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

Abstract

The diversity of cell types is a challenge for quantifying aging and its reversal. Here we develop ‘aging clocks’ based on single-cell transcriptomics to characterize cell-type-specific aging and rejuvenation. We generated single-cell transcriptomes from the subventricular zone neurogenic region of 28 mice, tiling ages from young to old. We trained single-cell-based regression models to predict chronological age and biological age (neural stem cell proliferation capacity). These aging clocks are generalizable to independent cohorts of mice, other regions of the brains, and other species. To determine if these aging clocks could quantify transcriptomic rejuvenation, we generated single-cell transcriptomic datasets of neurogenic regions for two interventions—heterochronic parabiosis and exercise. Aging clocks revealed that heterochronic parabiosis and exercise reverse transcriptomic aging in neurogenic regions, but in different ways. This study represents the first development of high-resolution aging clocks from single-cell transcriptomic data and demonstrates their application to quantify transcriptomic rejuvenation.

Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types

“…Collectively, our computational matrices and web portals provide unprecedented data that can be further explored to form working hypotheses for future studies. Similar to other recent reports 89,105,106 , our study advances fundamental understanding of the mechanisms underlying the aging process and potential interventions that go beyond descriptive studies of cell states. Our work extends current knowledge about the effects of heterochronic parabiosis on the aging process and supports the key role of the brain vasculature in mediating these effects.…”

Dbx2, an aging-related homeobox gene, inhibits the proliferation of adult neural progenitors

“…Although some of the genes modulated upon Dbx2 overexpression showed opposite changes in aged NSPC cultures expressing Dbx2 -targeting shRNAs (our unpublished observations), this approach yielded a modest Dbx2 knockdown in our hands (Lupo et al , 2018). Of note, Dbx2 is a NSC-specific component of the recently reported molecular aging clocks in the mouse SVZ, and its age-associated modulation can be reversed by exercise (Buckley et al , 2022). Gene function analyses in vivo by conditional genetic manipulation in adult NSPCs are expensive and time consuming; our in vitro analyses do not conclusively demonstrate a functional role of Dbx2 in neurogenic aging but provide a strong case for future studies investigating this gene in the context of in vivo neurogenic niches.…”

A spectral method for assessing and combining multiple data visualizations

“…To demonstrate the computational efficiency of the proposed method for large and high-dimensional datasets, we evaluated the proposed method on real single-cell transcriptomic datasets 43 of various sample sizes (n ∈ {1000, 2000, 4000, 8000, 14000} cells of nine different cell types from the neurogenic regions of mice) and dimensions (p ∈ {500, 1000, 2000} genes). For each dataset, we obtained 11 candidate visualizations and applied Algorithm 1 to generate the final meta-visualization (Methods).…”

“…We considered the single-cell transcriptomic dataset 43 that contains more than 20,000 cells of different cell types from the neurogenic regions of 28 mice. For each n ∈ {1000, 2000, 4000, 8000, 14000}, we randomly select n cells of nine different cell types, and selected subsets of p ∈ {500, 1000, 2000} genes to obtain an n × p count matrix.…”