Integrated Multi-Omics Network by Physical Exercise Across Aging: Molecular Adaptation Beyond Single Signaling Pathways.

Aging is characterized by progressive molecular dysregulation across interconnected biological systems, involving alterations in epigenetic regulation, gene expression, protein homeostasis, and metabolic function. Although physical exercise is widely recognized as one of the most effective non-pharmacological interventions to promote healthy aging, the integrative molecular mechanisms underlying its systemic effects remain incompletely understood. This review proposes a multi-omic framework in which exercise acts as a coordinated biological stimulus capable of remodeling age-associated molecular dysfunction across genomic, epigenomic, transcriptomic, proteomic, and metabolomic layers. We discuss evidence showing that exercise modulates DNA methylation patterns associated with inflammation, oxidative stress, and tissue regeneration. Epigenetically, exercise is associated with attenuation of age-associated hypermethylation in promoter regions and modulation of genes involved in oxidative stress defense and tissue regeneration. Transcriptomic studies further show that exercise is associated with more youthful expression patterns while attenuating inflammatory and senescence-related gene programs. Proteomic studies reveal that training is associated with mitochondrial metabolism, extracellular matrix remodeling, and muscle contractile protein abundance, reducing proteostatic dysfunction. Metabolomic analyses demonstrate that exercise improves metabolic flexibility and remodels cellular energy networks. Importantly, the unique contribution of this review lies in synthesizing emerging evidence that these adaptations are highly cell- and tissue-specific, involving immune cells, skeletal muscle satellite cells, endothelial cells, microglia, and intestinal stem cells. Rather than acting through isolated pathways, exercise may induce convergent adaptations across interconnected molecular systems, supporting the concept that healthy aging is dynamically regulated and that age-associated molecular dysfunction retains a degree of biological plasticity.