Digging into the Details of Why a Young Environment Restores the Activity of Old Cells

Heterochronic parabiosis is the unwieldy name given to the process of linking the circulatory systems of an old and a young individual. Over the past decade, researchers have used this technique in mice to demonstrate that the declining activity of many types of old stem cells is driven more by changing protein levels in the environment than by any damage inherent to the cells themselves. Restore a youthful environment to some degree, and stem cells pick up their activities.

The decline in stem cell activity with aging, the loss of tissue maintenance and resulting frailty and dysfunction, is thought to be an evolutionary adaptation to reduce cancer risk, with the later stages of life painted as a balancing act between risk of cancer due to the activities of damaged cells on the one hand versus the need to maintain tissue function on the other. As the medical community becomes ever better at controlling cancer, there may be no real objection to removing the environmental triggers that are turning down stem cell activity. That of course requires the identification of these triggers, which is presently an ongoing topic of research.

I see this as a stop-gap approach, however. It might prove fairly beneficial, but it doesn't address the underlying reasons as to why the environment within the body has changed. That change is presumably a response to higher levels of damage to cells and macromolecules. Thus the development of rejuvenation treatments that repair that damage will lead to a restoration of the environment to youthful patterns of protein levels and cellular responses to those protein levels.

Although commonly considered a disease of white matter, gray matter demyelination is increasingly recognized as an important component of multiple sclerosis (MS) pathogenesis, particularly in the secondary progressive disease phase. Extent of damage to gray matter is strongly correlated to decline in memory and cognitive dysfunction in MS patients. Aging likewise occurs with cognitive decline from myelin loss, and age-associated failure to remyelinate significantly contributes to MS progression.

However, recent evidence demonstrates that parabiotic exposure of aged animals to a youthful systemic milieu can promote oligodendrocyte precursor cell (OPC) differentiation and improve remyelination. In the current study, we focus on this potential for stimulating remyelination, and show it involves serum exosomes that increase OPCs and their differentiation into mature myelin-producing cells - both under control conditions and after acute demyelination.

Environmental enrichment (EE) of aging animals produced exosomes that mimicked this promyelinating effect. Additionally, stimulating OPC differentiation via exosomes derived from environmentally enriched animals is unlikely to deplete progenitors, as EE itself promotes proliferation of neural stem cells. We found that both young and EE serum-derived exosomes were enriched in miR-219, which is necessary and sufficient for production of myelinating oligodendrocytes by reducing the expression of inhibitory regulators of differentiation. Accordingly, protein transcript levels of these miR-219 target mRNAs decreased following exosome application to slice cultures. Finally, nasal administration of exosomes to aging rats also enhanced myelination. Thus, peripheral circulating cells in young or environmentally enriched animals produce exosomes that may be a useful therapy for remyelination.

Link: http://dx.doi.org/10.1002/glia.22606


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