Diabetes drug to the rescue. Making old cells young again

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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 diarrheanausea, 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

metformin

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.

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MouseDoctor

21 comments

  • I started Metformin this past year after being diagnosed with Diabetes. I really hadn’t noticed any difference in my MS Symptoms. But, hey, if it might help, why not? Time for some human studies 🐁

    • Thanks for your personal view and highlights that if there is an effect it is probably going to be subtle, so lets not hype this out of proportion and I would argue lets wait for the trials that are planned.

      Any more wishing to comment it would be appreciated.

  • My point exactly. Surely there are enough people out there who have the right diet to prove or disapprove diet effect on MS. Then You rubbished the article as unscientifoc. Now when someone is testing compound if it is beneficial in MS you rubbish it again. Am I noticing a pattern? A compound that doesn’t make pharma billions is not worth considering? Out of curiosity how many repurposed compounds thst won’t make pharma billions is barts testing? My guess is none.

    • I rubbished the article as being unscientific. I do not accept I did anything of the sort.
      I rubbish someone testing a compound….Again I do not accept that either. Take a chill pill and read the article. I have pointed out that there were previous supporting studies.

      A compound that doesn’t make pharma millions is not worth considering….Are you serious?

      How many repurposed compounds testing, we have tested…hundreds including metformin

      Look at our publication history we have used plenty of agents that are not patented or patentable for MS, we did a trial with oxcarbazepine, we spent years with off-label cladribine…OK the offshoot was that pharma brought it back and made millions, we campaigned for the drugs repurposing act.

      Will this drug go anywhere?I suspect there will be trials. They may be successful if the design is right, but the point is, then what. So far we have yet to see any agent that does not have pharma backing…fly. You will note if you read the paper, patents have been filed. Maybe allowing pharma to make millions.

      As to the point about differences between humans and animals, it is not my work.

      It is all well and dandy to have a pop at me, but please get your facts straight

      • Spot on Mouse Doctor. You and your people have done more than anyone I know to challenge the status quo. The criticism above is outrageous.

  • Thanks for this article MD.

    Without a functioning nerve, I don’t see how Metformin (or any other remyelination agent for that matter) will have a large clinically significant effect to patients with progressive disease even if it is shown to stimulate oligodendrocyte function.

    Maybe Metformin will help those with early RRMS? Maybe Metformin should be added early in the course of MS as a myelinated nerve protects from axon breakdown. Maybe every level of the Dr. G’s treatment pyramid should have been treated equally or concurrently and not sequentially?

    If Pharma with its paid neurologists stopped focusing for the last night 30-40 years for profit on meaningless endpoints (ARR, relapses, GAD+ MRI) and focused on the measurement and cause of the “slow burn” or the pathologic innate immunity, progressive MS patients would not be in their current predicament.

  • Another unscientific response from me
    Appreciate this update on the studies into metformin, especially as I am someone who is the wrong side of 55years. This post does cause me to need to put my sensible head on though – have two friends with Type2 on metformin both of whom have offered to supply me with it and I’m having to remind myself I’m not a rodent (well, I don’t think so😂) and to decline their offer.
    Secondly, I guess I’m right in saying that what isn’t known about is the accumulative effect: Intermittent fasting, exercise, supplements such as lipoic acid and meds such as metformin. Thus far I’m untilising those things that have provided some evidence of potential benefit, but as I say I’m sitting on my hands when it comes to metformin.
    I hope that studies or database material produce valid results asap, before my resolve crumbles and I’m reaching for the metformin belonging to my mates!

  • Did i read read fasting ? 🙂

    So Metformin decreases your blood glucose

    Guess what ?

    Fasting does that too 🙂 (way cheaper)

    Apparently some cells look younger ,but thats just one of the effects of fasting memetics like

    rapamin,rapalog

    Actually that was already been done to oligodedrocites of pwms

    “Expression of cellular senescence genes in PPMS NPCs was found to be reversible by treatment with rapamycin, which then enhanced PPMS NPC support for oligodendrocyte (OL) differentiation”

    Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis

    https://www.pnas.org/content/116/18/9030

    Just one more

    Autophagy Promotes Oligodendrocyte Survival and Function following Dysmyelination in a Long-Lived Myelin Mutant

    The Long–Evans shaker (les) rat has a mutation in myelin basic protein that results in severe CNS dysmyelination and subsequent demyelination during development. During this time, les oligodendrocytes accumulate cytoplasmic vesicles, including lysosomes and membrane-bound organelles. However, the mechanism and functional relevance behind these oligodendrocyte abnormalities in les have not been investigated. Using high-magnification electron microscopy, we identified the accumulations in les oligodendrocytes as early and late autophagosomes. Additionally, immunohistochemistry and Western blots showed an increase in autophagy markers in les. However, autophagy did not precede the death of les oligodendrocytes. Instead, upregulating autophagy promoted membrane extensions in les oligodendrocytes in vitro. Furthermore, upregulating autophagy in les rats via intermittent fasting increased the proportion of myelinated axons as well as myelin sheath thickness in les and control rats. Overall, this study provides insight into the abnormalities described in les as well as identifying a novel mechanism that promotes the survival and function of oligodendrocytes.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128639/

    So you dont need the drugs

    Ok maybe a trial 🙂

  • More mettformin

    An investigation into the SFK-AMPK signaling axis and its role in CNS myelination

    Src family kinases (SFK) are a family of non-receptor tyrosine kinases that integrate and transduce information
    about the extracellular environment to regulate downstream intracellular processes. The SFK member Fyn is
    needed for normal myelin production, with a global knockout of Fyn or loss of Fyn kinase activity resulting in
    severe hypomyelination. Conversely, we found that constitutive activation of Fyn in oligodendrocytes (via loss of
    C-terminal Src Kinase (Csk), a negative SFK regulator) leads to increased myelin wrapping (hypermyelination) in
    the brain and spinal cord. Hypermyelination in Csk knockouts was, surprisingly, not accompanied by detectable
    changes in MAPK or mTOR pathway activity, two pathways known to control the extent of myelin wrapping.
    Instead, Csk loss was accompanied by a 7-fold increase in AMP-kinase (AMPK) transcripts. AMPK acts as the
    metabolic sensor in the cell and is activated during energy intensive processes (e.g., myelination) to regulate the
    activity or expression of proteins involved in ATP synthesis. Exogenous activation of AMPK can be achieved with
    metformin, a drug used to treat type 2 diabetes. We found that metformin treatment of oligodendrocyte
    progenitor cells increases the expression of myelin proteins (MBP, CNP) and accelerates the generation of
    mature oligodendrocytes. Studies to evaluate the ability of metformin to influence myelination and/or myelin
    repair are currently underway. The ability to manipulate the SFK-AMPK signaling axis may prove to be beneficial
    in the development of remyelination therapies aimed at combating demyelinating diseases such as Multiple
    Sclerosis.

    Glia porto 2019

    A conference you were in

    A diabetes drug promotes brain repair—but it only works in females

    https://medicalxpress.com/news/2019-09-diabetes-drug-brain-repairbut-females.html

    • And possibly exercise as well?

      It is well known that even a small amount of effortful activity will quickly reduce glucose in your blood – much quicker than any diet if only temporariiy. Is it possibly that prolonged activity has the same effect as IF?

      When I used to be strong I would go walking / climbing for ten to twelve hours with very little food apart from water, appetite was suppressed. This is not news to those weirdos like me who enjoy the challenge of wearing yourself out. Now I can do far less, but given that I have to work much harder, perhaps it has similar effects? (It would be nice to think so!)

    • (intermittent fasting, caloric restriction, ketogenic), metformin and DMF

      They all drive your glucose down

      Dmf acts on the glycolytic pathway

      Activated immune cells undergo a metabolic switch to aerobic glycolysis akin to the Warburg effect, presenting a potential therapeutic target in autoimmune disease. Dimethyl fumarate, a derivative of the Krebs cycle intermediate fumarate, is an immunomodulatory drug used to treat multiple sclerosis and psoriasis. Although its therapeutic mechanism remains uncertain, it covalently modifies cysteine residues in a process termed “succination.” Here, we show that dimethyl fumarate succinates and inactivates the catalytic cysteine of the glycolytic enzyme GAPDH both in vitro and in vivo. It thereby downregulates aerobic glycolysis in activated myeloid and lymphoid cells, which mediates its anti-inflammatory effects. Our findings provide mechanistic insight into immune modulation by dimethyl fumarate and represent a proof of concept that aerobic glycolysis is a therapeutic target in autoimmunity.

      We next asked whether inhibition of GAPDH and aero-bic glycolysis mediated the immunologic actions of DMF. We first addressed this question in macrophages. We repro-duced previous findings that both DMF and glycolytic blockade prevent classical macrophage activation (fig. S10, A to D) (3, 25) and then determined that the inhibition of cy-tokine production by DMF was unrelated to its effects on OXPHOS (fig. S10E). We next measured the production of IL-1β under low (0.5 mM) or high (10 mM) glucose concen-trations and found that DMF was much less effective in the presence of high glucose (Fig. 3A), suggesting that its anti-inflammatory effect can be overcome by driving glycolysis higher with saturating concentrations of glucose.

      10.1126/science.aan4665 (2018).

    • What do you think about adding NAD+, MitoQ, lipoic acid etc.?

      There are many supplements that provide “mitochondrial support.” The recent Cell article seems to suggest that they do *not* work at cross purposes with the fasting or Metformin, but would actually HELP those interventions work. (I know you do not want to endorse supplements, etc. – but interested in thoughts from you and others about the interaction.)

      Since 2017, I have been taking all the above + fasting regularly. I am walking farther and my stamina has increased. Not doing great by any means, but there is a slight noticeable improvement.

      • For me, I should emphasize, the change is not really “slight.” I can go from walking barely 1/2 a mile to walking over 1 mile on a good day. So, given the context of a really devastating condition, my improvement is dramatic.

        A regular fit adult walking with me in a group would think I’m extremely slow and impaired. But to me the improvement is life-changing.

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