Clonal hematopoiesis, inflammaging, and vascular disease: mechanisms, risk stratification, and therapeutic frontiers in older adults.

Aging is associated with both a chronic pro-inflammatory state ("inflammaging") and the accumulation of somatic mutations in hematopoietic stem cells leading to clonal hematopoiesis. Clonal hematopoiesis of indeterminate potential (CHIP) is now recognized as a common phenomenon in older adults, defined by the expansion of blood cell clones bearing leukemia-associated mutations in the absence of overt malignancy. Mounting evidence links CHIP to an increased risk of cardiovascular disease (CVD) in older adults, particularly atherosclerotic disease, through inflammatory mechanisms that intersect with inflammaging. In this review, we outline the biology of clonal hematopoiesis in aging and its relationship with age-related inflammation, discuss mechanistic insights into how mutated hematopoietic clones accelerate vascular pathology, and explore emerging approaches for risk stratification and therapy. Key mutations (e.g., in DNMT3A, TET2, ASXL1, JAK2) drive clonal expansions that not only predispose to hematologic malignancies but also contribute to a pro-inflammatory milieu that promotes atherosclerosis, heart failure, and other vascular complications. We examine how the concept of inflammaging provides a framework for understanding the bidirectional interplay between aging immune clones and cardiovascular risk. Finally, we review therapeutic frontiers, from aggressive management of conventional risk factors to novel anti-inflammatory strategies and potential clone-targeted interventions. Greater understanding of clonal hematopoiesis in older patients could transform risk assessment and usher in personalized strategies to mitigate cardiovascular disease in our aging population. For the purposes of this review, we use "older adults" to refer to individuals aged ≥ 65 years (unless otherwise specified).