Should we all be taking metformin? As you know metformin is being tested in a remyelination therapy trial in MS; it rejuvenates senescent oligodendrocyte precursors making them more likely to make myelin.
The biology of metformin is fascinating as it also activates NRF2 the master transcription factor for programmed cell survival, which downregulates NFKappa-B the master pro-inflammatory transcription factor. I was surprised to find this paper below which shows the anti-ageing effects of metformin are not only limited to the brain but the thymus and the immune system as well.
Please note that ketogenic diets and fumarates (dimethyl fumarate and diroximel fumarate) also transactivate NRF2 and are potentially anti-ageing. It is a great pity Biogen pulled the plug on the DMF secondary progressive MS trial. I think we should revisit fumarates in progressive MS in combination with other potential agents that target mechanisms that drive smouldering MS.
The question I have is that in addition to a ketogenic diet should we all start taking metformin like so many other biohackers* are doing?
*Biohacking, also known as human augmentation or human enhancement, is do-it-yourself biology aimed at improving performance, health, and wellbeing through strategic interventions.
Epigenetic “clocks” can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans. Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age-related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (-2.5-year change compared to no treatment at the end of the study). The rate of epigenetic aging reversal relative to chronological age accelerated from -1.6 year/year from 0-9 month to -6.5 year/year from 9-12 month. The GrimAge predictor of human morbidity and mortality showed a 2-year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.
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.”
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.
I gave my first on using diet as a potential symptomatic and disease-modifying treatment for MS and as a preventative therapeutic strategy in MS, last night.
The symptomatic part of my talk was about food coma and using diet to prevent or reduce the impact of food coma. We are still studying why pwMS are so susceptible to food coma. I suspect it is because they have less cognitive reserve and food coma may interact with other medications to make it such a problem.
The really interesting part of my talk was using caloric restriction (CR), intermittent fasting (IF) or ketogenic (K) diet as a DMT. I suspect the mode of action of all these diets is via ketosis and inducing high levels of circulating β-hydroxybutyrate one of the ketone bodies. Ketone bodies are the source of energy the body uses when we have depleted our sugar stores (glycogen) and are fasting or not absorbing sugar from the gut.
Interestingly, β-hydroxybutyrate works via the hydroxycarboxylic acid receptor 2 (HCA2), which is also known as niacin receptor 1 (NIACR1) and GPR109A. Why is this so important? This is the same receptor that fumaric acid works on. Yes, ketosis works at a cellular level in the same way that dimethyl fumarate (DMF) and diroximel fumarate work, i.e licensed MS DMTs.
Yes, CR/IF/K diet may induce a metabolic pathway that is known to be disease-modifying in MS.
There is an extensive literature, which I discovered about two years ago, showing that β-hydroxybutyrate works via NRF2 and downregulates NFKappa-B, the master inflammatory transcription factor. In other words ketosis, in particular β-hydroxybutyrate promotes programmed cell survival via the NRF2 two pathway and is also anti-inflammatory. β-hydroxybutyrate may even be better than the fumarates as a treatment for MS because it is likely to penetrate the CNS better than oral fumarates.
The corollary of the above could also explain why a processed and ultra-processed high carbohydrate diet is pro-inflammatory. Most people put it down to the pro-inflammatory signals from adipose tissue, but it could be related to the fact that carbohydrates, via insulin, inhibit ketosis and suppress β-hydroxybutyrate levels in the body.
Another nugget of information I found is that metformin also works via NRF2, but not via the HCA2 receptor. This may explain why metformin promotes rejuvenation of oligodendrocyte precursors and is being explored as a potential remyelination therapy in MS.
I have also discovered whilst reading the NRF2 literature that some statins, including simvastatin, activate NRF2. Could this be a potential mode of action of simvastatin in MS?
I didn’t have time to discuss MS prevention last night. However, we think that about 10-20% of the increase in MS incidence may be caused by childhood and adolescent obesity. This is why we are pushing for policy on sugar and a national campaign to tackle this problem.
So when I say I have declared war on sugar, I mean it in more ways than you realise.
Despite observational evidence showing that pwMS do well on CR/IF/K diets, the studies show that they are generally safe. However, we need controlled evidence before promoting these pwMS as a potential adjunctive treatment for MS. The good news is that there are ongoing studies looking into this. The one below is actually using MRI to see if a ketogenic diet has an impact on MRI activity, i.e. the inflammatory component of MS.
Are you up for biohacking your metabolism as a treatment for your MS?
Background: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system in young adults that may lead to progressive disability. Since pharmacological treatments may have substantial side effects, there is a need for complementary treatment options such as specific dietary approaches. Ketone bodies that are produced during fasting diets (FDs) and ketogenic diets (KDs) are an alternative and presumably more efficient energy source for the brain. Studies on mice with experimental autoimmune encephalomyelitis showed beneficial effects of KDs and FDs on disease progression, disability, cognition and inflammatory markers. However, clinical evidence on these diets is scarce. In the clinical study protocol presented here, we investigate whether a KD and a FD are superior to a standard diet (SD) in terms of therapeutic effects and disease progression.
Methods: This study is a single-center, randomized, controlled, parallel-group study. One hundred and eleven patients with relapsing-remitting MS with current disease activity and stable immunomodulatory therapy or no disease-modifying therapy will be randomized to one of three 18-month dietary interventions: a KD with a restricted carbohydrate intake of 20-40 g/day; a FD with a 7-day fast every 6 months and 14-h daily intermittent fasting in between; and a fat-modified SD as recommended by the German Nutrition Society. The primary outcome measure is the number of new T2-weighted MRI lesions after 18 months. Secondary endpoints are safety, changes in relapse rate, disability progression, fatigue, depression, cognition, quality of life, changes of gut microbiome as well as markers of inflammation, oxidative stress and autophagy. Safety and feasibility will also be assessed.
Discussion: Preclinical data suggest that a KD and a FD may modulate immunity, reduce disease severity and promote remyelination in the mouse model of MS. However, clinical evidence is lacking. This study is the first clinical study investigating the effects of a KD and a FD on disease progression of MS.
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.
Your metabolism is a great integrator.
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.
Figure 4. Incorporation of Intermittent-Fasting Patterns into Health Care Practice and Lifestyles. As a component of medical school training in disease prevention, students could learn the basics of how intermittent fasting affects metabolism and how cells and organs respond adaptively to intermittent fasting, the major indications for intermittent fasting (obesity, diabetes, cardiovascular disease, and cancers), and how to implement intermittent-fasting prescriptions to maximize long-term benefits. Physicians can incorporate intermittent-fasting prescriptions for early intervention in patients with a range of chronic conditions or at risk for such conditions, particularly those conditions associated with overeating and a sedentary lifestyle. One can envision inpatient and outpatient facilities staffed by experts in diet, nutrition, exercise, and psychology that will help patients make the transition to sustainable intermittent-fasting and exercise regimens (covered by basic health insurance policies). As an example of a specific prescription, the patient could choose either a daily time-restricted feeding regimen (an 18-hour fasting period and a 6-hour eating period) or the 5:2 intermittent-fasting regimen (fasting [i.e., an intake of 500 calories] 2 days per week), with a 4-month transition period to accomplish the goal. To facilitate adherence to the prescription, the physician’s staff should be in frequent contact with the patient during the 4-month period and should closely monitor the patient’s body weight and glucose and ketone levels (from NEJM).
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.
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).
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.
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.
