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

Abstract

The mutation accumulation hypothesis suggests that weakened purifying selection at old age leads to the accumulation of late-acting deleterious variants in the gene pool, which may contribute to the evolution of aging. In accordance with this model, others and we have shown that sequence conservation among old-biased genes (with higher expression in old versus young adults) is weaker than among young-biased genes across several mammalian and insect species. However, it has remained unclear whether the observed patterns were driven by tissue and cell type composition shifts or by cell-autonomous expression changes during aging. How wide this trend would extend to non-mammalian metazoan aging was also uncertain. Here we analyzed bulk tissue as well as cell type-specific RNA sequencing data from diverse animal taxa across six different datasets from five species. We show that the previously reported age-related decrease in transcriptome conservation (ADICT) is commonly found in aging tissues of non-mammalian species, including non-mammalian vertebrates (chicken brain, killifish liver and skin) and invertebrates (fruit fly brain). Analyzing cell type-specific transcriptomes of adult mice, we further detect the same ADICT trend at the single cell type level. Old-biased genes are less conserved across most cell types analyzed in the lung, brain, liver, muscle, kidney, and skin, and these include both tissue-specific cell types, and also ubiquitous immune cell types. Our results support the notion that aging in metazoan tissues is shaped by the mutation accumulation process.