Metabolic Diseases and Aging

  • Arttatrana PalEmail author
  • Pramod C. RathEmail author


Aging symbolizes a convergence of gradual deterioration of organ or tissue functions in the maintenance of homeostatic veracity of the different physiological processes that serve our body and mind over time. The homeostatic imbalance of body systems, due to anomalous factors, is fertile ground for the development of structural and functional alterations of various biochemical, molecular, cellular, and tissue components and accumulated levels of damaged micro- and macromolecules that eventually influence the increased risk for diverse diseases and aging in human subjects. More importantly, aging starts with birth and accelerates with advancing age, leading to changes in structure and functions of physiological processes that are sometimes obvious but frequently go unnoticed for a long time. The aging process is dynamically affected by genetic, endocrine, metabolic, environmental factors and lifestyle behavior that ultimately lead to metabolic syndrome involving insulin resistance (IR), insulin-like growth factor-1 (IGF-1), changes in body composition, physiological abnormality in secretion of growth hormone (GH), and sex steroids. A number of hypotheses have been proposed to explain the metabolic disorder-related aging progress, such as increasing oxidative-nitrosative stress, accumulation of advanced glycation endproducts (AGEs), shortening and/or loss of telomere, accumulation of damaged DNA in cells, dysfunction of important cellular organelles, action of stress response genes in cellular compartments, and nutrient sensors. However, it is well established that aging is a major risk factor for several pathologies and the progression of various metabolic disturbances, including the progressive development of hyperglycemia, gradual deposition of fat, hyperinsulinemia, hypertension, and diabetes. Also, metabolic disturbances occur in response to changes in lifestyle and the consumption of high-fat-containing diet. A number of interventions designed in animal models and clinics to address features of metabolic syndrome-regulated aging, such as regular exercise, caloric restriction (CR), visceral fat depletion, restoration of cellular antioxidants, and attenuated oxidative-nitrosative stress, have succeeded in improving insulin action, better lifespan and minimizing the aging process. Meanwhile, pharmacologic interventions, anti-AGE therapeutics, attenuated mammalian target of rapamycin (mTOR) signaling, and hormonal perturbations have increased the lifespan of several mammalian species including human subjects without necessarily addressing features of metabolic syndrome-related decline in longevity. A major focus of this chapter will be metabolic syndrome (MS), diabetes and aging.


Metabolic disorder Diabetes Aging Mitochondrial dysfunction Signaling networks Abnormal endocrine function Insulin receptor DNA repair and telomere Strategies to delay aging 


  1. 1.
    Guo S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol. 2014;220:T1–T23.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Kumar P, Swain MM, Pal A. Hyperglycemia-induced inflammation caused down-regulation of 8-oxoG-DNA glycosylase levels in macrophages is mediated by oxidative-nitrosative stress-dependent pathways. Int J Biochem Cell Biol. 2016;73(2016):82–98.PubMedGoogle Scholar
  3. 3.
    Zhang X, Saaddine JB, Chou CF, Cotch MF, Cheng YJ, Geiss LS, et al. Prevalence of diabetic retinopathy in the United States, 2005–2008. JAMA. 2010;304:649–56.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Corriere M, Rooparinesingh N, Rita Rastogi Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;2013(6):10.Google Scholar
  5. 5.
    Stevens LA, Li S, Wang C, Huang C, Becker BN, Bomback AS, et al. Prevalence of CKD and comorbid illness in elderly patients in the United States: results from the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis. 2010;55(3 Suppl 2):S23–33.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Kalyani RR, Saudek CD, Brancati FL, Selvin E. Association of diabetes, comorbidities, and A1C with functional disability in older adults: results from the National Health and Nutrition Examination Survey (NHANES), 1999–2006. Diabetes Care. 1999;33(5):1055–60.Google Scholar
  7. 7.
    Höhn A, König J, Jung T. Metabolic syndrome, redox state, and the proteasomal system. Antioxid Redox Signal. 2016;25:902–17.PubMedGoogle Scholar
  8. 8.
    Barzilai N, Huffman DM, Muzumdar RH, Bartke A. The critical role of metabolic pathways in aging. Diabetes. 2012;61:1315–22.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Huffman DM, Barzilai N. Role of visceral adipose tissue in aging. Biochim Biophys Acta. 2009;1790:1117–23.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Atzmon G, Yang XM, Muzumdar R, Ma XH, Gabriely I, Barzilai N. Differential gene expression between visceral and subcutaneous fat depots. Horm Metab Res. 2002;34:622–8.PubMedGoogle Scholar
  11. 11.
    Muzumdar R, Allison DB, Huffman DM, et al. Visceral adipose tissue modulates mammalian longevity. Aging Cell. 2008;7:438–40.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res. 2005;96:939–49.PubMedGoogle Scholar
  13. 13.
    Evans WJ, Paolisso G, Abbatecola AM, et al. Frailty and muscle metabolism dysregulation in the elderly. Biogerontology. 2010;11:527–36.PubMedGoogle Scholar
  14. 14.
    Lee CG, Boyko EJ, Strotmeyer ES, et al. Osteoporotic Fractures in Men Study Research Group. Association between insulin resistance and lean mass loss and fat mass gain in older men without diabetes mellitus. J Am Geriatr Soc. 2011;59:1217–24.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Rossouw JE, Anderson GL, Prentice RL, et al. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321–33.PubMedGoogle Scholar
  16. 16.
    Rincon M, Muzumdar R, Atzmon G, Barzilai N. The paradox of the insulin/IGF-1 signaling pathway in longevity. Mech Ageing Dev. 2004;125:397–403.PubMedGoogle Scholar
  17. 17.
    Russell SJ, Kahn CR. Endocrine regulation of ageing. Nat Rev Mol Cell Biol. 2007;8:681–91.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Suh Y, Atzmon G, Cho MO, et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A. 2008;105:3438–344257.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Patricia W. Thyroid disease and diabetes. Clin Diab Winter 2000;18(1).Google Scholar
  20. 20.
    Ooka H, Shinkai T. Effects of chronic hyperthyroidism on the lifespan of the rat. Mech Ageing Dev. 1986;33:275–82.PubMedGoogle Scholar
  21. 21.
    Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ, Maghzal GJ, Stocker R, Van Remmen H, Kraegen EW, Cooney GJ, et al. Insulin resistance is a cellular antioxidant defense mechanism. Proc Natl Acad Sci. 2009;106:17787–92.PubMedGoogle Scholar
  22. 22.
    Ilkun O, Wilde N, Tuinei J, Pires KM, Zhu Y, Bugger H, Soto J, Wayment B, Olsen C, Litwin SE, Abel ED. Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome. J Mol Cell Cardiol. 2015;285:104–16.Google Scholar
  23. 23.
    Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin C, Kang L, Rabinovitch PS, Szeto HH, Houmard JA, Cortright RN, Wasserman DH, Neufer PD. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest. 2009;119(3):573–81.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Lee HY, Choi CS, Birkenfeld AL, Alves TC, Jornayvaz FR, Jurczak MJ, Zhang D, Woo DK, Shadel GS, Ladiges W, et al. Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab. 2010;12:668–74.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Moustafa SA, Webster JE, Mattar FE. Effects of aging and antioxidants on glucose transport in rat adipocytes. Gerontology. 1995;41:301–7.PubMedGoogle Scholar
  26. 26.
    Montgomery MK, Nigel TN. Mitochondrial dysfunction and insulin resistance: an update. Endocr Connect. 2015;4(1):R1–R15.PubMedGoogle Scholar
  27. 27.
    Luevano-Contreras C, Chapman-Novakofski K. Dietary advanced glycation end products and aging. Nutrients. 2010;2:1247–65.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Rahmadi A, Steiner N, Munch G. Advanced glycation endproducts as gerontotoxins and biomarkers for carbonyl-based degenerative processes in Alzheimer’s disease. Clin Chem Lab Med. 2011;49:385–91.PubMedGoogle Scholar
  29. 29.
    Gasser A, Forbes JM. Advanced glycation: implications in tissue damage and disease. Protein Pept Lett. 2008;15:385–91.PubMedGoogle Scholar
  30. 30.
    Cox TR, Erler JT. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis Model Mech. 2011;4(2):165–78.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol. 2014;18(1):1–14.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Wang W, Tan M, Yu J, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med. 2015;3(10):136.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Farrukh AS, Sharkey E, Creighton D, et al. Maillard reactions in lens proteins: methylglyoxal-mediated modifications in the rat lens. Exp Eye Res. 2000;70:369–80.Google Scholar
  34. 34.
    Saxena P, Saxena AK, Cui XL, et al. Transition metal-catalyzed oxidation of ascorbate in human cataract extracts: possible role of advanced glycation end products. Invest Ophthalmol Vis Sci. 2000;41:1473–81.PubMedGoogle Scholar
  35. 35.
    Kaji Y, Usui T, Oshika T, et al. Advanced glycation end products in diabetic corneas. Invest Ophthalmol Vis Sci. 2000;41:362–8.PubMedGoogle Scholar
  36. 36.
    Stitt AW. Advanced glycation: an important pathological event in diabetic and age related ocular disease. Br J Ophthalmol. 2001;85:746–53.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Stitt AW, Li YM, Gardiner TA, et al. Advanced glycation endproducts (AGEs) co-localise with AGE-receptors in the retinal vasculature of diabetic and AGE-infused rats. Am J Pathol. 1997;150:523–32.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Bonet-Costa V, Pomatto LC, Davies KJA. The proteasome and oxidative stress in Alzheimer’s disease. Antioxid Redox Signal. 2016;25:886–901.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Kumar P, Raman T, Swain MM, Mishra R, Pal A. Hyperglycemia-induced oxidative-nitrosative stress induces inflammation and neurodegeneration via augmented tuberous sclerosis complex-2 (TSC-2) activation in neuronal cells. Mol Neurobiol. 2017;54:238–54.PubMedGoogle Scholar
  40. 40.
    Greer EL, Brunet A. Signaling network in aging. J Cell Sci. 2008;121(4):407–12.PubMedPubMedCentralGoogle Scholar
  41. 41.
    White MF. Insulin signaling in health and disease. Science. 2003;302:1710–1.PubMedGoogle Scholar
  42. 42.
    Fafalios A, Ma J, Tan X, Stoops J, Luo J, Defrances MC, Zarnegar R. A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism. Nat Med. 2011;17:1577–84.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287:356359.Google Scholar
  44. 44.
    Johnson AM, Olefsky JM. The origins and drivers of insulin resistance. Cell. 2013;152:673–84.PubMedGoogle Scholar
  45. 45.
    Guo S. Molecular basis of insulin resistance: the role of IRS and Foxo1 in the control of diabetes mellitus and its complications. Drug Discov Today Dis Mech. 2013;10:e27–33.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Oshi RL, Lamothe B, Cordonnier N, Mesbah K, Monthioux E, Jami J, Bucchini D. Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality. EMBO J. 1996;15:1542–7.Google Scholar
  47. 47.
    Withers DJ, Burks DJ, Towery HH, Altamuro SL, Flint CL, White MF. Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nat Genet. 1999;23:32–40.PubMedGoogle Scholar
  48. 48.
    Araki E, Lipes MA, Patti ME, Bruning JC, Haag B 3rd, Johnson RS, Kahn CR. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 1994;372:186–90.PubMedGoogle Scholar
  49. 49.
    Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature. 1998;391:900–4.PubMedGoogle Scholar
  50. 50.
    Rask-Madsen C, Kahn CR. Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2012;32:2052–9.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Boucher J, Kahn CR. Differential role of insulin and IGF-1 receptors in brown and white adipose tissue and development of lipoatrophic diabetes. Diabetes. 2013;62:A37.Google Scholar
  52. 52.
    Lin HV, Accili D. Reconstitution of insulin action in muscle, white adipose tissue, and brain of insulin receptor knockout mice fails to rescue diabetes. J Biol Chem. 2011;286:9797–804.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Dong XC, Copps KD, Guo S, Li Y, Kollipara R, DePinho RA, White MF. Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab. 2008;8:65–76.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Qi Y, Xu Z, Zhu Q, Thomas C, Kumar R, Feng H, Dostal DE, White MF, Baker KM, Guo S. Myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by p38alpha MAPK during insulin resistance. Diabetes. 2013;62:3887–900.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Lu M, Wan M, Leavens KF, Chu Q, Monks BR, Fernandez S, Ahima RS, Ueki K, Kahn CR, Birnbaum MJ. Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat Med. 2012;18:388–95.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB 3rd, Kaestner KH, Bartolomei MS, Shulman GI, Birnbaum MJ. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science. 2001;292:1728–31.PubMedGoogle Scholar
  57. 57.
    George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, Soos MA, Murgatroyd PR, Williams RM, Acerini CL, et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science. 2004;304:1325–8.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Evans-Anderson HJ, Alfieri CM, Yutzey KE. Regulation of cardiomyocyte proliferation and myocardial growth during development by FOXO transcription factors. Circ Res. 2008;102:686–94.PubMedGoogle Scholar
  59. 59.
    Battiprolu PK, Hojayev B, Jiang N, Wang ZV, Luo X, Iglewski M, Shelton JM, Gerard RD, Rothermel BA, Gillette TG, et al. Metabolic stress-induced activation of FoxO1 triggers diabetic cardiomyopathy in mice. J Clin Invest. 2012;122:1109–18.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Guo S, Dunn SL, White MF. The reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling. Mol Endocrinol. 2006;20:3389–99.PubMedGoogle Scholar
  61. 61.
    Rui L, Fisher TL, Thomas J, White MF. Regulation of insulin/insulin-like growth factor-1 signaling by proteasome-mediated degradation of insulin receptor substrate-2. J Biol Chem. 2001;276:40362–7.PubMedGoogle Scholar
  62. 62.
    Bae EJ, Xu J, Oh DY, Bandyopadhyay G, Lagakos WS, Keshwani M, Olefsky JM. Liver-specific p70 S6 kinase depletion protects against hepatic steatosis and systemic insulin resistance. J Biol Chem. 2012;287:18769–80.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Hagiwara A, Cornu M, Cybulski N, Polak P, Betz C, Trapani F, Terracciano L, Heim MH, Ruegg MA, Hall MN. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab. 2012;15:725–38.PubMedGoogle Scholar
  64. 64.
    Liu HY, Cao SY, Hong T, Han J, Liu Z, Cao W. Insulin is a stronger inducer of insulin resistance than hyperglycemia in mice with type 1 diabetes mellitus (T1DM). J Biol Chem. 2009;284:27090–100.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Li M, Georgakopoulos D, Lu G, Hester L, Kass DA, Hasday J, Wang Y. p38 MAP kinase mediates inflammatory cytokine induction in cardiomyocytes and extracellular matrix remodeling in heart. Circulation. 2005;111:2494–502.PubMedGoogle Scholar
  66. 66.
    Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116:1793–801.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Bezy O, Tran TT, Pihlajamaki J, Suzuki R, Emanuelli B, Winnay J, Mori MA, Haas J, Biddinger SB, Leitges M, et al. PKCdelta regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans. J Clin Invest. 2011;121:2504–17.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Altomonte J, Richter A, Harbaran S, Suriawinata J, Nakae J, Thung SN, Meseck M, Accili D, Dong H. Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. Am J Physiol Endocrinol Metab. 2003;285:E718–28.PubMedGoogle Scholar
  69. 69.
    Taguchi A, Wartschow LM, White MF. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science. 2007;317:369–72.PubMedGoogle Scholar
  70. 70.
    Sadagurski M, Leshan RL, Patterson C, Rozzo A, Kuznetsova A, Skorupski J, Jones JC, Depinho RA, Myers MG Jr, White MF. IRS2 signaling in LepR-b neurons suppresses FoxO1 to control energy balance independently of leptin action. Cell Metab. 2012;15:703–12.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Boucher J, Kahn CR. Differential role of insulin and IGF-1 receptors in brown and white adipose tissue and development of lipoatrophic diabetes. Diabetes. 2013;62:A37.Google Scholar
  72. 72.
    Romeo GR, Lee J, Shoelson SE. Metabolic syndrome, insulin resistance, and roles of inflammation–mechanisms and therapeutic targets. Arterioscler Thromb Vasc Biol. 2012;32:1771–6.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Ye J, McGuinness OP. Inflammation during obesity is not all bad: evidence from animal and human studies. Am J Physiol Endocrinol Metab. 2013;304:E466–77.PubMedGoogle Scholar
  74. 74.
    Malato Y, Ehedego H, Al-Masaoudi M, Cubero FJ, Bornemann J, Gassler N, Liedtke C, Beraza N, Trautwein C. NF-kappaB essential modifier is required for hepatocyte proliferation and the oval cell reaction after partial hepatectomy in mice. Gastroenterology. 2012;143(6):1597––1608. e1511.Google Scholar
  75. 75.
    Guo S, Copps KD, Dong X, Park S, Cheng Z, Pocai A, Rossetti L, Sajan M, Farese RV, White MF. The Irs1 branch of the insulin signaling cascade plays a dominant role in hepatic nutrient homeostasis. Mol Cell Biol. 2009;29:5070–83.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Rhodes CJ, White MF, Leahy JL, Kahn SE. Direct autocrine action of insulin on beta-cells: does it make physiological sense? Diabetes. 2013;62:2157–63.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Nakae J, Park BC, Accili D. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J Biol Chem. 1999;274:15982–5.PubMedGoogle Scholar
  78. 78.
    Kitamura T. The role of FOXO1 in beta-cell failure and type 2 diabetes mellitus. Nat Rev Endocrinol. 2013;9:615–23.PubMedGoogle Scholar
  79. 79.
    Pehmoller C, Treebak JT, Birk JB, Chen S, Mackintosh C, Hardie DG, Richter EA, Wojtaszewski JF. Genetic disruption of AMPK signaling abolishes both contraction- and insulin-stimulated TBC1D1 phosphorylation and 14-3-3 binding in mouse skeletal muscle. Am J Physiol Endocrinol Metab. 2009;297:E665–75.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Hoehn KL, Turner N, Swarbrick MM, Wilks D, Preston E, Phua Y, Joshi H, Furler SM, Larance M, Hegarty BD, et al. Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole-body energy expenditure or adiposity. Cell Metab. 2010;11:70–6.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Rask-Madsen C, Li Q, Freund B, Feather D, Abramov R, Wu IH, Chen K, Yamamoto-Hiraoka J, Goldenbogen J, Sotiropoulos KB, et al. Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice. Cell Metab. 2010;11:379–89.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Kubota T, Kubota N, Kumagai H, Yamaguchi S, Kozono H, Takahashi T, Inoue M, Itoh S, Takamoto I, Sasako T, et al. Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle. Cell Metab. 2011;13:294–307.PubMedGoogle Scholar
  83. 83.
    Tsuchiya K, Tanaka J, Shuiqing Y, Welch CL, DePinho RA, Tabas I, Tall AR, Goldberg IJ, Accili D. FoxOs integrate pleiotropic actions of insulin in vascular endothelium to protect mice from atherosclerosis. Cell Metab. 2012;15:372–81.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Messmer-Blust AF, Philbrick MJ, Guo S, Wu J, He P, Li J. RTEF-1 attenuates blood glucose levels by regulating insulin-like growth factor binding protein-1 in the endothelium. Circ Res. 2012;111:991–1001.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Ferron M, Wei J, Yoshizawa T, Del Fattore A, DePinho RA, Teti A, Ducy P, Karsenty G. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell. 2010;142:296–308.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Rached MT, Kode A, Silva BC, Jung DY, Gray S, Ong H, Paik JH, DePinho RA, Kim JK, Karsenty G, et al. FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice. J Clin Invest. 2010;120:357–68.PubMedGoogle Scholar
  87. 87.
    Domenighetti AA, Wang Q, Egger M, et al. Angiotensin II-mediated phenotypic cardiomyocyte remodeling leads to age-dependent cardiac dysfunction and failure. Hypertension. 2005;46:426–32.PubMedGoogle Scholar
  88. 88.
    Yan L, Vatner DE, O’Connor JP, et al. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell. 2007;130:247–58.PubMedGoogle Scholar
  89. 89.
    Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ. Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin and IGF-1 levels and increased lifespan. Endocrinology. 2003;144:3799–810.PubMedGoogle Scholar
  90. 90.
    Shiraki-Iida T, Aizawa H, Matsumura Y, Sekine S, Iida A, Anazawa H, Nagai R, Kuro-o M, Nabeshima Y. Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett. 1998;424:6–10.PubMedGoogle Scholar
  91. 91.
    Roth GS, Lane MA, Ingram DK, Mattison JA, Elahi D, Tobin JD, Muller D, Metter EJ. Biomarkers of caloric restriction may predict longevity in humans. Science. 2002;297:811.PubMedGoogle Scholar
  92. 92.
    Hagiwara A, Cornu M, Cybulski N, Polak P, Betz C, Trapani F, Terracciano L, Heim MH, Ruegg MA, Hall MN. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab. 2012;15:725–38.PubMedGoogle Scholar
  93. 93.
    Yecies JL, Zhang HH, Menon S, Liu S, Yecies D, Lipovsky AI, Gorgun C, Kwiatkowski DJ, Hotamisligil GS, Lee CH, et al. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab. 2011;14:21–32.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Feng J, Bussière F, Siegfried HS. Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans. Dev Cell. 2001;1:633–44.PubMedGoogle Scholar
  95. 95.
    Lee YH, Giraud J, Davis RJ, White MF. c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem. 2003;278:2896–902.PubMedGoogle Scholar
  96. 96.
    Kudlow BA, Kennedy BK, Monnat RJ, RJ. Werner and Hutchinson–Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat Rev Mol Cell Biol. 2007;8:394–404.PubMedGoogle Scholar
  97. 97.
    Peter M, Nilsson PM. Genetics: telomere length and the metabolic syndrome—a causal link? Nat Rev Endocrinol. 2014;10:706–7.Google Scholar
  98. 98.
    Zhao J, Zhu Y, Lin J, et al. Short leukocyte telomere length predicts risk of diabetes in American Indians: the strong heart family study. Diabetes. 2013;63:354–62.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Elks CE, Scott RA. The long and short of telomere length and diabetes. Diabetes. 2014;63(1):65–7.PubMedGoogle Scholar
  100. 100.
    Serra V, Grune T, Sitte N, Saretzki G, von Zglinicki T. Telomere length as a marker of oxidative stress in primary human fibroblast cultures. Ann N Y Acad Sci. 2000;908:327–30.PubMedGoogle Scholar
  101. 101.
    Adaikalakoteswari A, Balasubramanyam M, Ravikumar R, Deepa R, Mohan V. Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy. Atherosclerosis. 2007;195:83–9.PubMedGoogle Scholar
  102. 102.
    Olivieri F, Lorenzi M, Antonicelli R, et al. Leukocyte telomere shortening in elderly Type2DM patients with previous myocardial infarction. Atherosclerosis. 2009;206:588–93.PubMedGoogle Scholar
  103. 103.
    Garth L. and Nicolson GL. (2007). Metabolic syndrome and mitochondrial function: molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function J Cell Biochem. 100:1352–1369Google Scholar
  104. 104.
    Nicolson GL, Ellithorpe R. Lipid replacement and antioxidant nutritional therapy for restoring mitochondrial function and reducing fatigue in chronic fatigue syndrome and other fatiguing illnesses. J Chronic Fatigue Syndr. 2006;13:57–68.Google Scholar
  105. 105.
    Suh Y, Atzmon G, Cho MO, et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci. 2008;105:3438–42.PubMedGoogle Scholar
  106. 106.
    Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460:392–5.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Polak P, Hall MN. mTOR and the control of whole body metabolism. Curr Opin Cell Biol. 2009;21:209–18.PubMedGoogle Scholar
  108. 108.
    Fry CS, Drummond MJ, Glynn EL, et al. Aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis. Skelet Muscle. 2011;1:11.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Si S, Pal A, Jagdeep M, Satapathy S. Gold nanostructure materials in diabetes management. J Phys D Appl Phys. 2017;50(13):134003.Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  1. 1.Department of Zoology, School of Life SciencesMahatma Gandhi Central UniversityMotihariIndia
  2. 2.Molecular Biology Laboratory, School of Life SciencesJawaharlal Nehru UniversityNew DelhiIndia

Personalised recommendations