Age- or lifestyle-induced accumulation of genotoxicity is associated with a generalized shutdown of long gene transcription

A causative role for DNA damage as a molecular driver of aging has long been advocated. Transcription-blocking lesions (TBLs) accumulate with age in a stochastic manner. Thus, gene expression data might reflect the gene length-dependent accumulation of TBLs. Here we present an analysis of gene expression as a function of gene length in several independent single-cell RNA sequencing datasets of mouse and human aging. We found a pervasive age-associated downregulation of long gene expression, which is seen across species, datasets, sexes, tissues and cell types. Furthermore, long gene downregulation was also observed in premature aging models such as UV-radiation and smoke exposure, and in gene expression data from progeroid diseases Cockayne syndrome and trichothiodystrophy. Finally, we analyzed the length of differentially expressed genes associated to age in both mice and humans. Downregulated genes were significantly longer than upregulated genes. These data highlight a previously undetected hallmark of cellular aging and provide strong support for age-associated accumulation of genotoxic damage inducing a generalized shutdown of RNA polymerase II-mediated long gene transcription. Abstract Figure