What has my age got to do with having MS?

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Barts-MS rose-tinted-odometer: ★★★ (some readers have asked for this feature to stay)

How old are you? It depends. You may be aware that there can be a disconnect between your chronological or actual age and your biological age. As ageing or senescence is a biological process driven by metabolic, genomic and environmental factors you can see how there can be a disconnect between the two. As a result, many of us in medicine are beginning to think about unhealthy or accelerated ageing as a disease process. Making ageing a disease will create incentives for pharmaceutical and nutraceutical companies to invest in ageing R&D with the hope of producing medications or dietary supplements to slow-down or reverse the effects of ageing. 

Ageing is important in MS as there is emerging evidence that MS causes premature ageing of the CNS (central nervous system), which means that pwMS are more likely to experience age-related neurodegeneration sooner than they have to and this almost certainly contributes to delayed disability worsening in pwMS. 

It is clear that ageing impacts one’s ability to recover from CNS damage. It has been known for some time from clinical and animal studies that remyelination and neuronal plasticity are less efficient as you get older, which is why older pwMS recover from relapses less well than younger people. The animal studies below show that there is real biology behind these observations. Oligodendrocyte (myelin-producing) progenitor cells (OPCs) isolated from the brains of neonate, young and aged female rats show an approximately 50% difference in the levels of proteins they make. Differences were noted in both myelin-associated proteins and proteins that control several metabolic pathways. This study has clinical implications and can act as a read-out for finding drugs that could be used as anti-ageing agents. 

There are several interesting biological targets and drugs that already exist for targeting ageing. Metformin, a drug for treating diabetes, is one of the lead compounds going in an MS clinical trial at the moment. It is believed that its antiageing effects of performing are mediated via the so-called NRF2 or programmed cell survival pathway. Interestingly, fumarates (e.g. dimethyl fumarate) and ketogenesis also activate this pathway. Could DMF, and the other fumarates, be the panacea antiageing drug we need for tackling progressive or more advanced MS? Yes, I think so but to convince Biogen to follow the money is proving more difficult than we anticipated. We approached them recently to do a combination DMF-plus trial with another class of drug to augment DMF’s response and they said no. Pity because I think they are missing a trick and an opportunity to create new intellectual property.

Physiological ketosis from caloric restriction, intermittent fasting or low-carbohydrate diets is another way of activating the NRF2 pathway. The biology behind this is probably via β-hydroxybutyrate, a ketone body, which works via the hydroxycarboxylic acid receptor 2 (HCA2). Interestingly, this is the same receptor DMF activates.

Other anti-ageing treatments and strategies include exercise and avoiding getting comorbidities, which accelerate ageing, in particular, the metabolic syndrome (obesity, hypertension, glucose intolerance or diabetes) and smoking. The driver of the metabolic syndrome seems to be hyperinsulinaemia and the diets referred to above are all very effective in suppressing or reducing circulating insulin levels. 

So in 2021 if you have MS you need to think seriously about what you can do to tackle early and accelerated ageing. Most of the things you can do now involve lifestyle changes, which are often hard to implement. My advice would be to implement the changes slowly and you may find over time that the behavioural changes you make will stick. There is a lot of evidence for this from the field of behavioural psychology.

The above advice is part of the holistic approach to the management of MS I have been pushing for several years and my adoption of the ‘marginal gains philosophy’ for managing MS. 

“If we break down everything we can think of that goes into improving MS outcomes, and then improving each by 1%, we will get a large improvement in MS outcome when we put them all together.”

“Ask not what your neurologist and HCP can do for you, but what you can do yourself to optimise your own MS management and long-term MS outcome.”

de la Fuente et al. Changes in the Oligodendrocyte Progenitor Cell Proteome with Ageing. Mol Cell Proteomics. 2020 Aug;19(8):1281-1302.

Following central nervous system (CNS) demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. Although remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis of OPCs freshly isolated from the brains of neonate, young and aged female rats. Approximately 50% of the proteins are expressed at different levels in OPCs from neonates compared with their adult counterparts. The amount of myelin-associated proteins, and proteins associated with oxidative phosphorylation, inflammatory responses and actin cytoskeletal organization increased with age, whereas cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC proteome, revealing the distinct features of OPCs at different ages. These studies provide new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases.

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

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.

32 comments

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  • Hi ProfG,

    Your comment about the fumarates is interesting (I’m a fan of dimethyl fumarate as it’s the DMT where I regained function I had previously lost – in my case cognitive).

    The current trial on metformin is, I believe, in combination with clemastine fumarate. Obviously they’re thinking the active ingredient involved would be the clemastine. But could it actually be the fumarate?

    Anyway, hopefully the conjunction of the two gives the results all us pwMS are desperate to see – an effective (and cheap) treatment to help us start to restore our battered `CNSes.

  • Meh. “Ask not what your neurologist can do for you” implies that lifestyle changes can do more for you than DMTs.

    I agree with the intended message and sentiment, but phrasing it like this is dangerous.

    • I am not sure what you mean by dangerous. What I am trying to say is that HCPs can only do so much to optimise MS outcomes, a lot of what needs to be done has to done by pwMS themselves.

      I think pwMS need to be proactive and not passive recipients of healthcare.

      For example, when I found out that I had hypertension I sorted it out myself with diet, exercise and other lifestyle modifications and avoided the follow-up consultation with my GP for antihypertensive medications. Pills are one potential solution to managing or preventing comorbidities.

      • I understand what you’re saying. I’m just worried that someone else might read it as ‘skip the medication, nutrition and exercise are more important to control MS’.

      • Prof G thanks for this. I try to advocate for myself all the time. On the rare occasions I see my neuro team (maybe once a year, recently was by phone) I have brought up Metformin and clemastine to them and I’m fobbed off, My gois not an expert in MS, so I don’t think it fair to ask them about Metformin and clemastine, but I may have to as the neuro team ignore my questions or I get “don’t worry about that”. Well I do worry, I have lost loads of weight, I want to stay mobile and functional for as long as possible. So why not start these two drugs? Their side effects are manageable, compared to being wheelchair bound and relying on car. Right? I really don’t want to bother my gp during covid, but this is my life and I have to do all to protect it. A friends father had progressive ms and passed early and she said if she could write the prescription herself for me she would as she would hate to see what happened her dad. She meant it from a good place not to scare me, but basically she was saying fight for it. I fight for my life every day and now I have to become a doctor too 😞

  • Im 29 physicaly active every day untill this started, eat well yet i had an attack that got me diagnosed last year and just keep getting worse my neuro said i have no signs of accelerated bvl and no black holes yet i have had three enhancing lesions noted on three seperate mri’s its now been 8 months since my symptoms started and i have just started tysabri. will i ever feel better ? If your going by age and health i should have recovered very well but i just keep getting new symptom after new symptom and weaker and weaker. At this point the better question would be what symptoms i dont have. I had never had any symptoms before my initial attack so i dont understand your telling me i should recover well but i havent really recovered at all

    • Re: ” you telling me I should recover well but I haven’t really recovered at all”

      I am referring to average effects. Please note that about 5% of pwMS on natalizumab develop neutralising antibodies (NABs) to natalizumab that stop the drug working. In my experience, ongoing disease activity on natalizumab is one indicator of NABs the other is infusion reactions.

      I am also discussing average effects, which don’t necessarily apply to individuals.

      • i have been like this for 8 months now and have only just started natalizumab i have had three lots of steroids for other flare ups of symptoms that seem to have settled but not gone away. hopefully my age, diet general health and the dmt will help me get some normality back like you say it should.

  • I had a suprapubic catheter operation and it has been disastrous. My MS has been crazy, all symptoms in overdrive. I cannot get back to my baseline. It has ruined my life.

    Surgery is ruinous to multiple sclerosis.

    • Yes and no. If you need surgery you should have it, but if you can avoid you should try. People with advanced MS handle anaesthesia very poorly and some simply don’t get back to baseline after a general anaesthetic. This observation is not unique to MS and is well described with other neurodegenerative diseases.

  • With ageing, once you get to a point, is there a place of no return? It’s somewhat obvious that the process of ageing can be slowed, and in some cases even halted. But is there a point past which it is impossible to reverse? I think it would be good for pwMS to understand whether they stand a chance to regain lost ability, improve their present status, or at least halt further progression. I think it would provide much needed relief from anxiety,

    • Re: “I think it would be good for pwMS to understand whether they stand a chance to regain lost ability, improve their present status, or at least halt further progression.”

      Dare I say the ‘Holy Grail’ of MS?

  • Hello ProfG, I am one of those who like the odometer so happy you keep it.
    A question regarding insulin. What for you is considered high level? What do you think of short transients of very high insulin levels?

    I have healthy friends on metformin because they have high levels after they have meals. On my side I have a weird situation where my insulin level raises above normal levels ie I have a peak 30′ after glucose intake and that peak is 5-10 folds higher than the average peak for people having glucose tolerance test. The glucose level in the blood reaches the lower limit of normal 60′ later but it does not clearly fall below it. I repeated the test twice with same results: the curves are normal in shape (increase from 0, peak at 30′ decrease at 60′ then flat to 180′) but the insulin peak is too high. I did not sweat not felt cold, anything, just got bored. Tests were done every 30 minutes for 3 hours so 7 points glucose/insulin curves. So, what I got at the end of this story is “your curve is strange” on top of a normal blood glucose level in the morning. Is there anything you would advice to understand what’s going on and if I need to take metformin?
    Thank you for you time and advices.

    • To the best of my knowledge, insulin-glucose response curves have not been studied in detail in response to MS outcomes. I suggest you discuss these results with a metabolic doctor. If you want to keep your insulin levels low you will need to cut carbohydrates out of your diet; the good news is that carbohydrates are the only macro-nutrients that are non-essential and that you live healthily on a low carbohydrate diet.

      • I will seek advice from a metabolic doctor a different one maybe. Does cut means total cut in your view? Or more something like “source maximum 10% of daily calories from carbs and the rest from proteins and fats”?

        Also I am a bit concerned from this type of diet because if I decrease carbs I have to increase fats and proteins. Mammalian meat proteins, as an alternative source of calories, have a high content of N-glycolylneuraminic acid (a sialic acid) that is not present in humans (we lack the functional gene copy to make it, CMAH). It is a known immunogen (under control in biotech drugs) and it is thought to play a role in chronic inflammation and tumours. Also, in animals (also mammals), it seems to be absent from CNS in animals. By the way, the monkeys that lack the gene develop a sort of MS. To me all of this (even if still at level of coincidence) sounds very suspicious: why did nature evolve this exclusion? If the incorporation in the CNS triggers neurologic diseases and you are an animal you become an easy prey. So, negative selection would be very effective in this context while in humans it may be altered by our behaviour as social animals that care for each other. If one eats Neu5gc then it could get incorporated in the CNS where it could become a target for autoimmunity as CNS proteins are very sialylated and usually sialic acids are exposed outside the protein surface to the cellular and intercellular medium. Therefore, mammalian meat becomes not so appealing as a source of energy. Birds are free of NGNA so chicken would be fine from this point of view (there are hormones antibiotics but this is another story). There is little literature for fish and sea animals on this but they seem fine as well. So, food sources would become more restricted without carbs and mammalian meat. I add a few papers below on the topic if it can be of interest. There are some known people in the MS field among the authors…
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024026/
        https://nn.neurology.org/content/7/2/e676
        https://pubmed.ncbi.nlm.nih.gov/26540733/
        https://pubmed.ncbi.nlm.nih.gov/23471785/

        • I am not sure about this. Man evolved as an omnivore and will have gotten a lot of calories from animal meat and fat. The terms perseverance hunter, bone-cracker man and pastoralists come to mind when describing our ancestors. I think human metabolism is well adapted to eating animal protein.

          • Good point and thank you for ansewering. I agree on your view. I am not concerned for the metabolic fitness of meat as it is probably the food that made humans develop big brains and it also tastes great. I am more concerned for side effects due to incorporation of a xeno sugar in human proteins. In some people tick bites trigger allergy to meat due to exposure to this sugar in ticks saliva… So it can have an impact on immune system 🙂 somebody to look for this sugar in MS brains?

  • Setting aside demyelination and assuming that the brain atrophy is the key driver for the accumulation of disabilities, how are the higher efficacy drugs returning functionality in some cases?

    • We presume spontaneous recovery although there is some weak evidence that some therapies such as alemtuzumab increase growth factors that promote recovery of function.

  • As a desperate person diagnosed with ppms at EDSS of 4 it is very easy to make lifestyle changes. I will to whatever it takes to keep walking. I have a daughter of 4 and she is my secret source of power. I am in the diet game since june of 2019: Swank, Walhs and now 2 months strict keto. At age 37 my NFL dropped from 6.8 to 4.4 over the course of 4 months. I hope it has something to do with diet as my ocrelizumab was being delayed ( let me dream)
    I have some questions:

    -Would pwms benefit from metabolic switching? Like making the G switch once every month or even week? Or is staying in ketosis all year around better?

    -What are your thoughts about that not only what, but also when you eat matters? There is a lot about it on the internet. It has my interest as i got sick after working in shifts for 18 years. Now I try to keep as regular a life as possible. But is there a point in fine tuning?

    BTW this Webinar from Annie Curtis about the topic really amazed me (the small parts that i understand of course) https://www.youtube.com/watch?v=nHsIqVa1zd4&list=LL&index=13&t=1383s

    The time you vaccinate people with the flu shot matters.
    The severity of EAE is dependent on time of day of immunisation

    Greetings,

    Paul

    • Re: “Would pwms benefit from metabolic switching? Like making the G switch once every month or even week? Or is staying in ketosis all year around better?”

      Sadly we don’t have an evidence base in MS, but some small exploratory trials are happening. I think from animal and human ageing studies intermittent ketosis seems to do the trick. I think staying ketotic continuously is simply not sustainable as a diet. Don’t forget there is more to a diet that simply eating calories. For more information on this read my Medium post on diet as a philosophy.

      https://gavingiovannoni.medium.com/diet-as-a-philosophy-a9f7759db4d2

  • Thank you for this very informative post. Since being diagnosed I have been looking for ways to help myself (and therefore feel less helpless in the face of an unpredictable desease). Most information regarding carbohydrate restriction and intermittent fasting seems to revolve around T2 diabetes so to read the reasons why ketogenesis may be beneficial for those with MS is incredibly helpful. Thank you again, I read all posts on this blog avidly even though many of them go over my head!

  • Do you have any suggestions for how to avoid switch to intermitent fasting and/or a low-carb diet without triggering migraines?

    • Try building up the time between meals slowly; i.e. extending the fasting time. Interestingly, some migraineurs report improvement in their headaches when they go keto, which is not surprising as ketosis is anticonvulsant and is used to treat epilepsy. Many anticonvulsants work by reducing the frequency of migraine attacks.

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