Single-cell multiregion dissection of central nervous system aging.

Area of Science:

• Neuroscience
• Genomics
• Aging Research

Background:

• Central nervous system (CNS) aging is a significant risk factor for neurological disorders like cerebrovascular disease and neurodegeneration.
• The specific cellular pathways and regional differences driving CNS aging are not well understood.

Purpose of the Study:

• To create a comprehensive transcriptomic atlas of the aging human CNS across multiple regions.
• To identify shared and region-specific cellular and molecular changes associated with aging in the brain.
• To provide a resource for understanding CNS aging mechanisms and identifying therapeutic targets.

Main Methods:

• Generation of a single-nucleus transcriptomic atlas from ~1.0 million nuclei across seven human CNS regions.
• Analysis of post-mortem samples from 200 neurologically normal donors aged 19-101 years.
• Integration of data on transcriptional noise, cell death, disease associations, metabolic changes, and transcriptomic remodeling.

Main Results:

• Identification of cross-regional vulnerabilities in astroglia, oligodendrocytes, and neurons (both excitatory and inhibitory).
• Demonstration that microglial and astrocytic activation is a conserved aging response across the CNS.
• Development of predictive models using aging-associated gene signatures for biomarker discovery.

Conclusions:

• This study provides a detailed, region-by-region map of the aging human CNS.
• Conserved aging responses in microglia and astrocytes suggest potential intervention targets.
• The atlas serves as a valuable resource for prioritizing cell types and regions for future anti-aging research and therapeutic development.