Linking single-cell transcriptomic and genomic in the aging human brain
Date:
Aging disrupts diverse biological processes across tissues, often driven by the gradual accumulation of stochastic damage in individual cells. While bulk transcriptome studies have mapped age-associated gene expression changes in the human brain, the cell-type-specific transcriptomic and genomic alterations that underlie non-pathological aging remain poorly understood.
Here, we integrated single-nucleus RNA sequencing, single-cell whole-genome sequencing, and spatial transcriptomics to identify transcriptomic and genomic changes in the prefrontal cortex of the 19 human brains across life span, from infancy to centenarian. Analyzing the transcriptome of 712,798 nuclei and cells, we identified infant-specific cell clusters marked by elevated expression of neurodevelopmental genes. Across cell types, aging was associated with a consistent downregulation of core homeostatic genes involved in ribosomal function, intracellular transport, and metabolism. Conversely, neuron-specific gene expression remained largely stable over time. Using single-cell genome sequencing of 100 neurons, we uncovered a somatic mutational signature shaped by gene length and expression level. Notably, short, highly expressed homeostatic genes accumulate somatic mutations faster with age—correlating with their reduced expression in older neurons.
Together, our study reveals coordinated transcriptomic and genomic changes of aging in the human brain, offering new insights into the cellular mechanisms that drive functional decline during aging.