Journal
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
Volume 73, Issue 11, Pages 1459-1464Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/gerona/glx247
Keywords
Human genetics; Longevity; Quantitative genetics; Caloric restriction
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Funding
- National Heart, Lung, and Blood Institute [NO1-HC-05102]
- National Institute on Aging [NO1-AG-4-2149, U01-AG-019349, R01-AG-038707, R01-AG-027060]
- Hawaii Community Foundation [2004-0463]
- Longevity Consortium grant [U19 AG023122]
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Longevity is a polygenic trait in which genetic predisposition is particularly important. We hypothesized that among genes differentially expressed in response to caloric restriction, several may be candidate longevity genes. We tested 459 single-nucleotide polymorphisms (SNPs) in 47 genes differentially expressed in calorically restricted mice and 12 other genes for association with longevity. Subjects were American men of Japanese ancestry, 440 aged >= 95 years and 374 with an average life span. Based on a dominant model of inheritance, an association with longevity at the p < .05 level was seen for SNPs in 13 of the genes. Testing by all possible models increased the number of genes to 18. After correction for multiple testing, four genes retained significance, namely, MAP3KS (p = .00004), SIRT7 (p = .00004), SIRTS (p = .0007), and PIK3R1 (p ..01). In a dominant model, association with longevity was seen for multiple adjacent SNPs within two of these genes (MAP3K5 and PIK3R1), as well as in FLT1, consistent with linkage disequilibrium with a causative variant in the vicinity of each respective SNP set. MAP3K5 and FLT1 haplotypes were associated with longevity. In conclusion, the present study implicates variation in MAP3K5, FLT1, PIK3R1, SIRT7, and SIRT5 in human longevity.
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