Small Extracellular Vesicles and the Balance of Signals Between Normal and Senescent Cells in Aging Tissues

In this study, researchers show that small extracellular vesicles can influence the functional status of old tissues. These vesicles are membrane-bound packages of molecules that are used by cells as a form of communication, constantly secreted and taken up. Delivery of vesicles isolated from young tissues (or normal, non-senescent cells) improves function and suppresses the markers of cellular senescence in aged tissues, while delivery of vesicles isolated from old tissues (or senescent cells) degrades the function of young tissues by encouraging cellular senescence. The authors postulate a signaling environment in every tissue that slowly tips towards favoring cellular senescence and dysfunction as aging progresses. Delivering suitable vesicles in large enough numbers, and for a long enough period of time, should tip the balance back - though it is an open question as to how long the benefits would last, given the other aspects of aging still extant and still driving dysfunction.

A few decades ago, the notion of rejuvenation or amelioration of aging seemed unfeasible. However, in the last decades, the concept of parabiosis re-emerging and the rejuvenating cellular and tissue plasticity acquired by induced pluripotent stem cells have changed our views on the subject. Interestingly, we previously found that small extracellular vesicles (sEVs) isolated from senescent cells induce paracrine senescence in proliferating cells. In this study, we are describing that sEVs derived from fibroblasts isolated from young human healthy donors (sEV-Ys) ameliorate senescence in old recipient cells and old mice. Thus, there seems to be a crosstalk between both cells types via EVs; EVs inducing senescence in young cells and EVs preventing senescence in old cells. We believe this situation is what really happens in vivo.

It is known that the tissue holds a mixture of senescent and proliferating cells. We believe that the predominance of functionality between sEV-Ys and sEVs derived from senescent cells will depend on the proportion of each cell present in the tissue. When the majority of cells existing in the tissue are senescent cells, the tissue homeostasis becomes compromised as there is transmission of paracrine senescence; however, during the earlier stages of aging or during tissue damage, when there are still plenty of proliferating cells, these can "repair" tissue dysfunction by ameliorating the senescent phenotype of damaged cells through soluble factors and via sEVs as shown in this study.

Although it is tempting to speculate that according to our results sEV-Ys have rejuvenating potential to young tissues in old mice, we must be cautious to reach such conclusions as more experimental data would be needed. However, we cannot deny that sEV-Ys are helping damaged tissues to repair, which is also a very attractive tool. It would be interesting to perform longer-term experiments to determine the time period by which sEV-Ys can have rejuvenating or repairing functions.

Link: https://doi.org/10.1016/j.cmet.2020.06.004

Comments

Manipulating signaling via MSCs, exosomes and apparently secvs seems to be quite effective on a localized basis, particularly for osteo arthritis. But it does not seem to work systemically. And I have not read a widely held rationale as to why an older body can not just make Its own signaling molecules.

Posted by: JohnD at July 21st, 2020 5:20 PM

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