Cerebromicrovascular senescence in vascular cognitive impairment: does accelerated microvascular aging accompany atherosclerosis?

Abstract

Vascular cognitive impairment (VCI) is a leading cause of age-related cognitive decline, driven by cerebrovascular dysfunction and cerebral small vessel disease (CSVD). Emerging evidence suggests that cerebromicrovascular endothelial senescence plays an important role in the pathogenesis of VCI by promoting cerebral blood flow dysregulation, neurovascular uncoupling, blood-brain barrier (BBB) disruption, and the development of cerebral microhemorrhages (CMHs). This review explores the concept of cerebromicrovascular senescence as a continuum of vascular aging, linking macrovascular atherosclerosis with microvascular dysfunction. It examines the mechanisms by which endothelial senescence drives neurovascular pathology and highlights the impact of cardiovascular risk factors in accelerating these processes. We examine preclinical and clinical studies that provide compelling evidence that atherosclerosis-induced microvascular senescence exacerbates cognitive impairment. In particular, findings suggest that targeting senescent endothelial cells through senolytic therapy can restore cerebrovascular function and improve cognitive outcomes in experimental models of atherosclerosis. Given the growing recognition of microvascular senescence as a therapeutic target, further research is warranted to explore novel interventions such as senolytics, anti-inflammatory agents, and metabolic modulators. The development of circulating biomarkers of vascular senescence (e.g., senescence-associated secretory phenotype [SASP] components and endothelial-derived extracellular vesicles) could enable early detection and risk stratification in individuals at high risk for VCI. Additionally, lifestyle modifications, including the Mediterranean diet, hold promise for delaying endothelial senescence and mitigating cognitive decline. In conclusion, cerebromicrovascular senescence is a key mechanistic link between atherosclerosis and cognitive impairment. Addressing microvascular aging as a modifiable risk factor through targeted interventions offers a promising strategy for reducing the burden of VCI and preserving cognitive function in aging populations.