Cellular Senescence in Blood Cells: A Link Between Metabolic Syndrome, Inflammaging and Cardiometabolic Disease

Abstract

Highlights What are the main findings? Metabolic stress promotes senescence across hematopoietic stem cells and circulating immune-cell populations through interconnected oxidative, mitochondrial, DNA-damage, nutrient-sensing, autophagic, epigenetic, and inflammatory pathways. Senescent blood cells amplify inflammaging and immune dysfunction, providing a mechanistic link between metabolic syndrome, clonal hematopoiesis, and cardiometabolic disease. What are the implications of the main findings? Composite blood-cell senescence signatures may complement conventional cardiometabolic risk assessment and treatment monitoring but require analytical standardization and prospective clinical validation. Senolytic, senomorphic, and inflammation-modulating strategies are promising, although longitudinal and interventional human studies are needed to establish causality, efficacy, and safety. Abstract Metabolic syndrome (MetS) is a complex metabolic disorder characterized by central obesity, insulin resistance, dyslipidemia, hypertension, and chronic low-grade inflammation, all of which contribute to an increased risk of type 2 diabetes mellitus, cardiovascular disease, and premature mortality. Emerging evidence suggests that cellular senescence plays a central role in the pathophysiology of MetS by linking metabolic stress to chronic inflammation, immune dysfunction, as well as cell and tissue damage. Although senescence has traditionally been studied in tissue-resident cells, growing attention has focused on the role of blood-cell senescence in the initiation and progression of metabolic disease. This review summarizes current knowledge regarding the molecular and cellular mechanisms driving senescence in hematopoietic stem cells and circulating blood-cells (BCs) and how these mechanisms affect specific blood-cell populations leading to altered immune function, impaired tissue homeostasis, and persistent inflammatory activation. The link between clonal hematopoiesis to immunosenescence and cardiometabolic disease is also highlighted, providing additional insight into the complex interactions between hematopoietic aging and metabolic dysfunction.