Targeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes

Thompson, Peter J.; Shah, Aatman; Ntranos, Vasilis; Gool, Frédéric Van; Atkinson, Mark A.; Bhushan, Anil

doi:10.1016/j.cmet.2019.01.021

Cited by 238 publications

(373 citation statements)

References 87 publications

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“…For example, it has been shown that β cells become senescent during the progression of Type I and Type II diabetes. Clearance of senescent β cells effectively restored β cell function and glucose homeostasis . Furthermore, ablation of senescent cells by transgenic clearance or treatment with senolytics improved pulmonary function and physical health in a murine model of idiopathic pulmonary fibrosis, a chronic respiratory disease the incident of which increases with aging .…”

Section: Organismal Aging and Cellular Senescencementioning

confidence: 96%

Organismal Aging and Oxidants beyond Macromolecules Damage

Clément

Luo

2020

Proteomics

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The relationship between oxidants and organismal aging was first articulated through the free radical theory of aging. One of the major predictions of the free radical theory of aging is that oxidative stress shortens organisms’ lifespan because of an increased level of oxidants, which are damaging to macromolecules. However, challenging the role of oxidants in age‐related diseases, there is now sufficient evidence that antioxidant supplements do not provide significant health benefits. Interestingly, in addition to an increase in oxidant‐mediated macromolecules damage, there is convincing experimental data to support the role of senescent cells in the process of aging. Here, the current knowledge regarding the role of oxidants and cellular senescence in organismal aging is reviewed and it is proposed that, in addition to the role of oxidants as inducers of macromolecular damage, oxidants may also function as regulators of signaling pathways involved in the establishment of cellular senescence. If this role for oxidants is established, it may be necessary to modify the free radical theory of aging from “Organisms age because cells accumulate reactive oxygen species‐dependent damage over time” to: “Organisms age because cells accumulate oxidants’‐dependent damage and oxidants’‐dependent senescent characteristics over time.”

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Section: Organismal Aging and Cellular Senescencementioning

confidence: 96%

Organismal Aging and Oxidants beyond Macromolecules Damage

Clément

Luo

2020

Proteomics

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“…Collection of CM from CD45-depleted islet cell cultures was performed as previously [3] where islets were pooled from five or ten 14 week NOD mice, depleted of CD45 + immune cells using MACS (BioLegend) and plated at 60,000-…”

Section: Culture Of Mouse Islets Inhibitors and Rnaimentioning

confidence: 99%

“…Human islets from IIDP were cultured as previously [3] in RPMI-1640 containing 10% FBS, 5.5 mM glucose and 1X antibiotic-antimycotic (Gibco). Islets were rested for 24 h in culture prior to inducing DNA damage with 50 µM bleomycin.…”

Section: Culture Of Human Islets and Inhibitorsmentioning

confidence: 99%

“…The conventional model for T1D pathogenesis posits a loss of peripheral tolerance resulting beta cell-specific autoimmunity of CD4 + and CD8 + T cells that carry out beta cell destruction with support from innate immune cells [1,2]. While T cell-mediated beta cell destruction is indeed the main driver of the disease, we recently demonstrated that beta cells actively participate in the process by undergoing DNA damage-induced senescence, upregulation of the pro-survival factor Bcl-2 and acquiring a senescence-associated secretory phenotype (SASP) [3]. Selective ablation of senescent beta cells with small molecule senolytic compounds targeting Bcl-2 prevented T1D in the NOD mouse model by halting the autoimmune destruction process and preserving beta cell mass [3].…”

Section: Introductionmentioning

confidence: 99%

“…While T cell-mediated beta cell destruction is indeed the main driver of the disease, we recently demonstrated that beta cells actively participate in the process by undergoing DNA damage-induced senescence, upregulation of the pro-survival factor Bcl-2 and acquiring a senescence-associated secretory phenotype (SASP) [3]. Selective ablation of senescent beta cells with small molecule senolytic compounds targeting Bcl-2 prevented T1D in the NOD mouse model by halting the autoimmune destruction process and preserving beta cell mass [3]. These results demonstrate a causal role for SASP beta cells in the pathogenesis of T1D, however the mechanisms of SASP activation in beta cells have not been determined.…”

Section: Introductionmentioning

confidence: 99%

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BET proteins are required for transcriptional activation of the senescent beta cell secretome in Type 1 Diabetes

Thompson

Shah

Apostolopolou

et al. 2019

Preprint

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OBJECTIVE: Type 1 Diabetes (T1D) results from progressive loss of pancreatic beta cells due to autoimmune destruction. We recently reported that during the natural history of T1D in humans and the female nonobese diabetic (NOD) mouse model, beta cells acquire a senescence-associated secretory phenotype (SASP) that is a major driver of disease onset and progression, but the mechanisms that activate SASP in beta cells were not explored. The objective of this study was to identify transcriptional mechanisms of SASP activation in beta cells. METHODS:We used the female NOD mouse model of spontaneous autoimmune T1D and ex vivo experiments on NOD mouse and human islets to test the hypothesis that Bromodomain Extra-Terminal domain (BET) proteins activate the beta cell SASP transcriptional program. RESULTS:Here we show that beta cell SASP is transcriptionally controlled by BET proteins, including BRD4. Chromatin analysis of key beta cell SASP genes in NOD islets revealed binding of BRD4 at active regulatory regions. BET protein inhibition in NOD islets diminished not only the transcriptional activation and secretion of SASP factors but also the non-cell autonomous activity. BET protein inhibition also decreased the extent of SASP induction in human islets exposed to DNA damage. The BET protein inhibitor iBET-762 prevented diabetes in NOD mice and also attenuated SASP in beta cells in vivo. CONCLUSIONS:Taken together, our findings support a crucial role for BET proteins in the activation of the beta cell SASP transcriptional program. These studies suggest avenues for preventing T1D by transcriptional inhibition of SASP.

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Mitochondrial dysfunction and cell senescence: deciphering a complex relationship

2019

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Cellular senescence and mitochondrial dysfunction have both been defined as classical hallmarks of the ageing process. Here, we review the intricate relationship between the two. In the context of ageing, it is now well regarded that cellular senescence is a key driver in both ageing and the onset of a number of age‐related pathologies. Emerging evidence has pinpointed mitochondria as one of the key modulators in the development of the senescence phenotype, particularly the pro‐inflammatory senescence associated secretory phenotype (SASP). This review focuses on the contribution of homeostatic mechanisms, as well as of reactive oxygen species and mitochondrial metabolites in the senescence programme. Furthermore, we discuss emerging pathways and mitochondrial‐mediated mechanisms that may be influencing the SASP and, subsequently, explore how these may be exploited to open up new therapeutic avenues.

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Targeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes

Cited by 238 publications

References 87 publications

Organismal Aging and Oxidants beyond Macromolecules Damage

Organismal Aging and Oxidants beyond Macromolecules Damage

BET proteins are required for transcriptional activation of the senescent beta cell secretome in Type 1 Diabetes

Mitochondrial dysfunction and cell senescence: deciphering a complex relationship

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