Aging is associated with a systemic length-driven transcriptome imbalance

Aging manifests itself through a decline in organismal homeostasis and a multitude of cellular and physiological functions¹. Efforts to identify a common basis for vertebrate aging face many challenges; for example, while there have been documented changes in the expression of many hundreds of mRNAs, the results across tissues and species have been inconsistent². We therefore analyzed age-resolved transcriptomic data from 17 mouse organs and 51 human organs using unsupervised machine learning^3–5 to identify the architectural and regulatory characteristics most informative on the differential expression of genes with age. We report a hitherto unknown phenomenon, a systemic age-dependent length-driven transcriptome imbalance that for older organisms disrupts the homeostatic balance between short and long transcript molecules for mice, rats, killifishes, and humans. We also demonstrate that in a mouse model of healthy aging, length-driven transcriptome imbalance correlates with changes in expression of splicing factor proline and glutamine rich (Sfpq), which regulates transcriptional elongation according to gene length⁶. Furthermore, we demonstrate that length-driven transcriptome imbalance can be triggered by environmental hazards and pathogens. Our findings reinforce the picture of aging as a systemic homeostasis breakdown and suggest a promising explanation for why diverse insults affect multiple age-dependent phenotypes in a similar manner.