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Caloric Restriction Restores Myelinating Cell Populations


A recent study published in Cell Stem Cell shows that fasting and metformin are effective in a mouse model of demyelination, which is caused in humans by such disorders as multiple sclerosis.

Myelin, demyelination, and remyelination

Myelin, a substance rich in beneficial proteins and fats, is an insulator and protector of nerve cells and helps nerve cells to conduct messages to one another.

Multiple sclerosis and other disorders, however, strip this myelin from nervous tissue, causing cells to malfunction. Normally, myelin in the central nervous system is restored through oligodendrocyte progenitor cells (OPCs), which differentiate in order to create the oligodendrocytes that naturally produce myelin. However, aging causes these stem cells to fail to differentiate even in the presence of differentiation signals, leaving a deficit of these crucial cells and leaving people vulnerable to progressive demyelinating diseases.

In a mouse model of demyelination, mice that were restricted from food for three days a week had more oligodendrocytes than their freely fed counterparts, showing that OPCs were more effectively able to differentiate [1]. The OPCs of calorically restricted mice were more efficient in other ways, including greater ATP availability and less DNA damage.

One well-known mimetic of caloric restriction is metformin, and the researchers also tested this compound in place of CR; the mice in this experiment showed similarly positive results as the fasting mice.


The 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.


While this is not a human study and metformin may not be effective for humans with MS or related disorders, it gives hope to sufferers of these diseases as it offers a starting point for additional research and clinical trials.

The study’s authors have also not yet ascertained exactly why aged OPCs are unable to properly differentiate. Mitochondrial dysfunction and genomic instability, two of the hallmarks of aging, are suggested to be the principal causes, but more research needs to be done in order to discover what biochemical processes are causing OPCs to fail to differentiate and why fasting and metformin are beneficial in combating this problem in mice.

Finally, this study provides additional evidence that caloric restriction provides mammals with limited protection from some of the effects of aging, a result that has been shown in previous human studies [2].

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[1] Neumann, B., Baror, R., Zhao, C., Segel, M., Dietmann, S., Rawji, K. S., … & Franklin, R. J. (2019). Metformin restores CNS remyelination capacity by rejuvenating aged stem cells. Cell stem cell, 25(4), 473-485.

[2] Ravussin, E., Redman, L. M., Rochon, J., Das, S. K., Fontana, L., Kraus, W. E., … & Smith, S. R. (2015). A 2-year randomized controlled trial of human caloric restriction: feasibility and effects on predictors of health span and longevity. The Journals of Gerontology: Series A, 70(9), 1097-1104.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called “real life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.
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