The new black death is ageing

T

I say to many of patients one of the most powerful predictors of progressive, or more correctly worsening, MS is ageing. Age also predicts recovery of function; the younger you are the better you do. This study shows that ageing restricts the ability of stem cells to make oligodendrocytes to promote remyelination.

As you are aware age also predicts response, or lack or response, to DMTs. The older you are the less effective DMTs are. The list linked to ageing and poor prognosis goes on ….

I have always said ‘life is a sexually transmitted neurodegenerative disease with a 100% mortality’. This usually gets a mutated laugh until people start pondering the joke and its implications and then gradually realise that I am being serious.

Evolution never designed, and selected, the human brain and nervous system to function much past the age of 35. It is only relatively recently that life expectancy has increased dramatically with the requirement of our brains to function into ‘old age’. It is clear that when we measure cognitive function, and brain volume, it is all downhill from about 35 years of age.

Those of us who are older than 35 notice the subtle cognitive impairments that increase with age and the gradual malfunction and deterioration in our nervous systems. When last have you tried tight-rope walking? Your failing balance system is simply a reflection of the global rot that is also shredding your cognition. Fortunately, we have enough reserve to adapt and cope with the slow decline in our mental faculties. However, if we live long enough we are all likely to become demented. Dementia in this setting is simply the reduction of cognition to a point when you can’t manage socially and occupationally. To prevent the inevitable consequence of ageing is there anything we can do to optimise our brain health so our ‘brains outlive’ our ‘bodies’?

There is a lot we can do to improve brain health. However, some of the interventions may require the administration of medications in the future. For the anti-ageing revolution to happen, and be adopted by society, we need to make ageing a disease.

By defining ageing as a disease it changes everything. Firstly, it creates incentives for the pharmaceutical industry to invest in the necessary R&D to get drugs to market. If ageing is a disease healthcare providers will pay for interventions. The corollary is that if ageing is not defined as a disease, any interventions to delay or modify ageing, will be limited to lifestyle interventions. By defining ageing as a disease it will allow us to develop tools for population screening to identify people who are either healthy or in the presymptomatic phase of known neurodegenerative disease. This will then allow us to test preventive strategies to delay the onset of symptomatic disease.

If on the other hand, you have MS we already know you have a neurodegenerative disease that shreds reserve capacity and brings forward ageing mechanisms, which is why we need to manage MS as early and as effectively as possible and holistically. This is why the new treatment target is ‘to maximise brain health for the lifetime of the person with MS’.

Please be aware that ageing is a biological process and hence we can target the biology with both lifestyle interventions and drugs. For example, recent evidence suggests metformin, a diabetes drug, may reverse some of the ageing programmes. Dimethyl fumarate (DMF), a licensed MS DMT, seems to activate antiageing pathways that overlap with pathways linked to specific dietary interventions, i.e. calorie-restricted, intermittent fasting and ketogenic diets. Should all MSers be on metformin and/or DMF and/or one of these diets? We need trials to test these hypotheses. But at least there are investigators exploring the questions.

Please let me know if you find the anti-ageing hypothesis of MS compelling; it overlaps with diet, sleep, exercise and many other things that I can discuss in future blog posts.

Rivera et al. Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination. Glia. 2019 Apr 30. doi: 10.1002/glia.23624.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.

CoI: multiple

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.

41 comments

  • Of course, the hypothesis is engaging! Who doesn’t want to cure, or at least ameliorate their MS symptoms whilst enjoying the benefits of youth that we once had?

    I think the philosophical and/or moral(?) discussions about death, quality of life, intervening to extend life is worth having.

    For example: if it isn’t one thing then perhaps it is another? At what point do you stop trying to treat symptom after symptom of ageing in the quest to sustain the life of someone whose will to live may have left them some time ago?

    You correctly observe that life an assured cause of death. It sounds like a very scientific game of whack-a-mole being played with life.

    Besides – Metformin tablets are disgustingly enormous. Just saying 😉

    Dominic

  • As someone with MS in my mid-50s, I find many of your posts quite depressing. You banged on about reclassifying MS as a dementing disease. I’ve know doubt that it is, but how do you think this impacts on a 22 year old who has just been diagnosed with MS. You constantly refer to MS as the shredder which whittles away you reserve. It’s easy to state this, but it doesn’t really help an MSer in their 40s, or 50s knowing that the retirement they had planned isn’t going to happen. We know well from your posts that MS shortens your life, leads to unemployment, increases the chances of relationship breakdowns etc. etc. And then you ponder as to why MSers get depressed, become suicidal or buy a one way ticket to Switzerland. I’m not after sugar coating, but your posts keep undermining any hope MSers might have that they have some sort of happy future – you’ve made it quite clear that MS is a whole brain disease and I’m guessing you are coming down on the side that MS is primarily a neurodegenerative disease where relapses are just a sideshow. From your various posts I’m coming to the conclusion that MS is just MND ‘light’ – I’ve seen PPMS at a late stage and see little difference between that and someone with MND. I’m not against your ‘warts and all’, “I tell it straight approach”, but could we have a post from you which is slightly more upbeat. Is there anything positive in the MS space? I’m starting to wonder what has been the point of MS research to date – the understanding of the disease keeps changing, the cause is still unknown and the treatments have limited impact on the disease process or have too many serious side effects and are pulled. You once suggested that Alemtuzumab could be a cure for some, but was a 15-20 year experiment. Where are we on this timeframe? What happened to the black swan? A tiny bit of good news / Hope would be welcome. You recently said that “we know things you don’t”. Please be the Gavin Williamson of MS research and let the cat out of the bag.

    • What I personally find depressing is those MSologists folks who are still stuck to what they learned from school and do not see the contradictions that take place in front of their very eyes. Spoting the actual problem and realising the landscape with clear eyes is more optimistic than my doctor’s “you will be fine” attitude.

    • Have you seen the Bladerunner? This quote by Roy Batty (portrayed by Rutger Hauer), a replicant, at the end of the movie sums it all up for me.

      “I’ve seen things you people wouldn’t believe. Attack ships on fire off the shoulder of Orion. I watched C-beams glitter in the dark near the Tannhauser gate. All those moments will be lost in time… like tears in rain… Time to die.”

      You can watch the scene on YouTube: https://www.youtube.com/watch?v=NoAzpa1x7jU

      Apart from possibly the end of the Great Gatsby, when he says “so we beat on, boats against the current, borne back ceaselessly into the past” (F. Scott Fitzgerald), Batty’s soliloquy sums up the futility of life and is a reminder that we are only mortals.

      CoI – The Bladerunner is my favourite movie

    • I agree completely. Also in my mid-50’s. MS for 35 years. Legs are shot. Arms are going. It seems, from this data, autologous mesenchymal stem cells just wouldn’t work that well for those of us in this age range. None of the DMT’s, even the newer, stronger generation of immune-modifiers have much use if there are no active lesions. So, we are left in the same position we were when I was diagnosed in 1984-to languish with platitudes that a cure is just around the corner.

    • MS is not MND-light. Immunomodulatory therapies can have a profound effect on the course of the disease – HSCT is almost a cure, and Alemtuzumab dramatically alters the course of the condition. There is nothing that alters the course of MND.

      MS is not primarily a neurodegenerative condition. It’s an immune mediated condition. MS is most common in young, healthy people, while all sporadic onset neurodegenerative conditions affect older people primarily or exclusively. MS almost does not occur in people over 60. MND occurs mainly in people over 60, as does every other neurodegenerative condition (Parkinsons, Alzheimers, FTD, you name it).

      If MS was a neurodegenerative condition it would not occur less in older people.

      Get alemtuzumab, protect your brain with ibudilast and pioglitazone, and I think you’ll be okay.

  • RRMS for 20 years and doing OK, all things considered. Thank you, Tysabri.

    Evidence does seem to suggest that the best way to keep to a minimum age-related damage of all sorts is to stay metabolically healthy and insulin-sensitive. But why bother with drugs when a low carb/high fat, real food way of eating might get the job done? For sure, people who are in bad metabolic shape might benefit from drugs, but most people can really improve things just by cleaning up their diet. For me, that means low(ish) carb/high fat. It is really no hardship to avoid sugar, flour and industrial seed oils, and doing so automatically eliminates 95% of processed rubbish. Real food – meat, veg, cheese, olive oil etc – is much nicer. And I feel so much better.

    • “But why bother with drugs when a low carb/high fat, real food way of eating might get the job done?”

      Delusion if you think diet is any match for disease. You still have brain reserve which is why
      you feel good but heading to 50 it will be gone soon. HSCT now might help you before
      progression sets in. I’d do it now otherwise spms will be in your near future.

      • Anox, I do not think diet is a match for MS. That is why I have been on Tysabri for 8 years and Avonex for 10 years before that. I’m not stupid. Thanks for the advice, though.

        • Tysabri..is not good at saving brain..just stops relapses..
          look into hsct it’s much more effective…some people don’t progress…but people progress on tysabri and rituximab.

        • “I have been on Tysabri for 8 years and Avonex for 10 years before that. I’m not stupid.”

          Realize those are not cures…smouldering ms they call it here..
          trust me you will need something stronger.

      • Omg. Where do we get the money for HSCT? We aren’t all in the US. It didn’t work for that bbc reporter did it? All that risk and money for no gain.
        I’ve given up trying diet to help. I just get on with Keto to lose weight and a double dose of a statin.
        After 6 months of natalizumab, my bladder has healed just as long as I get plenty of sleep and rest. I no longer need continence pads. It’s a. massive confidence boost. Medicine andctime has beaten the horrible bugger. I take betmiga just as a back up. Theres a down side. I can not work as a musician any more, the risk of attack and progression isn’t worth the effort.

  • My self experiment with Metformin lasted about 15 days and I didn’t feel great while taking it but had a burst of energy and wellness for another two weeks after I stoped taking it. I don’t know if the fatigue metfrormin caused is because I do not have any diabetes issues -it felt like I had low glycose which metformin is not supposed to cause, but is something I already get occassionally – or its effect on mitochondria (it didn’t feel like MS fatigue though). Anyway, after stopping its use I felt better than before starting it. This leads me to make a second attempt with it.

    • This is the popular video (with layman’s terms) with David Sinclair from Harvard explaining his ideas on antiageing and his self experiment with those two

  • I doubt whether the pharmaceutical industry will need much persuading to regard natural aging as a disease that a person can take a pill to cure. It sounds like a terrific business model to me. It will generate oodles of profit from the start, not least because the pills won’t work, and will therefore demand more research and more new pills that won’t work either. And so on.

    Meanwhile, the lifestyle interventions that we can already do for ourselves – real food, good sleep, relaxation techniques, fresh air, such exercise as our MS permits of, etc – require no research ££Ms, require no regulatory approval and don’t make a penny of profit for anyone. The only people who benefit are the people who improve their quality of life all by themselves. If I were the pharmaceutical industry, I would sense the danger of this and start straining every sinew to have aging classed as a disease to be medicated – and fast! 🙂

  • Lifestyle, diet etc. is what I stand by with my ‘PPMS’, no one would persuade me to take the industrial fungicide DMF. There are many awful ways to age, I don’t need the side effects of crude drugs on top of a chronic condition. I just would like to read more of progress with EBV.

  • https://hms.harvard.edu/news/do-wellness-programs-work

    Seems as if attempts to promote general health and well being just ain’t that easy!
    A result of human nature or pill-popping, junk food generations?

    Gavin, as a fan of Wellness, I was sorry to read this article. I’d thought to reply to your post with an emphasis on the provision of posts offering guidance and advice of how to live well.

    Despite the contents of the link I’ve provided, it is true that psychologically you shouldn’t knock people down with the truth without building them back up again – facilitation of their resilience etc. Even RD Laing, maverick or genius as he was, would endorse this!

    Have you seen the movie ‘Mad to be Normal’ yet? Your use of quoting him again has reminded me that I want to see it.

  • Good grief! I ‘enjoyed’ a year on DMF. You have to eat a mix of carbs and fat in order to metabolism the horrid stuff. That’s a non keto meal twice a day, or else vomiting happens. You can’t do DMF and low carb. Just high fat / high carb fattening meals.
    This is medic advice? It’s rubbish. DMF also destroyed my white blood platelets. It’s a horrible treatment and unhelpful advice. You should know better.

    • Agreed – I used to do IF before DMF, but nowadays restricted to a large meals at extremes of the day to tolerate the rising schedule. The impact of the side effects are under-estimated….

      • Crumbs. I’m glad I hopped across from Avonex to Tysabri without having to wrestle with DMF – it sounds horrid. Particularly now I’m so happily settled in the LCHF way of doing things.

      • I find it interesting that you and Normanski and I are all keen on variations of the general low carb/keto/IF approach.

        I didn’t get the idea from my NHS medical advisors, and I doubt whether you did either. Isn’t that a pity? I wonder how long it will take for the dreadful, faulty decades-old low-fat high-carb dietary orthodoxy juggernaut to change course? Not just for people with MS, but for people in general.

        In the meantime, individuals who are tired of being sick and fat and insulin resistant are taking their nutrition and general health into their own hands. But we’re a small fraction of the population, alas.

  • I find intermittent fasting is good for my MS and it doesn’t have to be extreme. A simple version of Time Restricted Eating only requires no eating in the evening.

    • You can’t do IF on DMF. It’s very frustrating when something works well, like IF, to have to make oneself eat just to get the best from a DMT. I’m on Tysabri now. It hasn’t changed my life for the better, much, but as it’s nearly 20 years since diagnosis, there are limits to its wondrous powers.at least I can get back to controlling blood glucose again with IF.

  • “…
    But pleasures are like poppies spread,
    You seize the flower, its bloom is shed;
    Or like the snow falls in the river,
    A moment white—then melts for ever;
    Or like the borealis race,
    That flit ere you can point their place;
    Or like the rainbow’s lovely form
    Evanishing amid the storm.—
    Nae man can tether time or tide;
    …”
    Robert Burns

  • Fasting leads to migraines (for me)
    Low carb also leads to migraines
    Big blocks of carbs seem essential

    Any suggestions what to do?
    I could give up the low-carb/fasting idea
    Or just keep the triptan handy and go ahead
    Any other ideas?

    • You need to persist. Keto junkies tell me that you need to get past the keto-adaptation phase that takes about 2 weeks and then it transforms them.

  • Re “one of the most powerful predictors of progressive, or more correctly worsening, MS is ageing. ”

    What is the extent of worsening with age?
    How much does it vary among people?
    Have you seen any/many MS patients who are healthy for their age? (Compared with their contemporaries)

    • ‘Evolution never designed, and selected, the human brain and nervous system to function much past the age of 35.’
      I’m not a great fan of evolutionary biology which often leads to a depressing fatalism that seems to afflict many neuros (perhaps they have seen too much)… What happened to three score years and ten? Which, you might recall was the expected life span well before the age of modern medicine for those who survived infectious disease, famine and war. Nature never wastes anything that might come in useful one day and back in pre-history surely found use for grandparents to help raise new generations successfully before the professionals moved in. Well I hope so because I’ve used up my allotted span and living on borrowed time – but not yet a vegetable, Gavin!
      More seriously, I’m sure Gavin is right to push ‘brain health’ as an early intervention , it is not just for MSers but for everyone. It is already pretty clear that following a simple, healthy lifestyle has already reduced the prevalence of dementia at any given age more than any drug. And it may improve the connectivity of your brain. Given that progressive MS damages your brain it seems common sense to ‘prolong active life’ if you can. (Isn’t the downside of ageing – brain shrinking and progressive MS – a feature of grey matter and not white matter, so not touched by current DMTs?) So eat sensibly, sleep well, stay active physically, mentally and socially; keep learning and adapting as things change. Oh and don’t smoke, but the occasional drink might help! The elixir of life may appear one day in a pill, and no doubt there are drugs out there that will one day be shown to impact progression but those of us at this stage can’t afford to just do nothing.

  • A study with Metformin

    Metabolic interference protects against a mouse model of multiple sclerosis.

    Results: Mice receiving the combination therapy showed marked protection against EAE compared to controls, exhibiting statistically significant differences in mean score from days 15-40 (p<0.0001 two way ANOVA with Bonferroni correction), total mean score (2.4 vs. 0.48, p<0.00001, two tailed t-test), disability onset (Day 13.6 vs. Day 22.85, p<0.0005, two tailed t-test), and peak score of disease (3.65 vs. 1.35, p<0.005, two tailed t-test). Of note, 40% of animals in the treatment group did not show any clinical symptoms. Immunohistochemistry for markers of immune cell infiltration, reactive astrocytosis and demyelination are in progress, as well as flow cytometry to measure changes in the patterns of monocyte and T cell differentiation.
    Conclusions: A pharmacologic regimen blocking glycolysis and glutamine metabolism demonstrates strong protective effects against a mouse model of MS, supporting the translational potential of metabolic interference in MS and other CNS autoimmune diseases. Immunomodulatory mechanisms of these agents are currently under active investigation.

    http://indexsmart.mirasmart.com/AAN2019/PDFfiles/AAN2019-003858.pdf

  • “For the anti-ageing revolution to happen, and be adopted by society, we need to make ageing a disease.”

    Where have you been smokers are ostracized now and drinkers are soon to be in another generation.
    Fitness revolution been going for 2 or 3 decades.

    Unfortunately our problems are MS..ALZ..Parkinsons and no real treatments for any of them….not old age.

By Prof G

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