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

Summary

Late-onset methionine restriction improved neuromuscular, metabolic, and lung function and reduced frailty, with sex-specific patterns; TDP inhibition did not confer benefits. Single-nucleus RNA/ATAC-seq showed cell type–specific muscle responses, and epigenetic clocks were largely unchanged in mice and in an 8-week human trial.

Key Findings

• Late-life methionine restriction improved neuromuscular function, metabolic health, lung function, and reduced frailty in mice; benefits were sex-specific.
• TDP inhibition did not yield healthspan benefits under the tested conditions.
• Single-nucleus RNA/ATAC-seq revealed cell type–specific muscle responses; epigenetic clocks were not significantly altered in mice or in an 8-week human MetR trial.

Clinical Implications

Dietary amino acid modulation (or MetR-mimetic drugs) may improve function in older adults without requiring long-term early-life interventions; biomarkers beyond epigenetic clocks are needed to track benefit.

Limitations

• Human intervention was short (8 weeks) and small, limiting clinical inference
• Sex-specific effects and mechanisms require deeper characterization

Future Directions

Develop MetR mimetics, test longer and diversified human trials, and identify responsive biomarkers beyond epigenetic clocks.