Longevity Briefs: Scientists Identify Another Potential Driver Of Ageing

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

While the DNA serves as the master instruction book for the production of all of the proteins the body needs to make, RNA fulfils a variety of functions and comes in many different forms. One such form is called circular RNA (cricRNA) which, as its name suggests, is a strand of RNA that has been formed into a closed loop. Scientists are still investigating the functions of circRNA. One standout characteristic of cricRNA is that, due to its circular structure, it has no ends. Since RNA-degrading enzymes usually target the ends of the RNA strand to break it down, this makes circRNA resistant to degradation, meaning that it tends to stick around and accumulate within cells over time.

circRNA levels have been found to be elevated in cells in old age, but it wasn’t clear if this buildup was a driver of the ageing process or merely some side-effect of ageing that has no actual consequence. In this study, researchers set out to answer this question, at least in model organisms.

The discovery:

To test whether circRNA was in some way contributing to ageing, researchers needed a way of experimentally altering circRNA levels. To this end, they used genetic screening techniques in order to look for a ribonuclease (RNA-degrading enzyme) with the ability to degrade circRNA within the genome of C.elegans worms (a short-lived worm commonly used in the study of ageing). They were able to identify such an enzyme called ribonuclease kappa, which is encoded by a gene called RNASEK. They also confirmed that in C.elegans worms, RNASEK expression declined with age, correlating with a buildup of circRNA within cells.

To test whether this decline in RNASEK activity was important in ageing, researchers genetically engineered worms with enhanced RNASEK expression. They found that these worms lived longer and remained healthy for longer compared to control worms, suggesting that RNASEK could play an active role in health and ageing.

Looking into the mechanism, researchers found that enhanced RNASEK expression seemed to exert its benefits via its effects on structures within ageing cells called stress granules. Stress granules are essentially concentrations of RNA and proteins that form when protein production stalls. Stress granules are part of a defence mechanism against cellular stress, as they are thought to help the cell ‘lock down’ damaged proteins, protect RNA and redirect energy away from protein production and towards other things. However, there is evidence that in old age, stress granules become disregulated and do not properly disassemble, contributing to a toxic buildup of damaged proteins.

The ribonuclease kappa encoded by RNASEK appeared to be working alongside another protein called heat shock protein 90 (HSP90, which helps prevent protein misfolding) in order to target circRNA within these stress granules and disassemble them, reducing their accumulation in aged cells. Importantly, RNASEK is also present within the mouse and human genomes, and the mechanism involving stress granules was found to be present in human cells. Conversely, researchers found that suppressing the activity of RNASEK in human cells led to signs of premature ageing.

The implications:

This research provides some early evidence that, rather than simply being a marker of ageing, circRNA is actively harmful during the ageing process, as enhancing its degradation by enzymes appears to extend lifespan and prolong health in worms. However, past research shows that it is much easier to extend the lifespan of small, short lived organisms. It will be interesting to see whether targeting circRNA will have much of an effect in mice. If it does, there may be hope for human applications as well. Given circRNA’s apparent role in stress granules, a cricRNA-degrading drug might be tested in diseases in which abnormal stress granule formation has been observed, most notably neurodegenerative diseases like Alzheimer’s. Unfortunately, such applications are hypothetical at this stage and probably a very long way off.