title: Genetic analysis of TOR complex gene variation with human longevity: a nested case-control study of American men of Japanese ancestry.
abstract: The mechanistic target of rapamycin (mTOR) pathway is crucial for life span determination in model organisms. The aim of the present study was to test tagging single-nucleotide polymorphisms that captured most of the genetic variation across key TOR complex 1 (TORC1) and TOR complex 2 (TORC2) genes MTOR, RPTOR, and RICTOR and the important downstream effector gene RPS6KA1 for association with human longevity (defined as attainment of at least 95 years of age) as well as health span phenotypes. Subjects comprised a homogeneous population of American men of Japanese ancestry, well characterized for aging phenotypes and who have been followed for 48 years. The study used a nested case-control design involving 440 subjects aged 95 years and older and 374 controls. It found no association of 6 tagging single-nucleotide polymorphisms for MTOR, 61 for RPTOR, 7 for RICTOR, or 5 for RPS6KA1 with longevity. Of 40 aging-related phenotypes, no significant association with genotype was seen. Thus common genetic variation (minor allele frequency ≥10%) in MTOR, RPTOR, RICTOR, and RPS6KA1 is not associated with extreme old age or aging phenotypes in this population. Further research is needed to assess the potential genetic contribution of other mTOR pathway genes to human longevity, gene expression, upstream and downstream targets, and clinically relevant aging phenotypes.
authors.affiliation: Honolulu Heart Program (HHP)/Honolulu-Asia Aging Study (HAAS), Department of Research, Kuakini Medical Center, Honolulu, Hawaii. Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii. Basic & Clinical Genomics Laboratory, School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia. brian.morris@sydney.edu.au.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Morris
authors.affiliation: Honolulu Heart Program (HHP)/Honolulu-Asia Aging Study (HAAS), Department of Research, Kuakini Medical Center, Honolulu, Hawaii.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Donlon
authors.affiliation: Honolulu Heart Program (HHP)/Honolulu-Asia Aging Study (HAAS), Department of Research, Kuakini Medical Center, Honolulu, Hawaii.
authors.forename: Qimei
authors.initials: Q
authors.lastname: He
authors.affiliation: Honolulu Heart Program (HHP)/Honolulu-Asia Aging Study (HAAS), Department of Research, Kuakini Medical Center, Honolulu, Hawaii. Public Health Sciences, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii.
authors.forename: John S
authors.initials: JS
authors.lastname: Grove
authors.affiliation: Honolulu Heart Program (HHP)/Honolulu-Asia Aging Study (HAAS), Department of Research, Kuakini Medical Center, Honolulu, Hawaii. Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
authors.forename: Kamal H
authors.initials: KH
authors.lastname: Masaki
authors.affiliation: Honolulu Heart Program (HHP)/Honolulu-Asia Aging Study (HAAS), Department of Research, Kuakini Medical Center, Honolulu, Hawaii.
authors.forename: Ayako
authors.initials: A
authors.lastname: Elliott
authors.affiliation: Honolulu Heart Program (HHP)/Honolulu-Asia Aging Study (HAAS), Department of Research, Kuakini Medical Center, Honolulu, Hawaii. Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii. Department of Human Welfare, Okinawa International University, Ginowan, Okinawa, Japan.
authors.forename: D Craig
authors.initials: DC
authors.lastname: Willcox
authors.affiliation: Institute for Biogenesis Research, University of Hawaii, Honolulu, Hawaii.
authors.forename: Richard
authors.initials: R
authors.lastname: Allsopp
authors.affiliation: Honolulu Heart Program (HHP)/Honolulu-Asia Aging Study (HAAS), Department of Research, Kuakini Medical Center, Honolulu, Hawaii. Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Willcox
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D001213:Asian / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D005787:Gene Frequency; D005838:Genotype; D006254:Hawaii; D006801:Humans; D007564:Japan / Q000208:ethnology; D008136:Longevity / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D020641:Polymorphism, Single Nucleotide; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C492571:RICTOR protein, human; C463659:RPTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; C546842:MTOR protein, human; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D058570:TOR Serine-Threonine Kinases
keywords: Genetic association analysis; Health span; Life span; Longevity; Target of rapamycin.