Melatonin for age-related vascular diseases: mechanistic rationale, translational barriers, and clinical prospects

Age-related vascular diseases (ARVDs) represent a growing global health burden characterized by progressive endothelial dysfunction, oxidative stress, chronic inflammation, mitochondrial injury, vascular senescence, and circadian dysregulation. Because endogenous melatonin production declines with age, melatonin has attracted interest as a candidate geroprotective adjunct for vascular aging. This narrative review critically synthesizes preclinical and clinical evidence regarding melatonin across major ARVD phenotypes, including pulmonary arterial hypertension, abdominal aortic aneurysm, vascular calcification, atherosclerosis, microvascular dysfunction, arterial stiffness, and cerebrovascular dysfunction. Experimental studies consistently indicate that melatonin can reduce oxidative stress, inflammatory signaling, apoptosis, mitochondrial dysfunction, vascular smooth muscle cell phenotypic switching, and endothelial impairment. However, human evidence remains limited and is largely based on surrogate vascular endpoints rather than hard clinical outcomes. Important translational barriers include allometric dose extrapolation from animal models, chronotherapeutic timing, formulation selection, interindividual circadian variability, polypharmacy in older adults, and absence of long-term efficacy and safety data. Overall, melatonin should be viewed as a promising but preliminary adjunctive strategy targeting shared mechanisms of vascular aging rather than as an established stand-alone therapy. Large, adequately powered, chronotherapy-informed clinical trials are required before melatonin can be recommended for routine geriatric cardiovascular care.