Throughout time all cells age gradually, contributing to the development of several diseases. Inducing cellular regeneration is one of the strategies used to fight diseases associated with cellular ageing. However, aged cells tend to be highly resistant to any type of manipulation intended to induce regeneration.

Ribonucleic acid, or RNA, is responsible for protein synthesis inside cells. However, a specific type of molecule named non-coding RNA is never translated into protein. In fact, since the mapping of the human genome in 2001 it is known that only about 2% is actually translated into proteins.

Now, the team used a genetically modified mouse model to study cellular ageing and regeneration. Authors show that fibroblasts from old mice express higher levels of Zeb2, a transcription factor that activates epithelial-to-mesenchymal transition. Synthesis of Zeb2 protein is controlled by a natural antisense transcript named Zeb2-NAT.

They found that cells derived from the skin of old mice produced higher amounts of a long non-coding RNA molecule named Zeb2-NAT when compared to cells from young mice. By reducing the amount of this specific RNA molecule, it was possible to efficiently regenerate old cells.

Authors also show that transfection of adult fibroblasts with specific LNA Gapmers induces a robust downregulation of Zeb2-NAT transcripts and Zeb2 protein and enhances the reprogramming of old fibroblasts into pluripotent cells.

They further demonstrate that Zeb2-NAT expression is precociously activated by differentiation stimuli in embryonic stem (ES) cells. By knocking down Zeb2-NAT, authors were able to maintain ES cells challenged with commitment signals in the ground state of pluripotency. 

"These results are an important step to be able to regenerate diseased tissues in older people," said the senior author.

https://imm.medicina.ulisboa.pt/en/imm-lisboa/news/archive/scientists-discover-molecule-could-revert-celular-ageing/

https://www.nature.com/articles/s41467-017-01921-6