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Current Vascular Pharmacology

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ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

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Review Article

Vascular Dysfunction and Insulin Resistance in Aging

Author(s): Agnieszka Baranowska-Bik* and Wojciech Bik

Volume 17, Issue 5, 2019

Page: [465 - 475] Pages: 11

DOI: 10.2174/1570161117666181129113611

Price: $65

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Abstract

Insulin was discovered in 1922 by Banting and Best. Since that time, extensive research on the mechanisms of insulin activity and action has continued. Currently, it is known that the role of insulin is much greater than simply regulating carbohydrate metabolism. Insulin in physiological concentration is also necessary to maintain normal vascular function.

Insulin resistance is defined as a pathological condition characterized by reduced sensitivity of skeletal muscles, liver, and adipose tissue, to insulin and its downstream metabolic effects under normal serum glucose concentrations. There are also selective forms of insulin resistance with unique features, including vascular insulin resistance. Insulin resistance, both classical and vascular, contributes to vascular impairment resulting in increased risk of cardiovascular disease. Furthermore, in the elderly population, additional factors including redistribution of fat concentrations, low-grade inflammation, and decreased self-repair capacity [or cell senescence] amplify the vascular abnormalities related to insulin resistance.

Keywords: Insulin, insulin resistance, cardiovascular disease, vascular dysfunction, aging, DM.

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[1]
Escribano O, Beneit N, Rubio-Longas C, Lopez-Pastor AR, Gomez-Hernandez A. The role of insulin receptor isoforms in diabetes and its metabolic and vascular complications. J Diabetes Res 2017; 20171403206
[2]
Steiner DF, Park SY, Stoy J, Philipson LH, Bell GI. A brief perspective on insulin production. Diabetes Obes Metab 2009; 11: 189-96.
[3]
Artunc F, Schleicher E, Weigert C, Fritsche A, Stefan N, Haring HU. The impact of insulin resistance on the kidney and vasculature. Nat Rev Nephrol 2016; 12: 721-37.
[4]
Kellerer M, Lammers R, Ermel B, et al. Distinct alpha-subunit structures of human insulin receptor A and B variants determine differences in tyrosine kinase activities. Biochemistry 1992; 31: 4588-96.
[5]
Seino S, Bell GI. Alternative splicing of human insulin receptor messenger RNA. Biochem Biophys Res Commun 1989; 159: 312-6.
[6]
Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 2009; 30: 586-623.
[7]
Westermeier F, Saez T, Arroyo P, et al. Insulin receptor isoforms: an integrated view focused on gestational diabetes mellitus. Diabetes Metab Res Rev 2016; 32: 350-65.
[8]
Frasca F, Pandini G, Sciacca L, et al. The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem 2008; 114: 23-37.
[9]
Belfiore A, Malaguarnera R, Vella V, et al. Insulin receptor isoforms in physiology and disease: an updated view. Endocr Rev 2017; 38: 379-431.
[10]
Nandipati KC, Subramanian S, Agrawal DK. Protein kinases: Mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance. Mol Cell Biochem 2017; 426: 27-45.
[11]
Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: Insights into insulin action. Nat Rev Mol Cell Biol 2006; 7: 85-96.
[12]
Manning BD, Toker A. AKT/PKB Signaling: Navigating the network. Cell 2017; 169: 381-405.
[13]
Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol 2014; 6pii: a009191
[14]
Garg PK, Biggs ML, Kaplan R, Kizer JR, Heckbert SR, Mukamal KJ. Fasting and post-glucose load measures of insulin resistance and risk of incident atrial fibrillation: The Cardiovascular Health Study. Nutr Metab Cardiovasc Dis 2018; 28: 716-21.
[15]
Reho JJ, Rahmouni K. Oxidative and inflammatory signals in obesity-associated vascular abnormalities. Clin Sci (Lond) 2017; 131: 1689-700.
[16]
Petrie JR, Guzik TJ, Touyz RM. Diabetes, hypertension, and cardiovascular disease: Clinical insights and vascular mechanisms. Can J Cardiol 2018; 34: 575-84.
[17]
Frasca D, Blomberg BB, Paganelli R. Aging, obesity, and inflammatory age-related diseases. Front Immunol 2017; 8: 1745.
[18]
Manrique C, Sowers JR. Insulin resistance and skeletal muscle vasculature: Significance, assessment and therapeutic modulators. Cardiorenal Med 2014; 4: 244-56.
[19]
DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: The missing links. The Claude Bernard lecture 2009. Diabetologia 2010; 53: 1270-87.
[20]
Rask-Madsen C, Kahn CR. Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2012; 32: 2052-9.
[21]
Wasserman DH, Wang TJ, Brown NJ. The vasculature in prediabetes. Circ Res 2018; 122: 1135-50.
[22]
Merdzo I, Rutkai I, Tokes T, Sure VN, Katakam PV, Busija DW. The mitochondrial function of the cerebral vasculature in insulin-resistant Zucker obese rats. Am J Physiol Heart Circ Physiol 2016; 310: 830-8.
[23]
Tubbs E, Chanon S, Robert M, et al. Disruption of mitochondria-associated endoplasmic reticulum membrane (MAM) integrity contributes to muscle insulin resistance in mice and humans. Diabetes 2018; 67: 636-50.
[24]
Cade WT. The manifold role of the mitochondria in skeletal muscle insulin resistance. Curr Opin Clin Nutr Metab Care 2018; 21: 267-72.
[25]
Fazakerley DJ, Minard AY, Krycer JR, et al. Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation. J Biol Chem 2018; 293: 7315-28.
[26]
Fisher-Wellman KH, Weber TM, Cathey BL, et al. Mitochondrial respiratory capacity and content are normal in young insulin-resistant obese humans. Diabetes 2014; 63: 132-41.
[27]
Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsoe R, Dela F. Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia 2007; 50: 790-6.
[28]
Alberti KG, Zimmet P, Shaw J. Metabolic syndrome-a new world-wide definition. A consensus statement from the international diabetes federation. Diabet Med 2006; 23: 469-80.
[29]
Kendall DM, Harmel AP. The metabolic syndrome, type 2 diabetes, and cardiovascular disease: Understanding the role of insulin resistance. Am J Manag Care 2002; 8: 635-53.
[30]
Ju SY, Lee JY, Kim DH. Association of metabolic syndrome and its components with all-cause and cardiovascular mortality in the elderly: A meta-analysis of prospective cohort studies. Medicine (Baltimore) 2017; 96e8491
[31]
Guo S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models to disease mechanisms. J Endocrinol 2014; 220: 1-23.
[32]
Muniyappa R, Sowers JR. Role of insulin resistance in endothelial dysfunction. Rev Endocr Metab Disord 2013; 14: 5-12.
[33]
Muniyappa R, Yavuz S. Metabolic actions of angiotensin II and insulin: Aa microvascular endothelial balancing act. Mol Cell Endocrinol 2013; 378: 59-69.
[34]
Underwood PC, Adler GK. The renin angiotensin aldosterone system and insulin resistance in humans. Curr Hypertens Rep 2013; 15: 59-70.
[35]
Manrique C, Lastra G, Sowers JR. New insights into insulin action and resistance in the vasculature. Ann N Y Acad Sci 2014; 1311: 138-50.
[36]
Hitomi H, Kiyomoto H, Nishiyama A, et al. Aldosterone suppresses insulin signaling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells. Hypertension 2007; 50: 750-5.
[37]
Sherajee SJ, Fujita Y, Rafiq K, et al. Aldosterone induces vascular insulin resistance by increasing insulin-like growth factor-1 receptor and hybrid receptor. Arterioscler Thromb Vasc Biol 2012; 32: 257-63.
[38]
Savoia C, Touyz RM, Volpe M, Schiffrin EL. Angiotensin type 2 receptor in resistance arteries of type 2 diabetic hypertensive patients. Hypertension 2007; 49: 341-6.
[39]
Lastra G, Dhuper S, Johnson MS, Sowers JR. Salt, aldosterone, and insulin resistance: Impact on the cardiovascular system. Nat Rev Cardiol 2010; 7: 577-84.
[40]
King GL, Park K, Li Q. Selective insulin resistance and the development of cardiovascular diseases in diabetes: The 2015 Edwin Bierman award lecture. Diabetes 2016; 65: 1462-71.
[41]
Barrett EJ, Wang H, Upchurch CT, Liu Z. Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature. Am J Physiol Endocrinol Metab 2011; 301: 252-63.
[42]
Jialal I, Crettaz M, Hachiya HL, et al. Characterization of the receptors for insulin and the insulin-like growth factors on micro- and macrovascular tissues. Endocrinology 1985; 117: 1222-9.
[43]
Wang H, Wang AX, Barrett EJ. Caveolin-1 is required for vascular endothelial insulin uptake. Am J Physiol Endocrinol Metab 2011; 300: 134-44.
[44]
Wang H, Wang AX, Aylor K, Barrett EJ. Caveolin-1 phosphorylation regulates vascular endothelial insulin uptake and is impaired by insulin resistance in rats. Diabetologia 2015; 58: 1344-53.
[45]
Huang PL. eNOS, metabolic syndrome and cardiovascular disease. Trends Endocrinol Metab 2009; 20: 295-302.
[46]
Grandl G, Wolfrum C. Hemostasis, endothelial stress, inflammation, and the metabolic syndrome. Semin Immunopathol 2018; 40: 215-24.
[47]
Denninger JW, Marletta MA. Guanylate cyclase and the NO/cGMP signaling pathway. Biochim Biophys Acta 1999; 1411: 334-50.
[48]
Schulman IH, Zhou MS, Jaimes EA, Raij L. Dissociation between metabolic and vascular insulin resistance in aging. Am J Physiol Heart Circ Physiol 2007; 293: 853-9.
[49]
Silva L, Subiabre M, Araos J, et al. Insulin/adenosine axis linked signalling. Mol Aspects Med 2017; 55: 45-61.
[50]
Frisbee JC. Remodeling of the skeletal muscle microcirculation increases resistance to perfusion in obese Zucker rats. Am J Physiol Heart Circ Physiol 2003; 285: 104-11.
[51]
Meijer RI, De Boer MP, Groen MR, et al. Insulin-induced microvascular recruitment in skin and muscle are related and both are associated with whole-body glucose uptake. Microcirculation 2012; 19: 494-500.
[52]
Mita T, Azuma K, Goto H, et al. IRS-2 deficiency in macrophages promotes their accumulation in the vascular wall. Biochem Biophys Res Commun 2011; 415: 545-50.
[53]
Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: Analysis of worldwide data. Lancet 2005; 365: 217-23.
[54]
Munoz-Durango N, Fuentes CA, Castillo AE, et al. Role of the renin-angiotensin-aldosterone system beyond blood pressure regulation: Molecular and cellular mechanisms involved in end-organ damage during arterial hypertension. Int J Mol Sci 2016; 17pii: E797
[55]
Bochud M, Nussberger J, Bovet P, et al. Plasma aldosterone is independently associated with the metabolic syndrome. Hypertension 2006; 48: 239-45.
[56]
Raheja P, Price A, Wang Z, et al. Spironolactone prevents chlorthalidone-induced sympathetic activation and insulin resistance in hypertensive patients. Hypertension 2012; 60: 319-25.
[57]
Henriksen EJ, Prasannarong M. The role of the renin-angiotensin system in the development of insulin resistance in skeletal muscle. Mol Cell Endocrinol 2013; 378: 15-22.
[58]
Mazak I, Fiebeler A, Muller DN, et al. Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells. Circulation 2004; 109: 2792-800.
[59]
Selvaraj J, Sathish S, Mayilvanan C, Balasubramanian K. Excess aldosterone-induced changes in insulin signaling molecules and glucose oxidation in gastrocnemius muscle of adult male rat. Mol Cell Biochem 2013; 372: 113-26.
[60]
Luther JM, Luo P, Kreger MT, et al. Aldosterone decreases glucose-stimulated insulin secretion in vivo in mice and in murine islets. Diabetologia 2011; 54: 2152-63.
[61]
Luther JM. Effects of aldosterone on insulin sensitivity and secretion. Steroids 2014; 91: 54-60.
[62]
Samad F, Ruf W. Inflammation, obesity, and thrombosis. Blood 2013; 122: 3415-22.
[63]
Emeis JJ, van den Eijnden-Schrauwen Y, van den Hoogen CM, de Priester W, Westmuckett A, Lupu F. An endothelial storage granule for tissue-type plasminogen activator. J Cell Biol 1997; 139: 245-56.
[64]
Brown NJ, Kim KS, Chen YQ, et al. Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production. J Clin Endocrinol Metab 2000; 85: 336-44.
[65]
Festa A, D’Agostino R, Tracy RP, Haffner SM. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: The insulin resistance atherosclerosis study. Diabetes 2002; 51: 1131-7.
[66]
Li M, Qian M, Xu J. Vascular endothelial regulation of obesity-associated insulin resistance. Front Cardiovasc Med 2017; 4: 51.
[67]
El Husseny MW, Mamdouh M, Shaban S, et al. Adipokines: Potential therapeutic targets for vascular dysfunction in type II diabetes mellitus and obesity. J Diabetes Res 2017; 20178095926
[68]
Antuna-Puente B, Feve B, Fellahi S, Bastard JP. Adipokines: The missing link between insulin resistance and obesity. Diabetes Metab 2008; 34: 2-11.
[69]
Cantley J. The control of insulin secretion by adipokines: Current evidence for adipocyte-beta cell endocrine signalling in metabolic homeostasis. Mamm Genome 2014; 25: 442-54.
[70]
Sorop O, Olver TD, van de Wouw J, et al. The microcirculation: A key player in obesity-associated cardiovascular disease. Cardiovasc Res 2017; 113: 1035-45.
[71]
Flammer AJ, Anderson T. Celermajer, et al. The assessment of endothelial function: from research into clinical practice. Circulation 2012; 126: 753-67.
[72]
De Boer MP, Meijer RI, Wijnstok NJ, et al. Microvascular dysfunction: A potential mechanism in the pathogenesis of obesity-associated insulin resistance and hypertension. Microcirculation 2012; 19: 5-18.
[73]
Tabit CE, Chung WB, Hamburg NM, Vita JA. Endothelial dysfunction in diabetes mellitus: Molecular mechanisms and clinical implications. Rev Endocr Metab Disord 2010; 11: 61-74.
[74]
Brant LCC, Wang N, Ojeda FM, et al. Relations of metabolically healthy and unhealthy obesity to digital vascular function in three community‐based cohorts: A meta‐analysis. J Am Heart Assoc 2017; 6pii:e004199
[75]
Kaminska D, Hamalainen M, Cederberg H, et al. Adipose tissue INSR splicing in humans’ associates with fasting insulin level and is regulated by weight loss. Diabetologia 2014; 57: 347-51.
[76]
Kachur S, Morera R, De Schutter A, Lavie CJ. Cardiovascular risk in patients with prehypertension and the metabolic syndrome. Curr Hypertens Rep 2018; 20: 15.
[77]
Laakso M. Cardiovascular disease in type 2 diabetes from population to man to mechanisms: The Kelly West award lecture 2008. Diabetes Care 2010; 33: 442-9.
[78]
Madonna R, Novo G, Balistreri CR. Cellular and molecular basis of the imbalance between vascular damage and repair in ageing and age-related diseases: As biomarkers and targets for new treatments. Mech Ageing Dev 2016; 159: 22-30.
[79]
von Bibra H, Paulus W, St John Sutton M. Cardiometabolic syndrome and increased risk of heart failure. Curr Heart Fail Rep 2016; 13: 219-29.
[80]
Abel ED, O’Shea KM, Ramasamy R. Insulin resistance: Metabolic mechanisms and consequences in the heart. Arterioscler Thromb Vasc Biol 2012; 32: 2068-76.
[81]
Varma U, Koutsifeli P, Benson VL, Mellor KM, Delbridge LMD. Molecular mechanisms of cardiac pathology in diabetes - experimental insights. Biochim Biophys Acta 2018; 1864: 1949-59.
[82]
Chou E, Suzuma I, Way KJ, et al. Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic States: A possible explanation for impaired collateral formation in cardiac tissue. Circulation 2002; 105: 373-9.
[83]
Farb MG, Karki S, Park SY, et al. WNT5A-JNK regulation of vascular insulin resistance in human obesity. Vasc Med 2016; 21: 489-96.
[84]
Balistreri CR, Candore G, Accardi GB, et al. Centenarian offspring: A model for understanding longevity. Curr Vasc Pharmacol 2014; 12: 718-25.
[85]
Boudina S. Cardiac aging and insulin resistance: Could Insulin/insulin-like Growth Factor (IGF) signaling be used as a therapeutic target? Curr Pharm Des 2013; 19: 5684-94.
[86]
Barzilai N, Ferrucci L. Insulin resistance and aging: A cause or a protective response? J Gerontol A Biol Sci Med Sci 2012; 67: 1329-31.
[87]
Wilson PW, Kannel WB. Obesity, diabetes, and risk of cardiovascular disease in the elderly. Am J Geriatr Cardiol 2002; 11: 119-23.
[88]
Li QX, Xiong ZY, Hu BP, et al. Aging-associated insulin resistance predisposes to hypertension and its reversal by exercise: The role of vascular vasorelaxation to insulin. Basic Res Cardiol 2009; 104: 269-84.
[89]
Kalogeropoulos A, Georgiopoulou V, Harris TB, et al. Glycemic status and incident heart failure in elderly without history of diabetes mellitus: The health, aging, and body composition study. J Card Fail 2009; 15: 593-9.
[90]
Inuzuka Y, Okuda J, Kawashima T, et al. Suppression of phosphoinositide 3-kinase prevents cardiac aging in mice. Circulation 2009; 120: 1695-703.
[91]
Olivieri F, Recchioni R, Marcheselli F, et al. Cellular senescence in cardiovascular diseases: potential age-related mechanisms and implications for treatment. Curr Pharm Des 2013; 19: 1710-9.
[92]
Madonna R, Renna FV, Cellini C, et al. Age-dependent impairment of number and angiogenic potential of adipose tissue-derived progenitor cells. Eur J Clin Invest 2011; 41: 126-33.
[93]
Cepeda M, Muka T, Ikram MA, Franco OH, Schoufour JD. Seasonality of insulin resistance, glucose, and insulin among middle-aged and elderly population: The rotterdam study. J Clin Endocrinol Metab 2018; 103: 946-55.
[94]
Carvalho-Filho MA, Ueno M, Hirabara SM, et al. S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt: A novel mechanism of insulin resistance. Diabetes 2005; 54: 959-67.
[95]
Evans JL, Goldfine ID. Aging and insulin resistance: Just say iNOS. Diabetes 2013; 62: 346-8.
[96]
Ropelle ER, Pauli JR, Cintra DE, et al. Targeted disruption of inducible nitric oxide synthase protects against aging, S-nitrosation, and insulin resistance in muscle of male mice. Diabetes 2013; 62: 466-70.
[97]
Bartke A. Insulin and aging. Cell Cycle 2008; 7: 3338-43.
[98]
Nabuco HCG, Tomeleri CM, Sugihara Junior P, et al. Lower protein and higher carbohydrate intake are related with altering metabolic syndrome components in elderly women: A cross-sectional study. Exp Gerontol 2018; 103: 132-7.
[99]
Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European working group on Sarcopenia in older people. Age Ageing 2010; 39: 412-23.
[100]
Sepe A, Tchkonia T, Thomou T, Zamboni M, Kirkland JL. Aging and regional differences in fat cell progenitors - a mini-review. Gerontology 2011; 57: 66-75.
[101]
Stefanska A, Bergmann K, Sypniewska G. Metabolic syndrome and menopause: Pathophysiology, clinical and diagnostic significance. Adv Clin Chem 2015; 72: 1-75.
[102]
Fonseca MIH, da Silva IT, Ferreira SRG. Impact of menopause and diabetes on atherogenic lipid profile: Is it worth to analyse lipoprotein subfractions to assess cardiovascular risk in women? Diabetol Metab Syndr 2017; 9: 22.
[103]
Hallajzadeh J, Khoramdad M, Izadi N, et al. Metabolic syndrome and its components in premenopausal and postmenopausal women: A comprehensive systematic review and meta-analysis on observational studies. Menopause 2018; 25: 1155-64.
[104]
Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB. The metabolic syndrome: Prevalence and associated risk factor findings in the US population from the third national health and nutrition examination survey, 1988-1994. Arch Intern Med 2003; 163: 427-36.
[105]
Facchini FS, Hua N, Abbasi F, Reaven GM. Insulin resistance as a predictor of age-related diseases. J Clin Endocrinol Metab 2001; 86: 3574-8.
[106]
Park MH, Kim DH, Lee EK, et al. Age-related inflammation and insulin resistance: A review of their intricate interdependency. Arch Pharm Res 2014; 37: 1507-14.
[107]
Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 2012; 18: 363-74.
[108]
Stout MB, Justice JN, Nicklas BJ, Kirkland JL. Physiological aging: links among adipose tissue dysfunction, diabetes, and frailty. Physiology (Bethesda) 2017; 32: 9-19.
[109]
Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 2014; 69: 4-9.
[110]
Stump CS, Short KR, Bigelow ML, Schimke JM, Nair KS. Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci USA 2003; 100: 7996-01.
[111]
Petersen KF, Befroy D, Dufour S, et al. Mitochondrial dysfunction in the elderly: Possible role in insulin resistance. Science 2003; 300: 1140-2.
[112]
Park D, Lee EK, Jang EJ, et al. Identification of the dichotomous role of age-related LCK in calorie restriction revealed by integrative analysis of cDNA microarray and interactome. Age (Dordr) 2013; 35: 1045-60.
[113]
Hong SE, Heo HS, Kim DH, et al. Revealing system-level correlations between aging and calorie restriction using a mouse transcriptome. Age (Dordr) 2010; 32: 15-30.
[114]
Frasca D, Blomberg BB. Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology 2016; 17: 7-19.
[115]
Xu M, Palmer AK, Ding H, et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife 2015; 4e12997
[116]
Palmer AK, Tchkonia T, LeBrasseur NK, Chini EN, Xu M, Kirkland JL. Cellular senescence in type 2 diabetes: A therapeutic opportunity. Diabetes 2015; 64: 2289-98.
[117]
Atzmon G, Schechter C, Greiner W, Davidson D, Rennert G, Barzilai N. Clinical phenotype of families with longevity. J Am Geriatr Soc 2004; 52: 274-7.
[118]
Kojima T, Kamei H, Aizu T, et al. Association analysis between longevity in the Japanese population and polymorphic variants of genes involved in insulin and insulin-like growth factor 1 signaling pathways. Exp Gerontol 2004; 39: 1595-8.
[119]
Barbieri M, Bonafe M, Rizzo MR, et al. Gender specific association of genetic variation in peroxisome proliferator-activated receptor (PPAR) gamma-2 with longevity. Exp Gerontol 2004; 39: 1095-100.

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