Research Paper Volume 15, Issue 10 pp 3967—3983
Vascular endothelial growth factor receptor 1 gene (FLT1) longevity variant increases lifespan by reducing mortality risk posed by hypertension
- 1 NIH Center of Biomedical Research Excellence for Clinical and Translational Research on Aging, Kuakini Medical Center, Honolulu, HI 96817, USA
- 2 Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA
- 3 School of Medical Sciences, University of Sydney, Sydney, New South Wales 2006, Australia
- 4 Department of Cell and Molecular Biology and Department of Pathology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA
- 5 Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA
Received: November 10, 2022 Accepted: May 4, 2023 Published: May 12, 2023
https://doi.org/10.18632/aging.204722How to Cite
Copyright: © 2023 Morris 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
Longevity is written into the genes. While many so-called “longevity genes” have been identified, the reason why particular genetic variants are associated with longer lifespan has proven to be elusive. The aim of the present study was to test the hypothesis that the strongest of 3 adjacent longevity-associated single nucleotide polymorphisms – rs3794396 – of the vascular endothelial growth factor receptor 1 gene, FLT1, may confer greater lifespan by protecting against mortality risk from one or more adverse medical conditions of aging – namely, hypertension, coronary heart disease (CHD), stroke, and diabetes. In a prospective population-based longitudinal study we followed 3,471 American men of Japanese ancestry living on Oahu, Hawaii, from 1965 until death or to the end of December 2019 by which time 99% had died. Cox proportional hazards models were used to assess the association of FLT1 genotype with longevity for 4 genetic models and the medical conditions. We found that, in major allele recessive and heterozygote disadvantage models, genotype GG ameliorated the risk of mortality posed by hypertension, but not that posed by having CHD, stroke or diabetes. Normotensive subjects lived longest and there was no significant effect of FLT1 genotype on their lifespan. In conclusion, the longevity-associated genotype of FLT1 may confer increased lifespan by protecting against mortality risk posed by hypertension. We suggest that FLT1 expression in individuals with longevity genotype boosts vascular endothelial resilience mechanisms to counteract hypertension-related stress in vital organs and tissues.