The Molecular Mechanism of Exercise in Slowing Muscle Aging: From Pathway Regulation to Epigenetic Remodeling

As the largest metabolic organ in the human body, skeletal muscle not only supports movement and respiratory functions but also maintains whole-body energy homeostasis. Its aging process directly determines the quality of healthy aging. With increasing age, sarcopenia—characterized by reduced muscle mass, diminished strength, and impaired regenerative capacity—has become a primary cause of disability among the elderly. Exercise has long been recognized as the most effective non-pharmacological intervention for delaying muscle aging, yet the underlying molecular mechanisms have remained a key focus of scientific inquiry.

In recent years, studies published in top-tier journals such as Proceedings of the National Academy of Sciences and Advanced Science have gradually unraveled the molecular mechanisms by which exercise slows muscle aging, spanning signaling pathway regulation, epigenetic modifications, stem cell metabolic reprogramming, and more. These findings not only clarify the scientific basis of exercise’s anti-aging effects but also provide theoretical support for developing precise interventions for sarcopenia.

1. Core Pathway Regulation: The “Balance Reset” of the FOXO-DEAF1-mTORC1 Axis

A key molecular feature of muscle aging is the imbalance in protein metabolism. Dysfunction of the mechanistic target of rapamycin complex 1 (mTORC1)—a central pathway regulating protein synthesis and clearance—is a major contributor to sarcopenia. Research from the Duke-NUS Medical School team has identified the regulatory network formed by the transcription factor DEAF1 and the FOXO protein family as a critical target through which exercise restores this imbalance.

In aging muscle, the mTORC1 pathway exhibits an abnormal state of “overactivation but functional imbalance”—it increasingly drives new protein synthesis while significantly suppressing the degradation of damaged proteins, leading to the accumulation of toxic proteins and structural degeneration in muscle cells. Further studies reveal that elevated expression of the DEAF1 gene in aging muscle directly promotes mTOR gene transcription, pushing mTORC1 into an “overloaded” state and exacerbating proteostasis imbalance. Under normal physiological conditions, DEAF1 is suppressed by the FOXO protein family. However, FOXO activity declines with age, releasing the brake on DEAF1 and creating a vicious cycle of “DEAF1 upregulation → mTORC1 overload → muscle aging.”

Exercise breaks this cycle by activating the FOXO protein family. Regular exercise significantly enhances FOXO activity, thereby suppressing abnormal DEAF1 expression and restoring mTORC1 balance—maintaining necessary protein synthesis for muscle fiber repair while reactivating mechanisms to clear damaged proteins. This process reshapes muscle protein metabolism homeostasis. Researchers liken it to exercise sending a “system reset” signal to the muscle. However, if DEAF1 remains chronically elevated or FOXO activity is severely compromised, exercise alone may not fully reverse muscle repair capacity. This explains why exercise interventions may show limited effectiveness in some very elderly individuals.

Additionally, exercise activates the AMPK (AMP-activated protein kinase) pathway, forming a synergistic regulatory network with mTORC1. As an “energy sensor,” AMPK is activated during exercise-induced energy expenditure. It promotes mitochondrial biogenesis and fatty acid oxidation to enhance metabolic efficiency while temporally regulating mTORC1 activity to prevent insulin resistance caused by its overactivation, further stabilizing muscle metabolic homeostasis.

2. Epigenetic Remodeling: The “Age-Reversing” Role of Histone Lactylation

Beyond classical signaling pathways, exercise can regulate gene expression through epigenetic modifications to reverse muscle aging. Collaborative research by Tao Wei’s group at Peking University’s School of Life Sciences and Xie Wenbing’s group at the University of Science and Technology of China has revealed the central role of histone lactylation modification in exercise-induced anti-muscle aging, establishing a novel “metabolism-epigenetics” interaction model.

Histone lactylation is an epigenetic mechanism integrating metabolic signals with gene regulation, and its levels are closely related to cellular glycolytic activity. Studies show that histone lactylation levels are significantly reduced in aging cells and the skeletal muscle of elderly mice, accompanied by decreased lactyl-CoA levels. This directly suppresses the expression of genes involved in cell cycle regulation and DNA repair, accelerating muscle aging. Exercise, by enhancing skeletal muscle glycolytic activity, increases lactyl-CoA production, thereby restoring histone lactylation levels, reactivating DNA repair and protein homeostasis pathways, and reversing muscle aging phenotypes.

Experiments confirm that inhibiting key regulators of histone lactylation (such as the p300 acetyltransferase or HDAC1 deacetylase) significantly accelerates muscle aging. Conversely, exercise intervention can reshape this modification network, improving the regenerative capacity and function of aged skeletal muscle. This discovery elucidates for the first time the molecular pathway through which exercise delays muscle aging via metabolic reprogramming and epigenetic regulation, offering new insights for developing epigenetic-targeted anti-aging strategies.

3. Stem Cell Homeostasis Maintenance: Metabolic Reprogramming and Self-Renewal of Satellite Cells

Skeletal muscle satellite cells, serving as the “stem cell reservoir” of muscle tissue, experience declines in self-renewal capacity and differentiation potential, which form the core cellular basis for reduced muscle regeneration. Exercise can regulate the metabolic patterns of satellite cells to maintain their stemness, providing a “cellular-level” protective mechanism against muscle aging.

Research from the Karolinska Institute in Sweden found that endurance exercise induces metabolic reprogramming in satellite cells, significantly reducing mitochondrial oxygen consumption in the resting state and enhancing glycolysis-dependent energy metabolism. This, in turn, improves the self-renewal capacity and expression of stemness markers in satellite cells. During muscle injury repair, satellite cells from exercise-conditioned individuals form more myogenic colonies while reducing inflammatory responses and fibrosis, significantly enhancing muscle regeneration efficiency. Further experiments show that artificially inhibiting mitochondrial respiration can mimic the regulatory effects of exercise on satellite cells, indicating that metabolic remodeling is a key mechanism through which exercise maintains satellite cell homeostasis.

Moreover, exercise can optimize the activity cycle of satellite cells by regulating circadian rhythm pathways. Core circadian regulators such as CLOCK and BMAL1 are involved in regulating satellite cell proliferation and differentiation. Circadian rhythm disruption during aging exacerbates satellite cell dysfunction. Exercise can reset the circadian rhythms of skeletal muscle, synchronizing satellite cell activation, proliferation, and repair processes with the body’s physiological cycles, further enhancing muscle regeneration capacity and delaying the onset of sarcopenia.

4. Inflammatory Microenvironment Regulation: Transforming “Pro-Aging Inflammation” into “Repair-Promoting Inflammation”

Chronic low-grade inflammation (“inflammaging”) is a hallmark of aging. During muscle aging, elevated levels of pro-inflammatory factors such as IL-6 and TNF-α inhibit muscle protein synthesis, accelerate muscle fiber apoptosis, and hinder satellite cell activation. Exercise can remodel the muscle inflammatory microenvironment through multiple mechanisms, achieving an “anti-inflammatory, pro-repair” effect.

On one hand, exercise activates the NRF2 antioxidant pathway, suppressing the transcription and release of pro-inflammatory factors and reducing oxidative stress damage to muscle tissue. On the other hand, exercise-induced secretion of “myokines” (such as irisin and BDNF) can regulate immune cell infiltration, promote the recruitment of anti-inflammatory macrophages, and accelerate muscle injury repair. Research from a Chinese Academy of Sciences team also found that long-term exercise increases the activity of renal choline dehydrogenase (CHDH), promoting betaine production. Betaine can inhibit TBK1 kinase activity, blocking the NF-κB inflammatory pathway and reducing inflammatory factor levels in aged tissues by over 50%, significantly improving the muscle inflammatory microenvironment.

The gut microbiota, as an important “remote target” in inflammation regulation, also plays a role in exercise’s modulation of muscle aging. Patients with sarcopenia often exhibit reduced beneficial bacteria (such as Bifidobacterium and Faecalibacterium) and increased harmful bacteria, leading to insufficient production of anti-inflammatory metabolites like short-chain fatty acids (SCFAs). Exercise can reshape gut microbiota composition, increase SCFA production, and regulate muscle inflammation responses and mitochondrial function via the “gut-muscle axis,” forming a multi-organ synergistic network for exercise-induced anti-aging.

5. Scientific Exercise Recommendations: Targeted Interventions Based on Molecular Mechanisms

Based on the molecular mechanisms outlined above, targeted exercise interventions can maximize the delay of muscle aging. Individuals of different age groups may consider the following recommendations:

1. Exercise Type: Combined Training Outperforms Single-Modality Training
   Resistance training (e.g., weightlifting, resistance band exercises) directly activates the positive regulatory functions of the mTORC1 pathway, promoting muscle protein synthesis and maintaining muscle mass. Endurance training (e.g., brisk walking, swimming) more readily activates the AMPK pathway and histone lactylation, enhancing muscle metabolic efficiency and satellite cell stemness. Engaging in combined training 2–3 times per week (e.g., resistance + aerobic exercise) enables synergistic regulation across multiple molecular pathways, yielding superior results compared to single-modality training.

2. Exercise Intensity and Timing: Tailored to Age and Circadian Rhythms
   Young and middle-aged individuals may adopt moderate- to high-intensity training (60%–80% of maximum heart rate), which more effectively induces balance resetting of the FOXO-DEAF1-mTORC1 axis. Older adults are advised to focus on low- to moderate-intensity exercise to avoid oxidative stress damage from overexertion. Aligning exercise with circadian rhythms—such as between 9–11 AM or 4–6 PM—can help reset muscle circadian rhythms and enhance intervention outcomes.

3. Adjunct Support: Synergistic Effects of Nutrition and Exercise
   Post-exercise supplementation with branched-chain amino acids (BCAAs) can enhance mTORC1 pathway-mediated muscle protein synthesis. Consuming foods rich in betaine (e.g., beets, spinach) may help suppress muscle inflammation. Ensuring adequate protein intake (1.2–1.6 g/kg body weight daily) provides raw materials for muscle repair, creating synergistic anti-aging effects with exercise.

Conclusion: The Molecular Code of Exercise Against Aging Paves a New Path for Healthy Aging

From the balanced regulation of the FOXO-DEAF1-mTORC1 axis and the epigenetic remodeling via histone lactylation to the metabolic reprogramming of satellite cells, recent research is gradually mapping the complete molecular network through which exercise delays muscle aging. These findings confirm that exercise is not merely about “strengthening muscles” but involves multidimensional, multi-target molecular regulation that reverses age-related metabolic imbalances, epigenetic abnormalities, and cellular functional decline, infusing muscle tissue with “anti-aging vitality.”

In the future, deeper insights into the molecular mechanisms of exercise may lead to the development of interventional drugs targeting key pathways such as the FOXO-DEAF1-mTORC1 axis and histone lactylation, offering alternatives for elderly individuals unable to adhere to regular exercise. For now, however, regular exercise remains the safest and most effective means to delay muscle aging and prevent sarcopenia. Through scientifically guided exercise interventions, everyone can maintain muscle function throughout the aging process, achieving a higher quality of healthy aging.

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