Is exercise druggable?

Exercise is the most underrated and under-utilised DMT. Why? 

Ever since I ditched football, or soccer as it is called in the Americas, as a skinny 13-year old for long-distance running I knew intuitively that there was something extraordinary about aerobic exercise. Running is not only mindfulness, but it makes you think clearer in general and lifts your mood. Long-distance running is a philosophy and it adds true meaning to life. For those of you who are exercise-junkies, you will know what I am talking about. For those of you who haven’t experienced the uplifting benefits of exercise, I would suggest reading Haruki Murakami’s book ‘What I Talk About When I Talk About Running’. Murakami is an extraordinary writer and brings a wonderful and mystical Japanese philosophical twist to the task at hand.

It is clear that running or exercise, in general, is one of the most underutilised treatments we have for multiple sclerosis and neurodegeneration in general. It is clear that exercise and diet have to be at the base of any brain health pyramid. As always there is biology that underpins the treatment effects of these simple lifestyle interventions. Most of us have assumed exercise works by simply stimulating growth factors and endorphins in the central nervous system. Growth factors are responsible for anti-ageing effects and endorphins for its mood-elevating effects and explain the runner’s high. However, the latest work just published in Science (see below) shows that the health benefits of exercise on ageing may be mediated by a hormone that is released from the liver. 

The circulating factor is glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (Gpld1), which increases after exercise and was shown to correlate with improved cognitive function in aged mice. Importantly blood levels of Gpld1 are increased in active healthy elderly humans. If this work is confirmed it means we may be able to hack exercise’s effects on this pathway and create a drug that you can take that will prevent you from ageing and if you have MS slow down your disease progression. Wouldn’t that be a remarkable innovation?

As always to create a viable market for anti-ageing drugs we need to classify ageing as a disease. This will create the incentive for Big Pharma to invest. If we don’t classify ageing as a disease antiageing medications will be confined to the consumer market, which makes it very difficult to study in diseases such as MS and get them licensed by the regulatory authorities as treatments for multiple sclerosis and other neurodegenerative diseases. If you interested in reading more on this issue please read my Medium post from three years ago where I make the case that ageing is a disease. 

Horowitz et al. Blood Factors Transfer Beneficial Effects of Exercise on Neurogenesis and Cognition to the Aged Brain. Science. 2020 Jul 10;369(6500):167-173. doi: 10.1126/science.aaw2622.

Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.

CoI: none in relation to this post

9 thoughts on “Is exercise druggable?”

  1. I remember a plastic surgery friend talking animatedly about a decreased incidence of myocardial infarction (heart attack) for a year after surgery, following procedures requiring a tourniquet (device that cuts off the circulation for the duration of surgery). I wonder if similar health benefits might be seen in the brain? He envisaged people going to the doctor for their annual tourniquet, but it must be mediated through a chemical(s) which pharma could make lots of money from. A really tight tourniquet would be very painful without an anaesthetic.

  2. Reading that reminded me of the joy I used to get from running every day in the 90’s. Unfortunately, many of us dx at that time had no access to DMTs & after my first major relapse, I totally lost the ability to run. It’s one of the things I miss most.

    1. I was diagnosed 2000 and no access then to DMTs. Only those that had been on trials or severe relapse. I exercised like you until I couldn’t.
      I’ve been doing Mr Motivator on YouTube. Seated. And joined his Zoom group on Saturdays. It’s so uplifting even if I can’t do it all and am seated. Never give up. 😊

  3. Prof G,

    I was a runner before I got MS (and a non-smoker, outdoor type), so not totally convinced by the exercise claim. Will exercise tackle the real MS?

    I exercise as much as I can, but we have to remember that MS is a progressive disease – it gets worse and worse over time. A spinal cord injury, perhaps caused in a crash, is much more likely to respond to physio / exercise as the injury is not getting continuously worse due to a biological disease.

    Diet stuff is helpful, exercise stuff is helpful, but I suspect will only mildly slow down the continuous worsening disability that comes with MS. I’m much more interested in whether the real MS is druggable.

    PS I like your twitter feed. There was a recent video about the MS Academy and thoughts on the EAN virtual conference. You were quite excited about the results of a Phase 2 drug trial which is going into Phase 3. Can I ask what drug trial this was? BTK?

    1. Likewise – I went to the gym about 4 times a week pre corona (now I do indoor rowing at home, running is not really an option anymore – not that I was ever a fan to begin with – and road cycling I am wary of). Probably kept me afloat to some degree before I was diagnosed (which took way too long) but the effect of ocrelizumab on brain fog vs exercise on brain fog is a night and day difference. IOW, it’s an addon to whatever heavy hitting approach you pursue.

      But yes, exercise is likely druggable to some degree – some consider our good friend metformin to be an exercise-mimetic (among other things) and resveratrol might very well be one, too. I think a lot of the somewhat outthere anti aging stuff is in that area as well. Sadly very little usable RCTs around, not even in healthy subjects…

  4. What if instead of thinking about drugs that mimic exercise, we would consider something like electric wave signalling, which would target the exact same areas of the brain/body that exercise affects? So instead of exercising, you would put a machine on that would stimulate the positive benefits?

  5. I’m so happy to see a Neuro staying this. On diagnosis 20 years ago I was advised to stop my exercise during winter to conserve my energy. I was fit, my symptoms were ON and terrible balance, and a weak arm. To me it made no sense. I was far fitter looking than the neurologist who was my age! So I continued with my running, yoga, gym, swimming and cycling. And the predicted 5 years to SPMS did not happen. It took about 14 years. I stopped running when walking became a challenge, stopped cycling when my balance was too bad I was falling of. And now, I do seated exercise everyday and will swim again one day. I’m glad I ignored him. It made no sense at all.
    We need to listen to our own bodies. I’m convinced it’s kept me relatively mobile despite needing wheels at times.

  6. Exercise is addictive but I can’t walk without a walking frame so it is not aerobic. My arms and shoulders are not affected by MS so I spend about 5 to 10 minutes every day punching with my arms, always feel better afterwards. I do go out for a 30 – 45 minute walk every day with my rollator Those two bits of exercise are a reason why I have not gone bonkers

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