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Erschienen in:

14.10.2022 | Obesity (K Gadde and P Singh, Section Editors)

Cellular Senescence in Obesity and Associated Complications: a New Therapeutic Target

verfasst von: Akilavalli Narasimhan, Rafael R. Flores, Christina D. Camell, David A. Bernlohr, Paul D. Robbins, Laura J. Niedernhofer

Erschienen in: Current Diabetes Reports | Ausgabe 11/2022

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Abstract

Purpose of Review

Obesity has increased worldwide recently and represents a major global health challenge. This review focuses on the obesity-associated cellular senescence in various organs and the role of these senescent cells (SnCs) in driving complications associated with obesity. Also, the ability to target SnCs pharmacologically with drugs termed senotherapeutics as a therapy for these complications is discussed.

Recent Findings

Several studies have shown a positive correlation between obesity and SnC burden in organs such as adipose tissue, liver, and pancreatic-β-cells. These SnCs produce several secretory factors which affect other cells and tissues in a paracrine manner resulting in organ dysfunction. The accumulation of SnCs in adipocytes affects their lipid storage and impairs adipogenesis. The inflammatory senescence-associated secretory phenotype (SASP) of SnCs downregulates the antioxidant capacity and mitochondrial function in tissues. Senescent hepatocytes cannot oxidize fatty acids, which leads to lipid deposition and senescence in β-cells decrease function. These and other adverse effects of SnCs contribute to insulin resistance and type-2 diabetes. The reduction in the SnC burden genetically or pharmacologically improves the complications associated with obesity.

Summary

The accumulation of SnCs with age and disease accelerates aging. Obesity is a key driver of SnC accumulation, and the complications associated with obesity can be controlled by reducing the SnC burden. Thus, senotherapeutic drugs have the potential to be an effective therapeutic option.

Cheng L, Wang J, Dai H, Duan Y, An Y, Shi L, et al. Brown and beige adipose tissue: a novel therapeutic strategy for obesity and type 2 diabetes mellitus. Adipocyte. 2021;10(1):48–65. https://doi.org/10.1080/21623945.2020.1870060.CrossRefPubMedPubMedCentral

Cheryl D. Fryar MDC, and Cynthia L. Ogden. Prevalence of overweight, obesity, and severe obesity among adults aged 20 and over: United States, 1960–1962 through 2017–2018. NCHS Health E-Stats. 2020.

Kelly T, Yang W, Chen CS, Reynolds K, He J. Global burden of obesity in 2005 and projections to 2030. Int J Obes (Lond). 2008;32(9):1431–7. https://doi.org/10.1038/ijo.2008.102.CrossRef

Kawai T, Autieri MV, Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am J Physiol Cell Physiol. 2021;320(3):C375–91. https://doi.org/10.1152/ajpcell.00379.2020.CrossRefPubMed

Roberto CA, Swinburn B, Hawkes C, Huang TT, Costa SA, Ashe M, et al. Patchy progress on obesity prevention: emerging examples, entrenched barriers, and new thinking. Lancet. 2015;385(9985):2400–9. https://doi.org/10.1016/s0140-6736(14)61744-x.CrossRefPubMed

Santos AL, Sinha S. Obesity and aging: molecular mechanisms and therapeutic approaches. Ageing Res Rev. 2021;67:101268. https://doi.org/10.1016/j.arr.2021.101268.CrossRefPubMed

Burton DGA, Faragher RGA. Obesity and type-2 diabetes as inducers of premature cellular senescence and ageing. Biogerontology. 2018;19(6):447–59. https://doi.org/10.1007/s10522-018-9763-7.CrossRefPubMedPubMedCentral

Lin L, Qin K, Chen D, Lu C, Chen W, Guo VY. Systematic review and meta-analysis of the association between paediatric obesity and telomere length. Acta Paediatr. 2021;110(10):2695–703. https://doi.org/10.1111/apa.15971.CrossRefPubMed

Al-Attas OS, Al-Daghri N, Bamakhramah A, Shaun Sabico S, McTernan P, Huang TT. Telomere length in relation to insulin resistance, inflammation and obesity among Arab youth. Acta Paediatr. 2010;99(6):896–9. https://doi.org/10.1111/j.1651-2227.2010.01720.x.CrossRefPubMed

10.

Clemente DBP, Maitre L, Bustamante M, Chatzi L, Roumeliotaki T, Fossati S, et al. Obesity is associated with shorter telomeres in 8 year-old children. Sci Rep. 2019;9(1):18739. https://doi.org/10.1038/s41598-019-55283-8.CrossRefPubMedPubMedCentral

11.

Lamprokostopoulou A, Moschonis G, Manios Y, Critselis E, Nicolaides NC, Stefa A, et al. Childhood obesity and leucocyte telomere length. Eur J Clin Invest. 2019;49(12):e13178. https://doi.org/10.1111/eci.13178.CrossRefPubMed

12.

Licea-Cejudo RC, Arenas-Sandoval LK, Salazar-León J, Martínez-Martínez MV, Carreón-Rodríguez A, Pedraza-Alva G, et al. A dysfunctional family environment and a high body fat percentage negatively affect telomere length in Mexican boys aged 8–10 years. Acta Paediatr. 2020;109(10):2091–8. https://doi.org/10.1111/apa.15234.CrossRefPubMed

13.

Welendorf C, Nicoletti CF, Pinhel MAS, Noronha NY, de Paula BMF, Nonino CB. Obesity, weight loss, and influence on telomere length: new insights for personalized nutrition. Nutrition. 2019;66:115–21. https://doi.org/10.1016/j.nut.2019.05.002.CrossRefPubMed

14.

García-Calzón S, Moleres A, Marcos A, Campoy C, Moreno LA, Azcona-Sanjulián MC, et al. Telomere length as a biomarker for adiposity changes after a multidisciplinary intervention in overweight/obese adolescents: the EVASYON study. PLoS One. 2014;9(2):e89828. https://doi.org/10.1371/journal.pone.0089828.CrossRefPubMedPubMedCentral

15.

Lee M, Martin H, Firpo MA, Demerath EW. Inverse association between adiposity and telomere length: the fels longitudinal study. Am J Hum Biol. 2011;23(1):100–6. https://doi.org/10.1002/ajhb.21109.CrossRefPubMedPubMedCentral

16.

Rode L, Nordestgaard BG, Weischer M, Bojesen SE. Increased body mass index, elevated C-reactive protein, and short telomere length. J Clin Endocrinol Metab. 2014;99(9):E1671–5. https://doi.org/10.1210/jc.2014-1161.CrossRefPubMed

17.

Palmer AK, Jensen MD, Tchkonia T, Kirkland JL. Chapter 11 - Senescence in obesity: causes and consequences. In: Serrano M, Muñoz-Espín D, editors. Cellular senescence in disease. Academic Press; 2022. p. 289–308.CrossRef

18.

d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426(6963):194–8. https://doi.org/10.1038/nature02118.CrossRefPubMed

19.

Beauséjour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. Embo j. 2003;22(16):4212–22. https://doi.org/10.1093/emboj/cdg417.CrossRefPubMedPubMedCentral

20.

d’Adda di Fagagna F. Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008;8(7):512–22. https://doi.org/10.1038/nrc2440.CrossRefPubMed

21.

Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118. https://doi.org/10.1146/annurev-pathol-121808-102144.CrossRefPubMedPubMedCentral

22.

Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008;133(6):1019–31. https://doi.org/10.1016/j.cell.2008.03.039.CrossRefPubMed

23.

Acosta JC, O’Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell. 2008;133(6):1006–18. https://doi.org/10.1016/j.cell.2008.03.038.CrossRefPubMed

24.

Kang C, Xu Q, Martin TD, Li MZ, Demaria M, Aron L, et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science. 2015;349(6255):aaa5612. https://doi.org/10.1126/science.aaa5612.

25.

Toso A, Revandkar A, Di Mitri D, Guccini I, Proietti M, Sarti M, et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 2014;9(1):75–89. https://doi.org/10.1016/j.celrep.2014.08.044.CrossRefPubMed

26.

Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S, Hanley CJ, et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Biol. 2015;17(9):1205–17. https://doi.org/10.1038/ncb3225.CrossRefPubMedPubMedCentral

27.

Tasdemir N, Banito A, Roe JS, Alonso-Curbelo D, Camiolo M, Tschaharganeh DF, et al. BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discov. 2016;6(6):612–29. https://doi.org/10.1158/2159-8290.Cd-16-0217.CrossRefPubMedPubMedCentral

28.

Hoare M, Ito Y, Kang TW, Weekes MP, Matheson NJ, Patten DA, et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat Cell Biol. 2016;18(9):979–92. https://doi.org/10.1038/ncb3397.CrossRefPubMedPubMedCentral

29.

Aird KM, Iwasaki O, Kossenkov AV, Tanizawa H, Fatkhutdinov N, Bitler BG, et al. HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci. J Cell Biol. 2016;215(3):325–34. https://doi.org/10.1083/jcb.201608026.CrossRefPubMedPubMedCentral

30.

Davalos AR, Kawahara M, Malhotra GK, Schaum N, Huang J, Ved U, et al. p53-dependent release of alarmin HMGB1 is a central mediator of senescent phenotypes. J Cell Biol. 2013;201(4):613–29. https://doi.org/10.1083/jcb.201206006.CrossRefPubMedPubMedCentral

31.

Zhang L, Pitcher LE, Prahalad V, Niedernhofer LJ, Robbins PD. Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. Febs j. 2022. https://doi.org/10.1111/febs.16350.CrossRefPubMed

32.

James EL, Michalek RD, Pitiyage GN, de Castro AM, Vignola KS, Jones J, et al. Senescent human fibroblasts show increased glycolysis and redox homeostasis with extracellular metabolomes that overlap with those of irreparable DNA damage, aging, and disease. J Proteome Res. 2015;14(4):1854–71. https://doi.org/10.1021/pr501221g.CrossRefPubMed

33.

Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, et al. Structure of mammalian AMPK and its regulation by ADP. Nature. 2011;472(7342):230–3. https://doi.org/10.1038/nature09932.CrossRefPubMedPubMedCentral

34.

Zu Y, Liu L, Lee MY, Xu C, Liang Y, Man RY, et al. SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. Circ Res. 2010;106(8):1384–93. https://doi.org/10.1161/circresaha.109.215483.CrossRefPubMed

35.

Le Pelletier L, Mantecon M, Gorwood J, Auclair M, Foresti R, Motterlini R, et al. Metformin alleviates stress-induced cellular senescence of aging human adipose stromal cells and the ensuing adipocyte dysfunction. Elife. 2021;10. https://doi.org/10.7554/eLife.62635.

36.

Pollard AE, Martins L, Muckett PJ, Khadayate S, Bornot A, Clausen M, et al. AMPK activation protects against diet induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue. Nat Metab. 2019;1(3):340–9. https://doi.org/10.1038/s42255-019-0036-9.CrossRefPubMedPubMedCentral

37.

Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA, Freund A, et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab. 2016;23(2):303–14. https://doi.org/10.1016/j.cmet.2015.11.011.CrossRefPubMed

38.

Liu Y, Zhu H, Yan X, Gu H, Gu Z, Liu F. Endoplasmic reticulum stress participates in the progress of senescence and apoptosis of osteoarthritis chondrocytes. Biochem Biophys Res Commun. 2017;491(2):368–73. https://doi.org/10.1016/j.bbrc.2017.07.094.CrossRefPubMed

39.

Cormenier J, Martin N, Deslé J, Salazar-Cardozo C, Pourtier A, Abbadie C, et al. The ATF6α arm of the unfolded protein response mediates replicative senescence in human fibroblasts through a COX2/prostaglandin E(2) intracrine pathway. Mech Ageing Dev. 2018;170:82–91. https://doi.org/10.1016/j.mad.2017.08.003.CrossRefPubMed

40.

Bent EH, Gilbert LA, Hemann MT. A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses. Genes Dev. 2016;30(16):1811–21. https://doi.org/10.1101/gad.284851.116.CrossRefPubMedPubMedCentral

41.

Hwang ES, Yoon G, Kang HT. A comparative analysis of the cell biology of senescence and aging. Cell Mol Life Sci. 2009;66(15):2503–24. https://doi.org/10.1007/s00018-009-0034-2.CrossRefPubMed

42.

Lee BY, Han JA, Im JS, Morrone A, Johung K, Goodwin EC, et al. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell. 2006;5(2):187–95. https://doi.org/10.1111/j.1474-9726.2006.00199.x.CrossRefPubMed

43.

Kurz DJ, Decary S, Hong Y, Erusalimsky JD. Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci. 2000;113(Pt 20):3613–22.CrossRef

44.

Korolchuk VI, Miwa S, Carroll B, von Zglinicki T. Mitochondria in cell senescence: is mitophagy the weakest link? EBioMedicine. 2017;21:7–13. https://doi.org/10.1016/j.ebiom.2017.03.020.CrossRefPubMedPubMedCentral

45.

Sadaie M, Salama R, Carroll T, Tomimatsu K, Chandra T, Young AR, et al. Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence. Genes Dev. 2013;27(16):1800–8. https://doi.org/10.1101/gad.217281.113.CrossRefPubMedPubMedCentral

46.

Cohen P, Spiegelman BM. Cell biology of fat storage. Mol Biol Cell. 2016;27(16):2523–7. https://doi.org/10.1091/mbc.E15-10-0749.CrossRefPubMedPubMedCentral

47.

Whitehead A, Krause FN, Moran A, MacCannell ADV, Scragg JL, McNally BD, et al. Brown and beige adipose tissue regulate systemic metabolism through a metabolite interorgan signaling axis. Nat Commun. 2021;12(1):1905. https://doi.org/10.1038/s41467-021-22272-3.CrossRefPubMedPubMedCentral

48.

Tsiloulis T, Watt MJ. Exercise and the regulation of adipose tissue metabolism. Prog Mol Biol Transl Sci. 2015;135:175–201. https://doi.org/10.1016/bs.pmbts.2015.06.016.CrossRefPubMed

49.

Fasshauer M, Blüher M. Adipokines in health and disease. Trends Pharmacol Sci. 2015;36(7):461–70. https://doi.org/10.1016/j.tips.2015.04.014.CrossRefPubMed

50.

Skurk T, Alberti-Huber C, Herder C, Hauner H. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab. 2007;92(3):1023–33. https://doi.org/10.1210/jc.2006-1055.CrossRefPubMed

51.

Suganami T, Tanaka M, Ogawa Y. Adipose tissue inflammation and ectopic lipid accumulation. Endocr J. 2012;59(10):849–57. https://doi.org/10.1507/endocrj.ej12-0271.CrossRefPubMed

52.

Shirakawa K, Yan X, Shinmura K, Endo J, Kataoka M, Katsumata Y, et al. Obesity accelerates T cell senescence in murine visceral adipose tissue. J Clin Invest. 2016;126(12):4626–39. https://doi.org/10.1172/jci88606.CrossRefPubMedPubMedCentral

53.

Khan S, Chan YT, Revelo XS, Winer DA. The immune landscape of visceral adipose tissue during obesity and aging. Front endocrinol Lausanne. 2020;11:267. https://doi.org/10.3389/fendo.2020.00267.CrossRefPubMedPubMedCentral

54.

Yamada T, Kamiya M, Higuchi M, Nakanishi N. Fat depot-specific differences of macrophage infiltration and cellular senescence in obese bovine adipose tissues. J Vet Med Sci. 2018;80(10):1495–503. https://doi.org/10.1292/jvms.18-0324.CrossRefPubMedPubMedCentral

55.

Alessio N, Acar MB, Demirsoy IH, Squillaro T, Siniscalco D, Bernardo GD, et al. Obesity is associated with senescence of mesenchymal stromal cells derived from bone marrow subcutaneous and visceral fat of young mice. Aging Albany NY. 2020;12(13):12609–21. https://doi.org/10.18632/aging.103606.CrossRefPubMedPubMedCentral

56.

Rouault C, Marcelin G, Adriouch S, Rose C, Genser L, Ambrosini M, et al. Senescence-associated β-galactosidase in subcutaneous adipose tissue associates with altered glycaemic status and truncal fat in severe obesity. Diabetologia. 2021;64(1):240–54. https://doi.org/10.1007/s00125-020-05307-0.CrossRefPubMed

57.

Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T, et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med. 2009;15(9):1082–7. https://doi.org/10.1038/nm.2014.CrossRefPubMed

58.

Pini M, Czibik G, Sawaki D, Mezdari Z, Braud L, Delmont T, et al. Adipose tissue senescence is mediated by increased ATP content after a short-term high-fat diet exposure. Aging Cell. 2021;20(8):e13421. https://doi.org/10.1111/acel.13421.CrossRefPubMedPubMedCentral

59.

Hafidi ME, Buelna-Chontal M, Sánchez-Muñoz F, Carbó R. Adipogenesis: a necessary but harmful strategy. Int J Mol Sci. 2019;20(15):3657. https://doi.org/10.3390/ijms20153657.

60.

Garaulet M, Hernandez-Morante JJ, Lujan J, Tebar FJ, Zamora S. Relationship between fat cell size and number and fatty acid composition in adipose tissue from different fat depots in overweight/obese humans. Int J Obes (Lond). 2006;30(6):899–905. https://doi.org/10.1038/sj.ijo.0803219.CrossRef

61.

Ishaq A, Tchkonia T, Kirkland JL, Siervo M, Saretzki G. Palmitate induces DNA damage and senescence in human adipocytes in vitro that can be alleviated by oleic acid but not inorganic nitrate. Exp Gerontol. 2022;163:111798. https://doi.org/10.1016/j.exger.2022.111798.CrossRefPubMedPubMedCentral

62.

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):1911–41. https://doi.org/10.1152/physrev.00034.2017.CrossRefPubMed

63.

Gustafson B, Nerstedt A, Smith U. Reduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells. Nat Commun. 2019;10(1):2757. https://doi.org/10.1038/s41467-019-10688-x.CrossRefPubMedPubMedCentral

64.

Mitterberger MC, Lechner S, Mattesich M, Zwerschke W. Adipogenic differentiation is impaired in replicative senescent human subcutaneous adipose-derived stromal/progenitor cells. J Gerontol A Biol Sci Med Sci. 2014;69(1):13–24. https://doi.org/10.1093/gerona/glt043.CrossRefPubMed

65.

Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife. 2015;4:e12997. https://doi.org/10.7554/eLife.12997.CrossRefPubMedPubMedCentral

66.

Meyer SC, Levine RL. Molecular pathways: molecular basis for sensitivity and resistance to JAK kinase inhibitors. Clin Cancer Res. 2014;20(8):2051–9. https://doi.org/10.1158/1078-0432.Ccr-13-0279.CrossRefPubMedPubMedCentral

67.

Xu M, Tchkonia T, Ding H, Ogrodnik M, Lubbers ER, Pirtskhalava T, et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc Natl Acad Sci U S A. 2015;112(46):E6301–10. https://doi.org/10.1073/pnas.1515386112.CrossRefPubMedPubMedCentral

68.

Chen YW, Harris RA, Hatahet Z, Chou KM. Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities. Proc Natl Acad Sci U S A. 2015;112(33):E4556–64. https://doi.org/10.1073/pnas.1506954112.CrossRefPubMedPubMedCentral

69.

Li Q, Hagberg CE, Silva Cascales H, Lang S, Hyvönen MT, Salehzadeh F, et al. Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce. Nat Med. 2021;27(11):1941–53. https://doi.org/10.1038/s41591-021-01501-8.CrossRefPubMed

70.

Herold J, Kalucka J. Angiogenesis in adipose tissue: the interplay between adipose and endothelial cells Front Physiol 2021;11:624903 https://doi.org/10.3389/fphys.2020.624903

71.

Monelli E, Villacampa P, Zabala-Letona A, Martinez-Romero A, Llena J, Beiroa D, et al. Angiocrine polyamine production regulates adiposity. Nat Metab. 2022;4(3):327–43. https://doi.org/10.1038/s42255-022-00544-6.CrossRefPubMed

72.

Villaret A, Galitzky J, Decaunes P, Estève D, Marques MA, Sengenès C, et al. Adipose tissue endothelial cells from obese human subjects: differences among depots in angiogenic, metabolic, and inflammatory gene expression and cellular senescence. Diabetes. 2010;59(11):2755–63. https://doi.org/10.2337/db10-0398.CrossRefPubMedPubMedCentral

73.

Briot A, Decaunes P, Volat F, Belles C, Coupaye M, Ledoux S, et al. Senescence alters PPARγ (peroxisome proliferator-activated receptor gamma)-dependent fatty acid handling in human adipose tissue microvascular endothelial cells and favors inflammation. Arterioscler Thromb Vasc Biol. 2018;38(5):1134–46. https://doi.org/10.1161/atvbaha.118.310797.CrossRefPubMed

74.

Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med. 2001;7(1):48–52.CrossRef

75.

Kennedy DJ, Kuchibhotla S, Westfall KM, Silverstein RL, Morton RE, Febbraio M. A CD36-dependent pathway enhances macrophage and adipose tissue inflammation and impairs insulin signalling. Cardiovasc Res. 2011;89(3):604–13.CrossRef

76.

Silverstein RL, Febbraio M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior. Science Signaling. 2009;2(72):re3. https://doi.org/10.1126/scisignal.272re3.

77.

Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM, Yawe JC, et al. Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab. 2014;19(1):162–71. https://doi.org/10.1016/j.cmet.2013.11.017.CrossRefPubMed

78.

Shimobayashi M, Albert V, Woelnerhanssen B, Frei IC, Weissenberger D, Meyer-Gerspach AC, et al. Insulin resistance causes inflammation in adipose tissue. J Clin Investig. 2018;128(4):1538–50. https://doi.org/10.1172/JCI96139.CrossRefPubMedPubMedCentral

79.

Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes. 2008;57(12):3239–46. https://doi.org/10.2337/db08-0872.CrossRefPubMedPubMedCentral

80.

Hill DA, Lim HW, Kim YH, Ho WY, Foong YH, Nelson VL, et al. Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. Proc Natl Acad Sci U S A. 2018;115(22):E5096–105. https://doi.org/10.1073/pnas.1802611115.CrossRefPubMedPubMedCentral

81.

Silva HM, Báfica A, Rodrigues-Luiz GF, Chi J, Santos PDA, Reis BS, et al. Vasculature-associated fat macrophages readily adapt to inflammatory and metabolic challenges. J Exp Med. 2019;216(4):786–806. https://doi.org/10.1084/jem.20181049.CrossRefPubMedPubMedCentral

82.

Frasca D, Romero M, Diaz A, Garcia D, Thaller S, Blomberg BB. B Cells with a senescent-associated secretory phenotype accumulate in the adipose tissue of individuals with obesity. LID. Int J Mol Sci. 2021;22(4):1839. https://doi.org/10.3390/ijms22041839.

83.

Carter S, Miard S, Caron A, Sallé-Lefort S, St-Pierre P, Anhê FF, et al. Loss of OcaB prevents age-induced fat accretion and insulin resistance by altering b-lymphocyte transition and promoting energy expenditure. Diabetes. 2018;67(7):1285–96. https://doi.org/10.2337/db17-0558.CrossRefPubMed

84.

Camell CD, Günther P, Lee A, Goldberg EL, Spadaro O, Youm YH, et al. Aging induces an Nlrp3 inflammasome-dependent expansion of adipose B cells that impairs metabolic homeostasis. Cell Metab. 2019;30(6):1024-39.e6. https://doi.org/10.1016/j.cmet.2019.10.006.CrossRefPubMedPubMedCentral

85.

Kim B, Hyun CK. B-cell-activating factor depletion ameliorates aging-dependent insulin resistance via enhancement of thermogenesis in adipose tissues. LID Int J Mol Sci. 2020;21(14):5121. https://doi.org/10.3390/ijms21145121.

86.

Winer DA, Winer S, Chng MH, Shen L, Engleman EG. B Lymphocytes in obesity-related adipose tissue inflammation and insulin resistance. Cell Mol Life Sci. 2014;71(6):1033–43. https://doi.org/10.1007/s00018-013-1486-y.CrossRefPubMed

87.

Curtis JM, Grimsrud PA, Wright WS, Xu X, Foncea RE, Graham DW, et al. Downregulation of adipose glutathione S-transferase A4 leads to increased protein carbonylation, oxidative stress, and mitochondrial dysfunction. Diabetes. 2010;59(5):1132–42. https://doi.org/10.2337/db09-1105.CrossRefPubMedPubMedCentral

88.

Long EK, Olson DM, Bernlohr DA. High-fat diet induces changes in adipose tissue trans-4-oxo-2-nonenal and trans-4-hydroxy-2-nonenal levels in a depot-specific manner. Free Radic Biol Med. 2013;63:390–8. https://doi.org/10.1016/j.freeradbiomed.2013.05.030.CrossRefPubMedPubMedCentral

89.

Shirakawa K, Yan X, Shinmura K, Endo J, Kataoka M, Katsumata Y, et al. Obesity accelerates T cell senescence in murine visceral adipose tissue. J Clin Investig. 2016;126(12):4626–39. https://doi.org/10.1172/JCI88606.CrossRefPubMedPubMedCentral

90.

Lau EYM, Carroll EC, Callender LA, Hood GA, Berryman V, Pattrick M, et al. Type 2 diabetes is associated with the accumulation of senescent T cells. Clin Exp Immunol. 2019;197(2):205–13.CrossRef

91.

Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009;15(8):930–9.CrossRef

92.

Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, et al. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature. 2012;486(7404):549–53.CrossRef

93.

Becker M, Levings MK, Daniel C. Adipose-tissue regulatory T cells: critical players in adipose-immune crosstalk. Eur J Immunol. 2017;47(11):1867–74. https://doi.org/10.1002/eji.201646739.CrossRefPubMed

94.

Arora S, Thompson PJ, Wang Y, Bhattacharyya A, Apostolopoulou H, Hatano R, et al. Invariant natural killer T cells coordinate removal of senescent cells. Med (New York, NY). 2021;2(8):938–50. https://doi.org/10.1016/j.medj.2021.04.014.CrossRef

95.

Piñeiro-Carrero VM, Piñeiro EO. Liver Pediatrics. 2004;113(4 Suppl):1097–106.CrossRef

96.

Bogdanos DP, Gao B, Gershwin ME. Liver immunology. Compr Physiol. 2013;3(2):567–98. https://doi.org/10.1002/cphy.c120011.CrossRefPubMedPubMedCentral

97.

Ogrodnik M, Miwa S, Tchkonia T, Tiniakos D, Wilson CL, Lahat A, et al. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun. 2017;8:15691. https://doi.org/10.1038/ncomms15691.CrossRefPubMedPubMedCentral

98.

Zhang X, Zhou D, Strakovsky R, Zhang Y, Pan YX. Hepatic cellular senescence pathway genes are induced through histone modifications in a diet-induced obese rat model. Am J Physiol Gastrointest Liver Physiol. 2012;302(5):G558–64. https://doi.org/10.1152/ajpgi.00032.2011.CrossRefPubMed

99.

Aravinthan A, Mells G, Allison M, Leathart J, Kotronen A, Yki-Jarvinen H, et al. Gene polymorphisms of cellular senescence marker p21 and disease progression in non-alcohol-related fatty liver disease. Cell Cycle. 2014;13(9):1489–94. https://doi.org/10.4161/cc.28471.CrossRefPubMedPubMedCentral

100.

Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol. 2007;27(24):8807–14. https://doi.org/10.1128/mcb.01636-07.CrossRefPubMedPubMedCentral

101.

Choudhury M, Jonscher KR, Friedman JE. Reduced mitochondrial function in obesity-associated fatty liver: SIRT3 takes on the fat. Aging Albany NY. 2011;3(2):175–8. https://doi.org/10.18632/aging.100289.CrossRefPubMedPubMedCentral

102.

Saisho Y, Butler AE, Manesso E, Elashoff D, Rizza RA, Butler PC. β-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care. 2013;36(1):111–7. https://doi.org/10.2337/dc12-0421.CrossRefPubMed

103.

Kou K, Saisho Y, Jinzaki M, Itoh H. Relationship between body mass index and pancreas volume in Japanese people. Jop. 2014;15(6):626–7. https://doi.org/10.6092/1590-8577/2858.CrossRefPubMed

104.

van Raalte DH, van der Zijl NJ, Diamant M. Pancreatic steatosis in humans: cause or marker of lipotoxicity? Curr Opin Clin Nutr Metab Care. 2010;13(4):478–85. https://doi.org/10.1097/MCO.0b013e32833aa1ef.CrossRefPubMed

105.

van Vliet S, Koh HE, Patterson BW, Yoshino M, LaForest R, Gropler RJ, et al. Obesity is associated with increased basal and postprandial β-cell insulin secretion even in the absence of insulin resistance. Diabetes. 2020;69(10):2112–9. https://doi.org/10.2337/db20-0377.CrossRefPubMedPubMedCentral

106.

Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52(1):102–10. https://doi.org/10.2337/diabetes.52.1.102.CrossRefPubMed

107.

Klein S, Gastaldelli A, Yki-Järvinen H, Scherer PE. Why does obesity cause diabetes? Cell Metab. 2022;34(1):11–20. https://doi.org/10.1016/j.cmet.2021.12.012.CrossRefPubMed

108.

Sone H, Kagawa Y. Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia. 2005;48(1):58–67. https://doi.org/10.1007/s00125-004-1605-2.CrossRefPubMed

109.

Aguayo-Mazzucato C, Andle J, Lee TB Jr, Midha A, Talemal L, Chipashvili V, et al. Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab. 2019;30(1):129-42.e4. https://doi.org/10.1016/j.cmet.2019.05.006.CrossRefPubMedPubMedCentral

110.

Aguayo-Mazzucato C, Midha A. β-cell senescence in type 2 diabetes. Aging Albany NY. 2019;11(22):9967–8. https://doi.org/10.18632/aging.102502.CrossRefPubMedPubMedCentral

111.

Liu Z, Wu KKL, Jiang X, Xu A, Cheng KKY. The role of adipose tissue senescence in obesity- and ageing-related metabolic disorders. Clin Sci (Lond). 2020;134(2):315–30. https://doi.org/10.1042/cs20190966.CrossRef

112.

Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011;11(2):85–97. https://doi.org/10.1038/nri2921.CrossRefPubMedPubMedCentral

113.

Fuchs A, Samovski D, Smith GI, Cifarelli V, Farabi SS, Yoshino J, et al. Associations among adipose tissue immunology, inflammation, exosomes and insulin sensitivity in people with obesity and nonalcoholic fatty liver disease. gastroenterology. 2021;161(3):968–81.e12. https://doi.org/10.1053/j.gastro.2021.05.008.

114.

Snel M, Jonker JT, Schoones J, Lamb H, de Roos A, Pijl H, et al. Ectopic fat and insulin resistance: pathophysiology and effect of diet and lifestyle interventions. Int J Endocrinol. 2012;2012:983814. https://doi.org/10.1155/2012/983814.CrossRefPubMedPubMedCentral

115.

Morino K, Petersen KF, Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes. 2006;55(Supplement_2):S9-S15. https://doi.org/10.2337/db06-S002.

116.

Pederson TM, Kramer DL, Rondinone CM. Serine/threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylation. Diabetes. 2001;50(1):24–31. https://doi.org/10.2337/diabetes.50.1.24.CrossRefPubMed

117.

Tanti JF, Jager J. Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Curr Opin Pharmacol. 2009;9(6):753–62. https://doi.org/10.1016/j.coph.2009.07.004.CrossRefPubMed

118.

Mitrakou A, Kelley D, Veneman T, Jenssen T, Pangburn T, Reilly J, et al. Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes. 1990;39(11):1381–90. https://doi.org/10.2337/diab.39.11.1381.CrossRefPubMed

119.

Schmitz-Peiffer C. Deconstructing the role of PKC Epsilon in glucose homeostasis. Trends Endocrinol Metab. 2020;31(5):344–56. https://doi.org/10.1016/j.tem.2020.01.016.CrossRefPubMed

120.

Birkenfeld AL, Shulman GI. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology. 2014;59(2):713–23. https://doi.org/10.1002/hep.26672.CrossRefPubMed

121.

Paolisso G, Gambardella A, Amato L, Tortoriello R, D’Amore A, Varricchio M, et al. Opposite effects of short- and long-term fatty acid infusion on insulin secretion in healthy subjects. Diabetologia. 1995;38(11):1295–9. https://doi.org/10.1007/BF00401761.CrossRefPubMed

122.

Prentki M, Peyot M-L, Masiello P, Madiraju SRM. Nutrient-induced metabolic stress, adaptation, detoxification, and toxicity in the pancreatic β-cell. Diabetes. 2020;69(3):279–90. https://doi.org/10.2337/dbi19-0014.CrossRefPubMed

123.

Wang L, Wang B, Gasek NS, Zhou Y, Cohn RL, Martin DE, et al. Targeting p21(Cip1) highly expressing cells in adipose tissue alleviates insulin resistance in obesity. Cell Metab. 2022;34(1):75-89.e8. https://doi.org/10.1016/j.cmet.2021.11.002.CrossRefPubMed

124.

Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24(8):1246–56. https://doi.org/10.1038/s41591-018-0092-9.CrossRefPubMedPubMedCentral

Titel: Cellular Senescence in Obesity and Associated Complications: a New Therapeutic Target
verfasst von: Akilavalli Narasimhan
Rafael R. Flores
Christina D. Camell
David A. Bernlohr
Paul D. Robbins
Laura J. Niedernhofer
Publikationsdatum: 14.10.2022
Verlag: Springer US
Erschienen in: Current Diabetes Reports / Ausgabe 11/2022
Print ISSN: 1534-4827
Elektronische ISSN: 1539-0829
DOI: https://doi.org/10.1007/s11892-022-01493-w

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Cellular Senescence in Obesity and Associated Complications: a New Therapeutic Target

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Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

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