127)
- Chiara Nicoletti (ORCID: https://orcid.org/0000-0002-0872-6506)
- Shweta Yadav (ORCID: https://orcid.org/0000-0001-9760-3382)
- Ulalume Hernández-Arciga (ORCID: https://orcid.org/0000-0003-4995-7172)
- Byron Chuan
- Robert T. Brooke (ORCID: https://orcid.org/0000-0001-8492-5198)
- Lisa C. Flores
- Amber Vandevender (ORCID: https://orcid.org/0000-0002-3719-0747)
- Gene P. Ables
- Amany Elshorbagy (ORCID: https://orcid.org/0000-0002-8624-860X)
- Diana Cooke
- Yuji Ikeno (ORCID: https://orcid.org/0000-0002-9234-8738)
- Hannibal Troensegaard (ORCID: https://orcid.org/0000-0002-2815-1092)
- Antônio F. M. Pinto (ORCID: https://orcid.org/0000-0002-1573-8011)
- Farazdaq Al hammood
- Matthew L. Steinhauser (ORCID: https://orcid.org/0000-0001-8900-9535)
- Aidan Graham
- Brenda McMahon
- Ceda Stamenkovic
- Christian Smarz
- Tiffany Fuentes Gonzalez
- Maitreyi U. Naikwadi
Institutions
- Salk Institute for Biological Studies (US)
- Norwegian Institute of Public Health (NO)
- The University of Texas at San Antonio Health Science Center (US)
- University of Pittsburgh (US)
- University of Oslo (NO)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Discovery Institute (US)
- Audie L. Murphy Memorial VA Hospital (US)
- Murphy Oil Corporation (United States) (US)
- University of Oxford (GB)
- Orentreich Foundation for the Advancement of Science (US)
- Alexandria University (EG)
Publication Details
- Journal
- Science Advances
- Published
- 2025-04-16
- DOI
- https://doi.org/10.1126/sciadv.ads1532
- Citations
- 8
- Primary Topic
- Health, Environment, Cognitive Aging
- Type
- article
- Field-Weighted Citation Impact
- 9.60