High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity

Brenda Gonzalez; Archana Tare; Seungjin Ryu; Simon C. Johnson; Gil Atzmon; Nir Barzilai; Matt Kaeberlein; Yousin Suh

doi:10.1007/s11357-022-00634-z

High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity

Brenda Gonzalez, Archana Tare, Seungjin Ryu, Simon C. Johnson, Gil Atzmon, Nir Barzilai, Matt Kaeberlein, Yousin Suh

Department of Human Biology

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Number of pages	20
Journal	GeroScience
Volume	45
Issue number	1
DOIs	https://doi.org/10.1007/s11357-022-00634-z
State	Published - Feb 2023

Bibliographical note

Funding Information:
This work was supported by NIH grants AG069750, DK127778, AG057433, AG061521, HL150521, AG055501, AG057341, AG057706, AG057909, and AG17242 (Y.S), a grant from The Paul F. Glenn Center for the Biology of Human Aging (Y.S.), a grant GCRLE-1320 (Y.S.) from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia-Echo Foundation, and a grant from The Simons Foundation (Y.S.). B. G. was supported by NIH pre-doctoral aging training grant 6T32AG023475-13. S.R. is the recipient of a Glenn/AFAR Scholarships for Research in the Biology of Aging. M.K. was supported by NIH grant P30AG013280.

Publisher Copyright:
© 2022, The Author(s).

Keywords

Aging
Centenarian
Genetic variant
Longevity
Mitochondria

ASJC Scopus subject areas

Aging
Veterinary (miscellaneous)
Complementary and alternative medicine
Geriatrics and Gerontology
Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s11357-022-00634-z

Cite this

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title = "High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity",

abstract = "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.",

keywords = "Aging, Centenarian, Genetic variant, Longevity, Mitochondria",

author = "Brenda Gonzalez and Archana Tare and Seungjin Ryu and Johnson, {Simon C.} and Gil Atzmon and Nir Barzilai and Matt Kaeberlein and Yousin Suh",

note = "Funding Information: This work was supported by NIH grants AG069750, DK127778, AG057433, AG061521, HL150521, AG055501, AG057341, AG057706, AG057909, and AG17242 (Y.S), a grant from The Paul F. Glenn Center for the Biology of Human Aging (Y.S.), a grant GCRLE-1320 (Y.S.) from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia-Echo Foundation, and a grant from The Simons Foundation (Y.S.). B. G. was supported by NIH pre-doctoral aging training grant 6T32AG023475-13. S.R. is the recipient of a Glenn/AFAR Scholarships for Research in the Biology of Aging. M.K. was supported by NIH grant P30AG013280. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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doi = "10.1007/s11357-022-00634-z",

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AU - Tare, Archana

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AU - Johnson, Simon C.

AU - Atzmon, Gil

AU - Barzilai, Nir

AU - Kaeberlein, Matt

AU - Suh, Yousin

N1 - Funding Information: This work was supported by NIH grants AG069750, DK127778, AG057433, AG061521, HL150521, AG055501, AG057341, AG057706, AG057909, and AG17242 (Y.S), a grant from The Paul F. Glenn Center for the Biology of Human Aging (Y.S.), a grant GCRLE-1320 (Y.S.) from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia-Echo Foundation, and a grant from The Simons Foundation (Y.S.). B. G. was supported by NIH pre-doctoral aging training grant 6T32AG023475-13. S.R. is the recipient of a Glenn/AFAR Scholarships for Research in the Biology of Aging. M.K. was supported by NIH grant P30AG013280. Publisher Copyright: © 2022, The Author(s).

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N2 - 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.

AB - 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.

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High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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