Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity

Ludmila Pawlikowska, Donglei Hu, Scott Huntsman, Andrew Sung, Catherine Chu, Justin Chen, Alexander H. Joyner, Nicholas J. Schork, Wen Chi Hsueh, Alexander P. Reiner, Bruce M. Psaty, Gil Atzmon, Nir Barzilai, Steven R. Cummings, Warren S. Browner, Pui Yan Kwok, Elad Ziv

Research output: Contribution to journalArticle

251 Scopus citations

Abstract

The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan ≥ 92 years (y), mean ± standard deviation (SD) = 95.3 ± 2.2y) and 603 average-lifespan controls (lifespan ≤ 79 y, mean = 75.7 ± 2.6 y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95%CI = 0.68-0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95%CI = 1.15-1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan.

Original languageEnglish (US)
Pages (from-to)460-472
Number of pages13
JournalAging cell
Volume8
Issue number4
DOIs
StatePublished - Jul 30 2009

Keywords

  • AKT1
  • FOXO3A
  • Gene
  • IGF1
  • Longevity
  • SNP

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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    Pawlikowska, L., Hu, D., Huntsman, S., Sung, A., Chu, C., Chen, J., Joyner, A. H., Schork, N. J., Hsueh, W. C., Reiner, A. P., Psaty, B. M., Atzmon, G., Barzilai, N., Cummings, S. R., Browner, W. S., Kwok, P. Y., & Ziv, E. (2009). Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging cell, 8(4), 460-472. https://doi.org/10.1111/j.1474-9726.2009.00493.x