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bioRxiv · 10.1101/691154

Aging is associated with a systemic length-driven transcriptome imbalance

Stoeger, T.·Grant, R. A.·McQuattie-Pimentel, A. C.·Anekalla, K.·Liu, S. S.·Tejedor-Navarro, H.·Singer, B. D.·Abdala-Valencia, H.·Schwake, M.·Tetreault, M.-P.·Perlman, H.·Balch, W. E.·Chandel, N.·Ridge, K.·Sznajder, J. I.·Morimoto, R. I.·Misharin, A. V.·Budinger, G. R. S.·Nunes Amaral, L. A.
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Abstract

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 learning3-5 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.

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Stoeger, T., Grant, R. A., McQuattie-Pimentel, A. C., Anekalla, K., Liu, S. S., Tejedor-Navarro, H., Singer, B. D., Abdala-Valencia, H., Schwake, M., Tetreault, M.-P., Perlman, H., Balch, W. E., Chandel, N., Ridge, K., Sznajder, J. I., Morimoto, R. I., Misharin, A. V., Budinger, G. R. S., Nunes Amaral, L. A.. 2019-07-03. Aging is associated with a systemic length-driven transcriptome imbalance. https://doi.org/10.1101/691154

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