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 (mitonuclear genes) that confer resistance against age-related mitochondrial dysfunction. Here we report an integrated functional genomics study to identify rare functional variants in similar to 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.

Automated summary

Mitochondrial dysfunction is a known factor contributing to aging, and this study aims to explore the mechanisms by which mitochondria affect human lifespan. The researchers hypothesize that individuals with exceptional longevity may carry rare variants in nuclear-encoded mitochondrial genes that offer protection against age-related mitochondrial dysfunction. Through their integrated functional genomics study, they identify and prioritize longevity-associated variants, genes, and mitochondrial pathways. The study suggests the functional role of specific mitonuclear genes and pathways in human longevity.