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.