Cellular Senescence Drives Diabetic Atherosclerosis: Aging Mechanisms and Integrative Therapeutic Implications.

Abstract

Cellular senescence is increasingly recognized as a key mechanism linking aging to chronic disease. Diabetic atherosclerosis (DAS), a major macrovascular complication of type 2 diabetes, often progresses despite standard metabolic and lipid-lowering therapies, highlighting the involvement of aging-related processes beyond classical metabolic and inflammatory pathways. This review synthesizes evidence to propose a conceptual framework in which stress-induced senescence is a key disease-oriented aging mechanism contributing to DAS initiation and progression. Hyperglycemia and lipotoxicity induce premature senescence in endothelial cells, vascular smooth muscle cells, and macrophages through oxidative stress, mitochondrial dysfunction, and activation of the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome. Senescent cells secrete a senescence-associated secretory phenotype (SASP), which amplifies chronic vascular inflammation, promotes plaque instability, and facilitates systemic propagation of senescence, thereby contributing to multi-organ dysfunction in the heart, brain, and kidneys. Together, these features position DAS as a representative model of stress-accelerated vascular aging. From a therapeutic perspective, we discuss emerging senescence-targeted strategies, including senolytics, senomorphics, and multi-target interventions derived from integrative medicine, with emphasis on their potential to modulate the aging tissue microenvironment and delay disease progression. By framing diabetic atherosclerosis within the context of aging biology, this review provides a disease-focused perspective on mechanisms and therapeutic opportunities underlying age-associated vascular disorders.