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bioRxiv · 10.64898/2026.04.05.716624

Microglia as transcriptional pacemakers of neuronal aging heterogeneity across individuals

Lim, C. M.·Vendruscolo, M.
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Abstract

Neuronal aging pace varies markedly between individuals, but what drives this variation remains unknown. Using cell-type-specific transcriptomic clocks applied to single-nucleus RNA sequencing data from 226 adults (ages 20-90), we quantified neuronal aging residuals as a donor-dominant phenotype. Variance decomposition revealed that microglial transcriptional programs predict inter-individual variation in neuronal aging residuals, a directional asymmetry consistent with a non-cell-autonomous relationship between microglial states and neuronal aging trajectories. This asymmetry is accompanied by an age-dependent shift from homeostatic to inflammatory microglial dominance beginning in midlife, with inflammatory dominance probability rising from 26% at age 35 to 92% by age 65, replicated in an independent cohort. IFN{gamma} signaling emerges as the dominant microglial program associated with accelerated neuronal aging in late adulthood. Candidate regulators of microglial IFN{gamma} activity (HIF1A, CEBPB, and EZH2) are computationally prioritized as intervention targets warranting functional validation.

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Lim, C. M., Vendruscolo, M.. 2026-04-08. Microglia as transcriptional pacemakers of neuronal aging heterogeneity across individuals. https://doi.org/10.64898/2026.04.05.716624

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