Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity

Abstract

Cellular senescence is a fundamental aging mechanism that has been implicated in many age-related diseases and is a significant cause of tissue dysfunction. Accumulation of senescent cells occurs during aging and is also seen in the context of obesity and diabetes. Senescent cells may play a role in type 2 diabetes pathogenesis through direct impact on pancreatic β-cell function, senescence-associated secretory phenotype (SASP)-mediated tissue damage, and involvement in adipose tissue dysfunction. In turn, metabolic and signaling changes seen in diabetes, such as high circulating glucose, altered lipid metabolism, and growth hormone axis perturbations, can promote senescent cell formation. Thus, senescent cells might be part of a pathogenic loop in diabetes, as both a cause and consequence of metabolic changes and tissue damage. Therapeutic targeting of a basic aging mechanism such as cellular senescence may have a large impact on disease pathogenesis and could be more effective in preventing the progression of diabetes complications than currently available therapies that have limited impact on already existing tissue damage. Therefore, senescent cells and the SASP represent significant opportunities for advancement in the prevention and treatment of type 2 diabetes and its complications.

Figure 1

Senescent cells may play a role in driving insulin resistance and diabetes complications. Senescent cells accumulate in tissues throughout the body with aging and obesity and in disease states. The SASP is a diverse group of proinflammatory cytokines, chemokines, and growth factors released by senescent cells, which may act both locally and systemically. The SASP may affect the function of neighboring cells within a tissue through paracrine mechanisms, contributing to tissue dysfunction and damage that can lead to diabetes complications. In addition, SASP factors may circulate and add to a chronic inflammatory state commonly implicated as a contributor in the development of insulin resistance.

Figure 2

Senolytic or SASP-inhibiting therapies present new opportunities for targeting type 2 diabetes and its complications. Senescent cells that accumulate during aging and obesity may contribute to inflammation, insulin resistance, metabolic dysfunction, and progenitor cell dysfunction through the SASP and direct effects of senescent cells in tissues. These effects might promote insulin resistance and type 2 diabetes as well as contribute to tissue damage and diabetes complications. Metabolic and immune perturbations in the diabetic state may, in turn, promote the formation of more senescent cells. Current glucose-lowering therapies (gray box) are able to exert a limited effect on this pathogenic loop established by senescent cells. As shown in the dotted box, by targeting senescent cells and their associated SASP, we speculate that the tissue dysfunction that leads to diabetes complications may be slowed or alleviated, and the pathogenic loop between cellular senescence, diabetes, and tissue dysfunction may be broken. GH, growth hormone.