Uncovering the signatures of aging and senescence in the human dorsolateral prefrontal cortex

TL;DR

This study explores how aging affects gene activity and cell types in a specific brain region, revealing changes linked to aging and cellular senescence.

Contribution

A transcriptomic atlas of aging and senescence in the human dorsolateral prefrontal cortex is created using spatial transcriptomics and single-nucleus RNA sequencing.

Findings

Loss of SST transcript and SST+ neuron density in the aging dlPFC.

Oligodendrocytes show increased senescence hallmarks and CDKN2A expression with age.

Astrocyte and vascular cell gene programs are enriched in aging and senescence.

Abstract

We performed Visium spatial transcriptomics (ST) and single-nucleus RNA sequencing (snRNA-seq) on a cohort of nonpathological human tissues to uncover signatures of aging and senescence in the dorsolateral prefrontal cortex (dlPFC). In doing so, we identified gene expression changes characteristic of aged cortical layers. The cellular composition of the dlPFC also changed with age, with increased homeostatic astrocyte abundance and with decreased somatostatin (SST) inhibitory neurons. Nuclei from dlPFC cell types displayed a strong decline in oxidative phosphorylation- and cytoplasmic translation-related genes with age. Additionally, oligodendrocytes showed several hallmarks of senescence and a linear increase in CDKN2A expression with age. Combined analysis of ST and snRNA-seq datasets revealed astrocyte- and vascular cell-related gene expression programs in the white matter and layer 1 that were strongly enriched with age and for senescence-associated genes. These findings will help facilitate future studies exploring the role of senescent cell subpopulations in the aging brain.

•In the aging dlPFC, we observe a loss of SST transcript and SST+ neuron density•Loss of nuclear oxidative phosphorylation- and cytoplasmic translation-related genes•Increased senescence hallmarks and CDKN2A transcript in oligodendrocytes•An enrichment of spatially coordinated astrocyte and vascular cell gene programs

In the aging dlPFC, we observe a loss of SST transcript and SST+ neuron density

Loss of nuclear oxidative phosphorylation- and cytoplasmic translation-related genes

Increased senescence hallmarks and CDKN2A transcript in oligodendrocytes

An enrichment of spatially coordinated astrocyte and vascular cell gene programs

A transcriptomic atlas of aging and senescence in the brain across the adult human lifespan is built utilizing 55 nonpathological dlPFC samples profiled using spatial transcriptomics and single-nucleus RNA sequencing. This atlas reveals important insights into how cortical layers and the cell types residing within them change with age.

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