Clonal hematopoiesis of indeterminate potential (CHIP) in cerebromicrovascular aging: implications for vascular contributions to cognitive impairment and dementia (VCID)

Abstract

Vascular contributions to cognitive impairment and dementia (VCID) represent a major public health challenge in the aging population, with age-related cerebromicrovascular dysfunction playing a critical role in its development. Understanding the mechanisms underlying cerebromicrovascular aging is crucial for devising strategies to mitigate this burden. Among the key hallmarks of aging, genomic instability and genetic heterogeneity have emerged as significant drivers of age-related diseases. Clonal hematopoiesis of indeterminate potential (CHIP) is a prominent manifestation of this instability, characterized by the non-malignant expansion of hematopoietic stem cell clones that harbor somatic mutations. CHIP is well-established as a contributor to atherosclerosis and cardiovascular disease through its promotion of chronic inflammation. Given that aging is also a major risk factor for cerebral small vessel disease (CSVD) and VCID, it is likely that the same aging processes driving large artery atherosclerosis in CHIP carriers also impair small vessels, including the cerebral microvasculature. While the role of CHIP in large vessel disease is well-documented, its specific contributions to cerebrovascular aging and microvascular dysfunction remain poorly understood. This review explores the potential role of CHIP in age-related cerebrovascular pathologies, with a particular focus on its contribution to CSVD. We discuss how CHIP-related mutations can promote inflammation and oxidative stress, potentially leading to endothelial dysfunction, dysregulation of cerebral blood flow (CBF), blood-brain barrier (BBB) disruption, microvascular inflammation, and cerebral microhemorrhages. Given the potential implications for VCID, elucidating these mechanisms is critical for developing targeted therapies aimed at reducing the burden of cognitive decline in aging populations. This review aims to highlight the current knowledge gaps and encourage further research into the intersection of CHIP, CSVD, and cognitive aging.

Keywords: Aging; Atherosclerosis; Blood–brain barrier; Cerebral blood flow; Cerebral hypoperfusion; Cerebral microhemorrhages; Cerebral small vessel disease; Cerebrovascular aging; Cognitive decline; Cognitive dysfunction; Endothelial dysfunction; Hematopoietic stem cells; Inflammaging; Inflammation; Microbleed; Microvascular dysfunction; Neurodegeneration; Neuroinflammation; Neurovascular coupling; Neurovascular unit; Oxidative stress; Stroke; VCI; Vascular aging; Vascular cognitive impairment and dementia; White matter hyperintensities.