title: Shorter men live longer: association of height with longevity and FOXO3 genotype in American men of Japanese ancestry.
abstract: OBJECTIVE
  To determine the relation between height, FOXO3 genotype and age of death in humans.
  
  
  METHODS
  Observational study of 8,003 American men of Japanese ancestry from the Honolulu Heart Program/Honolulu-Asia Aging Study (HHP/HAAS), a genetically and culturally homogeneous cohort followed for over 40 years. A Cox regression model with age as the time scale, stratified by year of birth, was used to estimate the effect of baseline height on mortality during follow-up. An analysis of height and longevity-associated variants of the key regulatory gene in the insulin/IGF-1 signaling (IIS) pathway, FOXO3, was performed in a HHP-HAAS subpopulation. A study of fasting insulin level and height was conducted in another HHP-HAAS subpopulation.
  
  
  RESULTS
  A positive association was found between baseline height and all-cause mortality (RR = 1.007; 95% CI 1.003-1.011; P = 0.002) over the follow-up period. Adjustments for possible confounding variables reduced this association only slightly (RR = 1.006; 95% CI 1.002-1.010; P = 0.007). In addition, height was positively associated with all cancer mortality and mortality from cancer unrelated to smoking. A Cox regression model with time-dependent covariates showed that relative risk for baseline height on mortality increased as the population aged. Comparison of genotypes of a longevity-associated single nucleotide polymorphism in FOXO3 showed that the longevity allele was inversely associated with height. This finding was consistent with prior findings in model organisms of aging. Height was also positively associated with fasting blood insulin level, a risk factor for mortality. Regression analysis of fasting insulin level (mIU/L) on height (cm) adjusting for the age both data were collected yielded a regression coefficient of 0.26 (95% CI 0.10-0.42; P = 0.001).
  
  
  CONCLUSIONS
  Height in mid-life is positively associated with mortality, with shorter stature predicting longer lifespan. Height was, moreover, associated with fasting insulin level and the longevity genotype of FOXO3, consistent with a mechanistic role for the IIS pathway.
authors.affiliation: Honolulu Heart Program/Honolulu-Asia Aging Study, Physicians' Office Tower, Kuakini Medical Center, Honolulu, Hawaii, United States of America; Pacific Health Research and Education Institute of the Veterans Affairs Pacific Islands Health Care System, Honolulu, Hawaii; Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Qimei
authors.initials: Q
authors.lastname: He
authors.affiliation: Honolulu Heart Program/Honolulu-Asia Aging Study, Physicians' Office Tower, Kuakini Medical Center, Honolulu, Hawaii, United States of America; School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Morris
authors.affiliation: Honolulu Heart Program/Honolulu-Asia Aging Study, Physicians' Office Tower, Kuakini Medical Center, Honolulu, Hawaii, United States of America; Department of Public Health, University of Hawaii at Manoa, Honolulu, Hawaii.
authors.forename: John S
authors.initials: JS
authors.lastname: Grove
authors.affiliation: Honolulu Heart Program/Honolulu-Asia Aging Study, Physicians' Office Tower, Kuakini Medical Center, Honolulu, Hawaii, United States of America; Pacific Health Research and Education Institute of the Veterans Affairs Pacific Islands Health Care System, Honolulu, Hawaii; Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Helen
authors.initials: H
authors.lastname: Petrovitch
authors.affiliation: Honolulu Heart Program/Honolulu-Asia Aging Study, Physicians' Office Tower, Kuakini Medical Center, Honolulu, Hawaii, United States of America; Pacific Health Research and Education Institute of the Veterans Affairs Pacific Islands Health Care System, Honolulu, Hawaii; Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Webster
authors.initials: W
authors.lastname: Ross
authors.affiliation: Honolulu Heart Program/Honolulu-Asia Aging Study, Physicians' Office Tower, Kuakini Medical Center, Honolulu, Hawaii, United States of America; Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Kamal H
authors.initials: KH
authors.lastname: Masaki
authors.affiliation: Honolulu Heart Program/Honolulu-Asia Aging Study, Physicians' Office Tower, Kuakini Medical Center, Honolulu, Hawaii, United States of America; Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America; Department of Public Health, University of Hawaii at Manoa, Honolulu, Hawaii; Instituto Tecnologico de Monterrey, Monterrey, Mexico.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Rodriguez
authors.affiliation: Honolulu Heart Program/Honolulu-Asia Aging Study, Physicians' Office Tower, Kuakini Medical Center, Honolulu, Hawaii, United States of America.
authors.forename: Randi
authors.initials: R
authors.lastname: Chen
authors.affiliation: Honolulu Heart Program/Honolulu-Asia Aging Study, Physicians' Office Tower, Kuakini Medical Center, Honolulu, Hawaii, United States of America; Department of Research, Kuakini Medical Center, Honolulu, Hawaii, United States of America.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Donlon
authors.affiliation: Honolulu Heart Program/Honolulu-Asia Aging Study, Physicians' Office Tower, Kuakini Medical Center, Honolulu, Hawaii, United States of America; Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America; Department of Human Welfare, Okinawa University, Ginowan, Okinawa, Japan.
authors.forename: D Craig
authors.initials: DC
authors.lastname: Willcox
authors.affiliation: Honolulu Heart Program/Honolulu-Asia Aging Study, Physicians' Office Tower, Kuakini Medical Center, Honolulu, Hawaii, United States of America; Pacific Health Research and Education Institute of the Veterans Affairs Pacific Islands Health Care System, Honolulu, Hawaii; Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America; Department of Research, Kuakini Medical Center, Honolulu, Hawaii, United States of America.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Willcox
mesh_terms: D000368:Aged; D001213:Asian / Q000706:statistics & numerical data; D001827:Body Height / Q000235:genetics / Q000502:physiology*; D005215:Fasting / Q000097:blood; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016016:Proportional Hazards Models
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007328:Insulin