Reductions in serum IGF-1 during aging impair health span

Zhenwei Gong, Oran Kennedy, Hui Sun, Yingjie Wu, Garry A. Williams, Laura Klein, Luis Cardoso, Ronald W. Matheny, Gene B. Hubbard, Yuji Ikeno, Roger P. Farrar, Mitchell B. Schaffler, Martin L. Adamo, Radhika H. Muzumdar, Shoshana Yakar

Research output: Contribution to journalArticle

Abstract

In lower or simple species, such as worms and flies, disruption of the insulin-like growth factor (IGF)-1 and the insulin signaling pathways has been shown to increase lifespan. In rodents, however, growth hormone (GH) regulates IGF-1 levels in serum and tissues and can modulate lifespan via/or independent of IGF-1. Rodent models, where the GH/IGF-1 axis was ablated congenitally, show increased lifespan. However, in contrast to rodents where serum IGF-1 levels are high throughout life, in humans, serum IGF-1 peaks during puberty and declines thereafter during aging. Thus, animal models with congenital disruption of the GH/IGF-1 axis are unable to clearly distinguish between developmental and age-related effects of GH/IGF-1 on health. To overcome this caveat, we developed an inducible liver IGF-1-deficient (iLID) mouse that allows temporal control of serum IGF-1. Deletion of liver Igf -1 gene at one year of age reduced serum IGF-1 by 70% and dramatically impaired health span of the iLID mice. Reductions in serum IGF-1 were coupled with increased GH levels and increased basal STAT5B phosphorylation in livers of iLID mice. These changes were associated with increased liver weight, increased liver inflammation, increased oxidative stress in liver and muscle, and increased incidence of hepatic tumors. Lastly, despite elevations in serum GH, low levels of serum IGF-1 from 1 year of age compromised skeletal integrity and accelerated bone loss. We conclude that an intact GH/IGF-1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology.

Original languageEnglish (US)
Pages (from-to)408-418
Number of pages11
JournalAging Cell
Volume13
Issue number3
DOIs
StatePublished - 2014

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Somatomedins
Growth Hormone
Health
Serum
Liver
Rodentia
Insulin-Like Growth Factor I
Puberty
Diptera
Oxidative Stress
Animal Models
Phosphorylation
Insulin

Keywords

  • Aging
  • Bone
  • Growth hormone
  • IGF
  • Insulin-sensitivity
  • LID
  • Lifespan
  • Liver
  • Tumor

ASJC Scopus subject areas

  • Cell Biology
  • Aging

Cite this

Gong, Z., Kennedy, O., Sun, H., Wu, Y., Williams, G. A., Klein, L., ... Yakar, S. (2014). Reductions in serum IGF-1 during aging impair health span. Aging Cell, 13(3), 408-418. https://doi.org/10.1111/acel.12188

Reductions in serum IGF-1 during aging impair health span. / Gong, Zhenwei; Kennedy, Oran; Sun, Hui; Wu, Yingjie; Williams, Garry A.; Klein, Laura; Cardoso, Luis; Matheny, Ronald W.; Hubbard, Gene B.; Ikeno, Yuji; Farrar, Roger P.; Schaffler, Mitchell B.; Adamo, Martin L.; Muzumdar, Radhika H.; Yakar, Shoshana.

In: Aging Cell, Vol. 13, No. 3, 2014, p. 408-418.

Research output: Contribution to journalArticle

Gong, Z, Kennedy, O, Sun, H, Wu, Y, Williams, GA, Klein, L, Cardoso, L, Matheny, RW, Hubbard, GB, Ikeno, Y, Farrar, RP, Schaffler, MB, Adamo, ML, Muzumdar, RH & Yakar, S 2014, 'Reductions in serum IGF-1 during aging impair health span', Aging Cell, vol. 13, no. 3, pp. 408-418. https://doi.org/10.1111/acel.12188
Gong Z, Kennedy O, Sun H, Wu Y, Williams GA, Klein L et al. Reductions in serum IGF-1 during aging impair health span. Aging Cell. 2014;13(3):408-418. https://doi.org/10.1111/acel.12188
Gong, Zhenwei ; Kennedy, Oran ; Sun, Hui ; Wu, Yingjie ; Williams, Garry A. ; Klein, Laura ; Cardoso, Luis ; Matheny, Ronald W. ; Hubbard, Gene B. ; Ikeno, Yuji ; Farrar, Roger P. ; Schaffler, Mitchell B. ; Adamo, Martin L. ; Muzumdar, Radhika H. ; Yakar, Shoshana. / Reductions in serum IGF-1 during aging impair health span. In: Aging Cell. 2014 ; Vol. 13, No. 3. pp. 408-418.
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abstract = "In lower or simple species, such as worms and flies, disruption of the insulin-like growth factor (IGF)-1 and the insulin signaling pathways has been shown to increase lifespan. In rodents, however, growth hormone (GH) regulates IGF-1 levels in serum and tissues and can modulate lifespan via/or independent of IGF-1. Rodent models, where the GH/IGF-1 axis was ablated congenitally, show increased lifespan. However, in contrast to rodents where serum IGF-1 levels are high throughout life, in humans, serum IGF-1 peaks during puberty and declines thereafter during aging. Thus, animal models with congenital disruption of the GH/IGF-1 axis are unable to clearly distinguish between developmental and age-related effects of GH/IGF-1 on health. To overcome this caveat, we developed an inducible liver IGF-1-deficient (iLID) mouse that allows temporal control of serum IGF-1. Deletion of liver Igf -1 gene at one year of age reduced serum IGF-1 by 70{\%} and dramatically impaired health span of the iLID mice. Reductions in serum IGF-1 were coupled with increased GH levels and increased basal STAT5B phosphorylation in livers of iLID mice. These changes were associated with increased liver weight, increased liver inflammation, increased oxidative stress in liver and muscle, and increased incidence of hepatic tumors. Lastly, despite elevations in serum GH, low levels of serum IGF-1 from 1 year of age compromised skeletal integrity and accelerated bone loss. We conclude that an intact GH/IGF-1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology.",
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AU - Kennedy, Oran

AU - Sun, Hui

AU - Wu, Yingjie

AU - Williams, Garry A.

AU - Klein, Laura

AU - Cardoso, Luis

AU - Matheny, Ronald W.

AU - Hubbard, Gene B.

AU - Ikeno, Yuji

AU - Farrar, Roger P.

AU - Schaffler, Mitchell B.

AU - Adamo, Martin L.

AU - Muzumdar, Radhika H.

AU - Yakar, Shoshana

PY - 2014

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