Exercise-Induced Epigenetic Modifications: Implications for Healthy Aging

Abstract

Aging is a complex biological process driven by the dynamic interplay among genetic, environmental, and lifestyle factors. Advances in epigenetics have significantly deepened our understanding of the molecular mechanisms underlying aging, underscoring the critical roles of reversible modifications such as DNA methylation, histone modifications, and noncoding RNA regulation. Emerging evidence suggests that exercise is a potent modulator of these epigenetic processes, capable of reshaping the epigenetic landscape to restore cellular homeostasis, modulate gene expression, and enhance physiological resilience. This review systematically synthesizes current knowledge on how exercise modulates epigenetic mechanisms implicated in aging and delineates the distinct epigenetic adaptations induced by variations in exercise modality, intensity, and duration. By integrating these molecular insights, this review provides a comprehensive mechanistic framework linking exercise-induced epigenetic remodeling to healthy aging, and underscores exercise as a promising intervention to counteract aging-related functional decline and disease progression.

Keywords

exercise - aging - epigenetics - DNA methylation - histone modification - non-coding RNA

Publication History

Received: 17 March 2025

Accepted after revision: 15 September 2025

Accepted Manuscript online:
16 September 2025

Article published online:
09 October 2025

• References

• 1 López-Otín C, Blasco MA, Partridge L. et al. Hallmarks of aging: An expanding universe. Cell 2023; 186: 243-278
• 2 Hogg SJ, Beavis PA, Dawson MA. et al. Targeting the epigenetic regulation of antitumour immunity. Nat Rev Drug Discovery 2020; 19: 776-800
• 3 Duan R, Fu Q, Sun Y. et al. Epigenetic clock: A promising biomarker and practical tool in aging. Ageing Res Rev 2022; 81: 101743
• 4 la Torre A, Lo Vecchio F, Greco A. Epigenetic Mechanisms of Aging and Aging-Associated Diseases. Cells 2023; 12: 1163
• 5 Rajado AT, Silva N, Esteves F. et al. How can we modulate aging through nutrition and physical exercise? An epigenetic approach. Aging 2023; 15: 3191-3217
• 6 Galkin F, Kovalchuk O, Koldasbayeva D. et al. Stress, diet, exercise: Common environmental factors and their impact on epigenetic age. Ageing Res Rev 2023; 88: 101956
• 7 Hunter DJ, James LS, Hussey B. et al. Impacts of Eccentric Resistance Exercise on DNA Methylation of Candidate Genes for Inflammatory Cytokines in Skeletal Muscle and Leukocytes of Healthy Males. Genes 2023; 14: 478
• 8 Sexton CL, Godwin JS, McIntosh MC. et al. Skeletal Muscle DNA Methylation and mRNA Responses to a Bout of Higher versus Lower Load Resistance Exercise in Previously Trained Men. Cells 2023; 12: 263
• 9 Rönn T, Volkov P, Davegårdh C. et al. A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue. PLoS Genet 2013; 9: e1003572
• 10 Lochmann TL, Thomas RR, Bennett JP. et al. Epigenetic Modifications of the PGC-1α Promoter during Exercise Induced Expression in Mice. PLoS One 2015; 10: e0129647
• 11 Lim C, Shimizu J, Kawano F. et al. Adaptive responses of histone modifications to resistance exercise in human skeletal muscle. PLoS One 2020; 15: e0231321
• 12 Ionescu-Tucker A, Butler CW, Berchtold NC. et al. Exercise Reduces H3K9me3 and Regulates Brain Derived Neurotrophic Factor and GABRA2 in an Age Dependent Manner. Front Aging Neurosci 2021; 13: 798297
• 13 Denham J, Prestes PR. Muscle-Enriched MicroRNAs Isolated from Whole Blood Are Regulated by Exercise and Are Potential Biomarkers of Cardiorespiratory Fitness. Front Genet 2016; 7: 196
• 14 Davidsen PK, Gallagher IJ, Hartman JW. et al. High responders to resistance exercise training demonstrate differential regulation of skeletal muscle microRNA expression. J Appl Physiol (Bethesda, Md: 1985) 2011; 110: 309-317
• 15 Lu J, Liu L, Chen J. et al. LncRNA HOTAIR in exercise-induced neuro-protective function in Alzheimer's disease. Folia Neuropathol 2022; 60: 414-420
• 16 Lee SY, Beom J, Choi JH. et al. Effectiveness and clinical application of multidisciplinary combined exercise and nutrition intervention for sarcopenic older adults with metabolic syndrome: study protocol for a multicentre randomised controlled trial. BMJ Open 2023; 13: e070252
• 17 Chen C, Wang Z, Ding Y. et al. DNA Methylation: From Cancer Biology to Clinical Perspectives. Front Biosci (Landmark Ed) 2022; 27: 326
• 18 Miyake Y, Adachi JI, Suzuki T. et al. TERT promoter methylation is significantly associated with TERT upregulation and disease progression in pituitary adenomas. J Neuro-oncology 2019; 141: 131-138
• 19 Hannon E, Knox O, Sugden K. et al. Characterizing genetic and environmental influences on variable DNA methylation using monozygotic and dizygotic twins. PLoS Genet 2018; 14: e1007544
• 20 Zaib S, Rana N, Khan I. Histone Modifications and their Role in Epigenetics of Cancer. Curr Med Chem 2022; 29: 2399-2411
• 21 Yan H, Bu P. Non-coding RNA in cancer. Essays Biochem 2021; 65: 625-639
• 22 Mishra S, Raval M, Kachhawaha AS. et al. Aging: Epigenetic modifications. Prog Mol Biol Transl Sci 2023; 197: 171-209
• 23 Widmann M, Nieß AM, Munz B. Physical Exercise and Epigenetic Modifications in Skeletal Muscle. Sports Med (Auckland, NZ) 2019; 49: 509-523
• 24 Guarasci F, D'Aquila P, Montesanto A. et al. Individual DNA Methylation Profile is Correlated with Age and can be Targeted to Modulate Healthy Aging and Longevity. Curr Pharm Des 2019; 25: 4139-4149
• 25 Xiao FH, Kong QP, Perry B. et al. Progress on the role of DNA methylation in aging and longevity. Brief Funct Genomics 2016; 15: 454-459
• 26 Salas-Pérez F, Ramos-Lopez O, Mansego ML. et al. DNA methylation in genes of longevity-regulating pathways: association with obesity and metabolic complications. Aging 2019; 11: 1874-1899
• 27 Ren H, Collins V, Clarke SJ. et al. Epigenetic changes in response to tai chi practice: a pilot investigation of DNA methylation marks. Evid Based Complement Alternat Med 2012; 2012: 841810
• 28 Murach KA, Dimet-Wiley AL, Wen Y. et al. Late-life exercise mitigates skeletal muscle epigenetic aging. Aging Cell 2022; 21: e13527
• 29 Horvath S. DNA methylation age of human tissues and cell types. Genome Biol 2013; 14: R115
• 30 Simpson DJ, Chandra T. Epigenetic age prediction. Aging Cell 2021; 20: e13452
• 31 Halling JF, Pilegaard H. PGC-1α-mediated regulation of mitochondrial function and physiological implications. Appl Physiol Nutr Metab 2020; 45: 927-936
• 32 Rius-Pérez S, Torres-Cuevas I, Millán I. et al. PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism. Oxid Med Cell Longev 2020; 2020: 1452696
• 33 Róna-Vörös K, Weydt P. The role of PGC-1α in the pathogenesis of neurodegenerative disorders. Curr Drug Targets 2010; 11: 1262-1269
• 34 Kang C, Chung E, Diffee G. et al. Exercise training attenuates aging-associated mitochondrial dysfunction in rat skeletal muscle: role of PGC-1α. Exp Gerontology 2013; 48: 1343-1350
• 35 Gill JF, Santos G, Schnyder S. et al. PGC-1α affects aging-related changes in muscle and motor function by modulating specific exercise-mediated changes in old mice. Aging Cell 2018; 17: e12697
• 36 Barrès R, Yan J, Egan B. et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab 2012; 15: 405-411
• 37 Maejima H, Kanemura N, Kokubun T. et al. Exercise enhances cognitive function and neurotrophin expression in the hippocampus accompanied by changes in epigenetic programming in senescence-accelerated mice. Neurosci Lett 2018; 665: 67-73
• 38 Hong C, Wang Z, Zheng SL. et al. Metrnl regulates cognitive dysfunction and hippocampal BDNF levels in D-galactose-induced aging mice. Acta Pharmacologica Sin 2023; 44: 741-751
• 39 Erickson KI, Miller DL, Roecklein KA. The aging hippocampus: interactions between exercise, depression, and BDNF. Neuroscientist 2012; 18: 82-97
• 40 Liao S, Tan M, Li M. et al. Tai chi improves depressive symptoms among community-dwelling older persons by mediating BDNF methylation: A preliminary study. Geriatric Nurs (New York, NY) 2022; 44: 137-142
• 41 Voisey J, Lawford B, Bruenig D. et al. Differential BDNF methylation in combat exposed veterans and the association with exercise. Gene 2019; 698: 107-112
• 42 Hizume K, Araki S, Hata K. et al. Nano-scale analyses of the chromatin decompaction induced by histone acetylation. Arch Histol Cytol 2010; 73: 149-163
• 43 Peleg S, Feller C, Ladurner AG. et al. The Metabolic Impact on Histone Acetylation and Transcription in Ageing. Trends Biochem Sci 2016; 41: 700-711
• 44 McGee SL, Fairlie E, Garnham AP. et al. Exercise-induced histone modifications in human skeletal muscle. J Physiol 2009; 587: 5951-5958
• 45 Luo L, Martin SC, Parkington J. et al. HDAC4 Controls Muscle Homeostasis through Deacetylation of Myosin Heavy Chain, PGC-1α, and Hsc70. Cell Rep 2019; 29: 749-763.e712
• 46 Niu Y, Wang T, Liu S. et al. Exercise-induced GLUT4 transcription via inactivation of HDAC4/5 in mouse skeletal muscle in an AMPKα2-dependent manner. Biochim Biophys Acta Mol Basis Dis 2017; 1863: 2372-2381
• 47 Liu Y, Randall WR, Schneider MF. Activity-dependent and -independent nuclear fluxes of HDAC4 mediated by different kinases in adult skeletal muscle. J Cell Biol 2005; 168: 887-897
• 48 Huang S, Zheng X, Zhang X. et al. Exercise improves high-fat diet-induced metabolic disorder by promoting HDAC5 degradation through the ubiquitin-proteasome system in skeletal muscle. Appl Physiol Nutr Metab 2022; 47: 1062-1074
• 49 de Meireles LCF, Galvão F, Walker DM. et al. Exercise Modalities Improve Aversive Memory and Survival Rate in Aged Rats: Role of Hippocampal Epigenetic Modifications. Mol Neurobiol 2019; 56: 8408-8419
• 50 Fraga I, Weber C, Galiano WB. et al. Effects of a multimodal exercise protocol on functional outcomes, epigenetic modulation and brain-derived neurotrophic factor levels in institutionalized older adults: a quasi-experimental pilot study. Neural Regener Res 2021; 16: 2479-2485
• 51 Yoshihara T, Machida S, Tsuzuki T. et al. Age-related changes in histone modification in rat gastrocnemius muscle. Exp Gerontology 2019; 125: 110658
• 52 Gensous N, Bacalini MG, Franceschi C. et al. Age-Related DNA Methylation Changes: Potential Impact on Skeletal Muscle Aging in Humans. Front Physiol 2019; 10: 996
• 53 McCormick R, Goljanek-Whysall K. MicroRNA Dysregulation in Aging and Pathologies of the Skeletal Muscle. Int Rev Cell Mol Biol 2017; 334: 265-308
• 54 Xu T, Zhou Q, Che L. et al. Circulating miR-21, miR-378, and miR-940 increase in response to an acute exhaustive exercise in chronic heart failure patients. Oncotarget 2016; 7: 12414-12425
• 55 Scuruchi M, Avenoso A, Aliquò F. et al. miR-21 attenuated inflammation targeting MyD88 in human chondrocytes stimulated with Hyaluronan oligosaccharides. Arch Biochem Biophys 2024; 759: 110112
• 56 Sun Y, Cui D, Zhang Z. et al. Voluntary wheel exercise alters the levels of miR-494 and miR-696 in the skeletal muscle of C57BL/6 mice. Comp Biochem Physiol B Biochem Mol Biol 2016; 202: 16-22
• 57 Aoi W, Naito Y, Mizushima K. et al. The microRNA miR-696 regulates PGC-1{alpha} in mouse skeletal muscle in response to physical activity. Am J Physiol Endocrinol Metab 2010; 298: E799-E806
• 58 Sarlak Z, Eidi A, Ghorbanzadeh V. et al. miR-34a/SIRT1/HIF-1α axis is involved in cardiac angiogenesis of type 2 diabetic rats: The protective effect of sodium butyrate combined with treadmill exercise. BioFactors (Oxford, Engl) 2023; 49: 1085-1098
• 59 Dastah S, Tofighi A, Bonab SB. The effect of aerobic exercise on the expression of mir-126 and related target genes in the endothelial tissue of the cardiac muscle of diabetic rats. Microvasc Res 2021; 138: 104212
• 60 Da Silva ND, Fernandes T, Soci UP. et al. Swimming training in rats increases cardiac MicroRNA-126 expression and angiogenesis. Med Sci Sports Exerc 2012; 44: 1453-1462
• 61 Nair VD, Ge Y, Li S. et al. Sedentary and Trained Older Men Have Distinct Circulating Exosomal microRNA Profiles at Baseline and in Response to Acute Exercise. Front Physiol 2020; 11: 605
• 62 Geng T, Liu Y, Xu Y. et al. H19 lncRNA Promotes Skeletal Muscle Insulin Sensitivity in Part by Targeting AMPK. Diabetes 2018; 67: 2183-2198
• 63 Zhou XC, Wang DX, Zhang CY. et al. Exercise promotes osteogenic differentiation by activating the long non-coding RNA H19/microRNA-149 axis. World J Orthopedics 2024; 15: 363-378
• 64 Zhao W, Yin Y, Cao H. et al. Exercise Improves Endothelial Function via the lncRNA MALAT1/miR-320a Axis in Obese Children and Adolescents. Cardiol Res Pract 2021; 2021: 8840698
• 65 Neppl RL, Wu CL, Walsh K. lncRNA Chronos is an aging-induced inhibitor of muscle hypertrophy. J Cell Biol 2017; 216: 3497-3507
• 66 Wohlwend M, Laurila PP, Williams K. et al. The exercise-induced long noncoding RNA CYTOR promotes fast-twitch myogenesis in aging. Sci Transl Med 2021; 13: eabc7367
• 67 Hawley JA. Molecular responses to strength and endurance training: are they incompatible?. Appl Physiol Nutr Metab 2009; 34: 355-361
• 68 Bodine SC. mTOR signaling and the molecular adaptation to resistance exercise. Med Sci Sports Exerc 2006; 38: 1950-1957
• 69 Figueiredo VC, Wen Y, Alkner B. et al. Genetic and epigenetic regulation of skeletal muscle ribosome biogenesis with exercise. J Physiol 2021; 599: 3363-3384
• 70 Maasar MF, Turner DC, Gorski PP. et al. The Comparative Methylome and Transcriptome After Change of Direction Compared to Straight Line Running Exercise in Human Skeletal Muscle. Front Physiol 2021; 12: 619447
• 71 Ramos AE, Lo C, Estephan LE. et al. Specific circulating microRNAs display dose-dependent responses to variable intensity and duration of endurance exercise. Am J Physiol Heart Circ Physiol 2018; 315: H273-H283
• 72 Alibegovic AC, Sonne MP, Højbjerre L. et al. Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men. Am J Physiol Endocrinol Metab 2010; 299: E752-E763
• 73 Seaborne RA, Strauss J, Cocks M. et al. Methylome of human skeletal muscle after acute & chronic resistance exercise training, detraining & retraining. Sci Data 2018; 5: 180213
• 74 Pilotto AM, Turner DC, Mazzolari R. et al. Human skeletal muscle possesses an epigenetic memory of high-intensity interval training. Am J Physiol Cell Physiol 2025; 328: C258-C272