In Nature Genetics, reesearchers have described how a defect in RNA transcription constitutes a previously undiscovered mechanism of aging.
When the blueprint becomes harder to read
Gene expression begins when a cell transcribes RNA from DNA protein codes. This process, like almost all others, is affected by aging. One key reason behind this is, of course, the hallmark of epigenetic alterations, which is when cells’ DNA gradually becomes methylated in a harmful way, causing the transcription of unwanted sequences and preventing the transcription of needed ones. Small, non-coding RNA segments known as microRNAs also contribute to this change in expression [1].
However, one transcriptomic analysis has found that such previously discovered mechanisms are not entirely at fault; there must be another reason behind why gene expression in organs tends to deteriorate in the same way [2]. Previous work with genetic damage, which is itself a hallmark of aging, has found similarities between chemically induced damage and this age-related change in transcription. Transcription-blocking lesions appear on the DNA, causing RNA to stall out in the middle of the process and summoning repair machinery [3]. Some previous work has found that these lesions appear with normal aging [4], but how much damage they cause to transcription was never before described.
These researchers, therefore, sought to close that knowledge gap, first by using naturally aging mice.
A decline in transcription
The researchers compared 15-week-old mice to 2-year-old mice; at that age, mice are nearly at the end of their lives. They injected the mice with a fluorescent chemical that bonds only to newly made RNA, and found that new transcriptions were significantly reduced in the old mice.
Looking more closely, the researchers analyzed the specific transcription compounds that these new RNA strands used. They found a significant decline in transcriptions that had used RNA polymerase II (RNAPII), despite the aged livers having substantially more of this polymerase than the younger livers. Mitochondrial RNA, RNAPI, and RNAPIII transcriptions, on the other hand, seemed to be largely unaffected; the researchers note later that these compounds are associated with considerably shorter sequences.
A closer look at how RNAPII was being used and synthesized confirmed the researchers’ hypothesis. The older cells were naturally calling for the same amount of RNAII-based transcriptions as the younger cells were. The underlying machinery simply wasn’t able to deliver as well.
Singling out the reason why
Through the use of antibodies, the researchers found that transcriptions with RNAII were beginning at the same rates in older and younger cells. The start of transcription, the first kilobase, was identical between the two. Confirming their previous result, the researchers found promotion of these sequences to be the same between young and old cells.
They then took a closer look at gene expression changes. They found first that their independently discovered results were the same as previously published work on transcriptional changes with age. They found also that, as the length of the genes increased, the more RNAPII sites they had and the less likely they were to be successfully transcribed in older animals. Transcription was beginning just fine; it was simply unable to finish.
The researchers returned to their original hypothesis, that DNA damage was the cause of this loss of transcription. Using cells from mice that are particularly prone to genetic damage, they found a direct relationship between the amount of genetic damage and the inability for longer RNA sequences to be transcribed. Damaging cells with UV radiation or oxidative stress yielded the same result.
Powerful downstream effects
Multiple genes related to known hallmarks of aging were found to be impacted by this increase in transcriptional stress. mTOR, insulin, and growth hormone signaling were all affected, as were autophagy, proteostasis, immune system function, and metabolism. Critically, a pathway related to oxidative stress was impacted, suggesting that this transcriptional dysregulation may be amplifying itself.
An analysis of other gene transcription banks, including data from fruit flies and human beings, confirmed that this phenomenon occurs across the animal kingdom and in multiple tissues. Cells that do not divide very much were found to be more vulnerable than proliferative cells, which divide frequently, suggesting that replication ameliorates the DNA lesions responsible for the RNAPII stalling.
This is an initial study that has noted the cause of a problem, and work on any potential solution has not yet been published. It is not known if any treatment could reduce the number of transcription-blocking DNA lesions and thus slow or reverse a very fundamental part of aging.
Literature
[1] Harries, L. W. (2014). MicroRNAs as mediators of the ageing process. Genes, 5(3), 656-670.
[2] Schaum, N., Lehallier, B., Hahn, O., Pálovics, R., Hosseinzadeh, S., Lee, S. E., … & Wyss-Coray, T. (2020). Ageing hallmarks exhibit organ-specific temporal signatures. Nature, 583(7817), 596-602.
[3] Lans, H., Hoeijmakers, J. H., Vermeulen, W., & Marteijn, J. A. (2019). The DNA damage response to transcription stress. Nature reviews Molecular cell biology, 20(12), 766-784.
[4] Wang, J., Clauson, C. L., Robbins, P. D., Niedernhofer, L. J., & Wang, Y. (2012). The oxidative DNA lesions 8, 5′‐cyclopurines accumulate with aging in a tissue‐specific manner. Aging cell, 11(4), 714-716.
View the article at lifespan.io
