Aging, Cellular Senescence, and Type 2 Diabetes: Unraveling the Links for Novel Therapeutic Approaches

Abstract

Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), is an escalating global health crisis, with projections indicating a rise from 537 million to 783 million affected individuals by 2045. Central to the progression of T2DM is the intricate interplay between insulin resistance, aging, and cellular senescence, especially in peripheral adipose tissues and pancreatic β-cells. This review highlights pathophysiological mechanisms underlying T2DM, emphasizing how aging exacerbates insulin resistance and impairs insulin secretion. We present evidence linking cellular senescence with increased adiposity and dysfunction in β-cells, illustrating how age-related changes foster a chronic inflammatory milieu that worsens metabolic dysregulation. Cellular senescence, characterized by the accumulation of dysfunctional cells producing the senescence-associated secretory phenotype (SASP), contributes significantly to the development and complications of diabetes. Notably, emerging therapies targeting senescent cells, such as senolytics and senomorphics, offer innovative strategies to mitigate diabetes-related decline. These therapeutic approaches aim to enhance insulin sensitivity and improve β-cell function, potentially reshaping diabetes management. This review underscores the importance of a nuanced understanding of cellular senescence in devising targeted senotherapies, advocating for a dual organ-oriented strategy to optimize treatment outcomes for diabetes and associated comorbidities