Cellular senescence: at the nexus between ageing and diabetes

Allyson K Palmer, Birgit Gustafson, James L Kirkland, Ulf Smith, Allyson K Palmer, Birgit Gustafson, James L Kirkland, Ulf Smith

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.

Keywords: Ageing; Cellular senescence; Dasatinib; Diabetes; Geroscience; Life course development; Quercetin; Review; Senolytics; Type 2 diabetes.

Conflict of interest statement

JLK and AKP have a financial interest related to this research. Patents on senolytic drugs are held by Mayo Clinic. This research has been reviewed by the Mayo Clinic and Buck Institute Conflict of Interest Review Boards and was conducted in compliance with Mayo Clinic and Buck Institute Conflict of Interest policies. Neither of the other two authors has a relevant conflict of financial interest.

Figures

Fig. 1
Fig. 1
Conditions associated with both advanced age and diabetes. This figure is available as part of a downloadable slideset
Fig. 2
Fig. 2
Consequences of fundamental ageing processes. ICU, intensive care unit; MCI, mild cognitive impairment. This figure is available as part of a downloadable slideset

References

    1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–1053.
    1. Aronson D, Edelman ER. Coronary artery disease and diabetes mellitus. Cardiol Clin. 2014;32(3):439–455.
    1. Morley JE. Diabetes, sarcopenia, and frailty. Clin Geriatr Med. 2018;24:455–469.
    1. Xu W, Caracciolo B, Wang H-X, Winblad B, Backman L, Qiu C, Fratiglioni L. Accelerated progression from mild cognitive impairment to dementia in people with diabetes. Diabetes. 2010;59(11):2928–2935.
    1. Kirkland JL. Translating advances from the basic biology of aging into clinical application. Exp Gerontol. 2013;48(1):1–5.
    1. Kirkland JL. Translating the science of aging into therapeutic interventions. Cold Spring Harb Perspect Med. 2016;6(3):a025908.
    1. Kirkland JL, Peterson C. Healthspan, translation, and new outcomes for animal studies of aging. J Gerontol A Biol Sci Med Sci. 2009;64:209–212.
    1. Kennedy BK, Berger SL, Brunet A, et al. Geroscience: linking aging to chronic disease. Cell. 2014;159(4):709–713.
    1. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–1217.
    1. Palmer AK, Kirkland JL. Aging and adipose tissue: potential interventions for diabetes and regenerative medicine. Exp Gerontol. 2016;86:97–105.
    1. Palmer AK, Tchkonia T, LeBrasseur NK, Chini EN, Xu M, Kirkland JL. Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes. 2015;64(7):2289–2298.
    1. Valdes AM, Andrew T, Gardner JP, et al. Obesity, cigarette smoking, and telomere length in women. Lancet. 2005;366(9486):662–664.
    1. Ghosh AK, O’Brien M, Mau T, Yung R. Toll-like receptor 4 (TLR4) deficient mice are protected from adipose tissue inflammation in aging. Aging (Albany NY) 2017;9(9):1971–1982.
    1. Furukawa S, Fujita T, Shimabukuro M, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114(12):1752–1761.
    1. Vlassara H, Palace MR. Diabetes and advanced glycation endproducts. J Intern Med. 2002;251(2):87–101.
    1. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014;69(Suppl 1):S4S9.
    1. Martyniak K, Masternak MM. Changes in adipose tissue cellular composition during obesity and aging as a cause of metabolic dysregulation. Exp Gerontol. 2017;94:59–63.
    1. Hammarstedt A, Gogg S, Hedjazifar S, Nerstedt A, Smith U. Impaired adipogenesis and dysfunctional adipose tissue in human hypertrophic obesity. Physiol Rev. 2018;98(4):1911–1941.
    1. Kirkland JL, Hollenberg CH, Gillon WS. Age, anatomic site, and the replication and differentiation of adipocyte precursors. Am J Phys. 1990;258(2):C206–C210.
    1. Danforth E., Jr Failure of adipocyte differentiation causes type II diabetes mellitus? Nat Genet. 2000;26(1):13.
    1. Gustafson B, Hammarstedt A, Hedjazifar S, Smith U. Restricted adipogenesis in hypertrophic obesity: the role of WISP2, WNT, and BMP4. Diabetes. 2013;62(9):2997–3004.
    1. Gustafson B, Hedjazifar S, Gogg S, Hammarstedt A, Smith U. Insulin resistance and impaired adipogenesis. Trends Endocrinol Metab. 2015;26(4):193–200.
    1. Kim SM, Lun M, Wang M, et al. Loss of white adipose hyperplastic potential is associated with enhanced susceptibility to insulin resistance. Cell Metab. 2014;20(6):1049–1058.
    1. Palmer AK, Xu M, Zhu Y, et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell. 2019;18(3):e12950.
    1. Ogrodnik M, Miwa S, Tchkonia T, et al. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun. 2017;8(1):15691.
    1. Kirkland JL, Tchkonia T. Cellular senescence: a translational perspective. EBioMedicine. 2017;21:21–28.
    1. Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013;123(3):966–972.
    1. Zhu Y, Armstrong JL, Tchkonia T, Kirkland JL. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr Opin Clin Nutr Metab Care. 2014;17(4):324–328.
    1. Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24(8):1246–1256.
    1. Minamino T, Orimo M, Shimizu I, et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med. 2009;15(9):1082–1087.
    1. Tchkonia T, Morbeck DE, Von Zglinicki T, et al. Fat tissue, aging, and cellular senescence. Aging Cell. 2010;9(5):667–684.
    1. Hannou SA, Wouters K, Paumelle R, Staels B. Functional genomics of the CDKN2A/B locus in cardiovascular and metabolic disease: what have we learned from GWASs? Trends Endocrinol Metab. 2015;26(4):176–184.
    1. Krstic J, Reinisch I, Schupp M, Schulz TJ, Prokesch A. p53 functions in adipose tissue metabolism and homeostasis. Int J Mol Sci. 2018;19:E2622.
    1. Vergoni B, Cornejo PJ, Gilleron J, et al. DNA damage and the activation of the p53 pathway mediate alterations in metabolic and secretory functions of adipocytes. Diabetes. 2016;65(10):3062–3074.
    1. Xu M, Palmer AK, Ding H, et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife. 2015;4:e12997.
    1. Zaragosi LE, Wdziekonski B, Villageois P, et al. Activin a plays a critical role in proliferation and differentiation of human adipose progenitors. Diabetes. 2010;59(10):2513–2521.
    1. Kuki S, Imanishi T, Kobayashi K, Matsuo Y, Obana M, Akasaka T. Hyperglycemia accelerated endothelial progenitor cell senescence via the activation of p38 mitogen-activated protein kinase. Circ J. 2006;70(8):1076–1081.
    1. Helman A, Klochendler A, Azazmeh N, et al. p16(Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion. Nat Med. 2016;22(4):412–420.
    1. Thompson PJ, Shah A, Ntranos V, Van Gool F, Atkinson M, Bhushan A. Targeted elimination of senescent beta cells prevents type 1 diabetes. Cell Metab. 2019;29(5):1045–1060.
    1. Zhu Y, Tchkonia TT, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644–658.
    1. Tchernof A, Despres JP. Pathophysiology of human visceral obesity: an update. Physiol Rev. 2013;93(1):359–404.
    1. Roos CM, Zhang B, Palmer AK, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016;15(5):973–977.
    1. Anderson R, Lagnado A, Maggiorani D, et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 2019;38(5):e100492.
    1. Lewis-McDougall FC, Ruchaya PJ, Domenjo-Villa E, et al. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell. 2019;18(3):e12931.
    1. Verzola D, Gandolfo MT, Gaetani G, et al. Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy. Am J Physiol Renal Physiol. 2008;295(5):F1563–F1573.
    1. Ogrodnik M, Zhu Y, Langhi LGP, et al. Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab. 2019;29(5):1233–1077.e8.
    1. Musi N, Valentine JM, Sickora KR, et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell. 2018;17(6):e12840.
    1. Zhang P, Kishimoto Y, Grammatikakis I et al (2019) Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci 22(5):719–728. 10.1038/s41593-019-0372-9
    1. Justice J, Miller JD, Newman JC, et al. Frameworks for proof-of-concept clinical trials of interventions that target fundamental aging processes. J Gerontol A Biol Sci Med Sci. 2016;71(11):1415–1423.
    1. Kirkland JL, Tchkonia T, Zhu Y, Niedernhofer LJ, Robbins PD. The clinical potential of senolytic drugs. J Am Geriatr Soc. 2017;65(10):2297–2301.
    1. Tchkonia T, Kirkland JL. Aging, cell senescence, and chronic disease: emerging therapeutic strategies. JAMA. 2018;320(13):1319–1320.
    1. Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18–28.
    1. Justice JN, Nambiar AM, Tchkonia T, et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine. 2019;40:554–563.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever