Cells transcribe active genes into messenger RNA (mRNA) molecules, using a crucial complex known as RNA polymerase II.
This analysis indicated that cells began to prefer producing mRNA transcripts from shorter genes.
There were also fewer transcripts of long genes related to neurodevelopment in the brains of aging mice and in aging humans.
Cells seem to be less inclined to generate mRNA transcripts from long genes as an organism ages.
"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.
Cells transcribe active genes into messenger RNA (mRNA) molecules, using a crucial complex known as RNA polymerase II. These mRNA transcripts are then translated into proteins by other cellular machinery. A new study has shown that the regulation of RNA polymerase II can go awry during the aging process. The study authors suggested that it may be possible to develop new therapeutics for diseases of aging by understanding more about this problem. The findings have been reported in the Proceedings of the National Academy of Sciences (PNAS).
In this study, the researchers used a technique called RNA sequencing to identify all of the genes that were active at one point in time in the individual cells of samples taken from the brains, kidneys, and livers of mice that were young (11 weeks of age) and old (72 weeks of age). The scientists were also able to obtain similar data on human samples using publicly available datasets on young and old human tissue samples. The gene activity in all of these cells was then compared.
The investigators determined that overall, the frequency and activity of transcription declined in aging tissues. This analysis indicated that cells began to prefer producing mRNA transcripts from shorter genes. Cells also tended to generate higher levels of short genes related to stress responses as they aged. There were also fewer transcripts of long genes related to neurodevelopment in the brains of aging mice and in aging humans.
Interactions between the RNA polymerase II complex and another molecular machine called the Mediator complex declined in aging too.
Cells seem to be less inclined to generate mRNA transcripts from long genes as an organism ages. The processing of mRNA transcripts was also less precise 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," explained study co-author Marta Iwanaszko, Ph.D., research associate professor of Biochemistry and Molecular Genetics at Northwestern University. Introns are normally spliced out of mRNA transcripts before they are made into proteins. The inclusion of introns could cause major problems for proteins, and as such, the cell as well.
"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," added co-first study author Saeid Parast, Ph.D., a postdoctoral fellow in the laboratory of senior study author Ali Shilatifard, Ph.D., the chair and Robert Francis Furchgott Professor of Biochemistry and Molecular Genetics at Northwestern University.
"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.”
Sources: Northwestern University, Proceedings of the National Academy of Sciences (PNAS)
