Aging linked to RNA-length imbalance
Aging is associated with a greater abundance of shorter RNA molecules across different cell types and organisms, according to NIA-funded scientists. For their study, published in Nature Aging, the researchers found that as humans, mice, rats, and killifish get older, the length of their RNA transcripts tends to shorten, creating an imbalance with longer transcripts. Shorter transcripts are linked to processes common in aging, such as inflammation, while longer transcripts tend to be associated with increased lifespan. The researchers hypothesize that this shift in RNA transcript length could represent a systemwide phenomenon driving functional losses during aging, rather than the traditional view that a few genes are responsible for what happens when living things grow older.
Ribonucleic acid (RNA) is a molecule that is present in the majority of living organisms and viruses. Transcription is the process of making an RNA copy of a gene’s DNA coding sequence, and it is the first step in gene expression. Transcription is followed by translation, the stage where proteins are made. The shift toward shorter transcripts implies that with aging, shorter genes are transcribed. For its discovery, the Northwestern University research team sequenced the transcriptomes — a collection of all RNA copies (transcripts) present in a cell — in 17 tissues from mice of various ages up to 24 months, which is considered old age for these rodents. Next, they looked for unique molecular features associated with age-related changes in the RNA. In middle-aged mice, they found the length of transcripts declined in nearly 60% of tissues, whereas in older mice, the decline in length of transcripts occurred in 75% of tissues. The decrease in the number of long genes and, therefore, long transcripts, results in an increase in the number of genes that make short transcripts. The researchers called it “length-associated transcriptome imbalance.”
To examine the extent of the imbalance, the team analyzed transcriptomes from the tissues of mice, rats, and killifish, and single cells from young and old mice. Nearly 80% of the tissues had an age-dependent decrease in long transcripts that was relatively consistent across different cell types. Similar results were found in human tissue, where the imbalance was strongest in brain cells.
Lastly, to test whether the imbalance could be reversed, the researchers evaluated the effects of 11 anti-aging interventions previously shown to extend the lifespan of mice. Seven of the interventions increased the number of long transcripts, restoring some balance to the transcriptome.
In contrast to studies examining age-related changes in the expression of individual genes, this research suggests that aging is associated with global changes in the transcriptome over time that shift gene expression. What causes the imbalance remains undetermined but may be due to environmental or age-related cellular events. Future research on the causes and effects of this phenomenon may improve the understanding of the aging process and potentially inform ways to reverse it.
This research was supported in part by NIA grants AG068544, AG071225, AG049665, AG054407, AG026647, AG057296, and AG059579.
Stoeger, T, et al. Aging is associated with a systemic length-associated transcriptome imbalance. Nature Aging. 2022;2(12):1191–1206. doi: 10.1038/s43587-022-00317-6.