Longevity Briefs: Using RNA To Treat ‘Zombie Cells’ And Ageing

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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:

Cellular senescence is a state in which cells are unable to divide, either because they have reached their replication limit or because they have become badly damaged. Senescence is important for preventing cancer – any cell that starts dividing too rapidly will soon reach its replication limit and become senescent, arresting its runaway division. Senescent cells then self-destruct or release signals that tell the immune system to remove them.

Unfortunately, in older age, the immune system cannot clear senescent cells fast enough, leading to an increase in their number. Large numbers of these ‘zombie cells’ become detrimental, as those same signals that are supposed to lead to their clearance by the immune system instead trigger inflammation and cause nearby cells to become senescent. Senescent cells contribute to most age-related diseases, and so it is thought that drugs that destroy senescent cells, called senolytics, might be able to delay disease onset and perhaps slow ageing in general. In this study, researchers investigate another strategy – restoring senescent cells to a normal state.

The discovery:

Researchers took human fibroblasts that had become senescent after reaching their replication limit. They then exposed those fibroblasts to exosomes harvested from human embryonic stem cells. Exosomes are tiny membrane-bound packages that contain signalling molecules and genetic material, and are released by cells as a means of long-distance communication. They found that these exosomes almost completely reversed all signs of senescence, including restoring the cells’ ability to divide.

The researchers then treated a total of fifty 20 month-old mice (roughly equivalent to 60 year-old humans) with either these same exosomes or a control treatment. Just as in cell culture, markers of senescence were reduced, but more importantly, the treatment seemed to improve the physical and cognitive performance of the mice. They were able to balance for longer on a rotating rod, had higher body weights and improved memory compared to mice given a control treatment.

Time mice were able to remain on a rotating rod before falling off (D) and the time it took mice to remember the location of a platform submerged under water (H) for control mice (orange) and treated mice (green).
Exosomal miR-302b rejuvenates aging mice by reversing the proliferative arrest of senescent cells

Finally, the researchers were able to identify a specific component within the exosomes – a microRNA called miR-302b – that might be responsible for these effects. microRNAs are small fragments of RNA that don’t code for anything themselves, but that can regulate the expression of genes – in this case a senescence-related gene called Cdkn1a. They found that giving miR-302b to mice within engineered exosomes reproduced all of the previously seen effects, suggesting that this RNA was primarily responsible for the senescence reversal.

The implications:

This miR-302b was able to reverse senescence and improve health in ageing mice. Could a similar strategy one day work in humans? That will first depend on whether senescence reversal in humans can be proven to be safe. As already mentioned, senescence helps prevent cancer by halting runaway division, and cancer cells need to develop mutations that circumvent senescence in order to continue to grow. That said, there were no signs that mice receiving miR-302 in this study had a higher rate of cancer.