Longevity Briefs: Do Extracellular Vesicles Contain The Essence Of Youth?

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.

Why is this research important: Just yesterday, we discussed a preprint study in which old rats were rejuvenated using injections of a portion of the blood plasma derived from piglets. Specifically, the researchers used a fraction of the plasma containing extracellular vesicles (EVs), which are tiny packages containing genetic material and signalling molecules. EVs are released by cells and allow for both short and long distance ‘communication’ with other cells via the blood. It is possible that by introducing enough EVs from a young organism into the blood of an older one, we can simulate a youthful signalling environment to rejuvenate the older organism’s tissues.

There have recently been several other articles studying the effects of EVs from young animals. In this double issue, we’ll look at two such studies published within the last month, both looking at rodents.

What did the researchers do: In the first study, researchers took serum from young mice. Serum is the fraction of the blood that remains after it has clotted – it contains no blood cells but still contains EVs. They then injected this serum into old (22-24 month-old) mice, either untreated or with the EVs removed, and studied the effects on mechanisms of ageing in the brain and on cognitive function in comparison to a control treatment.

In the other study (by a different set of authors), researchers isolated the specific EVs that were produced by stem cells in the hearts of young rats. They then gave these EVs to old (22 month-old) rats and studied the effects on mechanisms of ageing in the heart when compared to a control treatment.

Key takeaway(s) from this research:

• Treatment with serum containing EVs is associated with upregulation of longevity genes and improved cognitive function in mice.
• Treatment with EVs from cardiac stem cells is associated with signs of rejuvenation in heart, skeletal muscle and lung tissue, as well as improved physical performance and lifespan.
• It’s not clear exactly which components of EVs produce these benefits or how their effects translate to a diverse human population.

Both studies found evidence for benefits of EVs in their respective tissues. In the first study, brain regions of treated mice expressed genes associated with longevity, most notably Klotho. This is a longevity gene that encodes the klotho protein, and it is well established that it plays an important role in cognitive function. In line with this finding, treated mice had improved cognitive function when compared to the control mice. However, mice treated with serum with the EVs removed did not receive these benefits, suggesting that factors contained within the EVs of young mice were responsible for producing these changes in the brain.

In the second study, the hearts of treated mice showed signs of rejuvenation compared to controls: their telomeres were twice as long, and they had fewer markers of DNA damage and inflammation. More importantly, treated mice were fitter, with a 16% improvement in treadmill performance compared to controls. Benefits extended outside the heart: the rats had less fibrosis (scar tissue formation) in the heart, skeletal muscles and lungs, lower blood sugar, and less visceral fat (the worst kind) compared to the controls. Finally, though the researchers didn’t set out to study survival, treated rats lived longer than the controls on average during the 100 day followup.

So it looks like EVs may be very important contributors to the reported benefits of young plasma transfusions, though we still don’t know exactly which factors within the EVs are responsible for their effects. What are the chances that EVs will work in humans? There are some encouraging results showing that EVs from young human donors produce benefits in old human cells similar to those reported in animals. The second study specifically tested their cardiac derived EVs on aged human heart cells and observed rejuvenating effects. However, remember that all blood plasma contains EVs, and those few clinical trials using young plasma to treat age-related diseases in humans have not yet produced any mind-blowing results. We need more research to clarify some pressing issues. Mice used in scientific studies are usually genetically similar, but studies show that the cargo of human EVs varies with sex and race as well as age. Will this have implications for the therapeutic use of EVs in humans?