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Research Paper|Volume 12, Issue 23|pp 23509—23524

FOXO3 longevity genotype mitigates the increased mortality risk in men with a cardiometabolic disease

Randi Chen1, Brian J. Morris1,2,3, Timothy A. Donlon1,4,5, Kamal H. Masaki1,2, D. Craig Willcox1,6, Philip M.C. Davy1,7, Richard C. Allsopp7, Bradley J. Willcox1,2
  • 1Department of Research, Kuakini Medical Center, Honolulu, HI 96817, USA
  • 2Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA
  • 3School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia
  • 4Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA
  • 5Institute for Biogenesis Research, University of Hawaii, Honolulu, HI 96822, USA
  • 6Department of Pathology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA
  • 7Department of Human Welfare, Okinawa International University, Ginowan, Okinawa, Japan
Received: September 10, 2020Accepted: October 22, 2020Published: December 1, 2020
https://doi.org/10.18632/aging.202175

Copyright: © 2020 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

FOXO3 is a prominent longevity gene. To date, no-one has examined whether longevity-associated FOXO3 genetic variants protect against mortality in all individuals, or only in those with aging-related diseases. We therefore tested longevity-associated FOXO3 single nucleotide polymorphisms in a haplotype block for association with mortality in 3,584 elderly American men of Japanese ancestry, 2,512 with and 1,072 without a cardiometabolic disease (CMD). At baseline (1991–1993), 1,010 CMD subjects had diabetes, 1,919 had hypertension, and 738 had coronary heart disease (CHD). Follow-up until Dec 31, 2019 found that in CMD-affected individuals, longevity-associated alleles of FOXO3 were associated with significantly longer lifespan: haplotype hazard ratio 0.81 (95% CI 0.72-0.91; diabetes 0.77, hypertension 0.82, CHD 0.83). Overall, men with a CMD had higher mortality than men without a CMD (P=6x10-7). However, those men with a CMD who had the FOXO3 longevity genotype had similar survival as men without a CMD. In men without a CMD there was no association of longevity-associated alleles of FOXO3 with lifespan. Our study provides novel insights into the basis for the long-established role of FOXO3 as a longevity gene. We suggest that the FOXO3 longevity genotype increases lifespan only in at-risk individuals by protection against cardiometabolic stress.