The epigenetic control of inflammaging in skeletal muscle and adipose tissue

Metabolic inflexibility, mitochondrial dysfunction, and persistent low-grade inflammation are recognized as fundamental hallmarks of biological ageing and key drivers of the inflammaging process. Ageing is associated with a progressive decline in cellular function and systemic homeostasis, particularly affecting skeletal muscle and white adipose tissue, which are central to energy metabolism and inflammatory regulation. In skeletal muscle, ageing leads to reduced oxidative capacity, impaired mitochondrial turnover, and anabolic resistance. In adipose tissue, adipocytes exhibit hypertrophy, hypoxia, and increased immune cell infiltration. Together, these changes promote persistent activation of inflammatory pathways and contribute to systemic insulin resistance. Epigenetic regulation plays a key role in linking metabolic stress to gene expression, modulating mechanisms such as DNA methylation, histone acetylation, and hydroxymethylation, thereby influencing chromatin accessibility in genes involved in ageing. Importantly, lifestyle interventions, including caloric restriction and physical exercise, can partially reverse these effects by reprogramming the epigenome. Both aerobic and resistance exercise promote epigenetic modifications associated with improved mitochondrial function, enhanced myogenesis, better adipocyte health, and reduced inflammatory gene expression. Thus, inflammaging is a dynamic and modifiable process, in which epigenetic plasticity connects metabolic dysfunction to chronic inflammation while also enabling interventions that preserve metabolic health during ageing. • Progressive mitochondrial dysfunction and metabolic inflexibility in skeletal muscle and white adipose tissue sustain chronic low-grade inflammation characteristic of ageing. • The accumulation of lipids, cytokine signaling, and impaired mitochondrial quality control reinforces a systemic pro-inflammatory phenotype during ageing. • Caloric restriction and exercise training activate AMPK–SIRT1–PGC-1α pathways, suppressing inflammation through epigenetic reprogramming during ageing.