Metformin, a common diabetes treatment that works to mimic dietary fasting, was seen to promote remyelination in the stem cells of elderly rats, suggesting it may be useful in treating multiple sclerosis.
“Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells” was published in the journal Cell Stem Cell.
MS is characterized by the loss of myelin, the protective sheath around neurons (nerve cells) that helps them to communicate. As such, MS treatments that promote the replacement of lost myelin — a process called remyelination — are needed.
Myelin is made by cells called oligodendrocytes. These oligodendrocytes derive from specialized stem cells, which are called oligodendrocyte progenitor cells (OPCs).
Researchers in this study first showed that, as rats age, their OPCs lose the ability to readily mature into functional oligodendrocytes, a process common to aging. They found that, if given the proper stimuli, about 60% of OPCs from young rats grow into mature oligodendrocytes, while in aged rats less than 20% mature to oligodendrocyte cells.
The researchers then compared OPCs from old (20–24 months) and young animals (2–3 months), and found that aged OPCs exhibit certain cellular changes that are associated with cellular aging, particularly changes to their mitochondria (the cell’s powerhouses where energy is produced).
“As with most regenerative processes, the efficiency of remyelination declines progressively with aging to the extent that it becomes so slow that it eventually fails,” they wrote. “This has important implications for chronic demyelinating diseases such as multiple sclerosis (MS) that can extend over several decades. Delayed remyelination renders demyelinated axons susceptible to [the] irreversible degeneration” evident in later MS stages.
The team wondered if targeting these cellular changes could improve the ability of oligodendrocyte progenitor cells to turn into oligodendrocytes and, by extension, promote remyelination.
Researchers used two approaches with the animals. The first was a alternate day fasting, where rats only ate every other day, which is known to limit cellular aging; the second was giving them metformin, a “small-molecule fasting mimetic” used to lower blood-sugar levels in diabetics, which acts through a protein called AMPK. This protein plays an important role in helping mitochondria work to produce cellular energy as intended.
Results showed that both approaches could promote the formation of oligodendrocytes in elderly rats, leading to better myelin repair.
In rats with chemically induced lesions of myelin loss, both alternate day fasting and metformin also improved remyelination relative to rats given neither treatment approach.
“Overcoming the effects of aging on OPCs is important in generating a permissive environment for remyelination. Interventions such as dietary restriction or drugs that mimic its effects will likely alter the function of OPCs and other cell types that contribute to remyelination … and may thus have dual benefits for the treatment of chronic demyelinating neurodegenerative diseases,” the study concluded.
Robin Franklin, PhD, a professor at the University of Cambridge and study co-author, called the finding “one of the most significant advances in myelin repair therapies there has ever been,” he said in a U.K. MS Society news release.
“The findings shed light on why cells lose their ability to regenerate myelin, and how this process might be reversed. Although research so far has been done in rats, we hope to move it forward into humans soon,” Franklin added.
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