Role of Cellular Senescence in Type II Diabetes

Narasimhan, Akilavalli; Flores, Rafael R.; Robbins, Paul D.; Niedernhofer, Laura J.

doi:10.1210/endocr/bqab136

Cited by 57 publications

(39 citation statements)

References 148 publications

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“…Mice with short telomeres display impaired insulin secretion and glucose intolerance associated with an accumulation of senescence markers, which suggests a causal role for telomere shortening in this pathology. Senescent cell clearance improved glucose homeostasis and insulin sensitivity in obese and aged mice 103 .…”

Section: Idiopathic Pulmonary Fibrosis Idiopathic Pulmonary Fibrosis ...mentioning

confidence: 99%

Telomere dysfunction in ageing and age-related diseases

et al. 2022

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Section: Idiopathic Pulmonary Fibrosis Idiopathic Pulmonary Fibrosis ...mentioning

confidence: 99%

Telomere dysfunction in ageing and age-related diseases

et al. 2022

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“…Cellular senescence is referred to a state of irreversibly arrested cell cycle which can be induced by DNA damage, mitochondrial dysfunction, oncogenic activation, telomere erosion, chronic inflammation, and oxidative stress. 7 The key features of senescent cells include decreased cell proliferation, increased activity of senescence-associated β-galactosidase (SA-β-gal), and high expression of cyclin-dependent kinase inhibitor genes, such as p53, p21, and p16. Another remarkable feature of senescent cells is the transition into the senescence-associated secretory phenotype (SASP) that produces a complex secretome, including IL-1β, IL-6, and transforming growth factor-β1 (TGF-β1).…”

Section: Introductionmentioning

confidence: 99%

Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis

et al. 2022

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Immunoglobulin G4-related sialadenitis (IgG4-RS) is an immune-mediated fibro-inflammatory disease and the pathogenesis is still not fully understood. The aim of this study was to explore the role and mechanism of interleukin-13 (IL-13) in the cellular senescence during the progress of IgG4-RS. We found that the expression of IL-13 and IL-13 receptor α1 (IL-13Rα1) as well as the number of senescent cells were significantly higher in the submandibular glands (SMGs) of IgG4-RS patients. IL-13 directly induced senescence as shown by the elevated activity of senescence-associated β-galactosidase (SA-β-gal), the decreased cell proliferation, and the upregulation of senescence markers (p53 and p16) and senescence-associated secretory phenotype (SASP) factors (IL-1β and IL-6) in SMG-C6 cells. Mechanistically, IL-13 increased the level of phosphorylated signal transducer and activator of transcription 6 (p-STAT6) and mitochondrial-reactive oxygen species (mtROS), while decreased the mitochondrial membrane potential, ATP level, and the expression and activity of superoxide dismutase 2 (SOD2). Notably, the IL-13-induced cellular senescence and mitochondrial dysfunction could be inhibited by pretreatment with either STAT6 inhibitor AS1517499 or mitochondria-targeted ROS scavenger MitoTEMPO. Moreover, IL-13 increased the interaction between p-STAT6 and cAMP-response element binding protein (CREB)-binding protein (CBP) and decreased the transcriptional activity of CREB on SOD2. Taken together, our findings revealed a critical role of IL-13 in the induction of salivary gland epithelial cell senescence through the elevated mitochondrial oxidative stress in a STAT6–CREB–SOD2-dependent pathway in IgG4-RS.

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“…Importantly, not only aging itself but also metabolic stress, insulin resistance in particular induces and accelerates senescence of β cells ( 6 , 7 ). In C57BL6/J male mice, eight weeks of feeding a HFD increased the percentage of SA-β-Gal + cells in islets as well as expression of aging and SASP-related genes in islets ( 39 ).…”

Section: β Cell Senescence Under Metabolic Stressmentioning

confidence: 99%

“…Subsequently, declines in pancreatic β-cell function develops diabetes mellitus in susceptible subjects ( 4 ). Amounts and functions of adipose tissue are affected by aging as well as by calorie intake, physical activity, and other aspects of health status ( 5 , 6 ). Thus, it is well known that aging is associated with increased insulin resistance, suggesting an important potential contribution of cellular senescence in adipose tissue that affects the onset and progression of the disease ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Cellular Senescence in Diabetes Mellitus: Distinct Senotherapeutic Strategies for Adipose Tissue and Pancreatic β Cells

2022

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Increased insulin resistance and impaired insulin secretion are significant characteristics manifested by patients with type 2 diabetes mellitus (T2DM). The degree and extent of these two features in T2DM vary among races and individuals. Insulin resistance is accelerated by obesity and is accompanied by accumulation of dysfunctional adipose tissues. In addition, dysfunction of pancreatic β-cells impairs insulin secretion. T2DM is significantly affected by aging, as the β-cell mass diminishes with age. Moreover, both obesity and hyperglycemia-related metabolic changes in developing diabetes are associated with accumulation of senescent cells in multiple organs, that is, organismal aging. Cellular senescence is defined as a state of irreversible cell cycle arrest with concomitant functional decline. It is caused by telomere shortening or senescence-inducing stress. Senescent cells secrete proinflammatory cytokines and chemokines, which is designated as the senescence-associated secretory phenotype (SASP), and this has a negative impact on adipose tissues and pancreatic β-cells. Recent advances in aging research have suggested that senolysis, the removal of senescent cells, can be a promising therapeutic approach to prevent or improve aging-related diseases, including diabetes. The attenuation of a SASP may be beneficial, although the pathophysiological involvement of cellular senescence in diabetes is not fully understood. In the clinical application of senotherapy, tissue-context-dependent senescent cells are increasingly being recognized as an issue to be solved. Recent studies have observed highly heterogenic and complex senescent cell populations that serve distinct roles among tissues, various stages of disease, and different ages. For example, in high-fat-diet induced diabetes with obesity, mouse adipose tissues display accumulation of p21Cip1-highly-expressing (p21high) cells in the early stage, followed by increases in both p21high and p16INK4a-highly-expressing (p16high) cells in the late stage. Interestingly, elimination of p21high cells in visceral adipose tissue can prevent or improve insulin resistance in mice with obesity, while p16high cell clearance is less effective in alleviating insulin resistance. Importantly, in immune-deficient mice transplanted with fat from obese patients, dasatinib plus quercetin, a senolytic cocktail that reduces the number of both p21high and p16high cells, improves both glucose tolerance and insulin resistance. On the other hand, in pancreatic β cells, p16high cells become increasingly predominant with age and development of diabetes. Consistently, elimination of p16high cells in mice improves both glucose tolerance and glucose-induced insulin secretion. Moreover, a senolytic compound, the anti-Bcl-2 inhibitor ABT263 reduces p16INK4a expression in islets and restores glucose tolerance in mice when combined with insulin receptor antagonist S961 treatment. In addition, efficacy of senotherapy in targeting mouse pancreatic β cells has been validated not only in T2DM, but also in type 1 diabetes mellitus. Indeed, in non-obese diabetic mice, treatment with anti-Bcl-2 inhibitors, such as ABT199, eliminates senescent pancreatic β cells, resulting in prevention of diabetes mellitus. These findings clearly indicate that features of diabetes are partly determined by which or where senescent cells reside in vivo, as adipose tissues and pancreatic β cells are responsible for insulin resistance and insulin secretion, respectively. In this review, we summarize recent advances in understanding cellular senescence in adipose tissues and pancreatic β cells in diabetes. We review the different potential molecular targets and distinctive senotherapeutic strategies in adipose tissues and pancreatic β cells. We propose the novel concept of a dual-target tailored approach in senotherapy against diabetes.

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Role of Cellular Senescence in Type II Diabetes

Cited by 57 publications

References 148 publications

Telomere dysfunction in ageing and age-related diseases

Telomere dysfunction in ageing and age-related diseases

Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis

Cellular Senescence in Diabetes Mellitus: Distinct Senotherapeutic Strategies for Adipose Tissue and Pancreatic β Cells

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