Cited by 703Genetics, Aging, and Longevity in Model OrganismsGrowth Hormone and Insulin-like Growth FactorsGenetics and Physical Performance

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

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Suh, Yousin, Atzmon, Gil, Cho, Mi-Ook, Hwang, David, Liu, Bingrong, Leahy, Daniel J., Barzilai, Nir, Cohen, Pinchas·2008·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0705467105PMC PMC2265137

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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.

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Authors: Suh, Y., Atzmon, G., Cho, M.-O., Hwang, D., Liu, B., Leahy, D. J., Barzilai, N., & Cohen, P.
Affiliations: Albert Einstein College of Medicine (US)
Yeshiva University (US)
University of California, Los Angeles (US)
Johns Hopkins University (US)
ORCID: Suh, Yousin
Atzmon, Gil
Liu, Bingrong
Leahy, Daniel J.
Barzilai, Nir
Cohen, Pinchas
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2008-03-04
Volume: 105
Issue: 9
Pages: 3438-3442
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0705467105
PMC: PMC2265137
OpenAlex: W2096452837
Cited by: 703
References: 36
Citations by year: 2026: 12 · 2025: 15 · 2024: 15 · 2023: 26 · 2022: 33 · 2021: 40 · 2020: 38 · 2019: 37 · 2018: 41 · 2017: 55 · 2016: 39 · 2015: 36 · 2014: 38 · 2013: 35 · 2012: 54
FWCI: 18.58
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute on Aging (AG024391, P01AG027734, R01AG024391, R03AG023292, AG023292)
National Institute of General Medical Sciences (R01GM099321)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
Keywords: IGF-1 receptor, centenarians, human longevity, lifespan extension, heterozygous mutation, female offspring, height, evolutionary trade-offs
MeSH terms: Aged, 80 and over, DNA Mutational Analysis, Family Health, Heterozygote, Humans, Insulin-Like Growth Factor I, Jews, Longevity, Lymphocytes, Mutation, Sex Factors, Cohort Studies, Receptor, IGF Type 1, Body Size

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

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