Barts-MS rose-tinted-odometer ★★
You know something is happening when it gets its own review article in the New England Journal of Medicine. The review article in last weeks issue covers the science and medicine around intermittent fasting (IF) and its effects on health, ageing and disease. The article even includes a few lines on IF and its potential impact on MS.
In my ‘2020 Vision’ post yesterday under #ThinkMetabolic I glibly made the comment that ‘we are our metabolism and that MS is first and foremost a metabolic disease’. I truly believe this. Let me tell you why.
MS is a complex disease due to an interaction between the environment (macro- and micro-environment) and our genomes (DNA code, epigenome or DNA modifications, and our metagenome or microbiome). Studying each component in isolation is difficult. However, the complexity comes together in the metabolome or our metabolism, i.e. in how the body and its organ systems function on a day-to-day basis. Similarly, when we treat MS we modify our metabolism. So the way to integrate all influences on the body is to study our metabolism.
The question I pose is can we hack our metabolism in a way that will improve MS outcomes? I am sure we can and one way of doing this is through diet. There is mounting evidence that caloric restriction (CR), intermittent fasting (IF) and ketogenic diets (KD) does this, which is why if I had MS I would be exploring these as potential complementary treatment options.
Common to caloric restriction (CE), intermittent fasting (IF) and ketogenic diets (KD) is a metabolic switch that triggers anti-inflammatory, neuroprotective and antiageing mechanisms. The body responds to these diets by an adaptive stress response that leads to upregulation of antioxidant defences, DNA repair, protein quality control, mitochondrial biogenesis and autophagy, and down-regulation of inflammation. Animals maintained on intermittent-fasting regimens show improved function and resistance to a broad range of stressors.
Ketosis alters cell signalling mechanisms and increases the nuclear factor erythroid 2–related factor 2 (NRF2) transcription factors, which are part of the programmed cell survival pathway. Interestingly, this pathway is the one that dimethyl fumarate works via. In fact, many of the metabolic changes that are seen with ketosis are similar to that which are seen with DMF. Similarly, metformin the antiageing diabetes drug triggers a similar metabolic switch to ketosis. Could DMF and metformin be mimicking IF or ketosis? I say yes!
Similarly, IF and KD trigger antiageing mechanisms and potentially rejuvenate senescent cells. The recent observation that CR and metformin rejuvenate senescent oligodendrocyte precursor cells and augmented remyelination in older animals suggests that these mechanisms are inter-related.
There are several dietary trials in MS exploring IF and KD as a potential DMT. Some of the preliminary results are very interesting. I suspect interesting enough for many of you to have already adopted IF or ketosis as a treatment option. So if you are wanting to hack your metabolism you may want to read the NEJM review; figure 4 from the article gives some advice on how to incorporate IF patterns into your daily life.
If you have given CR, IF or KD a try please let us know how they make you feel. It is clear from our ‘Food Coma Survey‘ that many people with MS and food coma are already using dietary manipulation to manage their symptoms.
de Cabo & Mattson. Effects of Intermittent Fasting on Health, Aging, and Disease. N Engl J Med 2019; 381:2541-2551
Choi IY, Piccio L, Childress P, et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Rep 2016;15:2136-2146.
Dietary interventions have not been effective in the treatment of multiple sclerosis (MS). Here, we show that periodic 3-day cycles of a fasting mimicking diet (FMD) are effective in ameliorating demyelination and symptoms in a murine experimental autoimmune encephalomyelitis (EAE) model. The FMD reduced clinical severity in all mice and completely reversed symptoms in 20% of animals. These improvements were associated with increased corticosterone levels and regulatory T (Treg) cell numbers and reduced levels of pro-inflammatory cytokines, TH1 and TH17 cells, and antigen-presenting cells (APCs). Moreover, the FMD promoted oligodendrocyte precursor cell regeneration and remyelination in axons in both EAE and cuprizone MS models, supporting its effects on both suppression of autoimmunity and remyelination. We also report preliminary data suggesting that an FMD or a chronic ketogenic diet are safe, feasible, and potentially effective in the treatment of relapsing-remitting multiple sclerosis (RRMS) patients (NCT01538355).
Cignarella F, Cantoni C, Ghezzi L, et al. Intermittent fasting confers protection in CNS autoimmunity by altering the gut microbiota. Cell Metab 2018;27(6):1222.e6-1235.e6.
Multiple sclerosis (MS) is more common in western countries with diet being a potential contributing factor. Here we show that intermittent fasting (IF) ameliorated clinical course and pathology of the MS model, experimental autoimmune encephalomyelitis (EAE). IF led to increased gut bacteria richness, enrichment of the Lactobacillaceae, Bacteroidaceae, and Prevotellaceae families and enhanced antioxidative microbial metabolic pathways. IF altered T cells in the gut with a reduction of IL-17 producing T cells and an increase in regulatory T cells. Fecal microbiome transplantation from mice on IF ameliorated EAE in immunized recipient mice on a normal diet, suggesting that IF effects are at least partially mediated by the gut flora. In a pilot clinical trial in MS patients, intermittent energy restriction altered blood adipokines and the gut flora resembling protective changes observed in mice. In conclusion, IF has potent immunomodulatory effects that are at least partially mediated by the gut microbiome.
Fitzgerald KC, Vizthum D, Henry-Barron B, et al. Effect of intermittent vs. daily calorie restriction on changes in weight and patient-reported outcomes in people with multiple sclerosis. Mult Scler Relat Disord 2018;23:33-39.
An intermittent fasting or calorie restriction diet has favorable effects in the mouse forms of multiple sclerosis (MS) and may provide additional anti-inflammatory and neuroprotective advantages beyond benefits obtained from weight loss alone. We conducted a pilot randomized controlled feeding study in 36 people with MS to assess safety and feasibility of different types of calorie restriction (CR) diets and assess their effects on weight and patient reported outcomes in people with MS. Patients were randomized to receive 1 of 3 diets for 8 weeks: daily CR diet (22% daily reduction in energy needs), intermittent CR diet (75% reduction in energy needs, 2 days/week; 0% reduction, 5 days/week), or a weight-stable diet (0% reduction in energy needs, 7 days/week). Of the 36 patients enrolled, 31 (86%) completed the trial; no significant adverse events occurred. Participants randomized to CR diets lost a median 3.4 kg (interquartile range [IQR]: -2.4, -4.0). Changes in weight did not differ significantly by type of CR diet, although participants randomized to daily CR tended to have greater weight loss (daily CR: -3.6 kg [IQR: -3.0, -4.1] vs. intermittent CR: -3.0 kg [IQR: -1.95, -4.1]; P = 0.15). Adherence to study diets differed significantly between intermittent CR vs. daily CR, with lesser adherence observed for intermittent CR (P = 0.002). Randomization to either CR diet was associated with significant improvements in emotional well-being/depression scores relative to control, with an average 8-week increase of 1.69 points (95% CI: 0.72, 2.66). CR diets are a safe/feasible way to achieve weight loss in people with MS and may be associated with improved emotional health.
CoI: multiple
Wow!!!! Who would of thought Prof G would come out in favour of diet as a complementary treatment for MS? I suspect your colleagues will have something to say about this.
I would even go as far as saying diet should be a complementary treatment for life. The proposed benefits of diet apply to Brain Health in general. We have allowed the industrial-food complex to hijack our metabolism and it is now time to push back, apply evolutionary medicine principles, and take back control of our own metabolisms.
Very interesting. I followed the Wahls protocol and Overcoming Multiple Sclerosis protocol/ Swan diet for 2 to 3 years directly after my MS diagnosis (2012) next to Rebif. However this couldn’t prevent my MS turning aggressive resulting in major relapses (brain stem and spinal lesions) within 3 months and went from an EDSS of 1.5 directly to 7 and I didn’t recover from that despite of multiple high dosage infusions of steroids and switching to Tecfidera. Because of various contra indications I couldn’t take tysabri, fingolimod or lemtrada back in 2015. Ocrevus wasn’t available yet and off label treatment with rituximab wasn’t protocol in the Netherlands so I was out op options and I stayed like that for 8 months until I found out that I could acces HSCT in Uppsala Sweden for compassionate use. Dr Burman accepted to treat me as my MS was extremely active with high levels of NFL. Since then my ms is in remission and my edss improved to 5.5 / 6 which isn’t great but at least it’s stable. I would like to prevent ms from returning if that’s possible and therefore trying to implement diet and life style modifications. Interremitting fasting would be one of those, but since my experiences with Wahls , Swan and OMS weren’t great I do struggle with finding the best option. For now it’s mainly a vegan diet (with sometimes meat or fish) with also fasting. Hopefully this will aid in staying in remission or even prevent a new trigger since it’s unclear what actually causes MS.
Hi there, I have similar experience. Interferon > copaxone > failed fingolimod. In the meantime OMS / Swank and Whal’s (bullsh**). But my RRMS got aggressive and drove me to EDSS 7.0 during long lasting relapse. Had AHSCT in Poland 5 years ago and came back to EDSS 2.0 until I have relapsed last year. I have tried IF and 2/5 fasting as well.
To the point – I’m on DMT right now and wondering how to combine it with IF, while you should take it during/after your meal. Any ideas?
Would you classify yourself as an HSCT success or failure?
Hi. It was (well, still is) a big success! from very aggressive RRMS (relapse to relapse) to 4 years in remission and lowering down EDSS to very low level. Also, some liaisons in my brain has decreased significantly.
So far I had 2 mild relapses before I have started DMF. So now, trying to keep my health on current level.
If I understood correctly IF and DMF will work even better together? As mentioned by @Fernando Alonso – I should also cut out sugar from my diet (damn, I’m a sugar boy and I love sweets :)).
If these diets (may) work by the same pathways as DMF, wouldn’t it be wise to switch to another dtm (covering other pathways than dmf) and start IF? In such way you may get a combination of intervention which cover more pathways?
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.
Stay away from sugar
We next measured the production of IL-1β under low (0.5 mM) or high (10 mM) glucose concentrations and found that DMF was much less effective in the presence of high glucose (Fig. 3A), suggesting that its antiinflammatory effect can be overcome by driving glycolysis higher with saturating concentrations of glucose.
Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity
https://www.ncbi.nlm.nih.gov/pubmed/29599194
How would it work for people who don’t need to diet? Whilst interested in theory, I get properly grumpy if any meal is delayed! And since my MS is stable, I try and exercise as much as possible so I wouldn’t want to lose energy that allows me to do this. I’ve declared 2020 my year of Sport and have signed up for several events already – I find this my way of dealing with your less cheerful posts about long term effects 😉 do them now before I could lose the ability in the future….
It takes time to keto adapt; I discuss it in one of my Medium posts from 2 years ago. If you get past the initial few weeks it takes to adapt to IF or Keto you will be okay. I don’t recommend CR itself you can get the benefits from IF and KD. If you restrict calories too much you lose muscle mass.
I got awful migraines with every attempt to try keto or IF
I’ve found the info from Mark Mattson available on YouTube and online, very interesting and persuasive, especially as he’s now arguing the IF is beneficial to brain health and that it is ‘anti-ageing’ I was pleased too that he doesn’t think extreme fasting is necessary and says he usually eats within a five/six hour window.
I was already a sound weight, exercising and eating a reasonably healthy diet when I was diagnosed age 51 four years ago. Since learning of IF (assisted by this site and especially the links provided by Luis) I have adopted the 16/8 model. Working up to it slowly by pushing when I ate later and later in the morning worked for me. It wasn’t easy at first, so I decided not to chastise myself if I did have breakfast some mornings, instead to aim for this to be increasingly infrequent. I now routinely consume calories between 1pm-8pm. I’ve lost more weight as a result.
Having received Alemtuzumab in Nov 16/17 it’s not easy to state that the IF has made a key difference. For example I have less crippling fatigue, but this could be because of having NEDA. I do feel better for experiencing less sense of being stuffed or bloated and I don’t experience negative reactions to lack of food anymore – being angry/moody etc. Most importantly to me personally is the benefit of a positive perspective of myself – knowing I’m reducing inflammation, likely to be benefitting my brain health, that I’m now an optimum weight, etc, and all totally painlessly – food/eating doesn’t even cross my mind until at least 12.30pm anymore and some days I’ve gone through to around 4pm before I register I’ve not eaten anything. Even then it’s not a sense of starving hunger, but the trigger of thinking about producing the evening meal.
I’m very conscious of the ‘perfect storm’ you’ve highlighted ProfG of being a PwMS and ageing (56 last month) and I’m therefore hoping that the potential, of not guaranteed, benefits of IF contribute towards my well being as much as possible.
Interesting post. Thanks Dr. G.
Why do you think Biogen cancelled DMF trials in progressive patients? Also, is someone running trials in progressive patients with Metformin as a neuroprotectant and possibly for remyelination?
DMF in its RRMS trials showed a modest 38% reduction in disability progression, which is better than any other oral DMD, over a two year period in it’s DEFINE trial but not replicated in it’s CONFIRM trial.
Metformin and trials….watch this space can’t say more
+ clemastine & a DMT as suggested by Prof. Franklin?
Maybe and maybe other ideas, we will have to wait and see what gets funded and done
Thanks. I’ve done IF for about 4 years, which coincided with my CIS diagnosis. For the first 2 year I did 5:2, then shifted to time restricted (8 hour feeding window) which I’ve done for 2 years.
Practical issues are that the 5:2 style is incompatible with DMF/meds due to gastro AEs; it also doesn’t help B&B issues as gastro colic reflex is effected.
In terms of efficacy, I lost loads of weight and people tell me I look great, but I feel my ms is rubbish. My CIS converted to RMS, I started a DMF which I’ve been on a couple of years but it doesn’t seem to be working and I’ve spent most of Christmas in hospital after developing major bladders issues which I’ve been warned is probably just progression not inflammatory/short term. Not great in your early thirties.
So good for a boost if you want to feel healthier due to weight loss and may be useful in a marginal gains type setting, but it certainly hasn’t stopped the ms.
I’ve heard that more research on DMF shows that the Nrf2 pathway is rubbish as an explanation, but it seems the paper suggests IF works via Nrf2?
Interesting. I’m also in my early thirties. I too have been having Bladder issues and apparently since last week erectile dysfunction. I had a very stressful couple of month. I am on Aubagio and the doctor is reluctant to change it. My only hope that this is somehow reversible! In the absence of another relief I’m trying to starve my body out of it, most probably in vain.
Are you saying it is the ketosis and not the fasting that does it?
Yes, I think what is common to CR, IF and KD is ketosis. The metabolic switch is ketosis and you can do this with CR, IF or eating a very low carbohydrate, high-fat, high-protein diet ketogenic diet. You can also fool the body into making this switch by taking medication fumaric acid esters (DMF) and metformin are probably doing this to a greater or lesser extent.
What about other medicines?
Yes, many. We are in the process of preparing a grant application to study them in combination with DMF.
How can patients get access to Metformin?
Is it classed as an off-label for MS or is it just for Polycystic Ovary Syndrome?
BMI over 45 do it would you think? And high blood pressure?
If people have type 2 diabetes they may be treated with metformin. It must be possible to serch registries to see what the effect of metformin treatment is. Prof Coles has argued that they can’t get this data, I am not sure I buy this. I am sure the MS Register, NARCOMS or MSbase can be integrogated, as there will be loads of pwMS with type 2 diabetes and some will be treated by metformin. We have already done a study manuscript submitted.
However, this is going to be another problem of easy access treatment option. There are loads of people in US taking metformin as a “youth pill”
What’s your (or anyone else’s) thoughts on eliminating GLUTEN and other supposedly toxic or aggravating food types such as the nightshade family (potatoes, tomatoes), legumes and other foods containing lectins, grains, nuts and seeds, pasteurized dairy, GMO foods, non grass fed meat – I could go on but would think that’s enough for most people to think – what can I eat? The above list of no-no foods is stipulated by someone with a website who is supposedly now free of all her MS symptoms by eliminating those foods.
Very interesting. I will make a try in conjunction with DMF.
Prof G., about MS and biohacking, what do you think about the work of Pr. Charles Serhan (http://www.hms.harvard.edu/dms/bbs/fac/serhan.php) on specialized pro-resolving mediators (SPMs)?
I am not a specialist but I understand that these SPMs have been shown to reverse inflammation including neuroinflammation. Their precursors are the essential fatty acids, including the omega-3 fatty acids EPA and DHA, and arachidonic acid. So maybe we could take proactively omega-3 fatty acids? (and baby aspirin ?).
A good article here https://www.harvardmagazine.com/2019/05/inflammation-disease-diet
And a very interesting figure for another biohacking? (https://www.harvardmagazine.com/sites/default/files/inline_images/2019-MayJune/HM_Inflam_Chart.png)
Hi Anton. Are you going to try 8/16 with DMF? Ehh, I was doing 8/16 for few weeks before started DMF and I have lost few pounds, and it wasn’t my intention.
Hi Mike B. I was thinking about 5/2. The problem for me with daily IF is that the goal is 6/18 and it is way more difficult with my life style. The chance I have is that I have no flushing with DMF even when I eat verry little amount of food.
Such an interesting read, thank you for sharing! This one really touched home for me… I was significantly overweight and one day decided to start running (a lot) to lose the weight (nearly 15 years ago). I lost a lot of weight – fast – and that is when I first started feeling my first MS symptoms.
I have since meet SO many people with that same story – Overweight, lost a lot of weight and then experienced their first symptoms of what would later be diagnosed as MS. MS is considered to be environmental & genetic along with some trigger (EBV long suspected to be that trigger). Could it also be something in the metabolic cascade? Interesting stuff – Thank you for everything you do BartsMS!
As childhood and adolescent obesity is a risk factor for MS it may be something in the diet that causes MS, for example, sugar and other processed carbohydrates. I will do a blog post on this later.
I asked a similar question a few weeks ago: can a sudden increase in activity trigger MS? or uncover nascent MS?
Should at-risk people avoid such stresses?
I have done two cycles of 6 day calorie restriction similar to the fasting mimicing diet protocol of Prof Longo. During the 6 days I basically only drink peppermint tea, Hibiscus tea, soups and eat olives and I do not go beyond around 600-700 kcal per day. It is surprisingly easy to do specially if you are not big on carbs before starting. If you are then you may feel a bit sick the first two days but it is not a big deal. Generally what happens is that I feel a little week on this protocol but I feel great at the same time. Here is roughly what happened both times:
Sleep: First three/four days I slept much better than usual (even though I was going to bed hungry). After 5th day I started waking up early in the morning and 6th day I couldn’t fall sleep and decided to stop.
Symptoms of MS: It felt better than usual after second day, this includes L’hermits sign, tingling sensation in my hands and bladder issues. Improvements was little but tangible.
I feel so good on it that I would stay on this protocol if it wasn’t for fear of my BMI becoming too low. I usually lose 2kg each time and it takes some time to gain that back.
I think calorie restriction mimetics should be looked into for MS.
Hello! I am wondering does taking one pill of amitriptyline (25mg) before sleep breaks autophagy process? I am currently on 16:8 intermittent fasting and it is said in prescription that amitriptyline contains lactose and cornstarch.
I dont know