Arguing for Extracellular Vesicles to Mediate Beneficial Effects of Parabiosis

Cells communicate with one another constantly, and a large portion of that communication is not carried by individual secreted molecules, though there are certainly a lot of those, but rather takes the form of small membrane-bound packages of diverse molecules known as extracellular vesicles. Cells generate and secrete extracellular vesicles of various sizes, and other cells ingest them. Two important areas of active research into cell signaling are the way in which young tissue can restore the function of old cells, and the way in which senescent cells change the activity of surrounding cells for the worse. In both cases, extracellular vesicles are important in this process of communication and influence.

There is a substantial faction in the research community focused on potentially beneficial effects that derive from young blood, emerging from the study of heterochronic parabiosis in which the circulatory systems of a young and old mouse are linked. The old mouse benefits and shows some signs of reversal of the consequences of aging, the young mouse exhibits accelerated signs of aging. Is this in fact due to beneficial signals in young blood? There is good evidence that strongly supports the case that benefits result from a dilution of harmful factors in old blood, and that beneficial factors in young blood are not important. Nonetheless, there is further independent evidence in which factors or extracellular vesicles derived from young blood have been used to produce benefits in old mice. There are also a number of failures to show meaningful benefits from blood or plasma transfusion, in mice and humans. It is an interesting field, in which conflicting evidence abounds.

Extracellular vesicles circulating in young organisms promote healthy longevity

In the late 1950s, parabiosis experiments provided some scientific consistency to these beliefs. Indeed, a shared circulatory system was sufficient to increase bone weight and density of old mice when joined to younger ones. The same experimental design was applied to demonstrate a lifespan-enhancing effect of young blood. Many years later, elegant reports demonstrated a rejuvenation-promoting effect of young blood in a wide variety of cells and tissues, e.g. stem cells, muscle, brain, and the heart. However, the pursuit of the circulating factors responsible for such effects did not achieve the same success. In fact, the suggested pro-regeneration role of growth differentiation factor 11, a member of the TGFβ superfamily, has been questioned.

Extracellular vesicles (EVs) are membrane-coated nanoparticles actively released by almost all cell types. Increasing evidence indicates that both are able to shuttle and deliver functional proteins and nucleic acids in a paracrine and systemic manner. Blood contains a heterogeneous mixture of EVs of different origins, which are currently being characterized for therapeutic and diagnostic purposes. The effects of EVs are now attracting intense interest also in the context of ageing and age-related diseases (ARDs).

In particular, senescent cells (SCs) are emerging as major drivers of ageing and key contributors to inflammaging, the age-associated pro-inflammatory drift that promotes the development of ARDs. Recent evidence suggests that EVs are also central constituents of the SCs secretome. In particular, SCs secrete an increased amount of EVs, excreting pro-inflammatory DNA and possibly spreading pro-ageing signals. Conversely, a seminal paper suggests that a 4-month injection of small EVs derived from hypothalamic neural stem cells and rich in specific miRNAs into the hypothalamic third ventricle is sufficient to ameliorate some age-associated detrimental outcomes in C57BL/6 mice, including hypothalamic inflammation and the drop in physical activity.

These and other observations prompted the hypothesis that EVs are central mediators of the circulating communicosome fostering inflammaging. In that framework, we hypothesized that the chronic administration of EVs purified from a young healthy mouse to an old one should ameliorate some age-associated phenotypes. This experimental approach appeared to be enough feasible and robust to demonstrate a tangible role of EVs in the ageing process. Researchers have now shown a clear pro-longevity role for EVs isolated from young mouse plasma. Indeed, they injected EVs isolated from 4-to-12-month-old mice into 26-month-old female mice once a week until sacrifice and observed an increase of 10.2% and of 15.8% in median and maximal lifespan, respectively, in mice receiving the treatment vs. vehicle-treated mice of the same age.

Comments

Perhaps artificial EVs would work well to ameliorate some age-associated phenotypes. We have a lot to learn about what proteins are being trafficked by the youthful EVs. What would be the consequence of scavenging the SC EVs? Anything negative?

Posted by: MikeMaging at September 18th, 2019 8:19 AM

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