As you get older you do not repair as well, compared to when you are younger. This has been known for some time and a few years ago Prof Franklinstein sewed mice together and determined that young macrophages could allow old mice to repair. So it is an obvious thing to look for the elixior of youth. In other studies a blood protein promoted youthful effects in nerves
Metformin is a treatment of type 2 diabetes, particularly in people who are overweight. Metformin is generally well tolerated. Common side effects include diarrhea, nausea, and abdominal pain and should be avoided by people with significant liver disease or kidney problems. Metformin is a biguanide anti-hyperglycemic agent. It works by decreasing glucose production by the liver and increasing the insulin sensitivity of body tissues. In this study it is shown to an agent that rejuvenates oligodendrocyte precursors and allows them to remyeliate
So this could say current trials with pro-remyelinating drug may not work very well because the oligodendrocytes are aged, but if you combine the remyelinating drug with metformin or perhaps if you use metformin alone it may be the key.
So in summary
- Aged OPCs fail to respond to differentiation signals
- Aged OPCs acquire many of the hallmarks of cell aging
- Fasting and the fasting mimetic metformin rejuvenate poor remyelination in aged rodents
- Metformin reverses age-related changes, making OPCs respond to differentiation factors
I guess the first question is do we need a trial?, Surely there are enough people with MS that have type II diabetes who are taking metformin.
A study from 2006 found about 7% of their pwMS were type II diabetic and with the incidence of type II diabetes on the increase, it must be more. So if we have 10,000 pwMS in the North and East London area I wonder what ProfK can find in our data base.
Has there been a miraculous recovery. What is your experience?
The answer is probably not miraculous, because surely it would have been noted by now. I am sure the guys at MSBase and every registry in the land will be checking their databases for MS + diabetes verses MS + diabetes + metformin.
However, Metformin has already been tested in MS. Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis. Negrotto L, Farez MF, Correale J. JAMA Neurol. 2016; 73(5):520-8
Furthermore it is already known that metformin influences myelination, despite not being mentioned in the paper:-(. However this is a good thing as it says this study has replication.
Paintlia AS, Paintlia MK, Mohan S, Singh AK, Singh I. Am J Pathol. 2013;183:526-41. AMP-activated protein kinase signaling protects oligodendrocytes that restore central nervous system functions in an experimental autoimmune encephalomyelitis model.
Qi B, Hu L, Zhu L, Shang L, Sheng L, Wang X, Liu N, Wen N, Yu X, Wang Q, Yang Y. Metformin attenuates cognitive impairments in Hypoxia-Ischemia neonatal rats via improving remyelination. Cell Mol Neurobiol. 2017 Oct;37(7):1269-1278.
It was also used in EAE years ago
Likewise the influneces of diet on myelination was known
A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms. Choi IY, Piccio L, Childress P, Bollman B, Ghosh A, Brandhorst S, Suarez J, Michalsen A, Cross AH, Morgan TE, Wei M, Paul F, Bock M, Longo VD. Cell Rep. 2016; 15(10):2136-2146.
If you want to read about it
Metformin and Autoimmunity: A “New Deal” of an Old Drug.Ursini F, Russo E, Pellino G, D’Angelo S, Chiaravalloti A, De Sarro G, Manfredini R, De Giorgio R.Front Immunol. 2018 Jun 4;9:1236.
Metformin: a review of its potential indications.Wang YW, He SJ, Feng X, Cheng J, Luo YT, Tian L, Huang Q.Drug Des Devel Ther. 2017 Aug 22;11:2421-2429
Metformin: A Hopeful Promise in Aging Research.Novelle MG, Ali A, Diéguez C, Bernier M, de Cabo R. Cold Spring Harb Perspect Med. 2016 Mar 1;6(3):a025932.
So does it mean the ketogenic diet is back on the cards?
I suppose one key question is…Are the rodent studies really representative of the remyelination effect in humans. If it is, this study is good news. If not it may not do anything. Clearly repair trials are the next step.
So nice work from Bjorn and Robin and the Guys from Cambridge
Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cell Neumann et al., 2019, Cell Stem Cell 25, 473–485. https://doi.org/10.1016/j.stem.2019.08.015
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.