Young Serum Improves Muscle Regeneration in Old Mice
The consensus on heterochronic parabiosis, in which the circulatory systems of an old animal and young animal are joined, is that the old mouse exhibits reduced measures of age because harmful factors in old blood are diluted, not because beneficial factors are present in young blood. Nonetheless, there may still be some beneficial factors in young blood. Researchers here provide evidence for serum from young mice to improve muscle regeneration when injected into old mice, and argue that this is based on levels of klotho present in extracellular vesicles. Since the use of extracellular vesicles in the development of therapies is quite advanced, and several companies are developing therapies based on delivery of recombinant klotho, there are obvious paths forward to further assess this approach.
The new study builds on decades of research showing that when old mice are given blood from young mice, youthful features are restored to many cells and tissues. But until now, it was unclear which components of young blood confer these rejuvenating effects. Researchers collected serum, the fraction of blood that remains after removing blood cells and clotting factors, from young mice and injected it into aged mice with injured muscle. Mice that received young serum showed enhanced muscle regeneration and functional recovery compared to those that received a placebo treatment, but the serum's restorative properties were lost when extracellular vesicles (EVs) were removed, indicating that these vesicles mediate the beneficial effects of young blood.
Delving deeper, the researchers found that EVs deliver genetic instructions, or mRNA, encoding the anti-aging protein Klotho to muscle progenitor cells, a type of stem cell that is important for regeneration of skeletal muscle. EVs collected from old mice carried fewer copies of the instructions for Klotho than those from young mice, prompting muscle progenitor cells to produce less of this protein. With increasing age, muscle doesn't heal as well after damage because scar tissue is deposited instead of restoring original muscle structure. In earlier work, the team showed that Klotho is an important regulator of regenerative capacity in muscle progenitor cells and that this protein declines with age.
The new study shows for the first time that age-related shifts in EV cargo contribute to depleted Klotho in aged stem cells, suggesting that EVs could be developed into novel therapies for healing damaged muscle tissue.
EVs seem like an incredible way to get mRNA and other signals to various parts of the body, evading the immune system and not getting stuck in the liver. It seems like the body must have a way of directing the EVs to wherever they need to go. Why can't we copy what they are doing? Is it because we still don't know enough about how they do it? (E.g. what surface proteins they have…) Is it still too difficult to match their detailed surface structure? Is it because they aren't specific and they deposit their load everywhere? Etc. Why can't we use EVs to get high doses of whatever we want to the tissue we want and not much elsewhere?
@Neil
EV concept is fairly new. Being able to prove that is useful is pretty recent. It seems that EVs can be used with much less immune rejection issues. Probably even we can use EVs from other species. If this proves to be the case we can culture cell lines with the most desirable EVs, mass produce them, and keep them frozen until needed for a localized injection. However, the path from an idea to clinical applications is quite long, especially for such novel treatments.
In the recent interview with Morgan Levine on the Live Longer World podcast, she said her lab is interested in and is working on parabiosis. She wants to tease out what is actually going on at a molecular level. Looks like other labs have a similar idea... cool!
https://podcasts.google.com/feed/aHR0cHM6Ly9hbmNob3IuZm0vcy82MmNiZjFlNC9wb2RjYXN0L3Jzcw/episode/ZWFjZjU1MDUtNDI1Zi00MTM4LWEzMWQtNDdhYThhN2EyZThi
Have there been studies comparing the aging of people that donate blood regularly vs those that do not? I wonder if regularly drawing down on your blood and forcing production of new may affect the 'age' of you blood in circulation.
@Steven, I recently came across this article about plasma donation. It is a very small study, but there are more ongoing including a double-blind clinical trial with 2 arms, one with albumin and one without, but it won't be done for at least another year. It seems to me that if CSL Plasma decided to do a trial like this, they could complete it with a very large number of participants in a very short time. I'm not sure why they don't.