Insulin, aging, and the brain: Mechanisms and implications

Frontiers in Endocrinology

Volumn 6, Issue FEB, 2015, Pages

  Akintola, Abimbola A ^a   van Heemst, Diana ^a  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Accelerated aging; Brain; Delayed aging; Inflammation; Insulin; Insulin receptors; Longevity

Indexed keywords

FORKHEAD TRANSCRIPTION FACTOR; GLUCOSE TRANSPORTER 4; GLYCOGEN SYNTHASE KINASE 3; INSULIN; INSULIN RECEPTOR; INSULIN RECEPTOR SUBSTRATE; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3, 4, 5 TRISPHOSPHATE; PREPROINSULIN; PROTEIN KINASE B; SOMATOMEDIN C; STRESS ACTIVATED PROTEIN KINASE; UNCLASSIFIED DRUG;

AGING; BLOOD BRAIN BARRIER; BRAIN FUNCTION; BRAIN LEVEL; BRAIN STEM RESPONSE; CEREBROSPINAL FLUID; COGNITION; DIABETES MELLITUS; DIABETIC OBESITY; FOOD INTAKE; GLUCOSE HOMEOSTASIS; GLUCOSE METABOLISM; HORMONE ACTION; HUMAN; HYPERINSULINEMIA; HYPOTHALAMUS; INSULIN BLOOD LEVEL; INSULIN BRAIN LEVEL; INSULIN HYPOGLYCEMIA; INSULIN SENSITIVITY; INSULIN SYNTHESIS; LONGEVITY; MEMBRANE DEPOLARIZATION; METABOLIC REGULATION; METABOLIC SYNDROME X; NERVE CELL PLASTICITY; NONHUMAN; OXIDATIVE STRESS; PROTEIN SYNTHESIS REGULATION; REVIEW; SIGNAL TRANSDUCTION;

EID: 84926652116     PISSN: None     EISSN: 16642392     Source Type: Journal    
DOI: 10.3389/fendo.2015.00013     Document Type: Review

References (174)

1. Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature (2003) 421(6919):182-7. doi:10.1038/nature01298
2. Iser WB, Gami MS, Wolkow CA. Insulin signaling in Caenorhabditis elegans regulates both endocrine-like and cell-autonomous outputs. Dev Biol (2007) 303(2):434-47. doi:10.1016/j.ydbio.2006.04.467
3. Bartke A, Chandrashekar V, Dominici F, Turyn D, Kinney B, Steger R, et al. Insulin-like growth factor 1 (IGF-1) and aging: controversies and new insights. Biogerontology (2003) 4(1):1-8. doi:10.1023/A:1022448532248
4. Bluher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science (2003) 299(5606):572-4. doi:10.1126/science.1078223
5. Fulop T, Larbi A, Douziech N. Insulin receptor and ageing. Pathol Biol (2003) 51(10):574-80. doi:10.1016/j.patbio.2003.09.007
6. Fulop T Jr, Nagy JT, Worum I, Foris G, Mudri K, Varga P, et al. Glucose intolerance and insulin resistance with aging-studies on insulin receptors and post-receptor events. Arch Gerontol Geriatr (1987) 6(2):107-15. doi:10.1016/0167-4943(87)90003-3
7. Rozing MP, Westendorp RG, Frolich M, de Craen AJ, Beekman M, Heijmans BT, et al. Human insulin/IGF-1 and familial longevity at middle age. Aging (2009) 1(8):714-22.
8. Wijsman CA, Rozing MP, Streefland TC, le Cessie S, Mooijaart SP, Slagboom PE, et al. Familial longevity is marked by enhanced insulin sensitivity. Aging Cell (2011) 10(1):114-21. doi:10.1111/j.1474-9726.2010.00650.x
9. Barbieri M, Gambardella A, Paolisso G, Varricchio M. Metabolic aspects of the extreme longevity. Exp Gerontol (2008) 43(2):74-8. doi:10.1016/j.exger.2007.06.003
10. Barbieri M, Rizzo MR, Manzella D, Grella R, Ragno E, Carbonella M, et al. Glucose regulation and oxidative stress in healthy centenarians. Exp Gerontol (2003) 38(1-2):137-43. doi:10.1016/S0531-5565(02)00153-5
11. Paolisso G, Gambardella A, Ammendola S, D'Amore A, Balbi V, Varricchio M, et al. Glucose tolerance and insulin action in healthy centenarians. Am J Physiol (1996) 270(5 Pt 1):E890-4.
12. Duarte AI, Moreira PI, Oliveira CR. Insulin in central nervous system: more than just a peripheral hormone. J Aging Res (2012) 2012:384017. doi:10.1155/2012/384017
13. Schwartz MW, Seeley RJ, Tschop MH, Woods SC, Morton GJ, Myers MG, et al. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature (2013) 503(7474):59-66. doi:10.1038/nature12709
14. Gerozissis K. Brain insulin: regulation, mechanisms of action and functions. Cell Mol Neurobiol (2003) 23(1):1-25. doi:10.1023/A:1025021529347
15. Derakhshan F, Toth C. Insulin and the brain. Curr Diabetes Rev (2013) 9(2):102-16. doi:10.2174/1573399811309020002
16. Anisimov VN. Insulin/IGF-1 signaling pathway driving aging and cancer as a target for pharmacological intervention. Exp Gerontol (2003) 38(10):1041-9. doi:10.1016/S0531-5565(03)00169-4
17. Wolkow CA, Kimura KD, Lee MS, Ruvkun G. Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science (2000) 290(5489):147-50. doi:10.1126/science.290.5489.147
18. Taguchi A, Wartschow LM, White MF. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science (2007) 317(5836):369-72. doi:10.1126/science.1142179
19. Houston DK, Nicklas BJ, Zizza CA. Weighty concerns: the growing prevalence of obesity among older adults. J Am Diet Assoc (2009) 109(11):1886-95. doi:10.1016/j.jada.2009.08.014
20. Mozumdar A, Liguori G. Persistent increase of prevalence of metabolic syndrome among U.S. adults: NHANES III to NHANES 1999-2006. Diabetes Care (2011) 34(1):216-9. doi:10.2337/dc10-0879
21. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention (2011).
22. Alzheimer's Association. 2011 Alzheimer's disease facts and figures. Alzheimer Dement (2011) 7(2):208-44. doi:10.1016/j.jalz.2011.02.004
23. Schwartz MW, Porte D Jr. Diabetes, obesity, and the brain. Science (2005) 307(5708):375-9. doi:10.1126/science.1104344
24. Sherlock M, Toogood AA. Aging and the growth hormone/insulin like growth factor-I axis. Pituitary (2007) 10(2):189-203. doi:10.1007/s11102-007-0039-5
25. Frolich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer S, et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. J Neural Transm (1998) 105(4-5):423-38. doi:10.1007/s007020050068
26. Zeyda M, Stulnig TM. Obesity, inflammation, and insulin resistance-a mini-review. Gerontology (2009) 55(4):379-86. doi:10.1159/000212758
27. Haugaard N, Vaughan M, Haugaard ES, Stadie WC. Studies of radioactive injected labeled insulin. J Biol Chem (1954) 208(2):549-63.
28. Margolis RU, Altszuler N. Insulin in the cerebrospinal fluid. Nature (1967) 215(5108):1375-6. doi:10.1038/2151375a0
29. Havrankova J, Roth J, Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature (1978) 272(5656):827-9. doi:10.1038/272827a0
30. Havrankova J, Schmechel D, Roth J, Brownstein M. Identification of insulin in rat brain. Proc Natl Acad Sci U S A (1978) 75(11):5737-41. doi:10.1073/pnas.75.11.5737
31. Dorn A, Rinne A, Bernstein HG, Hahn HJ, Ziegler M. Insulin and C-peptide in human brain neurons (insulin/C-peptide/brain peptides/immunohistochemistry/radioimmunoassay). J Hirnforsch (1983) 24(5):495-9.
32. Dorn A, Bernstein HG, Rinne A, Ziegler M, Hahn HJ, Ansorge S. Insulin-and glucagon-like peptides in the brain. Anat Rec (1983) 207(1):69-77. doi:10.1002/ar.1092070108
33. Baskin DG, Woods SC, West DB, van Houten M, Posner BI, Dorsa DM, et al. Immunocytochemical detection of insulin in rat hypothalamus and its possible uptake from cerebrospinal fluid. Endocrinology (1983) 113(5):1818-25. doi:10.1210/endo-113-5-1818
34. Wallum BJ, Taborsky GJ Jr, Porte D Jr, Figlewicz DP, Jacobson L, Beard JC, et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J Clin Endocrinol Metab (1987) 64(1):190-4. doi:10.1210/jcem-64-1-190
35. Schechter R, Whitmire J, Holtzclaw L, George M, Harlow R, Devaskar SU. Developmental regulation of insulin in the mammalian central nervous system. Brain Res (1992) 582(1):27-37. doi:10.1016/0006-8993(92)90313-X
36. Hallschmid M, Schultes B. Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders? Diabetologia (2009) 52(11):2264-9. doi:10.1007/s00125-009-1501-x
37. Abraham MA, Filippi BM, Kang GM, Kim MS, Lam TK. Insulin action in the hypothalamus and dorsal vagal complex. Exp Physiol (2014) 99(9):1104-9. doi:10.1113/expphysiol.2014.079962
38. Frank HJ, Pardridge WM. A direct in vitro demonstration of insulin binding to isolated brain microvessels. Diabetes (1981) 30(9):757-61. doi:10.2337/diab.30.9.757
39. Havrankova J, Roth J, Brownstein MJ. Concentrations of insulin and insulin receptors in the brain are independent of peripheral insulin levels. Studies of obese and streptozotocin-treated rodents. J Clin Invest (1979) 64(2):636-42. doi:10.1172/JCI109504
40. Schechter R, Beju D, Gaffney T, Schaefer F, Whetsell L. Preproinsulin I and II mRNAs and insulin electron microscopic immunoreaction are present within the rat fetal nervous system. Brain Res (1996) 736(1-2):16-27. doi:10.1016/0006-8993(96)00664-6
41. Banks WA, Kastin AJ. Differential permeability of the blood-brain barrier to two pancreatic peptides: insulin and amylin. Peptides (1998) 19(5):883-9. doi:10.1016/S0196-9781(98)00018-7
42. Devaskar SU, Holekamp N, Karycki L, Devaskar UP. Ontogenesis of the insulin receptor in the rabbit brain. Horm Res (1986) 24(4):319-27. doi:10.1159/000180573
43. Banks WA. The source of cerebral insulin. Eur J Pharmacol (2004) 490(1-3):5-12. doi:10.1016/j.ejphar.2004.02.040
44. Baura GD, Foster DM, Porte D Jr, Kahn SE, Bergman RN, Cobelli C, et al. Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J Clin Invest (1993) 92(4):1824-30. doi:10.1172/JCI116773
45. Duffy KR, Pardridge WM. Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res (1987) 420(1):32-8. doi:10.1016/0006-8993(87)90236-8
46. Frank HJ, Jankovic-Vokes T, Pardridge WM, Morris WL. Enhanced insulin binding to blood-brain barrier in vivo and to brain microvessels in vitro in newborn rabbits. Diabetes (1985) 34(8):728-33. doi:10.2337/diab.34.8.728
47. Frank HJ, Pardridge WM. Insulin binding to brain microvessels. Adv Metab Disord (1983) 10:291-302. doi:10.1016/B978-0-12-027310-2.50016-5
48. Freude S, Plum L, Schnitker J, Leeser U, Udelhoven M, Krone W, et al. Peripheral hyperinsulinemia promotes tau phosphorylation in vivo. Diabetes (2005) 54(12):3343-8. doi:10.2337/diabetes.54.12.3343
49. Pardridge WM. Receptor-mediated peptide transport through the blood-brain barrier. Endocr Rev (1986) 7(3):314-30. doi:10.1210/edrv-7-3-314
50. Pardridge WM, Eisenberg J, Yang J. Human blood-brain barrier insulin receptor. J Neurochem (1985) 44(6):1771-8. doi:10.1111/j.1471-4159.1985.tb07167.x
51. Banks WA, Jaspan JB, Kastin AJ. Selective, physiological transport of insulin across the blood-brain barrier: novel demonstration by species-specific radioimmunoassays. Peptides (1997) 18(8):1257-62. doi:10.1016/S0196-9781(97)00198-8
52. Porte D Jr, Seeley RJ, Woods SC, Baskin DG, Figlewicz DP, Schwartz MW. Obesity, diabetes and the central nervous system. Diabetologia (1998) 41(8):863-81. doi:10.1007/s001250051002
53. Sankar R, Thamotharan S, Shin D, Moley KH, Devaskar SU. Insulin-responsive glucose transporters-GLUT8 and GLUT4 are expressed in the developing mammalian brain. Brain Res Mol Brain Res (2002) 107(2):157-65. doi:10.1016/S0169-328X(02)00487-4
54. Weindl A, Sofroniew MV. Relation of neuropeptides to mammalian circumventricular organs. Adv Biochem Psychopharmacol (1981) 28:303-20.
55. Pardridge WM. Transport of insulin-related peptides and glucose across the blood-brain barrier. Ann N Y Acad Sci (1993) 692:126-37. doi:10.1111/j.1749-6632.1993.tb26211.x
56. Blasberg RG, Patlak C, Fenstermacher JD. Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion. J Pharmacol Exp Ther (1975) 195(1):73-83.
57. Burbach JP. Neuropeptides from concept to online database www.neuropeptides.nl. Eur J Pharmacol (2010) 626(1):27-48. doi:10.1016/j.ejphar.2009.10.015
58. Clarke DW, Mudd L, Boyd FT Jr, Fields M, Raizada MK. Insulin is released from rat brain neuronal cells in culture. J Neurochem (1986) 47(3):831-6. doi:10.1111/j.1471-4159.1986.tb00686.x
59. Schechter R, Yanovitch T, Abboud M, Johnson G III, Gaskins J. Effects of brain endogenous insulin on neurofilament and MAPK in fetal rat neuron cell cultures. Brain Res (1998) 808(2):270-8. doi:10.1016/S0006-8993(98)00842-7
60. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol (2006) 7(2):85-96. doi:10.1038/nrm1837
61. Eijkelenboom A, Burgering BM. FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol (2013) 14(2):83-97. doi:10.1038/nrm3507
62. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature (2001) 414(6865):799-806. doi:10.1038/414799a
63. Heidenreich KA, Zahniser NR, Berhanu P, Brandenburg D, Olefsky JM. Structural differences between insulin receptors in the brain and peripheral target tissues. J Biol Chem (1983) 258(14):8527-30.
64. Boyd FT Jr, Raizada MK. Effects of insulin and tunicamycin on neuronal insulin receptors in culture. Am J Physiol (1983) 245(3):C283-7.
65. Zahniser NR, Goens MB, Hanaway PJ, Vinych JV. Characterization and regulation of insulin receptors in rat brain. J Neurochem (1984) 42(5):1354-62. doi:10.1111/j.1471-4159.1984.tb02795.x
66. van Houten M, Posner BI. Insulin binds to brain blood vessels in vivo. Nature (1979) 282(5739):623-5. doi:10.1038/282623a0
67. Raizada MK, Yang JW, Fellows RE. Binding of [125I]insulin to specific receptors and stimulation of nucleotide incorporation in cells cultured from rat brain. Brain Res (1980) 200(2):389-400. doi:10.1016/0006-8993(80)90929-4
68. van Houten M, Posner BI, Kopriwa BM, Brawer JR. Insulin binding sites localized to nerve terminals in rat median eminence and arcuate nucleus. Science (1980) 207(4435):1081-3. doi:10.1126/science.6986652
69. Wickelgren I. Tracking insulin to the mind. Science (1998) 280(5363):517-9. doi:10.1126/science.280.5363.517
70. Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, et al. Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem (1999) 274(49):34893-902. doi:10.1074/jbc.274.49.34893
71. Zhao WQ, Chen H, Quon MJ, Alkon DL. Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol (2004) 490(1-3):71-81. doi:10.1016/j.ejphar.2004.02.045
72. de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease. J Alzheimer Dis (2005) 7(1):45-61.
73. Avogaro A, de Kreutzenberg SV, Fadini GP. Insulin signaling and life span. Pflugers Arch (2010) 459(2):301-14. doi:10.1007/s00424-009-0721-8
74. Plum L, Schubert M, Bruning JC. The role of insulin receptor signaling in the brain. Trends Endocrinol Metab (2005) 16(2):59-65. doi:10.1016/j.tem.2005.01.008
75. Schulingkamp RJ, Pagano TC, Hung D, Raffa RB. Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci Biobehav Rev (2000) 24(8):855-72. doi:10.1016/S0149-7634(00)00040-3
76. Dickson BJ. Development. Wiring the brain with insulin. Science (2003) 300(5618):440-1. doi:10.1126/science.1084513
77. Song J, Wu L, Chen Z, Kohanski RA, Pick L. Axons guided by insulin receptor in Drosophila visual system. Science (2003) 300(5618):502-5. doi:10.1126/science.1081203
78. Torres-Aleman I. Insulin-like growth factors as mediators of functional plasticity in the adult brain. Horm Metab Res (1999) 31(2-3):114-9. doi:10.1055/s-2007-978707
79. Recio-Pinto E, Rechler MM, Ishii DN. Effects of insulin, insulin-like growth factor-II, and nerve growth factor on neurite formation and survival in cultured sympathetic and sensory neurons. J Neurosci (1986) 6(5):1211-9.
80. Puro DG, Agardh E. Insulin-mediated regulation of neuronal maturation. Science (1984) 225(4667):1170-2. doi:10.1126/science.6089343
81. Sugimoto K, Baba M, Suda T, Yasujima M, Yagihashi S. Peripheral neuropathy and microangiopathy in rats with insulinoma: association with chronic hyperinsulinemia. Diabetes Metab Res Rev (2003) 19(5):392-400. doi:10.1002/dmrr.395
82. Kremerskothen J, Wendholt D, Teber I, Barnekow A. Insulin-induced expression of the activity-regulated cytoskeleton-associated gene (ARC) in human neuroblastoma cells requires p21(ras), mitogen-activated protein kinase/extracellular regulated kinase and src tyrosine kinases but is protein kinase C-independent. Neurosci Lett (2002) 321(3):153-6.
83. Palovcik RA, Phillips MI, Kappy MS, Raizada MK. Insulin inhibits pyramidal neurons in hippocampal slices. Brain Res (1984) 309(1):187-91. doi:10.1016/0006-8993(84)91028-X
84. Barbaccia ML, Chuang DM, Costa E. Is insulin a neuromodulator? Adv Biochem Psychopharmacol (1982) 33:511-8.
85. Boyd FT Jr, Clarke DW, Muther TF, Raizada MK. Insulin receptors and insulin modulation of norepinephrine uptake in neuronal cultures from rat brain. J Biol Chem (1985) 260(29):15880-4.
86. Baskin DG, Brewitt B, Davidson DA, Corp E, Paquette T, Figlewicz DP, et al. Quantitative autoradiographic evidence for insulin receptors in the choroid plexus of the rat brain. Diabetes (1986) 35(2):246-9. doi:10.2337/diab.35.2.246
87. Miller DW, Keller BT, Borchardt RT. Identification and distribution of insulin receptors on cultured bovine brain microvessel endothelial cells: possible function in insulin processing in the blood-brain barrier. J Cell Physiol (1994) 161(2):333-41. doi:10.1002/jcp.1041610218
88. Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science (1997) 275(5300):661-5. doi:10.1126/science.275.5300.661
89. Takadera T, Sakura N, Mohri T, Hashimoto T. Toxic effect of a beta-amyloid peptide (beta 22-35) on the hippocampal neuron and its prevention. Neurosci Lett (1993) 161(1):41-4. doi:10.1016/0304-3940(93)90135-8
90. Tanaka M, Sawada M, Yoshida S, Hanaoka F, Marunouchi T. Insulin prevents apoptosis of external granular layer neurons in rat cerebellar slice cultures. Neurosci Lett (1995) 199(1):37-40. doi:10.1016/0304-3940(95)12009-S
91. Kern W, Peters A, Fruehwald-Schultes B, Deininger E, Born J, Fehm HL. Improving influence of insulin on cognitive functions in humans. Neuroendocrinology (2001) 74(4):270-80. doi:10.1159/000054694
92. Hallschmid M, Benedict C, Schultes B, Fehm HL, Born J, Kern W. Intranasal insulin reduces body fat in men but not in women. Diabetes (2004) 53(11):3024-9. doi:10.2337/diabetes.53.11.3024
93. Benedict C, Hallschmid M, Schultes B, Born J, Kern W. Intranasal insulin to improve memory function in humans. Neuroendocrinology (2007) 86(2):136-42. doi:10.1159/000106378
94. Woods SC, Lotter EC, McKay LD, Porte D Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature (1979) 282(5738):503-5. doi:10.1038/282503a0
95. Eikelis N, Esler M. The neurobiology of human obesity. Exp Physiol (2005) 90(5):673-82. doi:10.1113/expphysiol.2005.031385
96. Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature (2005) 434(7036):1026-31. doi:10.1038/nature03439
97. Spanswick D, Smith MA, Mirshamsi S, Routh VH, Ashford ML. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci (2000) 3(8):757-8. doi:10.1038/77660
98. Vidarsdottir S, Smeets PA, Eichelsheim DL, van Osch MJ, Viergever MA, Romijn JA, et al. Glucose ingestion fails to inhibit hypothalamic neuronal activity in patients with type 2 diabetes. Diabetes (2007) 56(10):2547-50. doi:10.2337/db07-0193
99. Schwartz MW, Sipols AJ, Marks JL, Sanacora G, White JD, Scheurink A, et al. Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology (1992) 130(6):3608-16. doi:10.1210/en.130.6.3608
100. Cotero VE, Routh VH. Insulin blunts the response of glucose-excited neurons in the ventrolateral-ventromedial hypothalamic nucleus to decreased glucose. Am J Physiol Endocrinol Metab (2009) 296(5):E1101-9. doi:10.1152/ajpendo.90932.2008
101. Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, et al. Role of brain insulin receptor in control of body weight and reproduction. Science (2000) 289(5487):2122-5. doi:10.1126/science.289.5487.2122
102. Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med (2002) 8(12):1376-82. doi:10.1038/nm1202-798
103. Kaiyala KJ, Prigeon RL, Kahn SE, Woods SC, Schwartz MW. Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. Diabetes (2000) 49(9):1525-33. doi:10.2337/diabetes.49.9.1525
104. Kenyon CJ. The genetics of ageing. Nature (2010) 464(7288):504-12. doi:10.1038/nature08980
105. Braendle C, Milloz J, Felix MA. Mechanisms and evolution of environmental responses in Caenorhabditis elegans. Curr Top Dev Biol (2008) 80:171-207. doi:10.1016/S0070-2153(07)80005-6
106. Klass M, Hirsh D. Non-ageing developmental variant of Caenorhabditis elegans. Nature (1976) 260(5551):523-5. doi:10.1038/260523a0
107. Shore DE, Carr CE, Ruvkun G. Induction of cytoprotective pathways is central to the extension of lifespan conferred by multiple longevity pathways. PLoS Genet (2012) 8(7):e1002792. doi:10.1371/journal.pgen.1002792
108. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science (1997) 277(5328):942-6. doi:10.1126/science.277.5328.942
109. Lin K, Dorman JB, Rodan A, Kenyon C. daf-16: an HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science (1997) 278(5341):1319-22. doi:10.1126/science.278.5341.1319
110. Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature (1997) 389(6654):994-9. doi:10.1038/40194
111. Apfeld J, Kenyon C. Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature (1999) 402(6763):804-9. doi:10.1038/45544
112. Broughton SJ, Slack C, Alic N, Metaxakis A, Bass TM, Driege Y, et al. DILP-producing median neurosecretory cells in the Drosophila brain mediate the response of lifespan to nutrition. Aging Cell (2010) 9(3):336-46. doi:10.1111/j.1474-9726.2010.00558.x
113. van Heemst D. Insulin, IGF-1 and longevity. Aging Dis (2010) 1(2):147-57.
114. Brown-Borg HM, Borg KE, Meliska CJ, Bartke A. Dwarf mice and the ageing process. Nature (1996) 384(6604):33. doi:10.1038/384033a0
115. Flurkey K, Papaconstantinou J, Miller RA, Harrison DE. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A (2001) 98(12):6736-41. doi:10.1073/pnas.111158898
116. Masternak MM, Panici JA, Bonkowski MS, Hughes LF, Bartke A. Insulin sensitivity as a key mediator of growth hormone actions on longevity. J Gerontol A Biol Sci Med Sci (2009) 64(5):516-21. doi:10.1093/gerona/glp024
117. Bartke A, Westbrook R. Metabolic characteristics of long-lived mice. Front Genet (2012) 3:288. doi:10.3389/fgene.2012.00288
118. Facchini FS, Hua N, Abbasi F, Reaven GM. Insulin resistance as a predictor of age-related diseases. J Clin Endocrinol Metab (2001) 86(8):3574-8. doi:10.1210/jcem.86.8.7763
119. Paolisso G, Scheen A, Lefebvre P. Glucose handling, diabetes and ageing. Horm Res (1995) 43(1-3):52-7. doi:10.1159/000184237
120. Bourey RE, Kohrt WM, Kirwan JP, Staten MA, King DS, Holloszy JO. Relationship between glucose tolerance and glucose-stimulated insulin response in 65-year-olds. J Gerontol (1993) 48(4):M122-7. doi:10.1093/geronj/48.4.M122
121. Elahi D, Muller DC, McAloon-Dyke M, Tobin JD, Andres R. The effect of age on insulin response and glucose utilization during four hyperglycemic plateaus. Exp Gerontol (1993) 28(4-5):393-409. doi:10.1016/0531-5565(93)90066-M
122. Pratley RE, Coon PJ, Muller DC, Rogus EM, Goldberg AP. The effects of single and sequential insulin infusions on glucose disposal in older men. Exp Gerontol (1993) 28(4-5):381-91. doi:10.1016/0531-5565(93)90065-L
123. Couet C, Delarue J, Constans T, Lamisse F. Age-related insulin resistance: a review. Horm Res (1992) 38(1-2):46-50. doi:10.1159/000182483
124. Fink RI, Kolterman OG, Griffin J, Olefsky JM. Mechanisms of insulin resistance in aging. J Clin Invest (1983) 71(6):1523-35. doi:10.1172/JCI110908
125. Rowe JW, Minaker KL, Pallotta JA, Flier JS. Characterization of the insulin resistance of aging. J Clin Invest (1983) 71(6):1581-7. doi:10.1172/JCI110914
126. Gumbiner B, Thorburn AW, Ditzler TM, Bulacan F, Henry RR. Role of impaired intracellular glucose metabolism in the insulin resistance of aging. Metabolism (1992) 41(10):1115-21. doi:10.1016/0026-0495(92)90296-M
127. Meneilly GS, Elahi D, Minaker KL, Sclater AL, Rowe JW. Impairment of noninsulin-mediated glucose disposal in the elderly. J Clin Endocrinol Metab (1989) 68(3):566-71. doi:10.1210/jcem-68-3-566
128. Paolisso G, Marrazzo G, de Riu S, Sgambato S, Varricchio M, d'Onofrio F, et al. Effects of mild-to-moderate hyperglycaemia per se on glucose production and uptake in the elderly. Eur J Med (1992) 1(1):6-12.
129. Schoenmaker M, de Craen AJ, de Meijer PH, Beekman M, Blauw GJ, Slagboom PE, et al. Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden longevity study. Eur J Hum Genet (2006) 14(1):79-84. doi:10.1038/sj.ejhg.5201508
130. Rozing MP, Westendorp RG, de Craen AJ, Frolich M, de Goeij MC, Heijmans BT, et al. Favorable glucose tolerance and lower prevalence of metabolic syndrome in offspring without diabetes mellitus of nonagenarian siblings: the Leiden longevity study. J Am Geriatr Soc (2010) 58(3):564-9. doi:10.1111/j.1532-5415.2010.02725.x
131. Westendorp RG, van Heemst D, Rozing MP, Frolich M, Mooijaart SP, Blauw GJ, et al. Nonagenarian siblings and their offspring display lower risk of mortality and morbidity than sporadic nonagenarians: the Leiden Longevity Study. J Am Geriatr Soc (2009) 57(9):1634-7. doi:10.1111/j.1532-5415.2009.02381.x
132. Wijsman CA, van Opstal AM, Kan HE, Maier AB, Westendorp RG, Slagboom PE, et al. Proton magnetic resonance spectroscopy shows lower intramyocellular lipid accumulation in middle-aged subjects predisposed to familial longevity. Am J Physiol Endocrinol Metab (2012) 302(3):E344-8. doi:10.1152/ajpendo.00455.2011
133. Dekker P, Maier AB, van Heemst D, de Koning-Treurniet C, Blom J, Dirks RW, et al. Stress-induced responses of human skin fibroblasts in vitro reflect human longevity. Aging Cell (2009) 8(5):595-603. doi:10.1111/j.1474-9726.2009.00506.x
134. Heijmans BT, Beekman M, Houwing-Duistermaat JJ, Cobain MR, Powell J, Blauw GJ, et al. Lipoprotein particle profiles mark familial and sporadic human longevity. PLoS Med (2006) 3(12):e495. doi:10.1371/journal.pmed.0030495
135. Hu FB, Willett WC, Li T, Stampfer MJ, Colditz GA, Manson JE. Adiposity as compared with physical activity in predicting mortality among women. N Engl J Med (2004) 351(26):2694-703. doi:10.1056/NEJMoa042135
136. McLaughlin T, Abbasi F, Lamendola C, Reaven G. Heterogeneity in the prevalence of risk factors for cardiovascular disease and type 2 diabetes mellitus in obese individuals: effect of differences in insulin sensitivity. Arch Intern Med (2007) 167(7):642-8. doi:10.1001/archinte.167.7.642
137. McLaughlin T, Sherman A, Tsao P, Gonzalez O, Yee G, Lamendola C, et al. Enhanced proportion of small adipose cells in insulin-resistant vs insulin-sensitive obese individuals implicates impaired adipogenesis. Diabetologia (2007) 50(8):1707-15. doi:10.1007/s00125-007-0708-y
138. Salans LB, Knittle JL, Hirsch J. The role of adipose cell size and adipose tissue insulin sensitivity in the carbohydrate intolerance of human obesity. J Clin Invest (1968) 47(1):153-65. doi:10.1172/JCI105705
139. Fontana L, Eagon JC, Trujillo ME, Scherer PE, Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes (2007) 56(4):1010-3. doi:10.2337/db06-1656
140. Hotamisligil GS. Inflammation and metabolic disorders. Nature (2006) 444(7121):860-7. doi:10.1038/nature05485
141. Goldstein BJ, Mahadev K, Wu X. Redox paradox: insulin action is facilitated by insulin-stimulated reactive oxygen species with multiple potential signaling targets. Diabetes (2005) 54(2):311-21. doi:10.2337/diabetes.54.2.311
142. Papaconstantinou J. Insulin/IGF-1 and ROS signaling pathway cross-talk in aging and longevity determination. Mol Cell Endocrinol (2009) 299(1):89-100. doi:10.1016/j.mce.2008.11.025
143. Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature (2006) 440(7086):944-8. doi:10.1038/nature04634
144. Samocha-Bonet D, Heilbronn LK, Lichtenberg D, Campbell LV. Does skeletal muscle oxidative stress initiate insulin resistance in genetically predisposed individuals? Trends Endocrinol Metab (2010) 21(2):83-8. doi:10.1016/j.tem.2009.09.008
145. Moro C, Galgani JE, Luu L, Pasarica M, Mairal A, Bajpeyi S, et al. Influence of gender, obesity, and muscle lipase activity on intramyocellular lipids in sedentary individuals. J Clin Endocrinol Metab (2009) 94(9):3440-7. doi:10.1210/jc.2009-0053
146. Heilbronn LK, Gregersen S, Shirkhedkar D, Hu D, Campbell LV. Impaired fat oxidation after a single high-fat meal in insulin-sensitive nondiabetic individuals with a family history of type 2 diabetes. Diabetes (2007) 56(8):2046-53. doi:10.2337/db06-1687
147. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med (2004) 350(7):664-71. doi:10.1056/NEJMoa031314
148. Reaven GM. Compensatory hyperinsulinemia and the development of an atherogenic lipoprotein profile: the price paid to maintain glucose homeostasis in insulin-resistant individuals. Endocrinol Metab Clin North Am (2005) 34(1):49-62. doi:10.1016/j.ecl.2004.12.001
149. Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest (2001) 108(12):1875-81. doi:10.1172/JCI14120
150. Bahceci M, Gokalp D, Bahceci S, Tuzcu A, Atmaca S, Arikan S. The correlation between adiposity and adiponectin, tumor necrosis factor alpha, interleukin-6 and high sensitivity C-reactive protein levels. Is adipocyte size associated with inflammation in adults? J Endocrinol Invest (2007) 30(3):210-4. doi:10.1007/BF03347427
151. Wang Z, Al-Regaiey KA, Masternak MM, Bartke A. Adipocytokines and lipid levels in Ames dwarf and calorie-restricted mice. J Gerontol A Biol Sci Med Sci (2006) 61(4):323-31. doi:10.1093/gerona/61.4.323
152. Atzmon G, Pollin TI, Crandall J, Tanner K, Schechter CB, Scherer PE, et al. Adiponectin levels and genotype: a potential regulator of life span in humans. J Gerontol A Biol Sci Med Sci (2008) 63(5):447-53. doi:10.1093/gerona/63.5.447
153. Bik W, Baranowska-Bik A, Wolinska-Witort E, Martynska L, Chmielowska M, Szybinska A, et al. The relationship between adiponectin levels and metabolic status in centenarian, early elderly, young and obese women. Neuro Endocrinol Lett (2006) 27(4):493-500.
154. Arai Y, Nakazawa S, Kojima T, Takayama M, Ebihara Y, Shimizu K-I, et al. High adiponectin concentration and its role for longevity in female centenarians. Geriatr Gerontol Int (2006) 6:32-9. doi:10.1111/j.1447-0594.2006.00304.x
155. Koch CE, Lowe C, Legler K, Benzler J, Boucsein A, Bottiger G, et al. Central adiponectin acutely improves glucose tolerance in male mice. Endocrinology (2014) 155(5):1806-16. doi:10.1210/en.2013-1734
156. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci (2014) 69(Suppl 1):S4-9. doi:10.1093/gerona/glu057
157. Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell (2008) 135(1):61-73. doi:10.1016/j.cell.2008.07.043
158. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes (2007) 56(7):1761-72. doi:10.2337/db06-1491
159. Kleinridders A, Schenten D, Konner AC, Belgardt BF, Mauer J, Okamura T, et al. MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab (2009) 10(4):249-59. doi:10.1016/j.cmet.2009.08.013
160. Scherer T, Lindtner C, Zielinski E, O'Hare J, Filatova N, Buettner C. Short term voluntary overfeeding disrupts brain insulin control of adipose tissue lipolysis. J Biol Chem (2012) 287(39):33061-9. doi:10.1074/jbc.M111.307348
161. Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest (2012) 122(1):153-62. doi:10.1172/JCI59660
162. Rapalino O, Lazarov-Spiegler O, Agranov E, Velan GJ, Yoles E, Fraidakis M, et al. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med (1998) 4(7):814-21. doi:10.1038/nm0798-814
163. Shechter R, London A, Varol C, Raposo C, Cusimano M, Yovel G, et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med (2009) 6(7):e1000113. doi:10.1371/journal.pmed.1000113
164. Shechter R, Raposo C, London A, Sagi I, Schwartz M. The glial scar-monocyte interplay: a pivotal resolution phase in spinal cord repair. PLoS One (2011) 6(12):e27969. doi:10.1371/journal.pone.0027969
165. Kunis G, Baruch K, Rosenzweig N, Kertser A, Miller O, Berkutzki T, et al. IFN-gamma-dependent activation of the brain's choroid plexus for CNS immune surveillance and repair. Brain (2013) 136(Pt 11):3427-40. doi:10.1093/brain/awt259
166. Gao Y, Ottaway N, Schriever SC, Legutko B, Garcia-Caceres C, de la Fuente E, et al. Hormones and diet, but not body weight, control hypothalamic microglial activity. Glia (2014) 62(1):17-25. doi:10.1002/glia.22580
167. Fontana L. Neuroendocrine factors in the regulation of inflammation: excessive adiposity and calorie restriction. Exp Gerontol (2009) 44(1-2):41-5. doi:10.1016/j.exger.2008.04.005
168. Cintra DE, Ropelle ER, Moraes JC, Pauli JR, Morari J, Souza CT, et al. Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity. PLoS One (2012) 7(1):e30571. doi:10.1371/journal.pone.0030571
169. Ford ES. Does exercise reduce inflammation? Physical activity and C-reactive protein among U.S. adults. Epidemiology (2002) 13(5):561-8. doi:10.1097/00001648-200209000-00012
170. Yi CX, Al-Massadi O, Donelan E, Lehti M, Weber J, Ress C, et al. Exercise protects against high-fat diet-induced hypothalamic inflammation. Physiol Behav (2012) 106(4):485-90. doi:10.1016/j.physbeh.2012.03.021
171. Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci (2002) 5(6):514-6. doi:10.1038/nn0602-849
172. Benedict C, Dodt C, Hallschmid M, Lepiorz M, Fehm HL, Born J, et al. Immediate but not long-term intranasal administration of insulin raises blood pressure in human beings. Metabolism (2005) 54(10):1356-61. doi:10.1016/j.metabol.2005.04.026
173. Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology (2004) 29(10):1326-34. doi:10.1016/j.psyneuen.2004.04.003
174. Benedict C, Brede S, Schioth HB, Lehnert H, Schultes B, Born J, et al. Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men. Diabetes (2011) 60(1):114-8. doi:10.2337/db10-0329