Functionally significant insulin-like growth factor I receptor mutations in centenarians
Open accessAbstract
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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The activity of IGF-1/IGFR that elevates PI3K/Akt/mTor has been shown to act against longevity in animal and human studies.
“The activity of IGF-1/IGFR that elevates PI3K/Akt/mTor has been shown to act against longevity in animal [110] and human studies [111,112].”
From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [111]
The Results (page unavailable) report that IGF1R mutations found in centenarians were associated with reduced receptor levels and reduced AKT phosphorylation. The Discussion (page unavailable) says this suggests a role for reduced IGF signaling in human longevity, but calls that role controversial. The paper does not establish that increased PI3K/Akt/mTOR activity acts against human longevity; PI3K and mTOR are not addressed in the cited passages. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPolymorphisms in two IIS pathway genes, the IGF-1 receptor and the downstream FOXO3 transcription factor, have been associated with longevity and healthy ageing in humans.
“Polymorphisms in two IIS pathway genes, the IGF-1 receptor and the downstream FOXO3 transcription factor, have been associated with longevity and healthy ageing in humans (62–64).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [63]
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“Moreover, IGF-1 receptor polymorphisms, which result in impaired receptor function, are present more frequently in human centenarians than in the general population (Suh et al., 2008).”
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Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends 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)
- 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
- 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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