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Lifespan extension conferred by mitogen-activated protein kinase kinase kinase 5 (MAP3K5) longevity-associated gene variation is confined to at-risk men with a cardiometabolic disease
Genetic variants of the kinase signaling gene MAP3K5 are associated with longevity. Here we explore whether the longevity-association involves protection against mortality in all individuals, or only in individuals with aging-related diseases. We tested the strongest longevity associated single nucl...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034933/ https://www.ncbi.nlm.nih.gov/pubmed/33739303 http://dx.doi.org/10.18632/aging.202844 |
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author | Morris, Brian J. Chen, Randi Donlon, Timothy A. Masaki, Kamal H. Willcox, D. Craig Allsopp, Richard C. Willcox, Bradley J. |
author_facet | Morris, Brian J. Chen, Randi Donlon, Timothy A. Masaki, Kamal H. Willcox, D. Craig Allsopp, Richard C. Willcox, Bradley J. |
author_sort | Morris, Brian J. |
collection | PubMed |
description | Genetic variants of the kinase signaling gene MAP3K5 are associated with longevity. Here we explore whether the longevity-association involves protection against mortality in all individuals, or only in individuals with aging-related diseases. We tested the strongest longevity associated single nucleotide polymorphism (SNP), rs2076260, for association with mortality in 3,516 elderly American men of Japanese ancestry. At baseline (1991–1993), 2,461 had either diabetes (n=990), coronary heart disease (CHD; n=724), or hypertension (n=1,877), and 1,055 lacked any of these cardiometabolic diseases (CMDs). The men were followed from baseline until Dec 31, 2019. Longevity-associated genotype CC in a major allele homozygote model, and CC+TT in a heterozygote disadvantage model were associated with longer lifespan in individuals having a CMD (covariate-adjusted hazard ratio [HR] 1.23 [95% CI: 1.12–1.35, p=2.5x10(–5)] in major allele homozygote model, and 1.22 [95% CI: 1.11–1.33, p=1.10x10(–5)] in heterozygote disadvantage model). For diabetes, hypertension and CHD, HR p-values were 0.019, 0.00048, 0.093, and 0.0024, 0.00040, 0.0014, in each respective genetic model. As expected, men without a CMD outlived men with a CMD (p=1.9x10(–6)). There was, however, no difference in lifespan by genotype in men without a CMD (p=0.21 and 0.86, respectively, in each genetic model). In conclusion, we propose that in individuals with a cardiometabolic disease, longevity-associated genetic variation in MAP3K5 enhances resilience mechanisms in cells and tissues to help protect against cardiometabolic stress caused by CMDs. As a result, men with CMD having longevity genotype live as long as all men without a CMD. |
format | Online Article Text |
id | pubmed-8034933 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Impact Journals |
record_format | MEDLINE/PubMed |
spelling | pubmed-80349332021-04-16 Lifespan extension conferred by mitogen-activated protein kinase kinase kinase 5 (MAP3K5) longevity-associated gene variation is confined to at-risk men with a cardiometabolic disease Morris, Brian J. Chen, Randi Donlon, Timothy A. Masaki, Kamal H. Willcox, D. Craig Allsopp, Richard C. Willcox, Bradley J. Aging (Albany NY) Research Paper Genetic variants of the kinase signaling gene MAP3K5 are associated with longevity. Here we explore whether the longevity-association involves protection against mortality in all individuals, or only in individuals with aging-related diseases. We tested the strongest longevity associated single nucleotide polymorphism (SNP), rs2076260, for association with mortality in 3,516 elderly American men of Japanese ancestry. At baseline (1991–1993), 2,461 had either diabetes (n=990), coronary heart disease (CHD; n=724), or hypertension (n=1,877), and 1,055 lacked any of these cardiometabolic diseases (CMDs). The men were followed from baseline until Dec 31, 2019. Longevity-associated genotype CC in a major allele homozygote model, and CC+TT in a heterozygote disadvantage model were associated with longer lifespan in individuals having a CMD (covariate-adjusted hazard ratio [HR] 1.23 [95% CI: 1.12–1.35, p=2.5x10(–5)] in major allele homozygote model, and 1.22 [95% CI: 1.11–1.33, p=1.10x10(–5)] in heterozygote disadvantage model). For diabetes, hypertension and CHD, HR p-values were 0.019, 0.00048, 0.093, and 0.0024, 0.00040, 0.0014, in each respective genetic model. As expected, men without a CMD outlived men with a CMD (p=1.9x10(–6)). There was, however, no difference in lifespan by genotype in men without a CMD (p=0.21 and 0.86, respectively, in each genetic model). In conclusion, we propose that in individuals with a cardiometabolic disease, longevity-associated genetic variation in MAP3K5 enhances resilience mechanisms in cells and tissues to help protect against cardiometabolic stress caused by CMDs. As a result, men with CMD having longevity genotype live as long as all men without a CMD. Impact Journals 2021-03-19 /pmc/articles/PMC8034933/ /pubmed/33739303 http://dx.doi.org/10.18632/aging.202844 Text en Copyright: © 2021 Morris et al. https://creativecommons.org/licenses/by/3.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Morris, Brian J. Chen, Randi Donlon, Timothy A. Masaki, Kamal H. Willcox, D. Craig Allsopp, Richard C. Willcox, Bradley J. Lifespan extension conferred by mitogen-activated protein kinase kinase kinase 5 (MAP3K5) longevity-associated gene variation is confined to at-risk men with a cardiometabolic disease |
title | Lifespan extension conferred by mitogen-activated protein kinase kinase kinase 5 (MAP3K5) longevity-associated gene variation is confined to at-risk men with a cardiometabolic disease |
title_full | Lifespan extension conferred by mitogen-activated protein kinase kinase kinase 5 (MAP3K5) longevity-associated gene variation is confined to at-risk men with a cardiometabolic disease |
title_fullStr | Lifespan extension conferred by mitogen-activated protein kinase kinase kinase 5 (MAP3K5) longevity-associated gene variation is confined to at-risk men with a cardiometabolic disease |
title_full_unstemmed | Lifespan extension conferred by mitogen-activated protein kinase kinase kinase 5 (MAP3K5) longevity-associated gene variation is confined to at-risk men with a cardiometabolic disease |
title_short | Lifespan extension conferred by mitogen-activated protein kinase kinase kinase 5 (MAP3K5) longevity-associated gene variation is confined to at-risk men with a cardiometabolic disease |
title_sort | lifespan extension conferred by mitogen-activated protein kinase kinase kinase 5 (map3k5) longevity-associated gene variation is confined to at-risk men with a cardiometabolic disease |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034933/ https://www.ncbi.nlm.nih.gov/pubmed/33739303 http://dx.doi.org/10.18632/aging.202844 |
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