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 |
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Pages (from-to) | 311-330 |
Number of pages | 20 |
Journal | GeroScience |
Volume | 45 |
Issue number | 1 |
DOIs | |
State | Published - Feb 2023 |
Bibliographical note
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