Aging causes a decline in tissue regeneration due to a loss of function in adult stem and progenitor cell populations 1. An important example is the deterioration of the regenerative capacity of the widespread and abundant population of central nervous system (CNS) multipotent stem cells known as oligodendrocyte progenitor cells (OPCs) 2. A relatively overlooked potential source for this loss of function is the stem cell niche, a source of cell-extrinsic cues including chemical and mechanical signalling 3,4. In this study, we show that the OPC microenvironment stiffens with age, and that this stiffening is sufficient to cause age-related OPC loss of function. Using biological and novel synthetic scaffolds to mimic the stiffness of young brain we find that isolated aged OPCs (aOPCs) cultured on these scaffolds are molecularly and functionally rejuvenated. When we Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

SummaryThe age-related failure to produce oligodendrocytes from oligodendrocyte progenitor cells (OPCs) is associated with irreversible neurodegeneration in multiple sclerosis (MS). Consequently, regenerative approaches have significant potential for treating chronic demyelinating diseases. Here, we show that the differentiation potential of adult rodent OPCs decreases with age. Aged OPCs become unresponsive to pro-differentiation signals, suggesting intrinsic constraints on therapeutic approaches aimed at enhancing OPC differentiation. This decline in functional capacity is associated with hallmarks of cellular aging, including decreased metabolic function and increased DNA damage. Fasting or treatment with metformin can reverse these changes and restore the regenerative capacity of aged OPCs, improving remyelination in aged animals following focal demyelination. Aged OPCs treated with metformin regain responsiveness to pro-differentiation signals, suggesting synergistic effects of rejuvenation and pro-differentiation therapies. These findings provide insight into aging-associated remyelination failure and suggest therapeutic interventions for reversing such declines in chronic disease.