Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate in aging fibroblasts.

The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in some non-human species. We investigated their association with human aging in two ways. First, we quantified Numts in 1,187 post-mortem brain and blood samples. Human brains exhibited a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex compared to the cerebellum, suggesting that they arose spontaneously during development or with aging. Moreover, more brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. Second, we tested the dynamic transfer of Numts in a repeated-measures WGS study in a human fibroblast model that recapitulates several molecular features of human aging. These longitudinal experiments revealed a gradual accumulation of one Numt every ~9 days, independent of large-scale genomic instability. Targeted genetic and pharmacological perturbations of mitochondrial oxidative phosphorylation did not affect numtogenesis, whereas chronic glucocorticoid stress increased the Numts transfer rate by 39.8%. Combined, our data document spontaneous numtogenesis in aging human cells and demonstrate an association between brain cortical somatic Numts and human lifespan.