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PNAS 105 (9): 3438-3442

Copyright © 2008 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / GENETICS

Functionally significant insulin-like growth factor I receptor mutations in centenarians

Yousin Suh*, Gil Atzmon{dagger}, Mi-Ook Cho*, David Hwang{ddagger}, Bingrong Liu{ddagger}, Daniel J. Leahy§, Nir Barzilai{dagger}, and Pinchas Cohen{ddagger}

*Departments of Medicine and Molecular Genetics, and {dagger}Institute for Aging Research, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461; {ddagger}Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and §Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205

Edited by Cynthia J. Kenyon, University of California, San Francisco, CA, and approved January 18, 2008

Received for publication June 11, 2007.

Abstract: 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 IGF1 and IGF1 receptor (IGF1R) genes of female centenarians showed overrepresentation of heterozygous mutations in the IGF1R 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 IGF1R 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.

Key Words: IGF1 receptor • human longevity • genetic variation


Freely available online through the PNAS open access option.

Author contributions: Y.S., N.B., and P.C. designed research; G.A., M.-O.C., D.H., and B.L. performed research; G.A. and D.J.L. contributed new reagents/analytic tools; Y.S., G.A., M.-O.C., D.J.L. and P.C. analyzed data; and Y.S., G.A., N.B., and P.C. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0705467105/DC1.

To whom correspondence should be addressed. E-mail: barzilai{at}aecom.yu.edu

© 2008 by The National Academy of Sciences of the USA


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