Nature communicationsDec 11, 2025

Distinct aging patterns and their controls in different human brain cell types

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

Human brain cell types showed distinct senescence signatures and regulators, with TFAP4 acting in a cell-type-dependent way.

Evidence

This preclinical profiling study tested five human brain cell lines under chronic 5-Bromodeoxyuridine stress and validated selected findings in primary cells and toxin-induced models.

Caveat

The work is based mainly on cell and model systems, so therapeutic relevance for human neurodegenerative disease remains indirect.

Simplified

contributes to age-related neurodegeneration, yet its manifestation varies across brain cell types and senescence-inducing stressors. Here, we investigated senescence hallmarks in five human brain cell lines - astrocytes, endothelial cells, microglia, oligodendrocytes, and dopaminergic-like neurons - using chronic 5-Bromodeoxyuridine treatment and validated our findings in primary cells and alternative toxin-induced models. Principal component analysis and transcriptional network inference identified both common and cell-type-specific (SATRs). Functional studies of TFAP4, a key SATR, revealed its role in modulating senescence phenotypes in a cell-type-dependent manner, with decreased TFAP4 expression observed in Parkinson's Disease patient tissue and in vivo models. These results delineate distinct senescence profiles across brain cell types and highlight transcriptional regulators that may underlie senescence heterogeneity, offering insights into targeted therapeutic strategies for neurodegenerative diseases.