OPCs on a Diet: A Youthful Serving of Remyelination
Authors: Charles W. White, Karishma Pratt, Saul A. Villeda
Journal: Cell Metabolism (2019)

Remyelination declines in the aging central nervous system due to oligodendrocyte precursor cell (OPC) dysfunction. In the latest issue of Cell Stem Cell, Neumann et al., 2019Neumann B. Baror R. Zhao C. Segel M. Dietmann S. Rawji K.S. Foerster S. McClain C.R. Chalut K. van Wijngaarden P. Franklin R.J.M. Metformin restores CNS remyelination capacity by rejuvenating aged stem cells.Cell Stem Cell. 2019; 25: 473-485.e8Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar demonstrate that aged OPCs are amenable to functional rejuvenation by systemic interventions involving alternate-day fasting or treatment with the fasting mimetic metformin. Remyelination declines in the aging central nervous system due to oligodendrocyte precursor cell (OPC) dysfunction. In the latest issue of Cell Stem Cell, Neumann et al., 2019Neumann B. Baror R. Zhao C. Segel M. Dietmann S. Rawji K.S. Foerster S. McClain C.R. Chalut K. van Wijngaarden P. Franklin R.J.M. Metformin restores CNS remyelination capacity by rejuvenating aged stem cells.Cell Stem Cell. 2019; 25: 473-485.e8Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar demonstrate that aged OPCs are amenable to functional rejuvenation by systemic interventions involving alternate-day fasting or treatment with the fasting mimetic metformin. Oligodendrocyte precursor cells (OPCs) differentiate into mature oligodendrocytes, which myelinate axons in the mammalian central nervous system (CNS), allowing for rapid propagation of action potentials and metabolic support of axons. While most myelination occurs during early postnatal development, OPCs persist in the adult brain, representing 5% of the cells in the adult CNS. Generation of oligodendrocytes from OPCs contributes to fine-tuning myelination and lifelong myelin turnover, and therefore offers an exciting avenue for regeneration in demyelinating diseases such as multiple sclerosis (MS). Notwithstanding, therapeutic potential is obstructed by an age-related decline in remyelination capacity, in which OPCs migrate to MS lesions but fail to differentiate and remyelinate axons. Rejuvenating systemic interventions, such as heterochronic parabiosis, have been shown to restore remyelination in the aged CNS (Ruckh et al., 2012Ruckh J.M. Zhao J.W. Shadrach J.L. van Wijngaarden P. Rao T.N. Wagers A.J. Franklin R.J. Rejuvenation of regeneration in the aging central nervous system.Cell Stem Cell. 2012; 10: 96-103Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar). However, whether age-related impairments in OPC function arise from the interplay between intrinsic drivers of stem cell aging and extrinsic cues from the aged systemic environment had yet to be investigated. In the latest issue of Cell Stem Cell, Neumann et al. demonstrate that aged OPCs acquire cellular hallmarks of aging that render them unresponsive to differentiation cues but remain amenable to functional rejuvenation by systemic interventions involving dietary restriction and metformin treatment (Figure 1). A long-standing impediment in investigating mechanisms of age-related regenerative decline has been the difficulty in isolating aged stem cells while maintaining their cellular hallmarks of aging in vitro. To overcome this obstacle, Neumann et al. first developed a new method for culturing aged rat OPCs, adapted from an immunopanning-based protocol (Dugas and Emery, 2013Dugas J.C. Emery B. Purification and culture of oligodendrocyte lineage cells.Cold Spring Harb. Protoc. 2013; 2013: 810-814Crossref PubMed Scopus (14) Google Scholar). This approach enabled the authors to begin to tease apart the cellular and molecular consequences of aging on OPC differentiation. They observed that aged OPCs differentiate at a slower rate than young OPCs, even in response to pro-differentiation factors. By comparing cultured young and aged OPCs using RNA sequencing, the authors demonstrate that aged OPCs lose their stem cell signature coincident with premature expression of early differentiation genes. The authors also show that several characteristic hallmarks of aging persist in cultured aged OPCs, with emphasis placed on those associated with increased mTOR activity—a nutrient-sensing pathway linked to aging (Saxton and Sabatini, 2017Saxton R.A. Sabatini D.M. mTOR signaling in growth, metabolism, and disease.Cell. 2017; 168: 960-976Abstract Full Text Full Text PDF PubMed Scopus (3117) Google Scholar) and regulation of stem cell function (Mihaylova et al., 2014Mihaylova M.M. Sabatini D.M. Yilmaz O.H. Dietary and metabolic control of stem cell function in physiology and cancer.Cell Stem Cell. 2014; 14: 292-305Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). While the contribution of this in vitro model system to the aging research field should be underscored, its ability to fully reflect an aged in vivo state will need to be further explored, as well as potential limitations in areas such as modeling cellular and functional heterogeneity. To examine the interplay between aged OPC function and systemic interventions in vivo, Neumann et al. set out to investigate whether dietary restriction could restore remyelination in the aged CNS (Figure 1). The authors used an alternate-day fasting (ADF) protocol wherein aged rats were fasted every other day for 6 months prior to receiving an acute demyelination lesion via stereotaxic injection of ethidium bromide into the cerebellum. While OPC populations adjacent to the lesion were similar in size 1 week after injury, long-term animals on ADF showed a marked increase in both OPC population size and degree of remyelination when compared to ad libitum-fed animals at later time points. Previously, studies have demonstrated that adhering to a fasting-mimicking diet improves remyelination in animal models of MS in part by promoting expansion of the OPC pool (Choi et al., 2016Choi I.Y. Piccio L. Childress P. Bollman B. Ghosh A. Brandhorst S. Suarez J. Michalsen A. Cross A.H. Morgan T.E. et al.A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms.Cell Rep. 2016; 15: 2136-2146Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar). Findings by Neumann et al. extend beyond disease models, providing compelling evidence for the rejuvenating effects of ADF on remyelination in physiological aging. Dietary interventions such as fasting are known to significantly reduce mTOR activity (Madeo et al., 2019Madeo F. Carmona-Gutierrez D. Hofer S.J. Kroemer G. Caloric restriction mimetics against age-associated disease: targets, mechanisms, and therapeutic potential.Cell Metab. 2019; 29: 592-610Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar). Given the rejuvenating effects of ADF on OPC function in vivo, and increased mTOR activity detected in aged OPCs in vitro, the authors next examined whether altering mTOR signaling could rejuvenate OPC function at a cellular level. The authors investigated the effects of treating cultured aged OPCs with the fasting mimetic metformin. While not a direct inhibitor of mTOR, metformin mimics fasting conditions by increasing AMPK activity, which in turn inhibits mTOR activity. Following treatment with metformin, aged OPCs exhibited a markedly increased differentiation capacity, reminiscent of young OPCs. Conversely, treating aged OPCs with metformin and the potent AMPK inhibitor dorsomorphin mitigated benefits on differentiation. These in vitro data implicate metformin and reduced mTOR activity in OPC rejuvenation. Building upon their promising in vitro data, Neumann et al. explored whether metformin treatment could recapitulate rejuvenating effects of ADF on remyelination in vivo (Figure 1). Aged rats were treated with metformin for 3 months and compared to age-matched animals undergoing 6 months of ADF or ad libitum feeding prior to injury. Remarkably, metformin-treated animals exhibited remyelination levels comparable to those of aged rats on ADF. These data indicate that metformin treatment alone is sufficient to restore the remyelination capacity of the aged OPC pool in vivo. From a translational perspective, these preclinical data are noteworthy as metformin is the most commonly used drug for treating type 2 diabetes, prescribed to nearly 120 million people worldwide (Viollet et al., 2012Viollet B. Guigas B. Sanz Garcia N. Leclerc J. Foretz M. Andreelli F. Cellular and molecular mechanisms of metformin: an overview.Clin. Sci. (Lond.). 2012; 122: 253-270Crossref PubMed Scopus (1212) Google Scholar). While these impressive observations assert the therapeutic potential of metformin in addressing demyelinating diseases such as MS, further studies will certainly need to investigate the effectiveness of metformin treatment delivered post- rather than pre-injury. A growing body of literature supports the idea that systemic interventions such as heterochronic parabiosis, exercise, and dietary restriction can rejuvenate regenerative capacity across aged tissues including the CNS (Fan et al., 2017Fan X. Wheatley E.G. Villeda S.A. Mechanisms of hippocampal aging and the potential for rejuvenation.Annu. Rev. Neurosci. 2017; 40: 251-272Crossref PubMed Scopus (68) Google Scholar, Horowitz and Villeda, 2017Horowitz A.M. Villeda S.A. Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease.F1000Res. 2017; 6: 1291Crossref PubMed Scopus (19) Google Scholar). Neumann et al. deepen our knowledge of the plasticity of the aged CNS, providing critical evidence for the benefits of fasting on remyelination that extend beyond traditional disease models not often utilized at old age. By demonstrating the rejuvenating potential of the fasting mimetic metformin on OPC function, the authors further the exciting possibility of repurposing known pharmaceuticals implicated in life and health extension, such as rapamycin and NAD+, for the treatment of aging-associated conditions. Ultimately, the authors’ use of a widely prescribed human therapeutic pushes the field of rejuvenation research ever closer to the realm of human health. Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem CellsNeumann et al.Cell Stem CellOctober 03, 2019In BriefNeumann et al. demonstrate that aging renders adult oligodendrocyte progenitor cells unresponsive to pro-differentiation factors, which can be reversed both in vitro and in vivo by calorie restriction (CR) and the CR mimetic metformin. Full-Text PDF Open Access