Age or lifestyle-induced accumulation of genotoxicity is associated with a length-dependent decrease in gene expression.

DNA damage has long been advocated as a molecular driver of aging. DNA damage occurs in a stochastic manner, and is therefore more likely to accumulate in longer genes. The length-dependent accumulation of transcription-blocking damage, unlike that of somatic mutations, should be reflected in gene expression datasets of aging. We analyzed gene expression as a function of gene length in several single-cell RNA sequencing datasets of mouse and human aging. We found a pervasive age-associated length-dependent underexpression of genes across species, tissues, and cell types. Furthermore, we observed length-dependent underexpression associated with UV-radiation and smoke exposure, and in progeroid diseases, Cockayne syndrome, and trichothiodystrophy. Finally, we studied published gene sets showing global age-related changes. Genes underexpressed with aging were significantly longer than overexpressed genes. These data highlight a previously undetected hallmark of aging and show that accumulation of genotoxicity in long genes could lead to reduced RNA polymerase II processivity.