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

Research output: Contribution to journalArticlepeer-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 languageEnglish
JournalGeroScience
DOIs
StateAccepted/In press - 2022

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

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