Inter-tissue convergence of gene expression during ageing suggests age-related loss of tissue and cellular identity

Abstract

Developmental trajectories of gene expression may reverse in their direction during ageing, a phenomenon previously linked to cellular identity loss. Our analysis of cerebral cortex, lung, liver and muscle transcriptomes of 16 mice, covering development and ageing intervals, revealed widespread but tissue-specific ageing-associated expression reversals. Cumulatively, these reversals create a unique phenomenon: mammalian tissue transcriptomes diverge from each other during postnatal development, but during ageing, they tend to converge towards similar expression levels, a process we term Divergence followed by Convergence, or DiCo. We found that DiCo was most prevalent among tissue-specific genes and associated with loss of tissue identity, which is confirmed using data from independent mouse and human datasets. Further, using publicly available single-cell transcriptome data, we showed that DiCo could be driven both by alterations in tissue cell type composition and also by cell-autonomous expression changes within particular cell types.

Lack of evidence for increased transcriptional noise in aged tissues

“…Transcriptional noise is here defined as the measured level of variation in gene expression among cells supposed to be identical (Raser and O'Shea, 2005). Later, similar findings have been reported as an increase in identity noise (Salzer et al, 2018), cell-cell heterogeneity (Kimmel et al, 2019), cell-to-cell variability (Martinez-Jimenez et al, 2019;Ximerakis et al, 2019), or loss of cellular identity in aged tissues (Solé-Boldo et al, 2020;Izgi et al, 2022). While all these claims have in common the notion of cells expressing their core transcriptional program or transcriptomic signature in a loose way, there are important methodological differences between the published reports that deserve further scrutiny.…”

“…Since aging is multifactorial and mutational load most likely leads to clonal expansion of aberrant cells that accumulate throughout the lifetime of the individual, other authors suggest that aging traits may be associated with cell type imbalance in aged organs ( Cagan et al, 2022 ). Another recent hypothesis is inter-tissue convergence through age-associated loss of specialization ( Izgi et al, 2022 ).…”

Molecular Modelling Hurdle in the Next-Generation Sequencing Era

“…The latter relates to ageing and dynamic evolution through tissue development. While at early stages of life the differentiation process requires most of the organism's energy, during ageing there is a reverse effect, leading to loss of tissue and cellular identity [56,57]. The interactome's trajectories can be shaped, and deviations over time can be modelled in a pathophysiological context [58].…”

Under the shadow: Old-biased genes are subject to weak purifying selection at both the tissue and cell type-specific levels

“…Pre-processing. Single cell expression data for six different tissues (lung, liver, muscle, brain, skin, and kidney) were downloaded from the Tabula Muris Senis dataset (The Tabula Muris Consortium, 2020) and processed following Izgi and co-authors (Izgi et al, 2022). For each cell type, the gene expression levels per individual were calculated as the mean expression value across cells of that cell type from a given individual, calculated separately for each gene, and separately in each tissue.…”