Remyelination and ageing: Reversing the ravages of time

Abstract

Remyelination is a neuroprotective regenerative response to demyelination that restores saltatory conduction and decreases the vulnerability of axons to irreversible degeneration. It is a highly efficient process: however, as with all regenerative processes, its efficiency declines with ageing. Here we argue that this age-related decline in remyelination has a major impact on the natural history of multiple sclerosis (MS), a disease often of several decades' duration. We describe recent work on (1) how ageing changes the function of oligodendrocyte progenitor cells (OPCs), the cells primarily responsible for generating new myelin-forming oligodendrocytes in remyelination, (2) how these changes are induced by age-related changes in the OPC niche and (3) how these changes can be reversed, thereby opening up the possibility of therapeutically maintaining remyelination efficiency throughout the disease, preserving axonal health and treating the progressive phase of MS.

Keywords: Remyelination; ageing; oligodendrocyte progenitor cell; stem cell.

Figure 1.

OPCs, like other adult stem cells, undergo functional decline with ageing: they have a diminished ability to self-renew and to differentiate. The dysfunction of aged OPCs is underlined by the acquisition of hallmarks of ageing, like DNA damage and mitochondrial dysfunction. The functional capacity of an OPC is determined by its environment (niche) as OPCs transplanted, irrespective of their own age, function like OPCs of the age of the host tissue (i.e. young or aged OPCs transplanted into a young brain behave like young OPCs). Many biochemical and histological changes that occur in the extracellular environment with ageing have been described, but our recent data demonstrate that the physical properties (stiffness) of the brain play a key role in the ageing process. Interventions, such as heterochronic parabiosis or treatment with metformin, restore a youthful niche and can reinstate the stem cell potential of OPCs and thereby their capacity for remyelination. Alternatively, aged OPCs can be reprogrammed to a more youthful state. The deletion of Piezo 1 prevents OPCs from sensing the stiffness of the niche. Thus, aged OPCs behave as young OPCs that are normally exposed to a soft environment. Therefore, strategies that restore a more youthful environment or that make OPCs impervious to extracellular changes that occur with ageing lead to a functional rejuvenation of OPCs and thereby store the capacity of aged animals for remyelination.