Exercise
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I see optimized mitochondria function as the key to health (1).
When I discuss our work in metabolic neurology, I emphasize the absolute importance of dietary lifestyle over any other component of health, including exercise. I do this for a very logical reason - in terms of the modern lifestyle, nothing has changed as much as dietary lifestyle has over the last 50ish years. There are two main changes. First, the introduction of extra meals and snacks throughout the day, such that the average person now eats 5-6 times a day (1). Essentially, a loss of fasting. Second, the introduction of excess processed carbohydrates into the diet, such that the average person now eats about 10% less fat than they did in the 1970s, which has been replaced by processed carbohydrates (2). Essentially, a loss of fat. These changes in modern dietary lifestyle represent the strongest correlate of the rise of the lifestyle disorders over the past 50ish years, the most dominant of which are atherosclerosis, cancer, neurodegenerative disorders, and the metabolic syndrome (1).
Compared with our 2-3 million years of existence in the hunter-gatherer lifestyle, or even that in the last 50 years, nothing has changed as much as dietary lifestyle, the main driving force behind mitochondria dysfunction.
However, an unhealthy exercise lifestyle is also a barrier - not just too little, but also too much. If we take the more extreme case of ultra-athletes (who are mostly runners), these people often have problems occurring throughout their body both during and for several hours or days after any event, which include pathological changes in the heart, skeletal muscles, kidneys, and immune and endocrine system (4). Moreover, 50-60% of these athletes are plagued by musculoskeletal problems after the event, and a number of them have upper respiratory tract infections, digestive problems, and gastrointestinal bleeding after the event (4). However, these are not the main health problems experienced by ultra-athletes.
The real problems ultra-athletes face are their long-term health concerns, defined as those lasting 1 year or longer to the point they require ongoing medical attention, or limit activities of daily living, or both (5). These long-term problems occur in multiple body systems - cardiovascular, respiratory, musculoskeletal, renal, immunological, gastrointestinal, and even neurological (5). The most pronounced abnormalities occur in the heart, notably right ventricle enlargement and potential scarring leading to right ventricule dysfunction and arrhythmias, the kidneys, including a potentially accelerated progression of chronic kidney disease, and the musculoskeletal system, which includes accelerated hip and knee osteoarthritis, as well as tendon injuries. |
This is atherosclerosis, also commonly known as "hardening" of the arteries (6). |
Arguably, the most concerning effects of exercise in athletes are shown by multiple studies that collectively demonstrate competitive endurance athletes (not necessarily ultra-athletes, and again mostly runners) have more coronary artery calcification compared with recreational athletes (7) and even sedentary non-athletes (8). Higher coronary artery calcification is a problem, as this indicates the presence of atherosclerosis, or "hardening" of the arteries, which leads to nearly all heart attacks and a large number of strokes and is thus the most common cause of death in the west today. Moreover, a very recent study recently showed that athletes who exercise at a "vigorous" or "very vigorous" intensity actually show a progression of their atherosclerosis (9).
What does this mean? Should we exercise at all? If we should, how should it be done?
Measuring Metabolic Output
Before exploring the ideal exercise regimen for health, we need to discuss and define the concept of Metabolic Equivalents of Task (METs), as this is how most studies measure exercise output. For ease of conceptualization, a MET may be defined as the ratio of the rate at which a person burns energy while performing some specific physical activity compared with the rate at which they burn energy when sitting quietly (10). For an even easier conceptualization, a MET is simply the metabolic cost of a physical activity. There exists a compendium of physical activities that shows the MET scores for various activities (I have referenced an older but freely available version below) (11).
Using METs, physical activities can be classified by intensity. Light intensity activities are those that require <3 METs and include things like working at a desk, walking slowly, and fishing. Moderate intensity activities cost 3 to 6 METs and include things like yoga, walking quickly, and sweeping a floor. Vigorous intensity activities cost 6 to 9 METs and include things like basketball, slow running, and carrying groceries upstairs. Very vigorous intensity activities are those that demand >9 METs and include things like skipping, fast running, and active scuba diving (as opposed to just floating in one spot).
METs allow all physical activity to be standardized and compared, but there are major limitations to their use. First, the METs for each activity described above are those that were determined from a 40-year-old man weighing 70 kg, so for anyone who is not that, the numbers may somewhat differ. Second, there are also inherent problems in defining what is light, moderate, vigorous, or very vigorous activity from one person to the next - what one person thinks is vigorous may differ from what another thinks is vigorous, and each will therefore think they are burning the same number of METs when they are not. But the third and most problematic issue of the METs concept is that it simply looks at one parameter, that of energy output, or calorie-burning, without considering the real benefits of exercise, which relate to fitness and include improved strength, speed, and endurance. |
Classification of Metabolic Equivalents of Task (METs). |
More importantly than any of these things, of course, is that METs do not measure the potentially beneficial effects of a physical activity on mitochondria function, the key to health.
Exercise - Healthy, Or Not?
There is no debate that at least some exercise is much better than none, but exercise can be taken too far, and that is where we have a problem. Let us more closely examine the three papers above that looked at coronary artery calcificaton scores. The first (7) showed worsened atherosclerosis in athletes exercising over 33.3 MET hours per week, which equated to 3-6 hours of vigorous or very vigorous exercise per week. The second (8) showed worsened atherosclerosis in athletes who undertook 7-8 hours per week of running or cycling. The third (9) showed actual progression of atherosclerosis in athletes who averaged 41.5 MET hours per week, which equated to 4-5 hours of vigorous or very vigorous exercise per week. Summing up these studies, 3-8 hours of vigorous exercise per week is associated with worsened atherosclerosis. Importantly, this does not necessarily mean the exercise contributed to the atherosclerosis - for example, these athletes might also have consumed tons of carbohydrates from pasta meals and energy drinks, which would also contribute to atherosclerosis. But I have to admit, given the lack of alternative explanations in these particular cases, it's suggestive.
Grading atherosclerotic plaques - the far right image shows a highly calcified plaque (12).
From a mitochondria-centric perspective of health, the above findings are not surprising - the concept of 3-8 hours of vigorous exercise per week inducing damage to the mitochondria in the arteries, followed by electron overflow, NADH excess, reactive oxygen species galore, and inflammation and a host of other metabolic abnormalities culminating in atherosclerosis, is in fact central to the theory (1). So should these athletes be exercising like this? The answer might seem to be a clear "no," however this is not so clear, for it all depends on a person's goals. If a person wants to be fit, so as to be stronger or run faster or further etc compared with over 99.9% of the population to win competitions, then this amount of exercise may be necessary and nobody can argue against a person doing that if fitness is their goal. Everyone makes their choice. But, if the goal is health, then 3 or more hours of vigorous or very vigorous exercise per week is simply unhealthy. This might seem counter-intuitive, but that doesn't make it less true.
Ideal Dietary And Exercise Lifestyles
A shared misconception between dietary and exercise lifestyles is that it is the "diet" or the "exercise" that lead to the greatest positive impacts on health, but this too is untrue - in fact, it is the periods between them (fasting periods in the case of diet, resting periods in the case of exercise) that matter more. In order of importance, dietary lifestyle can be broken down into frequency, duration, composition, and calorie intake (yes, calorie intake is the least important variable). Similarly, exercise lifestyle can be broken down into frequency, duration, composition, and calorie output, also in that order (yes, I think burning calories is the least important aspect). In both, it is the first two categories, which relate to timing, that are the most important. Rather than talking about "what is the best diet?" or "what is the best exercise?" we need to crucially address "how often and for how long should I fast" and "how often and for how long should I exercise?"
Logically, from a mitochondria, health-centric perspective, the ideal dietary lifestyle involves meals that are infrequent, low duration, low-carbohydrate or ketogenic, and non-restricted. In terms of frequency, this means intermittent fasting - for example, 1-2 meals a day rather than 5-6 meals. In terms of duration, this means restricting the eating window - for example, 1 hour per meal. In terms of composition, this means eating high-fat low-carbohydrate or ketogenic (high-carbohydrate, low-fat can also be ok if done properly, but for reasons of mitochondria health I will not go into here, I favour the former for most people in the world at this moment). Finally, in terms of restriction, this means a high calorie intake (80-90% of the maximum a person can eat in any meal), or eating to satiation (but not "over-eating" to 100% capacity, that's too much).
Likewise, from a mitochondria, health-centric perspective, the ideal exercise lifestyle involves workouts that are infrequent, low duration, a mix of resistance, biometric, or isometric, and high-intensity. In terms of frequency, this means 1-3 sessions per week involving vigorous or very vigorous (>6 METs) activity, no more. In terms of duration, this means a maximum 30 minutes per week of vigorous or very vigorous activity, no more (although this could be taken as high as 60 minutes per week in younger and more active people). In terms of composition, this means a mix of resistance, biometric (body-weight only), and isometric (no-movement) exercises, which emphasize muscle damage and growth while sparing most of the rest of the body from the damaging effects of exercise (skeletal muscles and the heart are good at repairing, other structures not so much). Finally, in terms of intensity, this means a high calorie output (80-90% of the maximum a person can generate), or getting the heart-rate within spitting range of its absolute maximum, as opposed to taking it to 100%, which is actually really hard to do unless it is a life-or-death situation.
To wrap this up, if your goal is to exercise for fitness, particularly to win a competition or some other similar endeavour, then that's a different story - exercise away, for as long as you need to. But understand there may well be a long-term price on health, which will eventually be paid.
By contrast, if it is health you seek, the optimal exercise lifestyle involves infrequent, short, muscle-damaging, high-intensity workouts, followed by lengthy rest periods. These can be done at any age or ability, as long as they are graded for age and ability.
When it comes to health, less truly is more - to a point, of course.
Solace.
References
(1) Phillips MCL. Metabolic Strategies in Healthcare: A New Era. Aging Dis 2022. https://pubmed.ncbi.nlm.nih.gov/35656107/.
(2) Kant AK. Eating Patterns of US Adults: Meals, Snacks, and Time of Eating. Physiol Behav 2018. https://pubmed.ncbi.nlm.nih.gov/29574043/.
(3) Ludwig DS. Dietary fat: From Foe to Friend? Science 2018..https://pubmed.ncbi.nlm.nih.gov/30442800/.
(4) Knechtle B and Nikolaidis PT. Physiology and Pathophysiology in Ultra-MArathon Running. Front Physiol 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992463/.
(5) Scheer V et al. Potential Long-Term Health Problems Associated with Ultra-Endurance Running: A Narrative Review. Sports Med 2022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450723/.
(6) University of Michigan website. https://medicine.umich.edu/dept/cardiac-surgery/patient-information/adult-cardiac-surgery/adult-conditions-treatments/coronary-artery-disease-cad.
(7) Aengevaeren V ert al. Relationship Between Lifelong Exercise Volume and Coronary Atherosclerosis in Athletes. Circulation 2017. https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.117.027834.
(8) Merghani A et al. Prevalence of Subclinical Coronary Artery Disease in Masters Endurance Athletes With a Low Atherosclerotic Risk Profile. Circulation 2017. https://pubmed.ncbi.nlm.nih.gov/28465287/.
(9) Aengevaeren V et al. Exercise Volume Versus Intensity and the Progression of Coronary Atherosclerosis in Middle-Aged and Older Athletes: Findings From the MARC-2 Study. Circulation 2023. https://pubmed.ncbi.nlm.nih.gov/36597865/.
(10) https://en.wikipedia.org/wiki/Metabolic_equivalent_of_task.
(11) Damiano CA. The 2011 Compendium of Physical Activities - Tracking Guide. https://en.calameo.com/books/001226887f083d70d1acc.
(12) Parikh P et al. Coronary Artery Calcium Scoring: Its Practicality and Clinical Utility in Primary Care. Cleve Clinc J Med 2018. https://www.ccjm.org/content/85/9/707.
