Reductions in serum IGF-1 during aging impair health span

Authors

  • Zhenwei Gong,

    1. Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA
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    • Equal contribution.
  • Oran Kennedy,

    1. Department of Orthopaedic Surgery, New York University, Hospital for Joint Diseases,  NY, NY, USA
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    • Equal contribution.
  • Hui Sun,

    1. David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA
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    • Equal contribution.
  • YingJie Wu,

    1. David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA
    Current affiliation:
    1. College of Integrative Medicine and Institute of Integrative Medicine, Dalian Medical University, Dalian, China
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    • Equal contribution.
  • Garry A Williams,

    1. David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA
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  • Laura Klein,

    1. Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA
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  • Luis Cardoso,

    1. Department of Biomedical Engineering, The City College of New York, New York, NY, USA
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  • Ronald W. Matheny Jr,

    1. Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA
    2. Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX, USA
    Current affiliation:
    1. US Army Research Institute of Environmental Medicine, Military Performance Division, Natick, MA 01760, USA
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  • Gene B. Hubbard,

    1. Department of Pathology, University of Texas Health Science Center, San Antonio, TX, USA
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  • Yuji Ikeno,

    1. Department of Pathology, University of Texas Health Science Center, San Antonio, TX, USA
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  • Roger P. Farrar,

    1. Department of Kinesiology and Health Education, University of Texas at Austin, Austin, TX, USA
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  • Mitchell B Schaffler,

    1. Department of Biomedical Engineering, The City College of New York, New York, NY, USA
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  • Martin L Adamo,

    1. Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA
    2. Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX, USA
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    • Shared senior PI.
  • Radhika H Muzumdar,

    1. Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA
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    • Shared senior PI.
  • Shoshana Yakar

    Corresponding author
    1. David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA
    • Correspondence

      Shoshana Yakar, PhD, Associate Professor, New York University College of Dentistry, David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology, 345 East 24th Street, New York, NY 10010-4086, USA. Tel.: +1 212 998 9721 Fax: +1 212 995 4087; e-mail: sy1007@nyu.edu

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    • Shared senior PI.

  • All authors concur with the submission. The material submitted for publication has not been previously reported and is not under consideration for publication elsewhere.

Summary

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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