The study found that faulty RNA processing can result in longer life.
RNA is an important information transmitter in our cells and acts as a blueprint for protein production. When freshly formed RNA is processed, introns are removed to produce mature mRNA coding for protein. This cutting is known as “splicing,” and it is controlled by a complex known as the “spliceosome.”
“We found a gene in worms, called PUF60, that is involved in RNA splicing and regulates life span,” says Max Planck scientist Dr. Wenming Huang who made the discovery.
This gene’s mutations resulted in inaccurate splicing and the retention of introns within certain RNAs. As a result, less of the corresponding proteins were produced from this RNA. Surprisingly, worms with the PUF60 gene mutation survived significantly longer than normal worms.
Particularly affected by this defective production were some proteins that play a role in the mTOR signalling pathway. This signalling pathway is an important sensor for the availability of food and serves as a control centre of cell metabolism. It has long been the focus of ageing research as a target of potential anti-ageing drugs. The researchers were also able to show in human cell cultures that reduced levels of PUF60 activity led to lower activity of the mTOR signalling pathway.
PUF60 mutation in humans
“We think that by altering the fate of introns in RNAs, we have discovered a novel mechanism that regulates mTOR signaling and longevity,” says Max Planck Director Adam Antebi who led the study. “Interestingly, there are also human patients with similar mutations in the PUF60 gene. These patients have growth defects and neurodevelopmental disorders. Perhaps in the future, these patients could be helped by administering drugs that control mTOR activity. But of course, this needs more research.”
Reference: “Decreased spliceosome fidelity and egl-8 intron retention inhibit mTORC1 signaling to promote longevity” by Wenming Huang, Chun Kew, Stephanie de Alcantara Fernandes, Anna Löhrke, Lynn Han, Constantinos Demetriades and Adam Antebi, 19 September 2022, Nature Aging.
The study was funded by the Max Planck Society.