Epigenetic Mechanisms of Vitamin D in the Aging Process: A Narrative Review.

Aging is driven by progressive epigenetic alterations-DNA methylation drift, aberrant histone modifications, chromatin remodeling, and non-coding RNA dysregulation. Vitamin D, acting through its nuclear receptor vitamin D receptor (VDR), modulates the epigenetic landscape to potentially counteract these age-related changes. This review first describes age-related epigenetic alterations, then outlines vitamin D signaling and its interface with the epigenetic machinery. Next, tissue-specific epigenetic actions of vitamin D in the immune, musculoskeletal, and nervous systems are discussed. Finally, clinical trial evidence is examined, interindividual variability is highlighted, and future research directions are proposed. However, large randomized controlled trials (RCTs) consistently show limited benefits of vitamin D monotherapy, with measurable anti-aging effects observed when combined with exercise and nutritional interventions. Its efficacy is constrained by interindividual variability, J-shaped dose-response, and tissue-specific barriers. For deficient individuals (serum 25-hydroxyvitamin D (25(OH)D) < 50 nmol/L), guided supplementation-typically 800-2000 international units (IU)/day-is warranted to achieve tentative target serum concentrations of 75-125 nmol/L, the range linked to favorable epigenetic and immune effects. For those already sufficient (e.g., serum 25(OH)D ≥ 50 nmol/L), indiscriminate supplementation without biochemical indication is not supported. Therefore, promoting healthy aging through vitamin D requires serum-monitored, individually titrated, and multimodal regimens, with supplementation reserved primarily for documented deficiency and integrated with lifestyle interventions.