GeroScience

, Volume 39, Issue 2, pp 129–145 | Cite as

IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan

  • Nicole M. Ashpole
  • Sreemathi Logan
  • Andriy Yabluchanskiy
  • Matthew C. Mitschelen
  • Han Yan
  • Julie A. Farley
  • Erik L. Hodges
  • Zoltan Ungvari
  • Anna Csiszar
  • Sixia Chen
  • Constantin Georgescu
  • Gene B. Hubbard
  • Yuji Ikeno
  • William E. Sonntag
Original Article

Abstract

Reduced circulating levels of IGF-1 have been proposed as a conserved anti-aging mechanism that contributes to increased lifespan in diverse experimental models. However, IGF-1 has also been shown to be essential for normal development and the maintenance of tissue function late into the lifespan. These disparate findings suggest that IGF-1 may be a pleiotropic modulator of health and aging, as reductions in IGF-1 may be beneficial for one aspect of aging, but detrimental for another. We postulated that the effects of IGF-1 on tissue health and function in advanced age are dependent on the tissue, the sex of the animal, and the age at which IGF-1 is manipulated. In this study, we examined how alterations in IGF-1 levels at multiple stages of development and aging influence overall lifespan, healthspan, and pathology. Specifically, we investigated the effects of perinatal, post-pubertal, and late-adult onset IGF-1 deficiency using genetic and viral approaches in both male and female igff/f C57Bl/6 mice. Our results support the concept that IGF-1 levels early during lifespan establish the conditions necessary for subsequent healthspan and pathological changes that contribute to aging. Nevertheless, these changes are specific for each sex and tissue. Importantly, late-life IGF-1 deficiency (a time point relevant for human studies) reduces cancer risk but does not increase lifespan. Overall, our results indicate that the levels of IGF-1 during development influence late-life pathology, suggesting that IGF-1 is a developmental driver of healthspan, pathology, and lifespan.

Keywords

Insulin-like growth factor-1 Somatomedin C Aging Longevity Cancer Pathology 

Supplementary material

11357_2017_9971_MOESM1_ESM.pdf (992 kb)
ESM 1(PDF 991 kb)

References

  1. Amato G et al (1993) Body composition, bone metabolism, and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab 77:1671–1676. doi:10.1210/jcem.77.6.8263158 PubMedGoogle Scholar
  2. Arum O, Rickman DJ, Kopchick JJ, Bartke A (2014) The slow-aging growth hormone receptor/binding protein gene-disrupted (GHR-KO) mouse is protected from aging-resultant neuromusculoskeletal frailty. Age 36:117–127. doi:10.1007/s11357-013-9551-x CrossRefPubMedGoogle Scholar
  3. Ashpole NM et al (2015) IGF-1 regulates vertebral bone aging through sex-specific and time-dependent mechanisms. J Bone Miner Res Off J Am Soc Bone Miner Res. doi:10.1002/jbmr.2689 Google Scholar
  4. Ashpole NM et al (2016a) Differential effects of IGF-1 deficiency during the life span on structural and biomechanical properties in the tibia of aged mice. Age 38:38. doi:10.1007/s11357-016-9902-5 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Ashpole NM et al (2016b) IGF-1 regulates vertebral Bone aging through sex-specific and time-dependent mechanisms. J Bone Miner Res Off J Am Soc Bone Miner Res 31:443–454. doi:10.1002/jbmr.2689 CrossRefGoogle Scholar
  6. Austad SN, Fischer KE (2016) Sex differences in lifespan. Cell Metab 23:1022–1033. doi:10.1016/j.cmet.2016.05.019 CrossRefPubMedGoogle Scholar
  7. Bailey-Downs LC et al (2012a) Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging. J Gerontol A Biol Sci Med Sci 67:313–329. doi:10.1093/gerona/glr164 CrossRefPubMedGoogle Scholar
  8. Bailey-Downs LC et al (2012b) Growth hormone and IGF-1 deficiency exacerbate high-fat diet-induced endothelial impairment in obese Lewis dwarf rats: implications for vascular aging. J Gerontol A Biol Sci Med Sci 67:553–564. doi:10.1093/gerona/glr197 CrossRefPubMedGoogle Scholar
  9. Bansal A, Zhu LJ, Yen K, Tissenbaum HA (2015) Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants. Proc Natl Acad Sci U S A 112:E277–E286. doi:10.1073/pnas.1412192112 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bartke A, Brown-Borg H (2004) Life extension in the dwarf mouse. Curr Top Dev Biol 63:189–225. doi:10.1016/S0070-2153(04)63006-7 CrossRefPubMedGoogle Scholar
  11. Bartke A et al (2000) Growth hormone and aging. Journal of the American Aging Association 23:219–225. doi:10.1007/s11357-000-0021-x PubMedPubMedCentralGoogle Scholar
  12. Bokov AF et al. (2011) Does reduced IGF-1R signaling in Igf1r(+/−) mice alter aging? Plos ONE 6:e26891. doi:10.1371/journal.pone.0026891
  13. Bronson RT, Lipman RD (1993) The role of pathology in rodent experimental gerontology. Aging-Clin Exp Res 5:253–257CrossRefGoogle Scholar
  14. Brown-Borg HM (2015) The somatotropic axis and longevity in mice. Am J Phys Endocrinol Metab 309:E503–E510. doi:10.1152/ajpendo.00262.2015 CrossRefGoogle Scholar
  15. Brown-Borg HM, Borg KE, Meliska CJ, Bartke A (1996) Dwarf mice and the ageing process. Nature 384:33. doi:10.1038/384033a0 CrossRefPubMedGoogle Scholar
  16. 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. doi:10.1210/endo.141.7.7586 PubMedGoogle Scholar
  17. 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. doi:10.1210/en.2003-0374 CrossRefPubMedGoogle Scholar
  18. De Boer H, Blok GJ, Voerman HJ, De Vries PM, van der Veen EA (1992) Body composition in adult growth hormone-deficient men, assessed by anthropometry and bioimpedance analysis. J Clin Endocrinol Metab 75:833–837. doi:10.1210/jcem.75.3.1517374 PubMedGoogle Scholar
  19. Eriksson JG, Forsen TJ, Kajantie E, Osmond C, Barker DJ (2007) Childhood growth and hypertension in later life. Hypertension 49:1415–1421. doi:10.1161/HYPERTENSIONAHA.106.085597 CrossRefPubMedGoogle Scholar
  20. Eriksson JG, Forsen T, Tuomilehto J, Winter PD, Osmond C, Barker DJ (1999) Catch-up growth in childhood and death from coronary heart disease: longitudinal study. BMJ 318:427–431CrossRefPubMedPubMedCentralGoogle Scholar
  21. Gong Z et al (2014) Reductions in serum IGF-1 during aging impair health span. Aging Cell 13:408–418. doi:10.1111/acel.12188 CrossRefPubMedGoogle Scholar
  22. Harrison DE et al (2014) Acarbose, 17-alpha-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell 13:273–282. doi:10.1111/acel.12170 CrossRefPubMedGoogle Scholar
  23. Hascup KN et al (2016) Enhanced cognition and hypoglutamatergic signaling in a growth hormone receptor knockout mouse model of successful aging. J Gerontol A Biol Sci Med Sci. doi:10.1093/gerona/glw088 PubMedGoogle Scholar
  24. Herenu CB, Cristina C, Rimoldi OJ, Becu-Villalobos D, Cambiaggi V, Portiansky EL, Goya RG (2007) Restorative effect of insulin-like growth factor-I gene therapy in the hypothalamus of senile rats with dopaminergic dysfunction. Gene Ther 14:237–245. doi:10.1038/sj.gt.3302870 CrossRefPubMedGoogle Scholar
  25. Holzenberger M et al (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421:182–187. doi:10.1038/nature01298 CrossRefPubMedGoogle Scholar
  26. Ikeno Y, Bronson RT, Hubbard GB, Lee S, Bartke A (2003) Delayed occurrence of fatal neoplastic diseases in Ames dwarf mice: correlation to extended longevity. J Gerontol a-Biol 58:291–296CrossRefGoogle Scholar
  27. Ikeno Y, Hubbard GB, Lee S, Richardson A, Strong R, Diaz V, Nelson JF (2005) Housing density does not influence the longevity effect of calorie restriction. J Gerontol a-Biol 60:1510–1517CrossRefGoogle Scholar
  28. Ikeno Y et al (2009) Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J Gerontol A Biol Sci Med Sci 64:522–529. doi:10.1093/gerona/glp017 CrossRefPubMedGoogle Scholar
  29. Johansson JO, Fowelin J, Landin K, Lager I, Bengtsson BA (1995) Growth hormone-deficient adults are insulin-resistant. Metab Clin Exp 44:1126–1129CrossRefPubMedGoogle Scholar
  30. Kajantie E, Osmond C, Barker DJ, Forsen T, Phillips DI, Eriksson JG (2005) Size at birth as a predictor of mortality in adulthood: a follow-up of 350 000 person-years. Int J Epidemiol 34:655–663. doi:10.1093/ije/dyi048 CrossRefPubMedGoogle Scholar
  31. Koenker R (2008) Censored quantile regression redux. J Stat Softw 27:1–25CrossRefGoogle Scholar
  32. Ladiges W, Van Remmen H, Strong R, Ikeno Y, Treuting P, Rabinovitch P, Richardson A (2009) Lifespan extension in genetically modified mice. Aging Cell 8:346–352. doi:10.1111/j.1474-9726.2009.00491.x CrossRefPubMedGoogle Scholar
  33. Markowska AL, Mooney M, Sonntag WE (1998) Insulin-like growth factor-1 ameliorates age-related behavioral deficits. Neuroscience 87:559–569CrossRefPubMedGoogle Scholar
  34. Merola B et al (1993) Cardiac structural and functional abnormalities in adult patients with growth hormone deficiency. J Clin Endocrinol Metab 77:1658–1661. doi:10.1210/jcem.77.6.8263155 PubMedGoogle Scholar
  35. Miller RA et al (2007) An Aging Interventions Testing Program: study design and interim report. Aging Cell 6:565–575. doi:10.1111/j.1474-9726.2007.00311.x CrossRefPubMedGoogle Scholar
  36. Miller RA et al (2011) Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 66:191–201. doi:10.1093/gerona/glq178 CrossRefPubMedGoogle Scholar
  37. Miller RA et al (2014) Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 13:468–477. doi:10.1111/acel.12194 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Milman S, Atzmon G, Huffman DM, Wan J, Crandall JP, Cohen P, Barzilai N (2014) Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell 13:769–771. doi:10.1111/acel.12213 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Osmond C, Kajantie E, Forsen TJ, Eriksson JG, Barker DJ (2007) Infant growth and stroke in adult life: the Helsinki birth cohort study. Stroke; a journal of cerebral circulation 38:264–270. doi:10.1161/01.STR.0000254471.72186.03 CrossRefGoogle Scholar
  40. Podlutsky A et al (2017) The GH/IGF-1 axis in a critical period early in life determines cellular DNA repair capacity by altering transcriptional regulation of DNA repair-related genes: implications for the developmental origins of cancer. Geroscience. doi:10.1007/s11357-017-9966-x PubMedGoogle Scholar
  41. Radaelli E, Arnold A, Papanikolaou A, Garcia-Fernandez RA, Mattiello S, Scanziani E, Cardiff RD (2009) Mammary tumor phenotypes in wild-type aging female FVB/N mice with pituitary prolactinomas. Vet Pathol 46:736–745. doi:10.1354/vp.08-VP-0280-R-FL CrossRefPubMedGoogle Scholar
  42. Ramsey MM, Weiner JL, Moore TP, Carter CS, Sonntag WE (2004) Growth hormone treatment attenuates age-related changes in hippocampal short-term plasticity and spatial learning. Neuroscience 129:119–127. doi:10.1016/j.neuroscience.2004.08.001 CrossRefPubMedGoogle Scholar
  43. Richardson A, Liu F, Adamo ML, Van Remmen H, Nelson JF (2004) The role of insulin and insulin-like growth factor-I in mammalian ageing. Best Pract Res Clin Endocrinol Metab 18:393–406. doi:10.1016/j.beem.2004.02.002 CrossRefPubMedGoogle Scholar
  44. Rincon M, Rudin E, Barzilai N (2005) The insulin/IGF-1 signaling in mammals and its relevance to human longevity. Exp Gerontol 40:873–877. doi:10.1016/j.exger.2005.06.014 CrossRefPubMedGoogle Scholar
  45. Sonntag WE, Csiszar A, deCabo R, Ferrucci L, Ungvari Z (2012) Diverse roles of growth hormone and insulin-like growth factor-1 in mammalian aging: progress and controversies. J Gerontol A Biol Sci Med Sci 67:587–598. doi:10.1093/gerona/gls115 CrossRefPubMedGoogle Scholar
  46. Sonntag WE, Lynch CD, Cefalu WT, Ingram RL, Bennett SA, Thornton PL, Khan AS (1999) Pleiotropic effects of growth hormone and insulin-like growth factor (IGF)-1 on biological aging: inferences from moderate caloric-restricted animals. J Gerontol A Biol Sci Med Sci 54:B521–B538CrossRefPubMedGoogle Scholar
  47. Sonntag WE, Lynch C, Thornton P, Khan A, Bennett S, Ingram R (2000) The effects of growth hormone and IGF-1 deficiency on cerebrovascular and brain ageing. J Anat 197(Pt 4):575–585CrossRefPubMedPubMedCentralGoogle Scholar
  48. Sonntag WE et al (2005) Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span. Endocrinology 146:2920–2932. doi:10.1210/en.2005-0058 CrossRefPubMedGoogle Scholar
  49. Suh Y et al (2008) Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A 105:3438–3442. doi:10.1073/pnas.0705467105 CrossRefPubMedPubMedCentralGoogle Scholar
  50. Toth P et al (2014) IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 34:1887–1897. doi:10.1038/jcbfm.2014.156 CrossRefGoogle Scholar
  51. Toth P et al (2015) IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell. doi:10.1111/acel.12372 Google Scholar
  52. van Dam PS et al (2005) Childhood-onset growth hormone deficiency, cognitive function and brain N-acetylaspartate. Psychoneuroendocrinology 30:357–363. doi:10.1016/j.psyneuen.2004.10.002 CrossRefPubMedGoogle Scholar
  53. van Heemst D et al (2005) Reduced insulin/IGF-1 signalling and human longevity. Aging Cell 4:79–85. doi:10.1111/j.1474-9728.2005.00148.x CrossRefPubMedGoogle Scholar
  54. Xu J, Gontier G, Chaker Z, Lacube P, Dupont J, Holzenberger M (2014) Longevity effect of IGF-1R(+/−) mutation depends on genetic background-specific receptor activation. Aging Cell 13:19–28. doi:10.1111/acel.12145 CrossRefPubMedGoogle Scholar
  55. Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, LeRoith D (1999) Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci U S A 96:7324–7329CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© American Aging Association 2017

Authors and Affiliations

  • Nicole M. Ashpole
    • 2
  • Sreemathi Logan
    • 1
  • Andriy Yabluchanskiy
    • 1
  • Matthew C. Mitschelen
    • 1
  • Han Yan
    • 1
  • Julie A. Farley
    • 1
  • Erik L. Hodges
    • 1
  • Zoltan Ungvari
    • 1
  • Anna Csiszar
    • 1
  • Sixia Chen
    • 3
  • Constantin Georgescu
    • 4
  • Gene B. Hubbard
    • 5
    • 6
  • Yuji Ikeno
    • 5
    • 6
  • William E. Sonntag
    • 1
  1. 1.Reynolds Oklahoma Center on Aging, Department of Geriatric MedicineUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.Department of BioMolecular SciencesUniversity of MississippiOxfordUSA
  3. 3.Department of Biostatistics and EpidemiologyUniversity of Oklahoma Health Sciences CenterOklahomaUSA
  4. 4.Oklahoma Medical Research FoundationOklahomaUSA
  5. 5.The Barshop Institute for Longevity and Aging Studies and Department of PathologyThe University of Texas Health Science Center at San AntonioSan AntonioUSA
  6. 6.Research ServiceAudie L. Murphy VA HospitalSan AntonioUSA

Personalised recommendations