Cell type-specific aging clocks to quantify aging and rejuvenation in regenerative regions of the brain

Abstract Aging manifests as progressive dysfunction culminating in death. The diversity of cell types is a challenge to the precise quantification of aging and its reversal. Here we develop a suite of ‘aging clocks’ based on single cell transcriptomic data to characterize cell type-specific aging and rejuvenation strategies. The subventricular zone (SVZ) neurogenic region contains many cell types and provides an excellent system to study cell-level tissue aging and regeneration. We generated 21,458 single-cell transcriptomes from the neurogenic regions of 28 mice, tiling ages from young to old. With these data, we trained a suite of single cell-based regression models (aging clocks) to predict both chronological age (passage of time) and biological age (fitness, in this case the proliferative capacity of the neurogenic region). Both types of clocks perform well on independent cohorts of mice. Genes underlying the single cell-based aging clocks are mostly cell-type specific, but also include a few shared genes in the interferon and lipid metabolism pathways. We used these single cell-based aging clocks to measure transcriptomic rejuvenation, by generating single cell RNA-seq datasets of SVZ neurogenic regions for two interventions – heterochronic parabiosis (young blood) and exercise. Interestingly, the use of aging clocks reveals that both heterochronic parabiosis and exercise reverse transcriptomic aging in the niche, but in different ways across cell types and genes. This study represents the first development of high-resolution aging clocks from single cell transcriptomic data and demonstrates their application to quantify transcriptomic rejuvenation.