DOI QR코드

DOI QR Code

Growth signaling and longevity in mouse models

  • Kim, Seung-Soo (Institute of Animal Molecular Biotechnology, Korea University) ;
  • Lee, Cheol-Koo (Institute of Animal Molecular Biotechnology, Korea University)
  • Received : 2018.11.19
  • Published : 2019.01.31

Abstract

Reduction of insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) extends the lifespan of various species. So far, several longevity mouse models have been developed containing mutations related to growth signaling deficiency by targeting growth hormone (GH), IGF1, IGF1 receptor, insulin receptor, and insulin receptor substrate. In addition, p70 ribosomal protein S6 kinase 1 (S6K1) knockout leads to lifespan extension. S6K1 encodes an important kinase in the regulation of cell growth. S6K1 is regulated by mechanistic target of rapamycin (mTOR) complex 1. The v-myc myelocytomatosis viral oncogene homolog (MYC)-deficient mice also exhibits a longevity phenotype. The gene expression profiles of these mice models have been measured to identify their longevity mechanisms. Here, we summarize our knowledge of long-lived mouse models related to growth and discuss phenotypic characteristics, including organ-specific gene expression patterns.

Keywords

References

  1. Barbieri M, Bonafe M, Franceschi C and Paolisso G (2003) Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans. Am J Physiol Endocrinol Metab 285, E1064-1071 https://doi.org/10.1152/ajpendo.00296.2003
  2. Fontana L, Partridge L and Longo VD (2010) Extending healthy life span--from yeast to humans. Science 328, 321-326 https://doi.org/10.1126/science.1172539
  3. Hwangbo DS, Gershman B, Tu MP, Palmer M and Tatar M (2004) Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429, 562-566 https://doi.org/10.1038/nature02549
  4. Holzenberger M, Dupont J, Ducos B et al (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182-187 https://doi.org/10.1038/nature01298
  5. Bonafe M and Olivieri F (2009) Genetic polymorphism in long-lived people: cues for the presence of an insulin/IGF-pathway-dependent network affecting human longevity. Mol Cell Endocrinol 299, 118-123 https://doi.org/10.1016/j.mce.2008.10.038
  6. Junnila RK, List EO, Berryman DE, Murrey JW and Kopchick JJ (2013) The GH/IGF-1 axis in ageing and longevity. Nat Rev Endocrinol 9, 366-376 https://doi.org/10.1038/nrendo.2013.67
  7. Zhang J and Liu F (2014) Tissue-specific insulin signaling in the regulation of metabolism and aging. IUBMB Life 66, 485-495 https://doi.org/10.1002/iub.1293
  8. Rask-Madsen C and Kahn CR (2012) Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler Thromb Vasc Biol 32, 2052-2059 https://doi.org/10.1161/ATVBAHA.111.241919
  9. Flurkey K, Papaconstantinou J, Miller RA and Harrison DE (2001) Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A 98, 6736-6741 https://doi.org/10.1073/pnas.111158898
  10. Flurkey K, Papaconstantinou J and Harrison DE (2002) The Snell dwarf mutation Pit1(dw) can increase life span in mice. Mech Ageing Dev 123, 121-130 https://doi.org/10.1016/S0047-6374(01)00339-6
  11. Lin L, Hale SP and Schimmel P (1996) Aminoacylation error correction. Nature 384, 33-34
  12. Zhou Y, Xu BC, Maheshwari HG et al (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 U S A 94, 13215-13220 https://doi.org/10.1073/pnas.94.24.13215
  13. Coschigano KT, Clemmons D, Bellush LL and Kopchick JJ (2000) Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141, 2608-2613 https://doi.org/10.1210/endo.141.7.7586
  14. Chen WY, Wight DC, Mehta BV, Wagner TE and Kopchick JJ (1991) Glycine 119 of bovine growth hormone is critical for growth-promoting activity. Mol Endocrinol 5, 1845-1852 https://doi.org/10.1210/mend-5-12-1845
  15. Chen WY, White ME, Wagner TE and Kopchick JJ (1991) Functional antagonism between endogenous mouse growth hormone (GH) and a GH analog results in dwarf transgenic mice. Endocrinology 129, 1402-1408 https://doi.org/10.1210/endo-129-3-1402
  16. Berryman DE, List EO, Coschigano KT, Behar K, Kim JK and Kopchick JJ (2004) Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Horm IGF Res 14, 309-318 https://doi.org/10.1016/j.ghir.2004.02.005
  17. Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A and 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 https://doi.org/10.1210/en.2003-0374
  18. Salminen A, Kaarniranta K and Kauppinen A (2017) Regulation of longevity by FGF21: Interaction between energy metabolism and stress responses. Ageing Res Rev 37, 79-93 https://doi.org/10.1016/j.arr.2017.05.004
  19. Kuro-o M (2012) Klotho and betaKlotho. Adv Exp Med Biol 728, 25-40 https://doi.org/10.1007/978-1-4614-0887-1_2
  20. Inagaki T, Lin VY, Goetz R, Mohammadi M, Mangelsdorf DJ and Kliewer SA (2008) Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab 8, 77-83 https://doi.org/10.1016/j.cmet.2008.05.006
  21. Zhang Y, Xie Y, Berglund ED et al (2012) The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. Elife 1, e00065 https://doi.org/10.7554/eLife.00065
  22. Bartke A (2003) Can growth hormone (GH) accelerate aging? Evidence from GH-transgenic mice. Neuroendocrinology 78, 210-216 https://doi.org/10.1159/000073704
  23. Doi T, Striker LJ, Quaife C et al (1988) Progressive glomerulosclerosis develops in transgenic mice chronically expressing growth hormone and growth hormone releasing factor but not in those expressing insulinlike growth factor-1. Am J Pathol 131, 398-403
  24. Yang CW, Striker LJ, Pesce C et al (1993) Glomerulosclerosis and body growth are mediated by different portions of bovine growth hormone. Studies in transgenic mice. Lab Invest 68, 62-70
  25. Chanson P and Salenave S (2008) Acromegaly. Orphanet J Rare Dis 3, 17 https://doi.org/10.1186/1750-1172-3-17
  26. Clayton PE, Banerjee I, Murray PG and Renehan AG (2011) Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol 7, 11-24 https://doi.org/10.1038/nrendo.2010.171
  27. Dozmorov I, Bartke A and Miller RA (2001) Array-based expression analysis of mouse liver genes: effect of age and of the longevity mutant Prop1df. J Gerontol A Biol Sci Med Sci 56, B72-80 https://doi.org/10.1093/gerona/56.2.B72
  28. Dozmorov I, Galecki A, Chang Y, Krzesicki R, Vergara M and Miller RA (2002) Gene expression profile of long-lived snell dwarf mice. J Gerontol A Biol Sci Med Sci 57, B99-108 https://doi.org/10.1093/gerona/57.3.B99
  29. Amador-Noguez D, Yagi K, Venable S and Darlington G (2004) Gene expression profile of long-lived Ames dwarf mice and Little mice. Aging Cell 3, 423-441 https://doi.org/10.1111/j.1474-9728.2004.00125.x
  30. Boylston WH, Gerstner A, DeFord JH et al (2004) Altered cholesterologenic and lipogenic transcriptional profile in livers of aging Snell dwarf (Pit1dw/dwJ) mice. Aging Cell 3, 283-296 https://doi.org/10.1111/j.1474-9728.2004.00115.x
  31. Tsuchiya T, Dhahbi JM, Cui X, Mote PL, Bartke A and Spindler SR (2004) Additive regulation of hepatic gene expression by dwarfism and caloric restriction. Physiol Genomics 17, 307-315 https://doi.org/10.1152/physiolgenomics.00039.2004
  32. Amador-Noguez D, Zimmerman J, Venable S and Darlington G (2005) Gender-specific alterations in gene expression and loss of liver sexual dimorphism in the long-lived Ames dwarf mice. Biochem Biophys Res Commun 332, 1086-1100 https://doi.org/10.1016/j.bbrc.2005.05.063
  33. Papaconstantinou J, Deford JH, Gerstner A et al (2005) Hepatic gene and protein expression of primary components of the IGF-I axis in long lived Snell dwarf mice. Mech Ageing Dev 126, 692-704 https://doi.org/10.1016/j.mad.2005.01.002
  34. Boylston WH, DeFord JH and Papaconstantinou J (2006) Identification of longevity-associated genes in long-lived Snell and Ames dwarf mice. Age (Dordr) 28, 125-144 https://doi.org/10.1007/s11357-006-9008-6
  35. Rossner R, Kaeberlein M and Leiser SF (2017) Flavincontaining monooxygenases in aging and disease: Emerging roles for ancient enzymes. J Biol Chem 292, 11138-11146 https://doi.org/10.1074/jbc.R117.779678
  36. Simard J, Ricketts ML, Gingras S, Soucy P, Feltus FA and Melner MH (2005) Molecular biology of the 3betahydroxysteroid dehydrogenase/delta5-delta4 isomerase gene family. Endocr Rev 26, 525-582 https://doi.org/10.1210/er.2002-0050
  37. Jones JM, Morrell JC and Gould SJ (2000) Identification and characterization of HAOX1, HAOX2, and HAOX3, three human peroxisomal 2-hydroxy acid oxidases. J Biol Chem 275, 12590-12597 https://doi.org/10.1074/jbc.275.17.12590
  38. Rowland JE, Lichanska AM, Kerr LM et al (2005) In vivo analysis of growth hormone receptor signaling domains and their associated transcripts. Mol Cell Biol 25, 66-77 https://doi.org/10.1128/MCB.25.1.66-77.2005
  39. Barclay JL, Nelson CN, Ishikawa M et al (2011) GH-dependent STAT5 signaling plays an important role in hepatic lipid metabolism. Endocrinology 152, 181-192 https://doi.org/10.1210/en.2010-0537
  40. Chang L, Qi H, Xiao Y et al (2016) Integrated analysis of noncoding RNAs and mRNAs reveals their potential roles in the biological activities of the growth hormone receptor. Growth Horm IGF Res 29, 11-20 https://doi.org/10.1016/j.ghir.2016.03.003
  41. Swindell WR (2007) Gene expression profiling of long-lived dwarf mice: longevity-associated genes and relationships with diet, gender and aging. BMC Genomics 8, 353 https://doi.org/10.1186/1471-2164-8-353
  42. Nicola NA and Babon JJ (2015) Leukemia inhibitory factor (LIF). Cytokine Growth Factor Rev 26, 533-544 https://doi.org/10.1016/j.cytogfr.2015.07.001
  43. Yano H, Readhead C, Nakashima M, Ren SG and Melmed S (1998) Pituitary-directed leukemia inhibitory factor transgene causes Cushing's syndrome: neuroimmune-endocrine modulation of pituitary development. Mol Endocrinol 12, 1708-1720 https://doi.org/10.1210/mend.12.11.0200
  44. Niedernhofer LJ, Garinis GA, Raams A et al (2006) A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444, 1038-1043 https://doi.org/10.1038/nature05456
  45. van der Pluijm I, Garinis GA, Brandt RM et al (2007) Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome. PLoS Biol 5, e2 https://doi.org/10.1371/journal.pbio.0050002
  46. Schumacher B, van der Pluijm I, Moorhouse MJ et al (2008) Delayed and accelerated aging share common longevity assurance mechanisms. PLoS Genet 4, e1000161 https://doi.org/10.1371/journal.pgen.1000161
  47. Jansson JO, Eden S and Isaksson O (1985) Sexual dimorphism in the control of growth hormone secretion. Endocr Rev 6, 128-150 https://doi.org/10.1210/edrv-6-2-128
  48. MacLeod JN, Pampori NA and Shapiro BH (1991) Sex differences in the ultradian pattern of plasma growth hormone concentrations in mice. J Endocrinol 131, 395-399 https://doi.org/10.1677/joe.0.1310395
  49. Mode A and Gustafsson JA (2006) Sex and the liver - a journey through five decades. Drug Metab Rev 38, 197-207 https://doi.org/10.1080/03602530600570057
  50. Waxman DJ and O'Connor C (2006) Growth hormone regulation of sex-dependent liver gene expression. Mol Endocrinol 20, 2613-2629 https://doi.org/10.1210/me.2006-0007
  51. Yang X, Schadt EE, Wang S et al (2006) Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res 16, 995-1004 https://doi.org/10.1101/gr.5217506
  52. Clodfelter KH, Holloway MG, Hodor P, Park SH, Ray WJ and Waxman DJ (2006) Sex-dependent liver gene expression is extensive and largely dependent upon signal transducer and activator of transcription 5b (STAT5b): STAT5b-dependent activation of male genes and repression of female genes revealed by microarray analysis. Mol Endocrinol 20, 1333-1351 https://doi.org/10.1210/me.2005-0489
  53. Clodfelter KH, Miles GD, Wauthier V et al (2007) Role of STAT5a in regulation of sex-specific gene expression in female but not male mouse liver revealed by microarray analysis. Physiol Genomics 31, 63-74 https://doi.org/10.1152/physiolgenomics.00055.2007
  54. Sjogren K, Liu JL, Blad K et al (1999) Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc Natl Acad Sci U S A 96, 7088-7092 https://doi.org/10.1073/pnas.96.12.7088
  55. Conover CA (2012) Key questions and answers about pregnancy-associated plasma protein-A. Trends Endocrinol Metab 23, 242-249 https://doi.org/10.1016/j.tem.2012.02.008
  56. Conover CA, Bale LK, Overgaard MT et al (2004) Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development. Development 131, 1187-1194 https://doi.org/10.1242/dev.00997
  57. Conover CA and Bale LK (2007) Loss of pregnancyassociated plasma protein A extends lifespan in mice. Aging Cell 6, 727-729 https://doi.org/10.1111/j.1474-9726.2007.00328.x
  58. Conover CA, Bale LK, Mader JR, Mason MA, Keenan KP and Marler RJ (2010) Longevity and age-related pathology of mice deficient in pregnancy-associated plasma protein-A. J Gerontol A Biol Sci Med Sci 65, 590-599
  59. Liu JP, Baker J, Perkins AS, Robertson EJ and Efstratiadis A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75, 59-72
  60. Lorenzini A, Salmon AB, Lerner C et al (2014) Mice producing reduced levels of insulin-like growth factor type 1 display an increase in maximum, but not mean, life span. J Gerontol A Biol Sci Med Sci 69, 410-419 https://doi.org/10.1093/gerona/glt108
  61. Accili D, Drago J, Lee EJ et al (1996) Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat Genet 12, 106-109 https://doi.org/10.1038/ng0196-106
  62. Nelson JF, Strong R, Bokov A, Diaz V and Ward W (2012) Probing the relationship between insulin sensitivity and longevity using genetically modified mice. J Gerontol A Biol Sci Med Sci 67, 1332-1338 https://doi.org/10.1093/gerona/gls199
  63. Yakar S, Liu JL, Stannard B et al (1999) Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci U S A 96, 7324-7329 https://doi.org/10.1073/pnas.96.13.7324
  64. Svensson J, Sjogren K, Faldt J et al (2011) Liver-derived IGF-I regulates mean life span in mice. PLoS One 6, e22640 https://doi.org/10.1371/journal.pone.0022640
  65. Novosyadlyy R and Leroith D (2012) Insulin-like growth factors and insulin: at the crossroad between tumor development and longevity. J Gerontol A Biol Sci Med Sci 67, 640-651 https://doi.org/10.1093/gerona/gls065
  66. Bokov AF, Garg N, Ikeno Y et al (2011) Does reduced IGF-1R signaling in Igf1r+/- mice alter aging? PLoS One 6, e26891 https://doi.org/10.1371/journal.pone.0026891
  67. Ladiges W, Van Remmen H, Strong R et al (2009) Lifespan extension in genetically modified mice. Aging Cell 8, 346-352 https://doi.org/10.1111/j.1474-9726.2009.00491.x
  68. Kurosu H, Yamamoto M, Clark JD et al (2005) Suppression of aging in mice by the hormone Klotho. Science 309, 1829-1833 https://doi.org/10.1126/science.1112766
  69. Kuro-o M, Matsumura Y, Aizawa H et al (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45-51 https://doi.org/10.1038/36285
  70. Selman C, Lingard S, Choudhury AI et al (2008) Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J 22, 807-818 https://doi.org/10.1096/fj.07-9261com
  71. Peng J and He L (2018) IRS posttranslational modifications in regulating insulin signaling. J Mol Endocrinol 60, R1-R8 https://doi.org/10.1530/JME-17-0151
  72. Previs SF, Withers DJ, Ren JM, White MF and Shulman GI (2000) Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo. J Biol Chem 275, 38990-38994 https://doi.org/10.1074/jbc.M006490200
  73. Selman C, Partridge L and Withers DJ (2011) Replication of extended lifespan phenotype in mice with deletion of insulin receptor substrate 1. PLoS One 6, e16144 https://doi.org/10.1371/journal.pone.0016144
  74. Withers DJ, Gutierrez JS, Towery H et al (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391, 900-904 https://doi.org/10.1038/36116
  75. Kushner JA, Ye J, Schubert M et al (2002) Pdx1 restores beta cell function in Irs2 knockout mice. J Clin Invest 109, 1193-1201 https://doi.org/10.1172/JCI0214439
  76. Kushner JA, Haj FG, Klaman LD et al (2004) Islet-sparing effects of protein tyrosine phosphatase-1b deficiency delays onset of diabetes in IRS2 knockout mice. Diabetes 53, 61-66 https://doi.org/10.2337/diabetes.53.1.61
  77. Kushner JA, Simpson L, Wartschow LM et al (2005) Phosphatase and tensin homolog regulation of islet growth and glucose homeostasis. J Biol Chem 280, 39388-39393 https://doi.org/10.1074/jbc.M504155200
  78. Taguchi A and White MF (2008) Insulin-like signaling, nutrient homeostasis, and life span. Annu Rev Physiol 70, 191-212 https://doi.org/10.1146/annurev.physiol.70.113006.100533
  79. Taguchi A, Wartschow LM and White MF (2007) Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317, 369-372 https://doi.org/10.1126/science.1142179
  80. Selman C, Lingard S, Gems D, Partridge L and Withers DJ (2008) Comment on "Brain IRS2 signaling coordinates life span and nutrient homeostasis". Science 320, 1012; author reply 1012
  81. Kubota N, Kubota T, Itoh S et al (2008) Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding. Cell Metab 8, 49-64 https://doi.org/10.1016/j.cmet.2008.05.007
  82. Guo S, Copps KD, Dong X et al (2009) The Irs1 branch of the insulin signaling cascade plays a dominant role in hepatic nutrient homeostasis. Mol Cell Biol 29, 5070-5083 https://doi.org/10.1128/MCB.00138-09
  83. Brunet A, Bonni A, Zigmond MJ et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857-868 https://doi.org/10.1016/S0092-8674(00)80595-4
  84. Martins R, Lithgow GJ and Link W (2016) Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell 15, 196-207 https://doi.org/10.1111/acel.12427
  85. Hannenhalli S and Kaestner KH (2009) The evolution of Fox genes and their role in development and disease. Nat Rev Genet 10, 233-240 https://doi.org/10.1038/nrg2523
  86. Shimokawa I, Komatsu T, Hayashi N et al (2015) The life-extending effect of dietary restriction requires Foxo3 in mice. Aging Cell 14, 707-709 https://doi.org/10.1111/acel.12340
  87. Boehm AM, Khalturin K, Anton-Erxleben F et al (2012) FoxO is a critical regulator of stem cell maintenance in immortal Hydra. Proc Natl Acad Sci U S A 109, 19697-19702 https://doi.org/10.1073/pnas.1209714109
  88. Webb AE, Kundaje A and Brunet A (2016) Characterization of the direct targets of FOXO transcription factors throughout evolution. Aging Cell 15, 673-685 https://doi.org/10.1111/acel.12479
  89. Page MM, Schuster EF, Mudaliar M, Herzyk P, Withers DJ and Selman C (2018) Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 (IRS1) in mice. Aging (Albany NY) 10, 1027-1052 https://doi.org/10.18632/aging.101446
  90. Stout MB, Tchkonia T, Pirtskhalava T et al (2014) Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice. Aging (Albany NY) 6, 575-586 https://doi.org/10.18632/aging.100681
  91. Stout MB, Swindell WR, Zhi X et al (2015) Transcriptome profiling reveals divergent expression shifts in brown and white adipose tissue from long-lived GHRKO mice. Oncotarget 6, 26702-26715 https://doi.org/10.18632/oncotarget.5760
  92. Masternak MM, Bartke A, Wang F et al (2012) Metabolic effects of intra-abdominal fat in GHRKO mice. Aging Cell 11, 73-81 https://doi.org/10.1111/j.1474-9726.2011.00763.x
  93. Bluher M, Michael MD, Peroni OD et al (2002) Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell 3, 25-38 https://doi.org/10.1016/S1534-5807(02)00199-5
  94. Bluher M, Patti ME, Gesta S, Kahn BB and Kahn CR (2004) Intrinsic heterogeneity in adipose tissue of fat-specific insulin receptor knock-out mice is associated with differences in patterns of gene expression. J Biol Chem 279, 31891-31901 https://doi.org/10.1074/jbc.M404569200
  95. Katic M, Kennedy AR, Leykin I et al (2007) Mitochondrial gene expression and increased oxidative metabolism: role in increased lifespan of fat-specific insulin receptor knock-out mice. Aging Cell 6, 827-839 https://doi.org/10.1111/j.1474-9726.2007.00346.x
  96. Kappeler L, De Magalhaes Filho C, Dupont J et al (2008) Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS Biol 6, e254 https://doi.org/10.1371/journal.pbio.0060254
  97. Sadagurski M, Cheng Z, Rozzo A et al (2011) IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease. J Clin Invest 121, 4070-4081 https://doi.org/10.1172/JCI46305
  98. Li Q and Ren J (2007) Influence of cardiac-specific overexpression of insulin-like growth factor 1 on lifespan and aging-associated changes in cardiac intracellular Ca2+ homeostasis, protein damage and apoptotic protein expression. Aging Cell 6, 799-806 https://doi.org/10.1111/j.1474-9726.2007.00343.x
  99. Ren J and Brown-Borg HM (2002) Impaired cardiac excitation-contraction coupling in ventricular myocytes from Ames dwarf mice with IGF-I deficiency. Growth Horm IGF Res 12, 99-105 https://doi.org/10.1054/ghir.2002.0267
  100. Um SH, D'Alessio D and Thomas G (2006) Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 3, 393-402 https://doi.org/10.1016/j.cmet.2006.05.003
  101. Selman C, Tullet JM, Wieser D et al (2009) Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140-144 https://doi.org/10.1126/science.1177221
  102. Lamming DW, Ye L, Katajisto P et al (2012) Rapamycininduced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638-1643 https://doi.org/10.1126/science.1215135
  103. Ranieri SC, Fusco S, Panieri E et al (2010) Mammalian life-span determinant p66shcA mediates obesity-induced insulin resistance. Proc Natl Acad Sci U S A 107, 13420-13425 https://doi.org/10.1073/pnas.1008647107
  104. Migliaccio E, Giorgio M, Mele S et al (1999) The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309-313 https://doi.org/10.1038/46311
  105. Tomilov AA, Bicocca V, Schoenfeld RA et al (2010) Decreased superoxide production in macrophages of long-lived p66Shc knock-out mice. J Biol Chem 285, 1153-1165 https://doi.org/10.1074/jbc.M109.017491
  106. Wientjes FB and Segal AW (1995) NADPH oxidase and the respiratory burst. Semin Cell Biol 6, 357-365 https://doi.org/10.1016/S1043-4682(05)80006-6
  107. Dang CV (2012) MYC on the path to cancer. Cell 149, 22-35 https://doi.org/10.1016/j.cell.2012.03.003
  108. Hofmann JW, Zhao X, De Cecco M et al (2015) Reduced expression of MYC increases longevity and enhances healthspan. Cell 160, 477-488 https://doi.org/10.1016/j.cell.2014.12.016
  109. Bartke A (2012) Healthy aging: is smaller better? - a mini-review. Gerontology 58, 337-343 https://doi.org/10.1159/000335166
  110. Wang S and Ren J (2018) Obesity Paradox in Aging: From Prevalence to Pathophysiology. Prog Cardiovasc Dis 61, 182-189 https://doi.org/10.1016/j.pcad.2018.07.011
  111. Murakami S (2006) Stress resistance in long-lived mouse models. Exp Gerontol 41, 1014-1019 https://doi.org/10.1016/j.exger.2006.06.061
  112. Tower J (2017) Sex-Specific Gene Expression and Life Span Regulation. Trends Endocrinol Metab 28, 735-747 https://doi.org/10.1016/j.tem.2017.07.002