Examining the Impact of Aging on Critical Cellular Processes

A new Northwestern Medicine study published in the Proceedings of the National Academy of Sciences has explored the impacts of aging on essential cellular processes, findings that could shape the development of future anti-aging therapeutic strategies.

Ali Shilatifard, PhD, the chair and Robert Francis Furchgott Professor of Biochemistry and Molecular Genetics, was senior author of the study.

Transcription by RNA polymerase II — a multiprotein complex that transcribes DNA into messenger RNA (mRNA) — is essential for protein-coding gene expression and cellular function, all of which becomes dysregulated with aging.

Characterizing the impacts of aging on this transcriptional machinery, therefore, may reveal new targets for the development of anti-aging therapies, Shilatifard said.

In the current study, the scientists used a multimodal approach to examine RNA extracted from liver, kidney and brain tissue cells of young (11 weeks old) and old (72 weeks old) mice. Similar analyses were performed using publicly available total RNA-seq data from young and aged human patient tissue samples.

Short-read RNA sequencing of these tissue samples revealed a reduction in overall transcription activity and frequency in aging tissues and no changes in elongation rates.

Subsequent transcriptomic analysis showed a shift to preferred expression of short genes in aging tissues, as well as the upregulation of short stress-response genes and the downregulation of long neurodevelopmental genes in the aging mouse brain. These results were also observed in human tissue.

Lastly, the scientists found that interactions between RNA polymerase II and the Mediator complex, which communicates regulatory signals from DNA-binding transcription factors to RNA polymerase II, were decreased in chromatin in aged mouse liver and brain tissues.

By integrating short-read and long-read RNA sequencing, the scientists gained further insight into why longer genes may be at a disadvantage in aging.

“Specifically, long-read sequencing revealed an increase in aberrant splice isoforms in the aged mouse brain, particularly mono-exonic isoforms, along with intron-retention events,” said study co-author Marta Iwanaszko, PhD, research associate professor of Biochemistry and Molecular Genetics, who designed the study’s computational methodology and supervised the analysis.

“Building on our recent discovery that the elongation factor ELOA regulates short genes during cellular senescence, we found that physiological aging causes a length-biased reduction in long neuronal genes alongside increased splicing defects. In this study, we also demonstrate that the expression of elongation factor SPT6 decreases with age. Future work will explore how these and other transcription elongation factors balance aging, as ELOA may drive stress gene expression while the loss of SPT6 shuts down long neuronal genes,” said Saeid Parast, PhD, a postdoctoral fellow in the Shilatifard laboratory and co-first author of the study.

The findings highlight potential transcriptional control targets for anti-aging drug development, and further work is warranted to identify the specific elongation factors that are essential for transcription of long genes, according to the authors.

“The present study does not assess elongation factor occupancy in brain tissue, or whether age-dependent changes in these elongation factors might correlate with (or potentially drive) the preferential loss of long neurodevelopmental gene expression. A more thorough mechanistic understanding of elongation control in aging could enable approaches to maintain or increase RNAPII processivity in hope of preventing or reversing aging at the cellular level,” the authors wrote.

Madhurima Das, PhD, a research associate in the Shilatifard laboratory, was also co-first author of the study.

Co-authors include Yue He, a student in the Driskill Graduate Program in Life Sciences (DGP), and Issam Ben-Sahra, PhD, the Thomas D. Spies Professor of Genetic Metabolism.

This work is supported via National Institutes of Health Grants R35CA197569, DP2HG012442, R50CA265372, T32CA281953 and R24GM137786.