Denigma: Willcox BJ et al., 2008

FOXO3A genotype is strongly associated with human longevity.

Authors: Willcox BJ; Donlon TA; He Q; Chen R; Grove JS; Yano K; Masaki KH; Willcox DC; Rodriguez B; Curb JD

Abstract: Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the FOXO3A gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 (P = 0.00009; adjusted P = 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with FOXO3A genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene, human longevity and other aging phenotypes is warranted in other populations.

Keywords: Aged; Aged, 80 and over; Case-Control Studies; Forkhead Transcription Factors/*genetics; Genotype; Health; Humans; Longevity/*genetics; Male; Phenotype

Journal: Proceedings of the National Academy of Sciences of the United States of America
Volume: 105
Issue: 37
Pages: 13987-92
Date: Sept. 4, 2008
PMID: 18765803

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Citation:

Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD (2008) FOXO3A genotype is strongly associated with human longevity. Proceedings of the National Academy of Sciences of the United States of America 105: 13987-92.

Lifespan Factors:

SIRT1 sirtuin 1

FOXO1 forkhead box O1

ADIPOQ10 adiponectin, C1Q and collagen domain containing

Longevity Variant Associations (p-value):

rs1063539 (0.2)

rs182052 (0.22)

rs266729 (0.08)

rs2755209 (0.48)

rs2721069 (0.62)

rs2755213 (0.77)

rs2764264 (0.0002)