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High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity
Mitochondrial dysfunction is a well-known contributor to aging and age-related diseases. The precise mechanisms through which mitochondria impact human lifespan, however, remain unclear. We hypothesize that humans with exceptional longevity harbor rare variants in nuclear-encoded mitochondrial genes...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9886794/ https://www.ncbi.nlm.nih.gov/pubmed/35948858 http://dx.doi.org/10.1007/s11357-022-00634-z |
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author | Gonzalez, Brenda Tare, Archana Ryu, Seungjin Johnson, Simon C. Atzmon, Gil Barzilai, Nir Kaeberlein, Matt Suh, Yousin |
author_facet | Gonzalez, Brenda Tare, Archana Ryu, Seungjin Johnson, Simon C. Atzmon, Gil Barzilai, Nir Kaeberlein, Matt Suh, Yousin |
author_sort | Gonzalez, Brenda |
collection | PubMed |
description | Mitochondrial dysfunction is a well-known contributor to aging and age-related diseases. The precise mechanisms through which mitochondria impact human lifespan, however, remain unclear. We hypothesize that humans with exceptional longevity harbor rare variants in nuclear-encoded mitochondrial genes (mitonuclear genes) that confer resistance against age-related mitochondrial dysfunction. Here we report an integrated functional genomics study to identify rare functional variants in ~ 660 mitonuclear candidate genes discovered by target capture sequencing analysis of 496 centenarians and 572 controls of Ashkenazi Jewish descent. We identify and prioritize longevity-associated variants, genes, and mitochondrial pathways that are enriched with rare variants. We provide functional gene variants such as those in MTOR (Y2396Lfs*29), CPS1 (T1406N), and MFN2 (G548*) as well as LRPPRC (S1378G) that is predicted to affect mitochondrial translation. Taken together, our results suggest a functional role for specific mitonuclear genes and pathways in human longevity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00634-z. |
format | Online Article Text |
id | pubmed-9886794 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-98867942023-02-01 High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity Gonzalez, Brenda Tare, Archana Ryu, Seungjin Johnson, Simon C. Atzmon, Gil Barzilai, Nir Kaeberlein, Matt Suh, Yousin GeroScience Original Article Mitochondrial dysfunction is a well-known contributor to aging and age-related diseases. The precise mechanisms through which mitochondria impact human lifespan, however, remain unclear. We hypothesize that humans with exceptional longevity harbor rare variants in nuclear-encoded mitochondrial genes (mitonuclear genes) that confer resistance against age-related mitochondrial dysfunction. Here we report an integrated functional genomics study to identify rare functional variants in ~ 660 mitonuclear candidate genes discovered by target capture sequencing analysis of 496 centenarians and 572 controls of Ashkenazi Jewish descent. We identify and prioritize longevity-associated variants, genes, and mitochondrial pathways that are enriched with rare variants. We provide functional gene variants such as those in MTOR (Y2396Lfs*29), CPS1 (T1406N), and MFN2 (G548*) as well as LRPPRC (S1378G) that is predicted to affect mitochondrial translation. Taken together, our results suggest a functional role for specific mitonuclear genes and pathways in human longevity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00634-z. Springer International Publishing 2022-08-10 /pmc/articles/PMC9886794/ /pubmed/35948858 http://dx.doi.org/10.1007/s11357-022-00634-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Gonzalez, Brenda Tare, Archana Ryu, Seungjin Johnson, Simon C. Atzmon, Gil Barzilai, Nir Kaeberlein, Matt Suh, Yousin High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity |
title | High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity |
title_full | High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity |
title_fullStr | High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity |
title_full_unstemmed | High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity |
title_short | High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity |
title_sort | high-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9886794/ https://www.ncbi.nlm.nih.gov/pubmed/35948858 http://dx.doi.org/10.1007/s11357-022-00634-z |
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