Functionally significant insulin-like growth factor I receptor mutations in centenarians
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- Yousin Suh
- *Departments of Medicine and Molecular Genetics, and
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- Gil Atzmon
- Institute for Aging Research, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461;
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- Mi-Ook Cho
- *Departments of Medicine and Molecular Genetics, and
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- David Hwang
- Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and
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- Bingrong Liu
- Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and
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- Daniel J. Leahy
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205
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- Nir Barzilai
- Institute for Aging Research, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461;
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- Pinchas Cohen
- Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and
Description
<jats:p> Rather than being a passive, haphazard process of wear and tear, lifespan can be modulated actively by components of the insulin/insulin-like growth factor I (IGFI) pathway in laboratory animals. Complete or partial loss-of-function mutations in genes encoding components of the insulin/IGFI pathway result in extension of life span in yeasts, worms, flies, and mice. This remarkable conservation throughout evolution suggests that altered signaling in this pathway may also influence human lifespan. On the other hand, evolutionary tradeoffs predict that the laboratory findings may not be relevant to human populations, because of the high fitness cost during early life. Here, we studied the biochemical, phenotypic, and genetic variations in a cohort of Ashkenazi Jewish centenarians, their offspring, and offspring-matched controls and demonstrated a gender-specific increase in serum IGFI associated with a smaller stature in female offspring of centenarians. Sequence analysis of the <jats:italic>IGF1</jats:italic> and <jats:italic>IGF1</jats:italic> receptor ( <jats:italic>IGF1R</jats:italic> ) genes of female centenarians showed overrepresentation of heterozygous mutations in the <jats:italic>IGF1R</jats:italic> gene among centenarians relative to controls that are associated with high serum IGFI levels and reduced activity of the IGFIR as measured in transformed lymphocytes. Thus, genetic alterations in the human <jats:italic>IGF1R</jats:italic> that result in altered IGF signaling pathway confer an increase in susceptibility to human longevity, suggesting a role of this pathway in modulation of human lifespan. </jats:p>
Journal
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 105 (9), 3438-3442, 2008-03-04
Proceedings of the National Academy of Sciences
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Details 詳細情報について
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- CRID
- 1360292619968075136
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- ISSN
- 10916490
- 00278424
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- Data Source
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- Crossref