One of the primary ways in which the beneficial, age-slowing response to calorie restriction is regulated is via sensing of methionine levels. Methionine is an essential amino acid, used in all protein synthesis, but not manufactured in the body. It must come from the diet. There is plenty of evidence for methionine restriction, meaning to construct a diet that is low in methionine without reducing calorie intake, to slow aging in rodents. Researchers here demonstrate that it remains beneficial when started in old age in mice. Interestingly, they also find that it doesn't affect epigenetic age, which is an intriguing outcome akin to the insensitivity of early epigenetic clocks to physical fitness.
We and others previously demonstrated that both steady-state levels of methionine and methionine flux are altered during aging using Drosophila as a model system. Moreover, targeting methionine metabolism via dietary manipulations of fly food, enzymatic degradation, or manipulation of enzymes either directly involved in methionine metabolism or those that affect the levels of methionine metabolism metabolites extend health- and lifespan. In addition to results seen in Drosophila, methionine restriction (MetR) extends lifespan in yeast, rodents, and human diploid fibroblasts.
Here, we determine whether targeting either methionine metabolism with dietary MetR started late in life in 18-month-old male and female C57BL/6J mice for 6 months affects various aspects of aging-related phenotypes. Dietary MetR does not affect mouse epigenetic clocks despite multiple improvements in different parameters of metabolic health, neuromuscular function, lung function, and frailty index. Similarly, we did not observe any effects of dietary MetR on human epigenetic clocks.
Using single-nucleus RNA sequencing (snRNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on the muscle tissues, we identified several subtype-specific processes and transcription factors (TFs) activated by dietary MetR that indicates a cell type-specific response to MetR. In addition, we confirm the beneficial effects of dietary MetR on neuromuscular function in a separate disease cohort using the Alzheimer's disease 5XFAD mouse model. Based on these mouse studies, targeting methionine metabolism holds great promise as an antiaging intervention in humans.
Link: https://doi.org/10.1126/sciadv.ads1532
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