Late‐life exercise mitigates skeletal muscle epigenetic aging

Abstract

There are functional benefits to exercise in muscle, even when performed late in life, but the contributions of epigenetic factors to late‐life exercise adaptation are poorly defined. Using reduced representation bisulfite sequencing (RRBS), ribosomal DNA (rDNA) and mitochondrial‐specific examination of methylation, targeted high‐resolution methylation analysis, and DNAge™ epigenetic aging clock analysis with a translatable model of voluntary murine endurance/resistance exercise training (progressive weighted wheel running, PoWeR), we provide evidence that exercise may mitigate epigenetic aging in skeletal muscle. Late‐life PoWeR from 22–24 months of age modestly but significantly attenuates an age‐associated shift toward promoter hypermethylation. The epigenetic age of muscle from old mice that PoWeR‐trained for eight weeks was approximately eight weeks younger than 24‐month‐old sedentary counterparts, which represents ~8% of the expected murine lifespan. These data provide a molecular basis for exercise as a therapy to attenuate skeletal muscle aging.

Muscle-Specific Cellular and Molecular Adaptations to Late-Life Voluntary Concurrent Exercise

“…We previously reported more youthful hypomethylated promoter region methylation levels of the splicing factor Rbm10 86 in gastrocnemius of aged mice after late-life PoWeR, which we confirmed with high-coverage targeted analysis. 85 Extending this finding, a CpG in the promoter region of Rbm10 was hypomethylated by PoWeR in soleus myonuclei of aged mice. In young mice, Rbm10 mRNA levels were 27% higher in the soleus after PoWeR (FDR = 0.10) but were not elevated after PoWeR in aged soleus ( Supplemental Table 2 ).…”

“…Late-life PoWeR mitigates skeletal muscle epigenetic aging in gastrocnemius muscle tissue and is specifically characterized by hypomethylation of promoter region CpGs. 85 By subjecting HSA-GFP mice to PoWeR from 22 to 24 mo of age, we could further interrogate myonuclear epigenetic regulation of gene expression with aging and exercise. In myonuclei, widespread hypomethylation across the genome was observed with PoWeR including in promoters, indicative of epigenetic plasticity with training in aged soleus muscle.…”

An Evidence-Based Narrative Review of Mechanisms of Resistance Exercise–Induced Human Skeletal Muscle Hypertrophy

“…Studies applying new methods, using in vivo measurement of rRNA synthesis, might bring additional input to assess the role of translational capacity in skeletal muscle hypertrophy, and endocrine-related factors, such as AR content in skeletal muscle and female sex hormones, may yet help us understand the role of these variables in skeletal muscle physiology and hypertrophy. More work is still required, but with the rapid development of technology, the up-to-date techniques in skeletal muscle, such as single-cell isolation and single-cell RNA-seq (139,140), could be considered to accelerate to uncover the mechanisms underpinning RET-induced skeletal muscle hypertrophy in humans.…”

The Aging Athlete: Paradigm of Healthy Aging

“…While this review highlights the wide-ranging benefits of lifelong aerobic exercise training on hallmark traits of aging (i. e., decreased aerobic capacity, sarcopenia, myocellular alterations), there are numerous research opportunities in this expanding cohort of unique individuals. Several of the deleterious effects of aging begin ~30 y in healthy non-exercisers and it is unknown to what extent, if any, that lifelong exercise confers additional health benefits compared to those who begin habitual exercise training in their midlife or late-life years [165]. Mode specific effects of chronic exercise across aerobic, resistance, and concurrent training likely have specific adaptations that contribute uniquely to overall health [166,167].…”