TY - JOUR T1 - Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. JF - Aging Cell Y1 - 2009 A1 - Pawlikowska, Ludmila A1 - Hu, Donglei A1 - Huntsman, Scott A1 - Sung, Andrew A1 - Chu, Catherine A1 - Chen, Justin A1 - Joyner, Alexander H A1 - Schork, Nicholas J A1 - Hsueh, Wen-Chi A1 - Reiner, Alexander P A1 - Psaty, Bruce M A1 - Atzmon, Gil A1 - Barzilai, Nir A1 - Cummings, Steven R A1 - Browner, Warren S A1 - Kwok, Pui-Yan A1 - Ziv, Elad KW - Aged KW - Aged, 80 and over KW - Female KW - Follow-Up Studies KW - Forkhead Box Protein O3 KW - Forkhead Transcription Factors KW - Genome, Human KW - Genotype KW - Humans KW - Insulin KW - Insulin-Like Growth Factor I KW - Longevity KW - Male KW - Osteoporosis KW - Polymorphism, Single Nucleotide KW - Proto-Oncogene Proteins c-akt KW - Signal Transduction AB -

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.

VL - 8 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19489743?dopt=Abstract ER -