Cellular senescence: at the nexus between ageing and diabetes

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Abstract

Ageing and diabetes lead to similar organ dysfunction that is driven by parallel molecular mechanisms, one of which is cellular senescence. The abundance of senescent cells in various tissues increases with age, obesity and diabetes. Senescent cells have been directly implicated in the generation of insulin resistance. Recently, drugs that preferentially target senescent cells, known as senolytics, have been described and recently entered clinical trials. In this review, we explore the biological links between ageing and diabetes, specifically focusing on cellular senescence. We summarise the current data on cellular senescence in key target tissues associated with the development and clinical phenotypes of type 2 diabetes and discuss the therapeutic potential of targeting cellular senescence in diabetes.

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Most cited references 36

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Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.

Sarah E Wild, Gojka Roglic, Anders Green … (2004)

The goal of this study was to estimate the prevalence of diabetes and the number of people of all ages with diabetes for years 2000 and 2030. Data on diabetes prevalence by age and sex from a limited number of countries were extrapolated to all 191 World Health Organization member states and applied to United Nations' population estimates for 2000 and 2030. Urban and rural populations were considered separately for developing countries. The prevalence of diabetes for all age-groups worldwide was estimated to be 2.8% in 2000 and 4.4% in 2030. The total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030. The prevalence of diabetes is higher in men than women, but there are more women with diabetes than men. The urban population in developing countries is projected to double between 2000 and 2030. The most important demographic change to diabetes prevalence across the world appears to be the increase in the proportion of people >65 years of age. These findings indicate that the "diabetes epidemic" will continue even if levels of obesity remain constant. Given the increasing prevalence of obesity, it is likely that these figures provide an underestimate of future diabetes prevalence.

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The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

Yi-Yi Zhu, Tamara Tchkonia, Tamar Pirtskhalava … (2015)

The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1 −/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1 −/Δ mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.

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Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study

Jamie N. Justice, Anoop M Nambiar, Tamar Tchkonia … (2019)

Background Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice. Methods A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored. Findings Fourteen patients with stable IPF were recruited. The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13/14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulat.ing SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines (23/48 markers r ≥ 0.50). Interpretation Our first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases. ClinicalTrials.gov identifier: NCT02874989 (posted 2016–2018).

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Author and article information

Contributors

James L. Kirkland: Kirkland.james@mayo.edu

Ulf Smith: ulf.smith@medic.gu.se

Journal

Journal ID (nlm-ta): Diabetologia

Journal ID (iso-abbrev): Diabetologia

Title: Diabetologia

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0012-186X

ISSN (Electronic): 1432-0428

Publication date (Electronic): 27 August 2019

Publication date PMC-release: 27 August 2019

Publication date (Print): 2019

Volume: 62

Issue: 10

Pages: 1835-1841

Affiliations

[1 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Robert and Arlene Kogod Center on Aging, , Mayo Clinic, ; 200 1st St SW, Rochester, MN USA

[2 ]ISNI 000000009445082X, GRID grid.1649.a, Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, , Sahlgrenska University Hospital and University of Gothenburg, ; 413 45 Gothenburg, Sweden

Article

Publisher ID: 4934

DOI: 10.1007/s00125-019-4934-x

PMC ID: 6731336

PubMed ID: 31451866

SO-VID: 60428d37-1ff5-4827-b4ec-897e3bc69f5d

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 15 March 2019

Date accepted : 21 May 2019

Funding

Funded by: University of Gothenburg

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: ageing,cellular senescence,dasatinib,diabetes,geroscience,life course development,quercetin,review,senolytics,type 2 diabetes

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: ageing, cellular senescence, dasatinib, diabetes, geroscience, life course development, quercetin, review, senolytics, type 2 diabetes

Cellular senescence: at the nexus between ageing and diabetes

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Most cited references 36

Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.

The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study

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