Targeting Methionine Metabolism to Improve Healthspan

As we age, our bodies accumulate molecular and cellular damage that leads to declining function across multiple systems. One promising avenue to counteract aging is dietary methionine restriction (MetR), which has shown lifespan and healthspan benefits in diverse organisms, from yeast to rodents. Recent work summarized on Fight Aging! evaluates whether initiating MetR in late life can still deliver functional gains.

Study Design and Intervention

Researchers placed 18-month-old male and female C57BL/6J mice on a methionine-restricted diet for six months, without cutting total calories. They compared metabolic markers, neuromuscular coordination, pulmonary function and frailty index between MetR and control groups. To uncover molecular mechanisms, they performed single-nucleus RNA sequencing (snRNA-seq) and ATAC-seq (assay for transposase-accessible chromatin) on muscle tissues.

Key Findings

• Metabolic improvements: MetR mice exhibited better glucose tolerance and more favorable lipid profiles, indicating enhanced metabolic resilience in aged animals.
• Functional gains: Measures of muscle strength, coordination and lung capacity improved under MetR, leading to a lower overall frailty index.
• No epigenetic clock shift: Despite broad physiological benefits, DNA methylation-based clocks remained unchanged in both mice and human fibroblasts, suggesting that functional health and epigenetic age measures can diverge.
• Cell-type responses: snRNA-seq and ATAC-seq analyses revealed activation of specific transcription factors and pathways in distinct muscle cell populations, pointing to targeted molecular adaptations triggered by methionine reduction.
• Validation in disease model: In the Alzheimer’s disease 5XFAD mouse model, a separate cohort confirmed neuromuscular improvements under MetR, demonstrating potential relevance for disease contexts.

Implications for Human Aging

These results underscore that even late-life dietary tweaks can deliver measurable improvements in healthspan metrics. While current epigenetic clocks did not capture these changes, functional benefits—metabolic, neuromuscular and pulmonary—highlight methionine metabolism as a tractable target. Ongoing research must explore optimal intervention timing and gauge long-term safety in human trials.

By illuminating cell-specific molecular responses, this work paves the way for precision dietary or pharmacological strategies to mimic MetR benefits without broad nutrient deprivation.

Key points

• Late-life methionine restriction enhances metabolic, neuromuscular and lung function in aged mice.
• Dietary MetR does not alter DNA methylation-based epigenetic age in mice or human cells.
• snRNA-seq and ATAC-seq reveal cell-type-specific molecular adaptations to MetR.