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

Aging Cell. 2009 Aug;8(4):460-72. doi: 10.1111/j.1474-9726.2009.00493.x. Epub 2009 May 31.

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 > or = 92 years (y), mean +/- standard deviation (SD) = 95.3 +/- 2.2y) and 603 average-lifespan controls (lifespan < or = 79y, mean = 75.7 +/- 2.6y). 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Female
  • Follow-Up Studies
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / genetics
  • Genome, Human
  • Genotype
  • Humans
  • Insulin / genetics*
  • Insulin / metabolism
  • Insulin-Like Growth Factor I / genetics*
  • Insulin-Like Growth Factor I / metabolism
  • Longevity / genetics*
  • Male
  • Osteoporosis / epidemiology
  • Osteoporosis / genetics
  • Polymorphism, Single Nucleotide*
  • Proto-Oncogene Proteins c-akt / genetics
  • Signal Transduction*

Substances

  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Insulin
  • Insulin-Like Growth Factor I
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt

Grant support