Somatic mutations and single-nucleus transcriptomics reveal uniquely human properties of neuronal aging
Year: 2026
Type: preprint
Abstract: Human brain aging is frequently studied in model mammals that rarely show the natural age-related neurodegenerative conditions that afflict humans, yet little is known about how genomic stability compares across species during aging. Although somatic single nucleotide variant (SNV) and short insertion/deletion (Indel) mutations accumulate at rates that inversely scale to lifespan in colon cells-leaving diverse mammals with similar end-of-life burdens of mutations -- here we show that cerebral cortical neurons accumulate SNVs at annual rates that are remarkably similar across six mammalian species (human, chimpanzee, rhesus macaque, marmoset, ferret, mouse) resulting in >12-fold more mutations in human neurons at the end of life compared to mouse neurons. Despite the conservation of overall annual mutation accumulation rates, mutational patterns--and hence likely mutagenic mechanisms--show sharp differences between species, with a nucleotide substitution pattern linked to neurodegenerative diseases accumulating almost exclusively in humans during aging. Coinciding with their higher mutational burden, single-nucleus transcriptomic analyses reveal pervasive age-associated proteostasis and mitochondrial dysregulation in human neurons that is far less pronounced in aged chimpanzees and rhesus macaques. These findings show that the pervasive effects of human neuronal aging might be linked to our long lifespan and are therefore not evident in animal models.
Language: English
Subfield: Aging
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Veterans Affairs, John Templeton Foundation, University of Wisconsin-Madison, University of Washington, National Institutes of Health, National Institute on Aging, National Institute of Mental Health, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke
Awards: Lifespan and Cardiovascular Health Effects on The Brain in Humans and Great Ape, G2613372040, A National Chimpanzee Brain Resource, Cellular resolution multi-omics of white matter tracts in developing human and non-human primate brain for cell atlases, Comparative Epigenomics of Primate Brains, One brain, many genomes: How the genomic individuality of cells defines human individuality, Development of an Efficient High Throughput Technique for the Identification of High-Impact Non-Coding Somatic Variants Across Multiple Tissue Types, Cell Identity Determination in Human Brain: Somatic Mutation and Cell Lineage, Development of an Efficient High Throughput Technique for the Identification of High-Impact Non-Coding Somatic Variants Across Multiple Tissue Types, Rates and mechanisms of age-related somatic mutation in normal and Alzheimer brain, Alzheimer's Disease Pathology in a Primate Model
OpenAlex ID: W7214158808