Temporal changes in metabolism guide oligodendrocyte precursor cell dynamics in aging and multiple sclerosis.

Tess Dierckx, Sarah E Wilson, Rebecca Buchanan, Themistoklis M Tsarouchas, Yuhsiang Cheng, Maria Sacconi Nunez, Kelly Strickland, Dena Kumsa, Yohan S S Auguste, Sam Vanherle, Sander Bouwman, Daniela Rojo, Louisa Dal Cengio, Celia Lerma-Martin, Yassene Mohammed, Lucas Schirmer, Jeroen F J Bogie, Bart J L Eggen, Erin M Gibson

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA. · pubmed

Paper

Abstract

Impaired oligodendrocyte precursor cell (OPC) differentiation limits myelin renewal in aging and contributes to multiple sclerosis (MS) progression. How aging drives OPC deficits remains incompletely understood. We find dysregulation of genes associated with the circadian clock, including Bmal1, and metabolism in aged compared with young OPCs. Targeted loss of Bmal1 in OPCs drives metabolic dysfunction, leading to cellular senescence and impaired dynamics. OPC proliferation and differentiation occur at different rates throughout the day in young adult mice and become disrupted with aging. Chronotherapeutic targeting of BMAL1-controlled sirtuin signaling restores Bmal1-disrupted OPC dynamics after demyelination via sirtuin 2 (Sirt2)-dependent mechanisms. Induced pluripotent stem cell (iPSC)-derived OPCs from MS patients and MS lesion oligodendroglia recapitulate BMAL1 and SIRT2 disruptions. These findings establish BMAL1 as a key regulator of OPC energy metabolism, sirtuin homeostasis, and senescence. We anticipate that this work will provide a foundation for future studies investigating the interconnected roles of aging, circadian disruption, and myelin biology.

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Research summary

The study identifies BMAL1-mediated metabolic dysfunction and senescence as a root cause of impaired oligodendrocyte precursor cell dynamics in aging, proposing that chronotherapeutic targeting of this pathway can restore myelin renewal mechanisms. This work is relevant because it addresses cellular senescence and metabolic regulation—hallmarks of aging—rather than merely treating the symptoms of multiple sclerosis, although the specific application to MS limits its broad impact on general lifespan extension.

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