细胞衰老与2型糖尿病的相关性研究进展
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摘要
2型糖尿病是目前公认的与衰老相关的重大疾病之一,发病年龄多在50岁以上。细胞衰老是指细胞应激致细胞产生不可逆的永久性细胞周期停滞的状态,是机体衰老的基础。细胞衰老与2型糖尿病的关系相当复杂,衰老的胰岛β细胞在组织内累积引起β细胞功能障碍、脂肪细胞衰老导致脂质代谢障碍等等,衰老的细胞还可间接通过衰老相关分泌表型使个体处于慢性低水平炎症状态,引起2型糖尿病及其并发症;反过来,糖尿病的高血糖、炎症微环境及脂毒性等能够促使细胞衰老并进一步累积。细胞衰老可能既是2型糖尿病发生的原因,又是其发展的结果。靶向细胞衰老的疗法可能为2型糖尿病提供新的治疗策略,现就细胞衰老在2型糖尿病的发生发展中的作用研究进展做一简要综述。
Type 2 diabetes mellitus(T2DM) is commonly considered as an aging and age-associated disease, with the majority of patients being over fifty years old. As a fundamental mechanism of aging, cellular senescence implicates in the development of type 2 diabetes. Physiological changes in diabetes, such as hyperglycemia, chronic inflammation, lipid toxicity lead to accumulation of senescent cells. In turn, cellular senescence, a process that imposes permanent proliferative arrest on cells, can definitely impair pancreatic β cells and cause lipid metabolism dysfunction. In addition, senescent cells can promote chronic, low-grade sterile inflammation through the senescence-associated secretory phenotype(SASP), thus cause development of T2DM and relative complications.Therefore, cellular senescence might be both a cause and a consequence of metabolic changes and tissue damage in diabetes. Treatment targeting cellular senescence may provide a novel and attractive strategy for diabetes therapy.Here the paper aims at the role of cellular senescence in the development of T2DM.
Type 2 diabetes mellitus(T2DM) is commonly considered as an aging and age-associated disease, with the majority of patients being over fifty years old. As a fundamental mechanism of aging, cellular senescence implicates in the development of type 2 diabetes. Physiological changes in diabetes, such as hyperglycemia, chronic inflammation, lipid toxicity lead to accumulation of senescent cells. In turn, cellular senescence, a process that imposes permanent proliferative arrest on cells, can definitely impair pancreatic β cells and cause lipid metabolism dysfunction. In addition, senescent cells can promote chronic, low-grade sterile inflammation through the senescence-associated secretory phenotype(SASP), thus cause development of T2DM and relative complications.Therefore, cellular senescence might be both a cause and a consequence of metabolic changes and tissue damage in diabetes. Treatment targeting cellular senescence may provide a novel and attractive strategy for diabetes therapy.Here the paper aims at the role of cellular senescence in the development of T2DM.
引文
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[12]Morsczeck C,Hullmann M,Reck A,et al.The cell cycle regulator protein P16 and the cellular senescence of dental follicle cells.Mol Cell Biochem,2018,439:45-52
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[14]Haff RF,Swim HE.Serial propagation of 3 strains of rabbit fibroblasts;their susceptibility to infection with vaccinia virus.Proc Soc Exp Biol Med,1956,93:200-4
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[21]Morocutti A,Erle KA,Sethi M,et al.Premature senescence of skin fibroblasts from insulin-dependent diabetic patients with kidney disease.Kidney Int,1996,50:250-6
[22]Chen J,Brodsky SV,Goligorsky DM,et al.Glycated collagen I induces premature senescence-like phenotypic changes in endothelial cells.Circ Res,2002,90:1290-8
[23]Collombat P,Xu X,Heimberg H,et al.Pancreaticβ-cells:from generation to regeneration.Semin Cell Dev Biol,2010,21:838-44
[24]Sone H,Kagawa Y.Pancreaticβcell senescence contributes to the pathogenesis of type 2 diabetes in high-fat dietinduced diabetic mice.Diabetologia,2005,48:58-67
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[26]Weir GC,Bonner-Weir S.Isletβcell mass in diabetes and how it relates to function,birth,and death.Ann N Y Acad Sci,2013,1281:92-105
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[29]Minamino T,Orimo M,Shimizu I,et al.A crucial role for adipose tissue p53 in the regulation of insulin resistance.Nat Med,2009,15:1082-7
[30]Shimizu I,Yoshida Y,Moriya J,et al.Semaphorin3E-induced inflammation contributes to insulin resistance in dietary obesity.Cell Metab,2013,18:491-504
[31]Salminen A,Kauppinen A,Kaarniranta K.Emerging role of NF-κB signaling in the induction of senescenceassociated secretory phenotype(SASP).Cell Signal,2012,24:835-45
[32]Jadhav KS,Dungan CM,Williamson DL.Metformin limits ceramide-induced senescence in C2C12 myoblasts.Mech Ageing Dev,2013,134:548-59
[33]Venable ME,Yin X.Ceramide induces endothelial cell senescence.Cell Biochem Funct,2009,27:547-51
[34]Mouton RE,Venable ME.Ceramide induces expression of the senescence histochemical marker,β-galactosidase,in human fibroblasts.Mech Ageing Dev,2000,113:169-81
[35]Blazer S,Khankin E,Segev Y,et al.High glucose-induced replicative senescence:point of no return and effect of telomerase.Biochem Biophys Res Commun,2002,296:93-101
[36]Yokoi T,Fukuo K,Yasuda O,et al.Apoptosis signalregulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells.Diabetes,2006,55:1660-5
[37]Cramer C,Freisinger E,Jones RK,et al.Persistent high glucose concentrations alter the regenerative potential of mesenchymal stem cells.Stem Cells Dev,2010,19:1875-84
[38]Favero G,Paganelli C,Buffoli B,et al.Endothelium and its alterations in cardiovascular diseases:life style intervention.Biomed Res Int,2014,2014:801896
[39]Hayashi T,Kotani H,Yamaguchi T,et al.Endothelial cellular senescence is inhibited by liver X receptor activation with an additional mechanism for its atheroprotection in diabetes.Proc Natl Acad Sci USA,2014,111:1168-73
[40]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:F1563-73
[41]Minamino T,Miyauchi H,Yoshida T,et al.Endothelial cell senescence in human atherosclerosis:role of telomere in endothelial dysfunction.Circulation,2002,105:1541-4
[42]Ksiazek K,Passos JF,Olijslagers S,et al.Mitochondrial dysfunction is a possible cause of accelerated senescence of mesothelial cells exposed to high glucose.Biochem Biophys Res Commun,2008,366:793-9
[43]Feng X,Gao W,Li Y.Caveolin-1 is involved in high glucose accelerated human glomerular mesangial cell senescence.Korean J Intern Med,2017,32:883-9
[44]Coppe JP,Patil CK,Rodier F,et al.Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.PLoSBiol,2008,6:2853-68
[45]Kuilman T,Peeper DS.Senescence-messaging secretome:SMS-ing cellular stress.Nat Rev Cancer,2009,9:81-94
[46]Orjalo AV,Bhaumik D,Gengler BK,et al.Cell surfacebound IL-1αis an upstream regulator of the senescenceassociated IL-6/IL-8 cytokine network.Proc Natl Acad Sci USA,2009,106:17031-6
[47]Kuilman T,Michaloglou C,Mooi WJ,et al.The essence of senescence.Genes Dev,2010,24:2463-79
[48]Freund A,Orjalo AV,Desprez PY,et al.Inflammatory networks during cellular senescence:causes and consequences.Trends Mol Med,2010,16:238-46
[49]Cooper ME,El-Osta A.Epigenetics:mechanisms and implications for diabetic complications.Circ Res,2010,107:1403-13
[50]Franceschi C,Bonafe M,Valensin S,et al.Inflamm-aging.an evolutionary perspective on immunosenescence.Ann NY Acad Sci,2000,908:244-54
[51]Leiherer A,Mundlein A,Drexel H.Phytochemicals and their impact on adipose tissue inflammation and diabetes.Vasc Pharmacol,2013,58:3-20
[52]Wallach D,Kang TB,Kovalenko A.Concepts of tissue injury and cell death in inflammation:a historical perspective.Nat Rev Immunol,2014,14:51-9
[53]Palmer AK,Tchkonia T,LeBrasseur NK,et al.Cellular senescence in type 2 diabetes:a therapeutic opportunity.Diabetes,2015,64:2289-98
[54]Kohlgruber A,Lynch L.Adipose tissue inflammation in the pathogenesis of type 2 diabetes.Curr Diab Rep,2015,15:92
[55]Xu M,Palmer AK,Ding H,et al.Targeting senescent cells enhances adipogenesis and metabolic function in old age.Elife,2015,4:e12997
[56]Testa R,Ceriello A.Pathogenetic loop between diabetes and cell senescence.Diabetes Care,2007,30:2974-5
[2]Byun HO,Lee YK,Kim JM,et al.From cell senescence to age-related diseases:differential mechanisms of action of senescence-associated secretory phenotypes.BMB Rep,2015,48:549-58
[3]Glance LG,Dick AW,Glantz JC,et al.Rates of major obstetrical complications vary almost fivefold among UShospitals.Health Aff(Millwood),2014,33:1330-6
[4]Perkisas S,Vandewoude M.Where frailty meets diabetes.Diabetes Metab Res Rev,2016,32 Suppl 1:261-7
[5]Flatt T.A new definition of aging?Front Genet,2012,3:148
[6]van Vugt MA,Yaffe MB.Cell cycle re-entry mechanisms after DNA damage checkpoints:giving it some gas to shut off the breaks!Cell Cycle,2010,9:2097-101
[7]Bendris N,Lemmers B,Blanchard JM.Cell cycle,cytoskeleton dynamics and beyond:the many functions of cyclins and CDK inhibitors.Cell Cycle,2015,14:1786-98
[8]Negrini S,Gorgoulis VG,Halazonetis TD.Genomic instability——an evolving hallmark of cancer.Nat Rev Mol Cell Biol,2010,11:220-8
[9]Kung CP,Murphy ME.The role of the p53 tumor suppressor in metabolism and diabetes.J Endocrinol,2016,231:R61-75
[10]d’Adda di Fagagna F.Living on a break:cellular senescence as a DNA-damage response.Nat Rev Cancer,2008,8:512-22
[11]Herbig U,Sedivy JM.Regulation of growth arrest in senescence:telomere damage is not the end of the story.Mech Ageing Dev,2006,127:16-24
[12]Morsczeck C,Hullmann M,Reck A,et al.The cell cycle regulator protein P16 and the cellular senescence of dental follicle cells.Mol Cell Biochem,2018,439:45-52
[13]童坦君,张宗玉.衰老机制及其学说.生理科学进展,2007,38:14-8
[14]Haff RF,Swim HE.Serial propagation of 3 strains of rabbit fibroblasts;their susceptibility to infection with vaccinia virus.Proc Soc Exp Biol Med,1956,93:200-4
[15]Hayflick L.The limited in vitro lifetime of human diploid cell strains.Exp Cell Res,1965,37:614-36
[16]Campisi J,d’Adda di Fagagna F.Cellular senescence:when bad things happen to good cells.Nat Rev Mol Cell Biol,2007,8:729-40
[17]Giaimo S,d’Adda di Fagagna F.Is cellular senescence an example of antagonistic pleiotropy?Aging Cell,2012,11:378-83
[18]Childs BG,Baker DJ,Kirkland JL,et al.Senescence and apoptosis:dueling or complementary cell fates?EMBORep,2014,15:1139-53
[19]Childs BG,Durik M,Baker DJ,et al.Cellular senescence in aging and age-related disease:from mechanisms to therapy.Nat Med,2015,21:1424-35
[20]Wang L,Gao P,Zhang M,et al.Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013.JAMA,2017,317:2515-23
[21]Morocutti A,Erle KA,Sethi M,et al.Premature senescence of skin fibroblasts from insulin-dependent diabetic patients with kidney disease.Kidney Int,1996,50:250-6
[22]Chen J,Brodsky SV,Goligorsky DM,et al.Glycated collagen I induces premature senescence-like phenotypic changes in endothelial cells.Circ Res,2002,90:1290-8
[23]Collombat P,Xu X,Heimberg H,et al.Pancreaticβ-cells:from generation to regeneration.Semin Cell Dev Biol,2010,21:838-44
[24]Sone H,Kagawa Y.Pancreaticβcell senescence contributes to the pathogenesis of type 2 diabetes in high-fat dietinduced diabetic mice.Diabetologia,2005,48:58-67
[25]Aguayo-Mazzucato C,van Haaren M,Mruk M,et al.βcell aging markers have heterogeneous distribution and are induced by insulin resistance.Cell Metab,2017,25:898-910.e5
[26]Weir GC,Bonner-Weir S.Isletβcell mass in diabetes and how it relates to function,birth,and death.Ann N Y Acad Sci,2013,1281:92-105
[27]Guo N,Parry EM,Li LS,et al.Short telomeres compromise-cell signaling and survival.PLoS One,2011,6:e17858
[28]Krishnamurthy J,Ramsey MR,Ligon KL,et al.p16INK4a induces an age-dependent decline in islet regenerative potential.Nature,2006,443:453-7
[29]Minamino T,Orimo M,Shimizu I,et al.A crucial role for adipose tissue p53 in the regulation of insulin resistance.Nat Med,2009,15:1082-7
[30]Shimizu I,Yoshida Y,Moriya J,et al.Semaphorin3E-induced inflammation contributes to insulin resistance in dietary obesity.Cell Metab,2013,18:491-504
[31]Salminen A,Kauppinen A,Kaarniranta K.Emerging role of NF-κB signaling in the induction of senescenceassociated secretory phenotype(SASP).Cell Signal,2012,24:835-45
[32]Jadhav KS,Dungan CM,Williamson DL.Metformin limits ceramide-induced senescence in C2C12 myoblasts.Mech Ageing Dev,2013,134:548-59
[33]Venable ME,Yin X.Ceramide induces endothelial cell senescence.Cell Biochem Funct,2009,27:547-51
[34]Mouton RE,Venable ME.Ceramide induces expression of the senescence histochemical marker,β-galactosidase,in human fibroblasts.Mech Ageing Dev,2000,113:169-81
[35]Blazer S,Khankin E,Segev Y,et al.High glucose-induced replicative senescence:point of no return and effect of telomerase.Biochem Biophys Res Commun,2002,296:93-101
[36]Yokoi T,Fukuo K,Yasuda O,et al.Apoptosis signalregulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells.Diabetes,2006,55:1660-5
[37]Cramer C,Freisinger E,Jones RK,et al.Persistent high glucose concentrations alter the regenerative potential of mesenchymal stem cells.Stem Cells Dev,2010,19:1875-84
[38]Favero G,Paganelli C,Buffoli B,et al.Endothelium and its alterations in cardiovascular diseases:life style intervention.Biomed Res Int,2014,2014:801896
[39]Hayashi T,Kotani H,Yamaguchi T,et al.Endothelial cellular senescence is inhibited by liver X receptor activation with an additional mechanism for its atheroprotection in diabetes.Proc Natl Acad Sci USA,2014,111:1168-73
[40]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:F1563-73
[41]Minamino T,Miyauchi H,Yoshida T,et al.Endothelial cell senescence in human atherosclerosis:role of telomere in endothelial dysfunction.Circulation,2002,105:1541-4
[42]Ksiazek K,Passos JF,Olijslagers S,et al.Mitochondrial dysfunction is a possible cause of accelerated senescence of mesothelial cells exposed to high glucose.Biochem Biophys Res Commun,2008,366:793-9
[43]Feng X,Gao W,Li Y.Caveolin-1 is involved in high glucose accelerated human glomerular mesangial cell senescence.Korean J Intern Med,2017,32:883-9
[44]Coppe JP,Patil CK,Rodier F,et al.Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.PLoSBiol,2008,6:2853-68
[45]Kuilman T,Peeper DS.Senescence-messaging secretome:SMS-ing cellular stress.Nat Rev Cancer,2009,9:81-94
[46]Orjalo AV,Bhaumik D,Gengler BK,et al.Cell surfacebound IL-1αis an upstream regulator of the senescenceassociated IL-6/IL-8 cytokine network.Proc Natl Acad Sci USA,2009,106:17031-6
[47]Kuilman T,Michaloglou C,Mooi WJ,et al.The essence of senescence.Genes Dev,2010,24:2463-79
[48]Freund A,Orjalo AV,Desprez PY,et al.Inflammatory networks during cellular senescence:causes and consequences.Trends Mol Med,2010,16:238-46
[49]Cooper ME,El-Osta A.Epigenetics:mechanisms and implications for diabetic complications.Circ Res,2010,107:1403-13
[50]Franceschi C,Bonafe M,Valensin S,et al.Inflamm-aging.an evolutionary perspective on immunosenescence.Ann NY Acad Sci,2000,908:244-54
[51]Leiherer A,Mundlein A,Drexel H.Phytochemicals and their impact on adipose tissue inflammation and diabetes.Vasc Pharmacol,2013,58:3-20
[52]Wallach D,Kang TB,Kovalenko A.Concepts of tissue injury and cell death in inflammation:a historical perspective.Nat Rev Immunol,2014,14:51-9
[53]Palmer AK,Tchkonia T,LeBrasseur NK,et al.Cellular senescence in type 2 diabetes:a therapeutic opportunity.Diabetes,2015,64:2289-98
[54]Kohlgruber A,Lynch L.Adipose tissue inflammation in the pathogenesis of type 2 diabetes.Curr Diab Rep,2015,15:92
[55]Xu M,Palmer AK,Ding H,et al.Targeting senescent cells enhances adipogenesis and metabolic function in old age.Elife,2015,4:e12997
[56]Testa R,Ceriello A.Pathogenetic loop between diabetes and cell senescence.Diabetes Care,2007,30:2974-5