Specific suppression of insulin sensitivity in growth hormone receptor gene-disrupted (GHR-KO) mice attenuates phenotypic features of slow aging

Aging Cell

Volumn 13, Issue 6, 2014, Pages 981-1000

  Arum, Oge ^a   Boparai, Ravneet K ^a   Saleh, Jamal K ^a   Wang, Feiya ^a   Dirks, Angela L ^a   Turner, Jeremy G ^a   Kopchick, John J ^b   Liu, Jun Li ^c   Khardori, Romesh K ^d   Bartke, Andrzej ^a  

^a SOUTHERN ILLINOIS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b OHIO UNIVERSITY   (United States)

^c MCGILL UNIVERSITY HEALTH CENTRE   (Canada)

^d EASTERN VIRGINIA MEDICAL SCHOOL   (United States)

Author keywords

(neuro)endocrinology of senescence; Endocrinology and metabolism; Growth hormone hormonal signaling; Insulin sensitivity; Longevity regulation

Indexed keywords

GROWTH HORMONE RECEPTOR; INSULIN; INTERLEUKIN 6; MONOCYTE CHEMOTACTIC PROTEIN 1; PLASMINOGEN ACTIVATOR INHIBITOR 1; TUMOR NECROSIS FACTOR ALPHA; SOMATOMEDIN C;

AGING; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BODY TEMPERATURE; CELL PROLIFERATION; CONTROLLED STUDY; ENZYME REPRESSION; ESTERIFICATION; FEMALE; GENE DISRUPTION; GLUCONEOGENESIS; GLUCOSE HOMEOSTASIS; GLUCOSE METABOLISM; HETEROZYGOSITY; INSULIN BLOOD LEVEL; INSULIN RELEASE; INSULIN SENSITIVITY; INSULIN SYNTHESIS; INSULIN TOLERANCE TEST; INTRAABDOMINAL FAT; LONGEVITY; MALE; METABOLIC REGULATION; MOUSE; NONHUMAN; PANCREAS ISLET BETA CELL; PHENOTYPE; PRIORITY JOURNAL; PROMOTER REGION; SENESCENCE; SEX DIFFERENCE; WHITE ADIPOSE TISSUE; ANIMAL; INSULIN RESISTANCE; KNOCKOUT MOUSE; METABOLISM; PHYSIOLOGY;

MUS;

AGING; ANIMALS; FEMALE; INSULIN; INSULIN RESISTANCE; INSULIN-LIKE GROWTH FACTOR I; LONGEVITY; MALE; MICE; MICE, KNOCKOUT; PHENOTYPE; RECEPTORS, SOMATOTROPIN;

EID: 84911457047     PISSN: 14749718     EISSN: 14749726     Source Type: Journal    
DOI: 10.1111/acel.12262     Document Type: Article

References (120)

1. Acheson K, Jequier E, Wahren J (1983) Influence of beta-adrenergic blockade on glucose-induced thermogenesis in man. J. Clin. Invest. 72, 981-986.
2. Acheson KJ, Ravussin E, Wahren J, Jequier E (1984) Thermic effect of glucose in man. J. Clin. Invest. 74, 1572-1580.
3. Anselmi CV, Malovini A, Roncarati R, Novelli V, Villa F, Condorelli G, Bellazzi R, Puca AA (2009) Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuvenation Res. 12, 95-104.
4. Arum O, Bonkowski MS, Rocha JS, Bartke A (2009) The growth hormone receptor gene-disrupted mouse fails to respond to an intermittent fasting diet. Aging Cell 8, 756-760.
5. Arum O, Rickman DJ, Kopchick JJ, Bartke A (2013) The slow-aging growth hormone receptor/binding protein gene-disrupted (GHR-KO) mouse is protected from aging-resultant neuromusculoskeletal frailty. Age (Dordr) 36, 117-127. doi: 10.1007/s11357-013-9551-x.
6. Arum O, Saleh JK, Boparai RK, Kopchick JJ, Khardori RK, Bartke A (2014) Preservation of blood glucose homeostasis in slow-senescing somatotrophism-deficient mice subjected to intermittent fasting begun at middle or old age. Age (Dordr) 36, 9651. doi: 10.1007/s11357-014-9651-2.
7. Avogaro A, de Kreutzenberg SV, Fadini GP (2010) Insulin signaling and life span. Pflugers Arch. 459, 301-314.
8. Barbieri M, Rizzo MR, Manzella D, Paolisso G (2001) Age-related insulin resistance: is it an obligatory finding? The lesson from healthy centenarians Diabetes Metab. Res. Rev. 17, 19-26.
9. Barbieri M, Bonafè M, Franceschi C, Paolisso G (2003) Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans. Am. J. Physiol. Endocrinol. Metab. 285, E1064-E1071.
10. Barbieri M, Boccardi V, Papa M, Paolisso G (2009) Metabolic journey to healthy longevity. Horm. Res. 71(Suppl 1), 24-27.
11. Bartke A (2005a) Insulin resistance and cognitive aging in long-lived and short-lived mice. J. Gerontol. A Biol. Sci. Med. Sci. 60, 133-134.
12. Bartke A (2005b) Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 146, 3718-3723.
13. Bartke A (2006) Long-lived Klotho mice: new insights into the roles of IGF-1 and insulin in aging. Trends Endocrinol. Metab. 17, 33-35.
14. Bartke A (2008) Insulin and aging. Cell Cycle 7, 3338-3343.
15. Bartke A (2011) Single-gene mutations and healthy ageing in mammals. Philos. Trans. R. Soc. Lond. B Biol. Sci. 366, 28-34.
16. Bartke A, Brown-Borg H (2004) Life extension in the dwarf mouse. Curr. Top. Dev. Biol. 63, 189-225.
17. Bartke A, Peluso MR, Moretz N, Wright C, Bonkowski M, Winters TA, Shanahan MF, Kopchick JJ, Banz WJ (2004) Effects of Soy-derived diets on plasma and liver lipids, glucose tolerance, and longevity in normal, long-lived and short-lived mice. Horm. Metab. Res. 36, 550-558.
18. Barzilai N, Bartke A (2009) Biological approaches to mechanistically understand the healthy life span extension achieved by calorie restriction and modulation of hormones. J. Gerontol. A Biol. Sci. Med. Sci. 64, 187-191.
19. Barzilai N, Huffman DM, Muzumdar RH, Bartke A (2012) The critical role of metabolic pathways in aging. Diabetes 61, 1315-1322.
20. Berryman DE, List EO, Coschigano KT, Behar K, Kim JK, Kopchick JJ (2004) Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Horm. IGF Res. 14, 309-318.
21. Berryman DE, Christiansen JS, Johannsson G, Thorner MO, Kopchick JJ (2008) Role of the GH/IGF-1 axis in lifespan and healthspan: lessons from animal models. Growth Horm. IGF Res. 18, 455-471.
22. Berryman DE, List EO, Palmer AJ, Chung MY, Wright-Piekarski J, Lubbers E, O'Connor P, Okada S, Kopchick JJ (2010) Two-year body composition analyses of long-lived GHR null mice. J. Gerontol. A Biol. Sci. Med. Sci. 65, 31-40.
23. Blüher M, Kahn BB, Kahn CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572-574.
24. Bonkowski MS, Rocha JS, Masternak MM, Al Regaiey KA, Bartke A (2006) Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc. Natl Acad. Sci. USA 103, 7901-7905.
25. Boparai RK, Arum O, Khardori R, Bartke A (2010) Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis. Biol. Chem. 391, 1149-1155.
26. Brown-Borg HM (2009) Hormonal control of aging in rodents: the somatotropic axis. Mol. Cell. Endocrinol. 299, 64-71.
27. Brown-Borg HM, Borg KE, Meliska CJ, Bartke A (1996) Dwarf mice and the ageing process. Nature 384, 33.
28. Butler AA, Kozak LP (2010) A recurring problem with the analysis of energy expenditure in genetic models expressing lean and obese phenotypes. Diabetes 59, 323-329.
29. Calnan DR, Brunet A (2008) The FoxO code. Oncogene 27, 2276-2288.
30. Cangelosi PR (2011) Baby Boomers: are we ready for their impact on health care? J. Psychosoc. Nurs. Ment. Health Serv. 49, 15-17.
31. Carrillo AE, Flouris AD (2011) Caloric restriction and longevity: effects of reduced body temperature. Ageing Res. Rev. 10, 153-162.
32. Centers for Disease Control and Prevention. (2011). Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services. National Diabetes Fact Sheet, 2011. URL http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf [accessed on August 2014].
33. Centers for Disease Control and Prevention (2012) Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services. Diabetes Report Card. URL http://www.cdc.gov/diabetes/pubs/pdf/DiabetesReportCard.pdf [accessed on August 2014].
34. Chatterjee R, Yeh HC, Edelman D, Brancati F (2011) Potassium and risk of Type 2 diabetes. Expert Rev. Endocrinol. Metab. 6, 665-672.
35. Chen YF, Wu CY, Kao CH, Tsai TF (2010) Longevity and lifespan control in mammals: lessons from the mouse. Ageing Res. Rev. 9(Suppl 1), S28-S35.
36. Choi D, Nguyen KT, Wang L, Schroer SA, Suzuki A, Mak TW, Woo M (2008) Partial deletion of Pten in the hypothalamus leads to growth defects that cannot be rescued by exogenous growth hormone. Endocrinology 149, 4382-4386.
37. Choudhury AI, Heffron H, Smith MA, Al-Qassab H, Xu AW, Selman C, Simmgen M, Clements M, Claret M, Maccoll G, Bedford DC, Hisadome K, Diakonov I, Moosajee V, Bell JD, Speakman JR, Batterham RL, Barsh GS, Ashford ML, Withers DJ (2005) The role of insulin receptor substrate 2 in hypothalamic and beta cell function. J. Clin. Invest. 115, 940-950.
38. Conover CA, Bale LK (2007) Loss of pregnancy-associated plasma protein A extends lifespan in mice. Aging Cell 6, 727-729.
39. Conover CA, Mason MA, Levine JA, Novak CM (2008) Metabolic consequences of pregnancy-associated plasma protein-A deficiency in mice: exploring possible relationship to the longevity phenotype. J. Endocrinol. 198, 599-605.
40. Conti B, Sanchez-Alavez M, Winsky-Sommerer R, Morale MC, Lucero J, Brownell S, Fabre V, Huitron-Resendiz S, Henriksen S, Zorrilla EP, de Lecea L, Bartfai T (2006) Transgenic mice with a reduced core body temperature have an increased life span. Science 314, 825-828.
41. Coschigano KT, et al. (1999) 81st Annual Meeting of The Endocrine Society. San Diego, CA.
42. Coschigano KT, Clemmons D, Bellush LL, Kopchick JJ (2000) Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141, 2608-2613.
43. Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ (2003) Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology 144, 3799-3810.
44. Crawley JN (2007) What's Wrong With My Mouse? Behavioral Phenotyping of Transgenic and Knockout Mice, 2nd edn. Hoboken, NJ: John Wiley & Sons Inc.
45. Däumer C, Flachsbart F, Caliebe A, Schreiber S, Nebel A, Krawczak M (2014) Adjustment for smoking does not alter the FOXO3A association with longevity. Age 36, 911-921.
46. Devedjian JC, George M, Casellas A, Pujol A, Visa J, Pelegrin M, Gros L, Bosch F (2000) Transgenic mice overexpressing insulin-like growth factor-II in β cells develop type 2 diabetes. J. Clin. Invest. 105, 731-740.
47. DiStefano PS, Curtis R, Geddes BJ (2007) Insulin resistance, glycemic control and adiposity: key determinants of healthy lifespan. Curr. Alzheimer Res. 4, 153-157.
48. Dominguez LJ, Paolisso G, Barbagallo M (2010) Glucose control in the older patient: from intensive, to effective and safe. Aging Clin. Exp. Res. 22, 274-280.
49. Dominici FP, Hauck S, Argentino DP, Bartke A, Turyn D (2002) Increased insulin sensitivity and upregulation of insulin receptor, insulin receptor substrate (IRS)-1 and IRS-2 in liver of Ames dwarf mice. J. Endocrinol. 173, 81-94.
50. Donlon TA, Curb JD, He Q, Grove JS, Masaki KH, Rodriguez B, Elliott A, Willcox DC, Willcox BJ (2012) FOXO3 gene variants and human aging: coding variants may not be key players. J. Gerontol. A Biol. Sci. Med. Sci. 67, 1132-1139. doi: 10.1093/gerona/gls067.
51. Fang Y, Westbrook R, Hill C, Boparai RK, Arum O, Spong A, Wang F, Javors MA, Chen J, Sun LY, Bartke A (2013) Duration of rapamycin treatment has differential effects on metabolism in mice. Cell Metab. 17, 456-462. doi: 10.1016/j.cmet.2013.02.008.
52. Flachsbart F, Caliebe A, Kleindorp R, Blanché H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A (2009) Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc. Natl Acad. Sci. USA 106, 2700-2705.
53. Flachsbart F, Moller M, Daeumer C, Gentschew L, Kleindorp R, Krawczak M, Caliebe A, Schreiber S, Nebel A (2013) Genetic investigation of FOXO3A requires special attention due to sequence homology with FOXO3B. Eur. J. Hum. Genet. 21, 240-242. doi: 10.1038/ejhg.2012.83.
54. Flurkey K, Papaconstantinou J, Miller RA, Harrison DE (2001) Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc. Natl Acad. Sci. USA 98, 6736-6741.
55. Fontana L, Klein S, Holloszy JO (2010) Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production. Age (Dordr). 32, 97-108.
56. Gannon M, Shiota C, Postic C, Wright CV, Magnuson M (2000) Analysis of the Cre-mediated recombination driven by rat insulin promoter in embryonic and adult mouse pancreas. Genesis 26, 139-142.
57. Gerozissis K (2003) Brain insulin: regulation, mechanisms of action and functions. Cell. Mol. Neurobiol. 23, 1-25.
58. Glantz SA. (2002). Primer of Biostatistics, 5thEdition. Chapter Two: How to Summarize Data. New York: The McGraw-Hill Companies, Inc.
59. Gong Z, Muzumdar RH (2012) Pancreatic function, type 2 diabetes, and metabolism in aging. Int. J. Endocrinol. 2012, 320482.
60. Greene DA (1986) Acute and chronic complications of diabetes mellitus in older patients. Am. J. Med. 80, 39-53.
61. Guo Y, Lu Y, Houle D, Robertson K, Tang Z, Kopchick JJ, Liu YL, Liu JL (2005) Pancreatic islet-specific expression of an insulin-like growth factor-I transgene compensates islet cell growth in growth hormone receptor gene-deficient mice. Endocrinology 146, 2602-2609.
62. Habener JF, Stanojevic V (2012) Alpha cells come of age. Trends Endocrinol. Metab. 24, 153-163.
63. Hamlin CR, Kohn RR, Luschin JH (1975) Apparent accelerated aging of human collagen in diabetes mellitus. Diabetes 24, 902-904.
64. Harper JM, Durkee SJ, Smith-Wheelock M, Miller RA (2005) Hyperglycemia, impaired glucose tolerance and elevated glycated hemoglobin levels in a long-lived mouse stock. Exp. Gerontol. 40, 303-314.
65. Holzenberger M (2004) The GH/IGF-I axis and longevity. Eur. J. Endocrinol. 151(Suppl 1), S23-S27.
66. Holzenberger M, Dupont J, Ducos B, Leneuve P, Géloën A, Even PC, Cervera P, Le Bouc Y (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182-187.
67. Iwersen M, Falkenberg U, Voigtsberger R, Forderung D, Heuwieser W (2009) Evaluation of an electronic cowside test to detect subclinical ketosis in dairy cows. J. Dairy Sci. 92, 2618-2624.
68. Kaushik S, Cuervo AM (2012a) Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 22, 407-417.
69. Kaushik S, Cuervo AM (2012b) Chaperones in autophagy. Pharmacol. Res. 66, 484-493.
70. Kent S (1976) Is diabetes a form of accelerated aging? Geriatrics, 31, 140, 145, 149-151.
71. Kenyon CJ (2010) The genetics of ageing. Nature 464, 504-512. Erratum in: Nature. 2010 Sep 30;467(7315):622.
72. Kinney BA, Coschigano KT, Kopchick JJ, Steger RW, Bartke A (2001a) Evidence that age-induced decline in memory retention is delayed in growth hormone resistant GH-R-KO (Laron) mice. Physiol. Behav. 72, 653-660.
73. Kinney BA, Meliska CJ, Steger RW, Bartke A (2001b) Evidence that Ames dwarf mice age differently from their normal siblings in behavioral and learning and memory parameters. Horm. Behav. 39, 277-284.
74. Kinney-Forshee BA, Kinney NE, Steger RW, Bartke A (2004) Could a deficiency in growth hormone signaling be beneficial to the aging brain? Physiol. Behav. 80, 589-594.
75. Kirkland JL, Peterson C (2009) Healthspan, translation, and new outcomes for animal studies of aging. J. Gerontol. A Biol. Sci. Med. Sci. 64, 209-212.
76. Knickman JR, Snell EK (2002) The 2030 problem: caring for aging baby boomers. Health Serv. Res. 37, 849-884.
77. Knight EM, Verkhratsky A, Luckman SM, Allan SM, Lawrence CB (2012) Hypermetabolism in a triple-transgenic mouse model of Alzheimer's disease. Neurobiol. Aging 33, 187-193.
78. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M (2005) Suppression of aging in mice by the hormone Klotho. Science 309, 1829-1833.
79. Landsberg L (1986) Diet, obesity and hypertension: an hypothesis involving insulin, the sympathetic nervous system, and adaptive thermogenesis. Q. J. Med. 61, 1081-1090.
80. Lane MA, Baer DJ, Rumpler WV, Weindruch R, Ingram DK, Tilmont EM, Cutler RG, Roth GS (1996) Calorie restriction lowers body temperature in rhesus monkeys, consistent with a postulated anti-aging mechanism in rodents. Proc. Natl Acad. Sci. USA 93, 4159-4164.
81. Li Y, Wang WJ, Cao H, Lu J, Wu C, Hu FY, Guo J, Zhao L, Yang F, Zhang YX, et al. (2009) Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum. Mol. Genet. 18, 4897-4904.
82. Liu JL, Coschigano KT, Robertson K, Lipsett M, Guo Y, Kopchick JJ, Kumar U, Liu YL (2004) Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice. Am. J. Physiol. Endocrinol. Metab. 287, E405-E413.
83. Longo VD, Finch CE (2003) Evolutionary medicine: from dwarf model systems to healthy centenarians? Science 299, 1342-1346.
84. Masoro EJ (2003) Subfield history: caloric restriction, slowing aging, and extending life. Sci. Aging Knowledge Environ. 2003, RE2.
85. Masternak MM, Panici JA, Bonkowski MS, Hughes LF, Bartke A (2009) Insulin sensitivity as a key mediator of growth hormone actions on longevity. J. Gerontol. A Biol. Sci. Med. Sci. 64, 516-521. doi: 10.1093/gerona/glp024.
86. Masternak MM, Bartke A, Wang F, Gesing A, Fang Y, Salmon AB, Hughes LF, Liberati T, Boparai R, Kopchick JJ, Westbrook R (2012) Metabolic effects of intra-abdominal fat in GHRKO mice. Aging Cell 11, 73-81.
87. Miller RA (2009) "Dividends" from research on aging-can biogerontologists, at long last, find something useful to do? J. Gerontol. A Biol. Sci. Med. Sci. 64, 157-160.
88. Miller RA, Burke D, Nadon N (1999) Announcement: four-way cross mouse stocks: a new, genetically heterogeneous resource for aging research. J. Gerontol. A Biol. Sci. Med. Sci. 54, B358-B360.
89. Monickaraj F, Aravind S, Gokulakrishnan K, Sathishkumar C, Prabu P, Prabu D, Mohan V, Balasubramanyam M (2012) Accelerated aging as evidenced by increased telomere shortening and mitochondrial DNA depletion in patients with type 2 diabetes. Mol. Cell. Biochem. 365, 343-350.
90. Mookerjee SA, Divakaruni AS, Jastroch M, Brand MD (2010) Mitochondrial uncoupling and lifespan. Mech. Ageing Dev. 131, 463-472.
91. Muzumdar R, Allison DB, Huffman DM, Ma X, Atzmon G, Einstein FH, Fishman S, Poduval AD, McVei T, Keith SW, Barzilai N (2008) Visceral adipose tissue modulates mammalian longevity. Aging Cell 7, 438-440.
92. Nass R, Johannsson G, Christiansen JS, Kopchick JJ, Thorner MO (2009) The aging population-is there a role for endocrine interventions? Growth Horm. IGF Res. 19, 89-100.
93. Nguyen KT, Tajmir P, Lin CH, Liadis N, Zhu XD, Eweida M, Tolasa-Karaman G, Cai F, Wang R, Kitamura T, Belsham DD, Wheeler MB, Suzuki A, Mak TW, Woo M (2006) Essential role of Pten in body size determination and pancreatic beta-cell homeostasis in vivo. Mol. Cell. Biol. 26, 4511-4518.
94. Olshansky SJ, Perry D, Miller RA, Butler RN (2007) Pursuing the longevity dividend: scientific goals for an aging world. Ann. N. Y. Acad. Sci. 1114, 11-13.
95. Pawlikowska L, Hu D, Huntsman S, Sung A, Chu C, Chen J, Joyner AH, Schork NJ, Hsueh WC, Reiner AP, Psaty BM, Atzmon G, Barzilai N, Cummings SR, Browner WS, Kwok PY, Ziv E (2009) Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell 8, 460-472.
96. Poehlman ET, Dvorak RV (1998) Energy expenditure in Alzheimer's disease. J. Nutr. Health Aging 2, 115-118.
97. Redman LM, Ravussin E (2009) Endocrine alterations in response to calorie restriction in humans. Mol. Cell. Endocrinol. 299, 129-136.
98. Ricketts TC (2011) The health care workforce: will it be ready as the boomers age? A review of how we can know (or not know) the answer. Annu. Rev. Public Health 2011, 417-430.
99. Roth GS, Lane MA, Ingram DK, Mattison JA, Elahi D, Tobin JD, Muller D, Metter EJ (2002) Biomarkers of caloric restriction may predict longevity in humans. Science 297, 811.
100. Rozing MP, Westendorp RG, de Craen AJ, Frölich M, de Goeij MC, Heijmans BT, Beekman M, Wijsman CA, Mooijaart SP, Blauw GJ, Slagboom PE, van Heemst D; Leiden Longevity Study Group (2010) 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. 58, 564-9.
101. Russell SJ, Kahn CR (2007) Endocrine regulation of ageing. Nat. Rev. Mol. Cell Biol. 8, 681-691.
102. Selman C, Withers DJ (2011) Mammalian models of extended healthy lifespan. Philos. Trans. R. Soc. Lond. B Biol. Sci. 366, 99-107.
103. Selman C, Lingard S, Choudhury AI, Batterham RL, Claret M, Clements M, Ramadani F, Okkenhaug K, Schuster E, Blanc E, Piper MD, Al-Qassab H, Speakman JR, Carmignac D, Robinson IC, Thornton JM, Gems D, Partridge L, Withers DJ (2008) Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J. 22, 807-818.
104. Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, Batterham RL, Kozma SC, Thomas G, Carling D, Okkenhaug K, Thornton JM, Partridge L, Gems D, Withers DJ (2009) Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140-144.
105. Singh R, Cuervo AM (2011) Autophagy in the cellular energetic balance. Cell Metab. 13, 495-504.
106. Soerensen M, Dato S, Christensen K, McGue M, Stevnsner T, Bohr VA, Christiansen L (2010) Replication of an association of variation in the FOXO3A gene with human longevity using both case-control and longitudinal data. Aging Cell 9, 1010-1017.
107. Taguchi A, Wartschow LM, White MF (2007) Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317, 369-372.
108. Tatar M (2009) Can we develop genetically tractable models to assess healthspan (rather than life span) in animal models? J. Gerontol. A Biol. Sci. Med. Sci. 64, 161-163.
109. Unger RH, Cherrington AD (2012) Glucagonocentric restructuring of dia-betes: a pathophysiologic and therapeutic makeover. J. Clin. Invest. 122, 4-12.
110. Unger RH, Orci L (2010) Paracrinology of islets and the paracrinopathy of diabetes. Proc. Natl Acad. Sci. 107, 16009-16012.
111. Valera A, Solanes G, Fernandez-Alvarez J, Pujol A, Ferrer J, Asins G, Gomis R, Bosch F (1994) Expression of GLUT-2 antisense RNA in β cells of transgenic mice leads to diabetes. J. Biol. Chem. 269, 28543-28546.
112. Viljoen A, Sinclair AJ (2011) Diabetes and insulin resistance in older people. Med. Clin. North Am. 95, 615-629, xi-ii.
113. Wallace TM, Meston NM, Gardner SG, Matthews DR (2001) The hospital and home use of a 30-second hand-held blood ketone meter: guidelines for clinical practice. Diabet. Med. 18, 640-645.
114. Wallace TM, Meston NM, Gardner SG, Matthews DR (2008) Use of a hand-held meter for the measurement of blood beta-hydroxybutyrate in dogs and cats. J. Vet. Emerg. Crit. Care 18, 86-87.
115. Warner HR, Sierra F (2009) The longevity dividend: why invest in basic aging research? Can. J. Aging 28, 391-394; French 395-8.
116. Westbrook R, Bonkowski MS, Strader AD, Bartke A (2009) Alterations in oxygen consumption, respiratory quotient, and heat production in long-lived GHRKO and Ames dwarf mice, and short-lived bGH transgenic mice. J. Gerontol. A Biol. Sci. Med. Sci. 64, 443-451.
117. Wijsman CA, Rozing MP, Streefland TC, le Cessie S, Mooijaart SP, Slagboom PE, Westendorp RG, Pijl H, Pijl H, Van Heemst D; Leiden Longevity Study group. (2011) Familial longevity is marked by enhanced insulin sensitivity. Aging Cell 10, 114-121
118. Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD (2008) FOXO3A genotype is strongly associated with human longevity. Proc. Natl Acad. Sci. USA 105, 13987-13992.
119. Zhou Y, Xu BC, Maheshwari HG, He L, Reed M, Lozykowski M, Okada S, Cataldo L, Coschigamo K, Wagner TE, Baumann G, Kopchick JJ (1997) A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc. Natl Acad. Sci. USA 94, 13215-13220.
120. Ziv E, Hu D (2011) Genetic variation in insulin/IGF-1 signaling pathways and longevity. Ageing Res. Rev. 10, 201-204.