Stem Cell Derived Extracellular Vesicles Reduce Epigenetic Age in Mice
As a strategy, the measurement of epigenetic age to assess the outcome of therapy intended to slow or reverse aging has its issues. Since it remains unknown as to how near all of the epigenetic marks on the genome are caused by the underlying processes of aging, it is quite possible that any given epigenetic clock will underestimate or overestimate the effects of a given approach to therapy, based on the choice and weighting of epigenetic marks used in the clock. It is suspected that the existing clocks are strongly influenced by only some of the mechanisms of aging.
Thus the assessment epigenetic age in a study of a potential treatment targeting aging should be considered exploratory at this time, a part of the ongoing and likely lengthy process of calibrating the clocks. It should be accompanied by a range of other measures of health and function.
Today's open access paper, covering an extracellular vesicle based intervention, is an example of going about this in the right way, in which epigenetic age is only one of a number of measures of the impact of aging on the mice involved. The use of extracellular vesicles derived from cultured stem cells is a logical evolution of early stem cell therapies, in which the benefits are derived near entirely from the signaling produced by the transplanted cells. Delivery of vesicles is a logistically easier approach, with evidence suggesting that this can produce similar outcomes to stem cell therapies.
Extracellular vesicles (EVs), small vesicles that are released by virtually all cell types, with an innate ability to mediate the transmission of signaling molecules (proteins, small RNAs, and DNA) between cells are among the factors that are involved in the communication between cells. Stem cells have intrinsic regenerative effects that are not only mediated by the repopulation of damaged tissue. The releasing of regulatory molecules is also proposed as one of the most important mechanisms in stem cell therapies. More specifically, small EVs (sEVs) derived from multiple stem cells have demonstrated their capacity to promote tissue regeneration after several types of damage. Compared to stem cells, sEVs are more stable, have no risk of aneuploidy, have a lower chance of immune rejection, and can provide an alternative therapy for various diseases.
Here, we show that sEVs from young adipose-derived stem cells (ADSC-sEVs) improve several functions that are impaired in old mice. Old mice that received young ADSC-sEVs showed lower levels of frailty and improvements on physical condition tests, fur regeneration, and renal function. ADSC-sEVs induced proregenerative effects in muscle and kidney of aged mice, as well as a decrease in oxidative stress, inflammation, and senescence markers. Moreover, predicted epigenetic age was lower in tissues of old mice treated with ADSC-sEVs and the metabolome of old mice treated with ADSC-sEVs changed from an old-like pattern to a youth-like one.
We observed a reduction of senescence in tissues and in vitro when sEVs were introduced; however, the mechanism of action remains unclear, as we did not find senolytic activity. They may probably act as senomorphics, molecules that suppress the senescent phenotype without the specific induction of apoptosis in senescent cells, probably through the inhibition of the senescence-associated secretory phenotype, as has been suggested recently.
We gained some insight into the microRNAs (miRNAs) contained in sEVs that might be responsible for the observed effects. We have explored miRNAs contained in young ADSC-sEVs and found that they are involved in several processes and pathways affected by aging, thus proposing miRNAs as possible mediators of the effects shown in mice. Taking into account our results and other preliminary studies, miR-214-3p may play a role in senescence. It is important to point out the debate on the relevance of miRNAs in the function of EVs, as recent studies have shown low levels of miRNAs in EVs, along with a limited delivery into target cells. More studies are needed to identify factors derived from stem cells that can assist tissue function and regeneration, as they could have an enormous impact on age-related pathologies, such as frailty or renal failure.
Are there differences between old and younger vesicle production and/or is it volume?
Would a combination with a senolytic be synergistic for general aging?
this seems like easily translatable to clinic with generic SVs generated en masse .
Key point : the study cites the use of the IV approach
however, of note, is that exosomes can be taken orally.
What is meant by "young stem cell"? It is known that the rate of division of stem cells in young organisms is almost 2 times more frequent than in old organisms. Have you measured the rate of stem cell division and thus determined whether you are young or old?