Fight Aging!

Exosomes are a class of extracellular vesicle, membrane-wrapped packages of molecules that carry a sizable fraction of the chemical communications that takes place between cells. The various types of extracellular vesicle are presently ordered in a taxonomy by their size rather than any more subtle combination of features. Those subtle features definitely exist; exosomes from different cell types and different environmental circumstances are quite different from one another in any number of ways. The present taxonomy of extracellular vesicles is indicative of a lack of detailed understanding regarding (a) the mechanisms determining formation of extracellular vesicles, as well as (b) the factors determining the contents of extracellular vesicles.

The stem cell therapies that have long been available via medical tourism, and were later approved by regulators, are slowly morphing into exosome therapies. Extracellular vesicles are more easily harvested, stored, and delivered than is the case for cells. Since transplanted cells die quickly, the benefits of first generation stem cell therapies, such as months-long reductions in chronic inflammation, are mediated by cell signaling, such as the release and uptake of extracellular vesicles. Exosome therapies are now broadly available in overseas clinics, and are working their way into the more heavily regulated medical system. It is even possible to purchase amniotic fluid derived exosomes from providers in the US, provided one has a physician who agrees to accept delivery and make use of them.

The approach to exosome therapy noted in today's open access paper is an interesting one. The source of cells is those that are shed into urine. When humans are the donors, this is a good way to obtain enough material for a mouse study, but a scaling process would have to be put in place for use in human patients. That means either a great deal of harvesting from many donors, or the more challenging approach of developing a well-managed cell line that can produce exosomes in bulk.

Extracellular vesicles from human urine-derived stem cells delay aging through the transfer of PLAU and TIMP1

Transplantation of young and healthy stem cells has been shown to increase health and lifespan in aged mice. A study has reported that the intraperitoneal injection of muscle stem/progenitor cells from young mice can extend healthspan and lifespan in progeroid mice. Interestingly, the transplanted cells are not detected in many rejuvenated tissues, suggesting that their anti-aging effects are mainly mediated by activating endogenous cells in the host through paracrine factors.

Secretion of extracellular vesicles (EVs) is a part of normal physiology in both prokaryotes and eukaryotes. EVs are selectively enriched with various molecules such as proteins and nucleic acids from their parent cells and serve as a key mediator of cell paracrine action by transferring these molecules to their recipient cells. Stem cells-derived EVs have become an attractive option for therapeutic uses because these nanoparticles have fewer safety concerns and are easy to store, transport, and use compared with stem cells themselves. Recent studies have reported that EVs from embryonic stem cells, induced pluripotent stem cells, adipose stem cells, hypothalamic stem/progenitor cells, and umbilical cord- or umbilical cord blood-derived mesenchymal stem cells (MSCs) can alleviate aging-related phenotypes in aged mice, indicating the promising potential of EVs as an anti-aging agent. Nevertheless, the use of these stem cells as the "factory" to harvest EV are limited by many problems, such as the ethical issue for cell use, the lack of enough source to obtain cells, or/and the requirement of fast, convenient, and invasive procedures for cell isolation.

As compared with stem cells from other sources, urine-derived stem cells (USCs) can be collected by a low-cost, simple, and safe method without ethical concerns. We have previously demonstrated that the local injection of USC-derived EVs (USC-EVs) can accelerate wound repair in diabetic mice by enhancing angiogenesis. We have also found that the intravenous injection of USC-EVs can reduce bone loss and enhance bone strength in osteoporotic mice. Moreover, these nanovesicles can exert protective effects against glucocorticoid-induced osteonecrosis by promoting angiogenesis, and suppress cell apoptosis after systemic administration. In our previous study, we obtained proteomic data regarding the differentially expressed proteins between USC-EVs and USCs. In this study, we further analyzed these data and found that a class of USC-EVs-enriched proteins have been previously shown to possess anti-aging function, such as tissue inhibitor of metalloproteinases 1 (TIMP1), plasminogen activator urokinase (PLAU), insulin-like growth factor binding protein 5, senescence marker protein-30, and connective tissue growth factor. Thus, we hypothesized that USC-EVs might be capable of rejuvenating old organs from aging via transferring of anti-aging proteins.

Here, we tested the effects of USC-EVs on cellular senescence in vitro and on the aging-related phenotypes in different organs of both senescence-accelerated mice and natural aging mice. The intravenous injection of USC-EVs improves cognitive function, increases physical fitness and bone quality, and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice. The anti-aging effects of USC-EVs are not obviously affected by the USC donors' ages, genders, or health status. Proteomic analysis reveals that USC-EVs are enriched with PLAU and TIMP1. These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases, cyclin-dependent kinase inhibitor 2A (P16INK4a), and cyclin-dependent kinase inhibitor 1A (P21cip1). These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.