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bioRxiv · 10.1101/2023.11.07.566050

Single-cell transcriptomic and genomic changes in the aging human brain

Jeffries, A. M.·Yu, T.·Ziegenfuss, J. S.·Tolles, A. K.·Kim, Y.·Weng, Z.·Lodato, M. A.
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Abstract

Aging brings dysregulation of various processes across organs and tissues, often stemming from stochastic damage to individual cells over time. Here, we used a combination of single-nucleus RNA-sequencing and single-cell whole-genome sequencing to identify transcriptomic and genomic changes in the prefrontal cortex of the human brain across life span, from infancy to centenarian. We identified infant-specific cell clusters enriched for the expression of neurodevelopmental genes, and a common down-regulation of cell-essential homeostatic genes that function in ribosomes, transport, and metabolism during aging across cell types. Conversely, expression of neuron-specific genes generally remains stable throughout life. We observed a decrease in specific DNA repair genes in aging, including genes implicated in generating brain somatic mutations as indicated by mutation signature analysis. Furthermore, we detected gene-length-specific somatic mutation rates that shape the transcriptomic landscape of the aged human brain. These findings elucidate critical aspects of human brain aging, shedding light on transcriptomic and genomics dynamics.

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Jeffries, A. M., Yu, T., Ziegenfuss, J. S., Tolles, A. K., Kim, Y., Weng, Z., Lodato, M. A.. 2023-11-07. Single-cell transcriptomic and genomic changes in the aging human brain. https://doi.org/10.1101/2023.11.07.566050

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