Researchers have found that by manipulating a single RNA molecule, they can reverse some aspects of cellular aging and regenerate aged cells.

Old cells resist regeneration

As we grow older, our cells gradually age, leading to the development of various diseases. Therefore, inducing cellular regeneration is one of the approaches that researchers are using to combat the age-related diseases associated with cellular aging. Unfortunately, aged cells are often highly resistant to therapies aimed at inducing regeneration.

Ribonucleic acid (RNA) is responsible for the creation of cellular proteins. However, a special type of molecule called non-coding RNA is never made into protein. In fact, when they mapped the human genome in 2001, they discovered that only around 2% of RNA is actually made into proteins.

Now, researchers have found a way to bypass the resistance of aged cells to being regenerated and becoming functionally more youthful.







What the study found out

In a recent Nature Communications paper, a team led by Dr. Bruno Bernardes de Jesus of the Instituto de Medicina Molecular (iMM) João Lobo Antunes in Lisboa discusses a technique that allowed the team to achieve easier cellular reprogramming of old fibroblasts into pluripotent cells[1].

Fibroblasts are connective tissue cells in animals that synthesize both the extracellular matrix, which is a “scaffolding” made up of extracellular molecules that provides structural and biochemical support to cells, and collagen, which is the main structural protein of connective tissues in animal bodies.

The study showed that the fibroblasts of old mice express higher levels of the transcription factor Zeb2. A transcription factor is a protein that regulates the DNA-to-messenger-RNA transcription rate, and Zeb2, in particular, induces epithelial cells to transition to mesenchymal cells. Epithelial cells are one of the four basic tissue types of animal cells, whereas mesenchymal cells are multipotent stem cells that give rise to fibroblasts, among others.

The synthesis of Zeb2 is controlled by the ribonucleic acid Zeb2-NAT (NAT stands for “natural antisense transcript”). What the scientists demonstrated in this paper is that by knocking down Zeb2-NAT in old mouse fibroblasts, Zeb2 can be downregulated significantly, which, in turn, leads to an enhanced fibroblast ability to turn into pluripotent cells rather than mesenchymal cells. The difference is that while mesenchymal cells can turn into only a certain range of related cells, pluripotent stem cells can turn into nearly all types of cells.







The way the researchers silenced Zeb2-NAT was by transfecting the fibroblasts with certain ribonucleic acid sequences—in other words, they introduced these sequences into the fibroblasts’ nuclei to modify their behavior.

Essentially, what they demonstrated is that aged cells that usually resist reprogramming can be regenerated by reducing the level of Zeb2-NAT without harming the cells’ developmental potency.

Conclusion

This study results spotlight the role of non-coding RNA in the fine-tuning and expression of protein-coding genes involved in pluripotency, differentiation, and reprogramming.

This opens the door for the regeneration of aged cells and tissues in an effort to prevent or reverse age-related diseases caused by cellular aging.







Literature

[1] Bernardes de Jesus, B., Pires Marinho, S., Barros, S., Sousa-Franco A., Alves-Vale, C., Carvalho, T., Carmo-Fonseca, M. (2018). Silencing of the lncRNA Zeb2-NAT facilitates reprogramming of aged fibroblasts and safeguards stem cell pluripotency. Nature Communications.