Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles

Cagdas Tazearslan, Jing Huang, Nir Barzilai, Yousin Suh

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Dampening of insulin/insulin-like growth factor-1 (IGF1) signaling results in the extension of lifespan in invertebrate as well as murine models. The impact of this evolutionarily conserved pathway on the modulation of human lifespan remains unclear. We previously identified two IGF1R mutations (Ala-37-Thr and Arg-407-His) that are enriched in Ashkenazi Jewish centenarians as compared to younger controls and are associated with the reduced activity of the IGF1 receptor as measured in immortalized lymphocytes. To determine whether these human longevity-associated IGF1R mutations affect IGF1 signaling, we engineered mouse embryonic fibroblasts (MEFs) expressing the different human IGF1R variants in a mouse Igf1r null background. The results indicate that MEFs expressing the human longevity-associated IGF1R mutations attenuated IGF1 signaling, as demonstrated by significant reduction in phosphorylation of both IGF1R and AKT after IGF1 treatment, in comparison with MEFs expressing the wild-type IGF1R. The impaired IGF1 signaling caused by the IGF1R mutations resulted in the reduced induction of the major IGF1-activated genes in MEFs, including EGR1, mCSF, IL3Rα, and TDAG51. Furthermore, the IGF1R mutations caused a delay in cell cycle progression after IGF1 treatment, indicating a dysfunctional physiological response to a cell proliferation signal. These results demonstrate that the human longevity-associated IGF1R variants are reduced-function mutations, implying that dampening of IGF1 signaling may be a longevity mechanism in humans.

Original languageEnglish (US)
Pages (from-to)551-554
Number of pages4
JournalAging Cell
Volume10
Issue number3
DOIs
StatePublished - Jun 2011

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Somatomedins
Alleles
Mutation
Fibroblasts
Somatomedin Receptors
Invertebrates
Cell Cycle
Phosphorylation
Cell Proliferation
Lymphocytes
Insulin
Therapeutics
Genes

Keywords

  • Gene expression
  • Genetic variation
  • Human longevity
  • Insulin/insulin-like growth factor-1 signaling

ASJC Scopus subject areas

  • Cell Biology
  • Aging

Cite this

Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles. / Tazearslan, Cagdas; Huang, Jing; Barzilai, Nir; Suh, Yousin.

In: Aging Cell, Vol. 10, No. 3, 06.2011, p. 551-554.

Research output: Contribution to journalArticle

Tazearslan, Cagdas ; Huang, Jing ; Barzilai, Nir ; Suh, Yousin. / Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles. In: Aging Cell. 2011 ; Vol. 10, No. 3. pp. 551-554.
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