Vitamin D and frailty: Clinical evidence, mechanistic insights, and translational challenges

Vitamin D is increasingly recognized as a multisystem hormone whose actions converge on physiological domains central to frailty. Low circulating 25-hydroxyvitamin D [25(OH)D] concentrations are associated with sarcopenia, bone loss, immune and cognitive dysfunction, and excess mortality, while observational cohort studies link vitamin D deficiency to frailty onset and progression. Mechanistic evidence provides a biologically coherent framework for these associations. Vitamin D receptor (VDR) signaling regulates myogenic differentiation, neuromuscular junction integrity, osteoblast-osteoclast coupling, and osteocyte-mediated mechanotransduction. It also modulates innate and adaptive immune responses, restrains inflammasome activation, and preserves mitochondrial function and metabolic flexibility. Disruption of VDR signaling promotes muscle atrophy, skeletal fragility, immunosenescence, and impaired bioenergetic capacity, processes that mirror key biological features of frailty. Despite this strong mechanistic plausibility, randomized controlled trials have largely yielded neutral results in community-dwelling adults with adequate vitamin D status. Clinical benefits appear confined to individuals with deficiency or heightened vulnerability, whereas intermittent high-dose bolus regimens have been associated with increased risks of falls and fractures. These discordant findings reflect persistent methodological limitations, including heterogeneous frailty definitions, insufficient follow-up duration, inter-assay variability in 25(OH)D measurement, and uncertainty regarding thresholds relevant to non-skeletal outcomes. In this narrative review, we integrate clinical, epidemiological, and mechanistic evidence to position vitamin D as a biomarker and potential modulator of vulnerability within a broader geroscience framework.