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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
12 Downloads (Pure)

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
Pages (from-to)311-330
Number of pages20
JournalGeroScience
Volume45
Issue number1
Early online date10 Aug 2022
DOIs
Publication statusPublished - 1 Feb 2023
Externally publishedYes

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