Aging and stress induced β cell senescence and its implication in diabetes development

Abstract

Cellular senescence is a well-established defensive mechanism for tumor suppression, and is also proposed to play a crucial role in embryonic development, wound repair, aging and age-related diseases. Senescent cell is characterized by the marked morphological changes and active metabolism along with a distinctive senescence associated secretion phenotype (SASP). Cellular senescence is triggered by multiple endogenous and exogenous stressors, which collectively induce three types of senescence. It is believed that senescence represents a programmed phenomenon to facilitate β cell functional maturation and, therefore, senescence has been suggested to be involved in β cell regeneration, insulin secretion and diabetes development. Nevertheless, despite past extensive studies, the exact impact of senescence on β cell viability, regeneration and functionality, and its relevance to the development of diabetes are yet to be fully addressed. In this review, we will summarize the recent progress in β cell senescence, through which we intend to spark more instructive discussion and perspective with regard to the mechanisms underlying β cell senescence and their links to the pathogenesis of diabetes and the development of therapeutic strategies.

Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?)

“…β-Cells are more sensitive than α-cells to environmental stimuli, as illustrated by studies conducted on islets challenged by metabolic stress mimicking pathophysiological conditions in type 2 diabetes (T2DM) 107 , 108 . In addition to the cytoprotective function, activation of the ER stress sensors is known to lead to a cascade of events promoting direct apoptosis via activation of the IRF–STAT1 pathway 98 , 109 , necroptosis via activation of TNFR1–RIP1 and necrosis by increased production of reactive oxygen species as well as induction of a form of β-cell senescence 108 , 110 , 111 (Fig. 2 ).…”

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

“…Senescent cells are highly metabolically active, but are arrested in the G0 phase of the cell cycle. Mostly, senescent cells acquire characteristic morphological changes like an increase in size, a tremendous re-arrangement of chromatin leading to senescence-associated heterochromatic foci (SAHF), and a distinct gene expression profile [42]. Furthermore, senescent cells can mediate paracrine effects to neighboring cells through secretion of cytokines, chemokines, growth factors, and proteases known as the senescence-associated secretory phenotype (SASP) [43][44][45][46].…”

Endoplasmic Reticulum-Mitochondria Crosstalk and Beta-Cell Destruction in Type 1 Diabetes

“…The SASP components are of diverse nature, including cytokines and chemokines but also a large range of soluble and insoluble factors, and can contribute to immune activation, by promoting infiltration of immune cells. Although further studies are definitely required, it has been recently reported that islets from T1D mice as well as betacells from T1D donors display increased markers of senescence during disease progression (95), suggesting that beta-cell senescence may be an adaptive response to prolonged cellular stress that can contribute to autoimmunity through SASPs (96). Interestingly, studies aiming at eliminating senescent beta-cells by using specific senolytic drugs show remarkable results in limiting T1D progression in mice models (95,97).…”