What has getting old got to do with MS?


The brain and spinal cord were not necessarily designed by evolution to last longer than approximately 35 years. It is only relatively recently that as a species we have extended our lifespans. Once you go beyond approximately 35 years of age there is a gradual loss of nerve cells, axons and synapses. This explains why as we get older we notice the effects of ageing; reduced vision, loss of hearing, poor balance and, sadly, age-related cognitive impairment. In short, life after 20 or 30 years is an age-dependent neurodegenerative disease, which is sexually transmitted.

If we live long enough we will all develop cognitive impairment. What protects us from age-related changes is so-called brain reserve, i.e. the size of the brain and spinal cord, and cognitive reserve, which relates to education level and environmental enrichment. We know that MS reduces both brain and cognitive reserve and as a result MSers have reduced reserve and hence the buffer that protects them from the impact of ageing. In other words MSers age earlier.

Another downside of ageing is that repair mechanisms also start to fail. In the paper below neural progenitor cells (NPCs) from MSers with progressive MS  have been found to express cellular ageing markers when compared with age-matched controls, implying that cellular ageing or senescence is an active process in progressive MS and contributes to limited remyelination and recovery.

I suspect one of the reasons why the effectiveness of DMTs fall-off with age is that some of the treatment effects are due to the recovery of function when you switch off inflammation. The less recovery of function the less the will be the relative effectiveness of the particular DMT being studied.

Can you do anything about premature or early ageing? Yes, you can. We know from studies in the general population there are many things that MSers can do to maximise brain and cognitive reserve. This is called Brain Health and involves lifestyle factors such as exercise, diet, sleep and avoiding smoking and excessive alcohol consumption. It is also important to screen pwMS for comorbidities or other diseases and have them treated; these include smoking, hypertension, diabetes, obesity and abnormal lipids. As for diet, there have not been any that have been studied extensively enough in MS. However, data from animal models and other fields indicate that calorie restricted, intermittent fasting and ketogenic diets have the most promise with regard to brain health. However, I need more evidence of their beneficial effects before promoting these diets as an adjunctive treatment for MS.

For those of you are interested dimethyl fumarate (DMF) triggers some of the anti-ageing pathways linked to these diets. Therefore, DMF may be working in MS as an anti-ageing drug already. The question I have is does enough DMF get into the CNS to have an effect on the end organ or is its potential anti-ageing mechanisms limited to the systemic compartment?

Please note that ageing is a biological process and as we decode the molecular programmes that cause ageing we may be able to develop treatments that reverse or slow down ageing. An example of this is metformin, a drug for treating diabetes that has recently been shown by Robin Franklin in Cambridge to reprogramme oligodendrocyte precursors in older animals to behave as if they were young cells and become more efficient at remyelinating axons. I, therefore, envisage a future in which we use anti-ageing drugs as add-on therapy to treat MS.

Nicaise et al. Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis. Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):9030-9039.

Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a proinflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases. We had previously determined that neural progenitor cells (NPCs) derived from induced pluripotent stem cell (iPSC) lines from patients with primary progressive multiple sclerosis (PPMS) failed to promote oligodendrocyte progenitor cell (OPC) maturation, whereas NPCs from age-matched control cell lines did so efficiently. Herein, we report that expression of hallmarks of cellular senescence were identified in SOX2+ progenitor cells within white matter lesions of human progressive MS (PMS) autopsy brain tissues and iPS-derived NPCs from patients with PPMS. 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. A proteomic analysis of the PPMS NPC secretome identified high-mobility group box-1 (HMGB1), which was found to be a senescence-associated inhibitor of OL differentiation. Transcriptome analysis of OPCs revealed that senescent NPCs induced expression of epigenetic regulators mediated by extracellular HMGB1. Lastly, we determined that progenitor cells are a source of elevated HMGB1 in human white matter lesions. Based on these data, we conclude that cellular senescence contributes to altered progenitor cell functions in demyelinated lesions in MS. Moreover, these data implicate cellular aging and senescence as a process that contributes to remyelination failure in PMS, which may impact how this disease is modeled and inform development of future myelin regeneration strategies.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • This is my terror scenario, losing my marbles.

    At 50 I feel as if I am somewhat mentally flailing around trying to navigate the least harmful path.

    Was on DMF but changed to Ocrelizumab with the aim of getting the most powerful drug the NHS wld be willing to provide me with.

    Trying to get the physical exercise right. Read a lot, write a bit and exercise the brain. There is the ghastly feeling that I am running out of options.

    A degree of cognitive dissonance exists and I have to fight the urges to chase eyerything in a reflex manmer.

    Do any other older pwMS feel the same way?

    Perhaps the DMT advice could be made age appropriate?

    • “Perhaps the DMT advice could be made age appropriate?”

      How so? If (i) all DMTs sole function is to control inflamation to allow the brain to heal itself and (ii) As the brain gets older it looses its capacity to heal itself.

      That is why that US meta-study published a year or 2 ago reached the conclusion that no DMTs are really effective after the age of 54. Luis could dig it out for you

      • Thank you, Tony. I am aware of it and it is what ticks away in my head. I feel like 8 am approaching the last chance saloon for pharmaceutical interventions.

        I am pretty good with diet, sleep, exercise and so on. Far less frequently these days do I enjoy a post-prandial cigar. Mostly because I don’t drink much at all.

        I follow a ketogenic diet, and am on Ocrelizumab, Modafinil, Duloxetineml. A neuro friend involved in the Lipoic Acid trial feels that the results are looking good so purely speculatively I am following the 600mg bd (1200mg daily) regime. My concern with this is buying otc preparations means they aren’t subject to the same rigorous QA that P or POM products are.

        I also work hard to keep my brain active by reading, writing and campaigning.

        I just want to decline at the same or similar rate to an ‘ordinary’ person. No desire to battle normal ageing.

  • It has been posts such as this and also vids from Aaron Boster, such as one of his latest ones on factors pertinent to a poor prognosis, that has facilitated my strong focus on self-care. However, some of your other posts also has me painfully aware of the wider issue of wealth and deprivation. Thanks to my husband I don’t have to work: sessions with a neuro physio – tick. Membership of a quality gym – tick. Expensive supplements – tick. Ready prepared veg so as to make easier consumption of healthy diet without fatigue worries – tick. Meals out with friends, downloading books, etc, etc.
    So much of being able to off- set my 55yrs of age, and meeting the factors for a poor prognosis, is being able to afford the costs. I watched last week’s DIY SOS and what has plagued me since is how can a society such as ours allow a guy with MS to sleep for two years in a chair and leave his blind mother in her seventies to provide his primary care?
    Of course it is vitally important for PwMS to self care as far as possible, but it’s morally wrong that those of us who can afford it are far better able to promote and maintain our own wellbeing! Consequently, I wish more notice would be taken of your suggesting that maybe exercise should be prescribed, almost like another DMT, due to the benefits. Obviously, provision such as this on the NHS could save the service money in the longer term as well as aiding those with MS.

  • Dr G. Thank you for putting it all together. For those who may have not active disease, the question always is, where do we go from here? Doctors need to look at the big picture as well.

  • 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.

    Rapamycin=It inhibits activation of T cells and B cells by reducing their sensitivity to interleukin-2 (IL-2) through mTOR inhibition.[7]

    mTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and amino acids.[10] mTOR also senses cellular nutrient, oxygen, and energy levels.[27] The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue,[28] and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.[29][30] Rapamycin inhibits mTOR by associating with its intracellular receptor FKBP12.[31][32] The FKBP12–rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity.[

    So Rapamycin its an inhibitor of mTOR pathway

    If you treat NPC with Rapamycin they promote oligodendrocyte (OL) differentiation

    mTOR its like an “antena” in a cell it senses stress, metabolic status of the organism (fed or fasted state) etc

    And supreses autophagy

    Now the interesting thing is that you can have that same effects without taking Rapamycin


    Simply …Fast

    Fasting is a very natural way of inhibiting the mTOR pathway


    Want to know more about


    Listen to the maven David Sabatini




    Like to know about autophagy

    Listen to the maven Dr Guido Kroemer


    Ps: I post this study when it came out but at the time no one care 🙁


  • This was on BBC radio 4 today. An interview with the researchers about diabetes drug metformin which mimics fasting and could be used for MS.

    • Maybe the data is surfacing today I’ll have a look….Not found. Was it the Cambridge Lab?.I have known this story for a couple of years or maybe it was

      Oligoprotective effect of metformin through the AMPK-dependent on restoration of mitochondrial hemostasis in the cuprizone-induced multiple sclerosis model. Largani SHH, Borhani-Haghighi M, Pasbakhsh P, Mahabadi VP, Nekoonam S, Shiri E, Kashani IR, Zendehdel A. J Mol Histol. 2019;50:263-271.

By Prof G



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