Senescence: a double-edged sword in beta-cell health and failure?

Abstract

Cellular senescence is a complex process marked by permanent cell-cycle arrest in response to a variety of stressors, and acts as a safeguard against the proliferation of damaged cells. Senescence is not only a key process underlying aging and development of many diseases, but has also been shown to play a vital role in embryogenesis as well as tissue regeneration and repair. In context of the pancreatic beta-cells, that are essential for maintaining glucose homeostasis, replicative senescence is responsible for the age-related decline in regenerative capacity. Stress induced premature senescence is also a key early event underlying beta-cell failure in both type 1 and type 2 diabetes. Targeting senescence has therefore emerged as a promising therapeutic avenue for diabetes. However, the molecular mechanisms that mediate the induction of beta-cell senescence in response to various stressors remain unclear. Nor do we know if senescence plays any role during beta-cell growth and development. In this perspective, we discuss the significance of senescence in beta-cell homeostasis and pathology and highlight emerging directions in this area that warrant our attention.

Keywords: aging; beta cells; diabetes; differentiation; epigenetics; maturation; proliferation; senescence.

Figure 1

Characteristics of a senescent cell. Senescence, which is a state of irreversible cell cycle arrest, is induced by a variety of stress conditions, resulting in several cellular and morphological changes. Cell cycle arrest in senescence is achieved through the activation of the p16/pRb and/or the p21/p53 pathways, depending upon the type of stress. Apart from cell cycle arrest, the senescent phenotype is heterogenous and may display a combination of morphological features. Overall, a senescent cell (right) exhibits a flattened and hypertrophic morphology compared to a non-senescent cell (left). The structure and function of several organelles is also altered during senescence, such as dysfunctional mitochondria with increased production of Reactive Oxygen Species (ROS), and increased lysosomal number and size along with the induction of a lysosomal senescence associated β-galactosidase (SA-β-gal). In contrast to the intact LaminB1 and structured Lamin Associated-Domains (LADs) in the nucleus of a non-senescent cell, a senescent cell displays an enlarged nucleus with disrupted LaminB1, formation of senescence-associated heterochromatin foci (SAHF), increased DNA breaks, and an elevated DNA damage response (DDR). Senescence can also involve the formation of cytoplasmic chromatin fragments (CCFs) that translocate from the nucleus to the cytosol, and activate the cytosolic DNA sensor cGAS-STING-TBK pathway which further activates the pro-inflammatory senescence associated secretory phenotype (SASP). The SASP response involves direct or extracellular-vesicle (EV) mediated secretion of extracellular matrix modulators, growth factors, cytokines, chemokines, to modulate the tissue micro-environment through autocrine/paracrine signaling.

Figure 2

Senescence in pancreatic beta-cell health and disease: (A) Aging induces p16 accumulation and leads to replicative senescence, which limits beta-cell self-renewal. Age associated transcriptional changes may also alter basal insulin secretion without any accompanying changes in glucose stimulated insulin secretion (GSIS). With aging, reduced Platelet Derived Growth Factor signaling (PDGF sig.) and increased Transforming Growth Factor-beta signaling (TGFb sig.) leads to alleviation of Polycomb (PcG)- mediated repression of p16 locus and drives Trithorax (TrxG)-mediated activation of p16 locus. (B) The duration or intensity of exposure to cellular-stress stimuli dictates the beta-cell response; either facilitating adaptation or causing maladaptation. Exposure to transient stress initiates DDR and unfolded protein response (UPR) and facilitates cellular repair and adaptation. However, prolonged stress exposure aggravates both DDR and UPR and induces SASP, leading to premature senescence. This can cause beta-cell dysfunction and maladaptation, and pre-dispose to diabetes. (C) Both intrinsic and extrinsic stress stimuli can induce DNA damage in beta-cells through a myriad of triggers such as replicative stress, ROS, and ER-stress, and result in beta-cell dysfunction and/or death. (D) We propose that unresolved DNA damage in the developing postnatal pancreas may trigger a p21 response and SASP to mediate the macrophage-mediated clearance of damaged beta-cells during this phase, allowing only health and fit beta-cells to mature. Our data shown in (E) imply that indeed the early postnatal beta-cell expansion phase is vulnerable to DNA damage accumulation. Top panel shows representative images of wild-type mouse pancreatic sections at postnatal day 7 (p7) and I month (1m), immuno-stained for the DNA damage marker γH2AX (red) along with Insulin (green) and DAPI (blue), while the lower panel show a quantification of % γH2AX+ beta-cells in the two stages, pointing to high DNA damage vulnerability in early postnatal beta-cells. Error-bars show SEM. ****P<0.001, determined by using a two-tailed Student’s t-test . Scale bar: 50 mm.