How a Primate-Specific RNA Strand Worsens Senescence

Researchers have discovered a primate-specific piece of non-coding RNA that is linked to aging and makes senescence worse.

The packing matters

While non-coding RNA strands (ncRNAs) do not themselves produce proteins, they serve crucial regulatory functions. Short ncRNAs, such as microRNAs, are involved in the fine-tuning of transcriptional pathways, modulating the proteins produced by coding RNAs [1]. Long ncRNAs (lncRNAs), on the other hand, serve significant transcriptional and regulatory purposes; some of them even encode micropeptides despite being noncoding as a whole [2]. Unsurprisingly, dysfunction of lncRNAs is associated with aging [3].

While protein-coding sequences are strongly conserved across mammalian evolution, lncRNAs are not. The total length of lncRNAs is associated with lifespan in mammalian species, and the length of lncRNAs in humans is nearly three times that of mice [4]. Some of these sequences have already been found to be associated with youth; for example, PCAT14, which exists in other primates but not in mice, is active in young human cells but declines with age, and this decline is associated with blood vessel degeneration [5]. LINC00507, which is specific to the primate cortex, is also altered with age [6].

Conserved across primates

In their initial examination, the researchers pulled data from the NONCODE database in order to find commonalities between species. While there were substantially fewer lncRNAs in other primate species than in people, the researchers note that this was most likely due to discrepancies in data collection; humans are, of course, more thoroughly studied than other primates.

However, even with this limited data, it was clear that many lncRNAs are conserved across primates. A subset of these sequences was found to be correlated with chronological age, and some of these expression changes were tissue-specific. While they found several promising candidates, the researchers settled on LINC01021 as the strongest and most representative lncRNA for their further experiments, as its expression significantly changes with aging in seven distinct tissues.

Another examination found that in an RNA sequencing database of senescent cells, LINC01021 is strongly upregulated in four distinct types of fibroblasts that had been driven senescent through two separate means. The researchers used a population of their own human embryonic lung fibroblasts (HELFs) to confirm this data, driving them senescent through radiation, doxorubicin toxicity, and replication; in all three groups, LINC01021 was indeed upregulated.

In order to determine if this lncRNA was a contributor to or a defense against senescence, the researchers then created a population of HELFs in which LINC01021 is overexpressed. These cells were more likely to become senescent than their unmodified counterparts, as measured by decreased proliferation and an increase in the crucial biomarker SA-β-gal. Other key senescence-related genes and their downstream proteins were similarly upregulated by increased LINC01021. Knocking down LINC01021, as expected, produced the opposite effect; HELFs without this lncRNA were significantly less likely to become senescent.

The precise mechanisms

Further work found that this is due to LINC01021‘s suppression of RBMX, which does encode a protein. Knocking down RBMX was found to cause significant upregulation of senescence-associated genes. This was found to be strongly linked to the tumor suppressor P53; knocking down RBMX drastically increased the levels of P53, while silencing P53 through RNA significantly diminished the effects of LINC01021. The researchers noted that this is distinct from the effects of this lncRNA in the context of cancer, as it has been found to promote tumor growth [7].

The researchers went into detail, discovering the mechanistic relationship between LINC01021 and RBMX. While there were weak links between the proteasome and this lncRNA, the strongest result was that overexpressing LINC01021 was found to deplete the levels of DAZAP1, a protein responsible for RNA stability. This lack of DAZAP1 was directly responsible for the rapid depletion of RBMX protein levels.

Premature aging in a mouse model

The researchers then created a humanized mouse with an LINC01021 knock-in. Compared to wild-type mice, mice with this alteration became frail earlier, as measured by multiple physical tests; while not all of these tests’ results reached the level of statistical significance, the altered mice took longer to cross a beam, and they had reduced grip strength. There were signs of increased inflammation, and they had significantly upregulated biomarkers of senescence.

This study serves as a sobering reminder that mice are not people, and some of the changes that occur with aging affect the very things that make us human. It also illustrates the serious difficulties involved in studying such changes, as there are no naturally occurring short-lived species that can be used to study them. Similarly, if an mRNA-based or gene therapy can be used to directly affect such apparently detrimental lncRNAs, we will be fortunate if it can possibly be tested on other primates first.

Literature

[1] Turko, R., Hajja, A., Magableh, A. M., Omer, M. H., Shafqat, A., Khan, M. I., & Yaqinuddin, A. (2025). The emerging role of miRNAs in biological aging and age-related diseases. Non-coding RNA research, 13, 131-152.

[2] Yao, R. W., Wang, Y., & Chen, L. L. (2019). Cellular functions of long noncoding RNAs. Nature cell biology, 21(5), 542-551.

[3] Marttila, S., Chatsirisupachai, K., Palmer, D., & de Magalhães, J. P. (2020). Ageing-associated changes in the expression of lncRNAs in human tissues reflect a transcriptional modulation in ageing pathways. Mechanisms of Ageing and Development, 185, 111177.

[4] Wang, A. (2025). Noncoding RNAs evolutionarily extend animal lifespan. Global Medical Genetics, 12(2), 100034.

[5] Drekolia, M. K., Talyan, S., Cordellini Emídio, R., Boon, R. A., Guenther, S., Looso, M., … & Bibli, S. I. (2022). Unravelling the impact of aging on the human endothelial lncRNA transcriptome. Frontiers in genetics, 13, 1035380.

[6] Mills, J. D., Ward, M., Chen, B. J., Iyer, A. M., Aronica, E., & Janitz, M. (2016). LINC00507 is specifically expressed in the primate cortex and has age-dependent expression patterns. Journal of molecular neuroscience, 59(4), 431-439.

[7] Kaller, M., Forné, I., Imhof, A., & Hermeking, H. (2024). LINC01021 Attenuates Expression and Affects Alternative Splicing of a Subset of p53-Regulated Genes. Cancers, 16(9), 1639.