Aging at the neurovascular interface: An integrative framework linking cardiovascular and cerebrovascular diseases

Aging is a fundamental driver of cardiovascular and cerebrovascular comorbidities, yet the mechanisms linking aging to concurrent heart and brain diseases remain incompletely understood. The neurovascular interface (NVI) refers to the structural and functional interface through which neural, vascular, and extracellular-matrix signals interact. In the CNS, this concept substantially overlaps with the classical neurovascular unit, whereas in the heart it refers to an emerging heart tissue-specific interface involving coronary microvessels, vascular cells, autonomic and sensory nerve fibers, cardiomyocytes, and extracellular-matrix components. Although direct experimental evidence that aging affects cardiovascular and cerebrovascular comorbidity through NVI is still accumulating, current evidence suggests that aging may disrupt shared neurovascular features. These changes are associated with hypertension, cerebral small vessel disease, heart failure, and related disorders. Moreover, genetic variants may act as susceptibility modifiers of neurovascular aging - from NOS3 regulating vascular tone to ADRB1 and COMT affecting autonomic balance. These variants are associated with cardiovascular and cerebrovascular disease risk and may represent upstream molecular determinants through which genetic susceptibility and aging-related stressors converge to alter NVI integrity and promote cardiovascular-cerebrovascular comorbidity. This review synthesizes current evidence on the structural and functional basis of the NVI, discusses how aging may disrupt its integrity, and evaluates its potential role as an integrative framework linking aging-related vascular, neural, inflammatory, and extracellular-matrix alterations to cardiovascular-cerebrovascular comorbidity. We also outline potential integrated strategies that may preserve interface function, including lifestyle interventions, senolytics, and gene-guided precision medicine.