Can exercise protect against respiratory infections?

Can exercise protect against respiratory infections?

OVERVIEW

  • Participants in more than 14 studies were randomly separated into two groups: one group who did not exercise and one who exercised regularly and under supervision.
  • Exercise did not reduce the incidence of acute respiratory infections.
  • Exercise appears to reduce the severity of symptoms associated with episodes of acute respiratory infections.
  • According to several other studies, exercise can improve the immune response to viruses, bacteria and other antigens. Regular physical activity and frequent exercise may reduce or delay the aging of the immune system.

COVID-19 caused by infection with the SARS-CoV-2 virus particularly affects people who have certain risk factors (advanced age, male) or a comorbidity such as chronic respiratory disease, obesity, cardiovascular disease, diabetes, hypertension and cancer (see this article). A healthy lifestyle, including eating well, not smoking, consuming alcohol in moderation, and exercising regularly, is the best way to prevent many diseases such as diabetes, cancer and cardiovascular disease. Also, certain conditions are associated with a decrease in immune activity, for example, stress, diabetes and the deficiency of certain dietary compounds like vitamin D and zinc. By its action on these conditions, exercise is likely to influence our resistance to infections.

Can exercise prevent acute respiratory infections, including COVID-19? Researchers at the Cochrane Library recently updated a systematic review of the effect of exercise on the occurrence, severity and duration of acute respiratory infections.  The systematic review included 14 studies of 1377 healthy individuals aged 18 to 85 who were followed for a median period of 12 weeks. The participants were randomly separated into two groups: one who did not exercise and one who exercised regularly. In most cases, the exercise was supervised and was performed at least three times per week. The exercise sessions lasted 30 to 45 minutes and consisted of moderate intensity exercise such as walking, cycling, treadmill or a combination of these exercises. Exercise did not have a significant effect on biochemical parameters, quality of life or number of injuries.

Exercise did not decrease the number of acute respiratory infections (ARI) episodes, nor the proportion of participants who had at least one episode of ARI during the study, or the number of days with symptoms during each of these episodes. On the other hand, exercise was associated with a decrease in symptom severity in two studies and in the number of days with symptoms during the total study duration (4 studies). The study authors indicate that certainty about the data is low and that data from ongoing or future studies may impact their conclusions.

Exercise and the immune system
The immune system is very responsive to exercise, depending on both the duration and the intensity of effort (see this review article). Exercise causes multiple micro-injuries to the muscles, triggering a local and systemic inflammation reaction. During a moderate to high intensity exercise session lasting less than 60 minutes, the number of leukocytes (white blood cells) and several cytokines (proteins produced by the immune system to stimulate the proliferation of defence cells) increases rapidly in the bloodstream. The increase in the number of neutrophils (a type of white blood cell) often lasts for up to 6 hours after the end of the exercise session. This physiological response to stress caused by exercise is followed, during the recovery period, by a drop in the number of leukocytes in the bloodstream to a level below that measured at the start of the exercise session.

Although exercise transiently increases markers of inflammation, including several cytokines (interleukins, chemokines, interferons, and others), at rest, people who exercise regularly have lower blood levels of these pro-inflammatory proteins than people who exercise little or not at all or who are obese. Regular exercise therefore appears to moderate the inflammatory response and promote an anti-inflammatory environment in the body. The persistent increase in markers of inflammation (chronic inflammation) is linked to several conditions and diseases, including obesity, osteoarthritis, atherosclerosis and cardiovascular disease, chronic kidney disease, liver disease, metabolic syndrome, insulin resistance, type 2 diabetes, chronic obstructive pulmonary disease, dementia, depression, and various types of cancers. In short, exercise reduces the negative effects on the immune system of a recognized factor that is diabetes and the associated insulin resistance.

It is known that in severe forms of COVID-19 an exaggerated inflammatory reaction called “cytokine storm” destroys the cells of the pulmonary endothelium that allow oxygenation of the blood and body. Could regular exercise that provides a less inflammatory environment protect us in the event of a SARS-CoV-2 virus infection? This has not been demonstrated, but it is certainly a hypothesis that will need to be examined. Moreover, it seems that in the elderly, immune aging (also called “immunosenescence”) is associated with a decline in the cells that regulate the immune response. It is because of this decline that we observe an increase in immune disorders such as autoimmune diseases and an increase in cancers. However, the cytokine storm would be secondary to the lack of control by these cells. A healthy immune system would be less likely to lack these “regulatory” cells.

Suppression of immunity in athletes: Myth or reality?
In recent decades, an idea has taken root in the scientific literature according to which aerobic exercise, particularly if it is vigorous and of long duration, can interfere with immunocompetence, i.e. the body’s ability to produce a normal immune response in response to exposure to an antigen. This idea is now increasingly questioned and has even been called a myth by some researchers. This hypothesis dates from the early 20th century, when fatigue was believed to contribute to infections that caused pneumonia, but it was not until the 1980s–1990s that studies verified this assertion with professional and amateur athletes. In general, it is increasingly certain that it is “psychological” stress rather than physical stress that is immunosuppressive. For example, a study in the 1980s among medical students showed that immune capacity collapsed within 24 to 48 hours of exams. The “mental” stress on the eve of competitions could be the comparison. Exercise is a great stress reliever for most people.

One of the studies indicated that one third of the 150 runners participating in the 1982 Two Oceans ultramarathon (56 km) in South Africa reported symptoms of upper respiratory tract infection (runny nose, sore throat, sneezing) within two weeks of the race. The control group reported half as many symptoms of upper respiratory tract infection than runners. Similar results were obtained from athletes who participated in the Los Angeles Marathon (42 km) in 1987. Among the 2311 participants who completed the race and who had not reported symptoms of infection in the week before the race, 12.9% reported symptoms of infection in the week following the race. Only 2.2% of participants who dropped out of the race (for reasons other than health reasons) reported symptoms of infection in the week after the race. Another study conducted at the same time did not find an association between aerobic exercise and the risk of upper respiratory tract infection for runs over shorter distances, namely 5 km, 10 km, and 21 km (half marathon). This suggested that the risk of infections increases only after exercising for a very long period of time.

The major problem with these studies is that they are questionnaire-based and none of the infections reported by athletes were confirmed in the laboratory. In a 2007 study, researchers took swabs and tested athletes who reported symptoms of upper respiratory tract infection over a period of 5 months. Only 30% of the cases reported by the participants were associated with the presence of viruses, bacteria, or mycoplasmas. These results suggest that the symptoms experienced by athletes in previous studies may not have been caused by infection, but rather by other causes, including allergies, asthma, inflammation of the mucous membranes, or trauma to the epithelial cells of the airways caused by increased breathing or exposure to cold air.

The decrease in leukocytes in the bloodstream that is observed after exercise has led to the so-called “open window” hypothesis that intense exercise causes transient immunosuppression during the recovery period. During this “open window”, athletes would be more susceptible to viral and bacterial infections. Another hypothesis would be that of the recruitment of white blood cells to repair small damage to the muscles. Indeed, tissue damage, whether mechanical or infectious, causes the release of cytokines, which “call” the defences to “see what happens.” Yet, contrary to the studies cited above, recent studies indicate that exercise is rather associated with a reduction in the incidence of infections. There are as many epidemiological studies that show that regular exercise is associated with a reduction in infections as there are that show that regular exercise is associated with an increase in infections, but the former are less taken into account than the latter in the literature on exercise immunology.

For example, a Swedish study of 1509 men and women aged 20 to 60 found that high levels of physical activity are associated with a reduced incidence of upper respiratory tract infections. Studies of ultramarathon runners, one of the most taxing sports, have shown that these people report fewer days of absence from school or work due to illness compared to the general population. For example, the average number of sick days reported annually was 1.5 days in a study of 1212 ultramarathon runners and 2.8 days in another study of 489 161-km ultramarathon runners, while that year the number of sick days reported in the American population was 4.4 days. An often overlooked aspect of outdoor exercise is its vitamin D intake with exposure to the sun. The longer the routes, the greater the exposure and endogenous skin production of vitamin D. Vitamin D intake would be beneficial for the regulatory cells of the immune system.

In summary, contrary to the immunosuppression (“open window”) hypothesis, regular exercise can be beneficial for the immune system, or at least not harmful. Exercise does not increase the risk of diagnosed opportunistic infections. Exercise can improve the immune response to viruses, bacteria, and other antigens. Regular physical activity and frequent exercise may reduce or delay the aging of the immune system.

To prevent cardiovascular disease, medication should not be a substitute for improved lifestyle

To prevent cardiovascular disease, medication should not be a substitute for improved lifestyle

OVERVIEW

  • Cardiovascular disease dramatically increases the risk of developing serious complications from COVID-19, again highlighting the importance of preventing these diseases in order to live long and healthy lives.
  • And it is possible! Numerous studies clearly show that more than 80% of cardiovascular diseases can be prevented by simply adopting 5 lifestyle habits (not smoking, maintaining a normal weight, eating a lot of vegetables, exercising regularly, and drinking alcohol moderately).

The current COVID-19 pandemic has exposed two major vulnerabilities in our society. The first is, of course, the fragility of our health care system, in particular everything related to the care of the elderly with a loss of autonomy. The pandemic has highlighted serious deficiencies in the way this care is delivered in several facilities, which has directly contributed to the high number of elderly people who have died from the disease. Hopefully, this deplorable situation will have a positive impact on the ways of treating this population in the future.

A second vulnerability highlighted by the pandemic, but much less talked about, is that COVID-19 preferentially affects people who present pre-existing conditions at the time of infection, in particular cardiovascular disease, obesity and type 2 diabetes. These comorbidities have a devastating impact on the course of the disease, with increases in the death rate of 5 to 10 times compared to people without pre-existing conditions. In other words, not only does poor metabolic health have a disastrous impact on healthy life expectancy, it is also a significant risk factor for complications from infectious diseases such as COVID-19. We are therefore not as helpless as we might think in the face of infectious agents such as the SARS-CoV-2 coronavirus: by adopting a healthy lifestyle that prevents the development of chronic diseases and their complications, we simultaneously greatly improve the probability of effectively fighting infection with this type of virus.

Preventing cardiovascular disease
Cardiovascular disease is one of the main comorbidities associated with severe forms of COVID-19, so prevention of these diseases can therefore greatly reduce the impact of this infectious disease on mortality. It is now well established that high blood pressure and high blood cholesterol are two important risk factors for cardiovascular disease. As a result, the standard medical approach to preventing these diseases is usually to lower blood pressure and blood cholesterol levels with the help of drugs, such as antihypertensive drugs and cholesterol-lowering drugs (statins). These medications are particularly important in secondary prevention, i.e. to reduce the risk of heart attack in patients with a history of cardiovascular disease, but they are also very frequently used in primary prevention, to reduce the risk of cardiovascular events in the general population.

The drugs actually manage to normalize cholesterol and blood pressure in the majority of patients, which can lead people to believe that the situation is under control and that they no longer need to “pay attention” to what they eat or be physically active on a regular basis. This false sense of security associated with taking medication is well illustrated by the results of a recent study, conducted among 41,225 Finns aged 40 and over. By examining the lifestyle of this cohort, the researchers observed that people who started medication with statins or antihypertensive drugs gained more weight over the next 13 years, an excess weight associated with an 82% increased risk of obesity compared to people who did not take medication. At the same time, people on medication reported a slight decrease in their level of daily physical activity, with an increased risk of physical inactivity of 8%.

These findings are consistent with previous studies showing that statin users eat more calories, have a higher body mass index than those who do not take this class of drugs, and do less physical activity (possibly due to the negative impact of statins on muscles in some people). My personal clinical experience points in the same direction; I have lost count of the occasions when patients tell me that they no longer have to worry about what they eat or exercise regularly because their levels of LDL cholesterol have become normal since they began taking a statin. These patients somehow feel “protected” by the medication and mistakenly believe that they are no longer at risk of developing cardiovascular disease. This is unfortunately not the case: maintaining normal cholesterol levels is, of course, important, but other factors such as smoking, being overweight, sedentary lifestyle, and family history also play a role in the risk of cardiovascular disease. Several studies have shown that between one third and one half of heart attacks occur in people with LDL-cholesterol levels considered normal. The same goes for hypertension as patients treated with antihypertensive drugs are still 2.5 times more likely to have a heart attack than people who are naturally normotensive (whose blood pressure is normal without any pharmacological treatment) and who have the same blood pressure.

In other words, although antihypertensive and cholesterol-lowering drugs are very useful, especially for patients at high risk of cardiovascular events, one must be aware of their limitations and avoid seeing them as the only way to reduce the risk of cardiovascular events.

Superiority of lifestyle
In terms of prevention, much more can be done by addressing the root causes of cardiovascular disease, which in the vast majority of cases are directly linked to lifestyle. Indeed, a very large number of studies have clearly shown that making only five lifestyle changes can very significantly reduce the risk of developing these diseases (see Table below).

The effectiveness of these lifestyle habits in preventing myocardial infarction is quite remarkable, with an absolute risk drop to around 85% (Figure 1). This protection is seen both in people with adequate cholesterol levels and normal blood pressure and in those who are at higher risk for cardiovascular disease due to high cholesterol and hypertension.

Figure 1. Decreased incidence of myocardial infarction in men combining one or more protective factors related to lifestyle. The comparison of the incidences of infarction was carried out in men who did not have cholesterol or blood pressure abnormalities (upper figure, in blue) and in men with high cholesterol levels and hypertension (lower figure, in orange). Note the drastic drop in the incidence of heart attacks in men who adopted all 5 protective lifestyle factors, even in those who were hypertensive and hypercholesterolemic. Adapted from Åkesson (2014).

Even people who have had a heart attack in the past and are being treated with medication can benefit from a healthy lifestyle. For example, a study conducted by Canadian cardiologist Salim Yusuf’s group showed that patients who modify their diet and adhere to a regular physical activity program after a heart attack have their risk of heart attack, stroke and mortality reduced by half compared to those who do not change their habits (Figure 2). Since all of these patients were treated with all of the usual medications (beta blockers, statins, aspirin, etc.), these results illustrate how lifestyle can influence the risk of recurrence.

Figure 2. Effect of diet and exercise on the risk of heart attack, stroke, and death in patients with previous coronary artery disease. Adapted from Chow et al. (2010).

In short, more than three quarters of cardiovascular diseases can be prevented by adopting a healthy lifestyle, a protection that far exceeds that provided by drugs. These medications must therefore be seen as supplements and not substitutes for lifestyle. The development of atherosclerosis is a phenomenon of great complexity, which involves a large number of distinct phenomena (especially chronic inflammation), and no drug, however effective, will ever offer protection comparable to that provided by a healthy diet, regular physical activity, and maintenance of a normal body weight.

Exercise reduces cardiovascular inflammation by modulating the immune system

Exercise reduces cardiovascular inflammation by modulating the immune system

OVERVIEW

  • Voluntary and regular exercise in mice decreases the number of inflammatory leukocytes (white blood cells) in the bloodstream.
  • Exercise causes a decrease in leptin (a digestive hormone) secreted by fat cells, which decreases the production of leukocytes by hematopoietic stem and progenitor cells in the bone marrow.
  • Cardiac patients who exercised four or more times a week had lower leptin and leukocyte blood levels.
  • These results suggest that a sedentary lifestyle contributes to cardiovascular risk through increased production of inflammatory leukocytes.

It is well established that regular exercise has many benefits for cardiovascular health, but the underlying mechanisms have not yet been fully identified and understood. A recent study published in Nature Medicine shows that in mice, voluntary exercise reduces the proliferation of hematopoietic stem and progenitor cells (HSPC), which has the effect of reducing the number of inflammatory leukocytes in the bloodstream. Remember that HSPC cells have the ability to transform into different types of cells that are involved in the immune response (leukocytes, lymphocytes, macrophages, etc.).

A sedentary lifestyle, chronic inflammation and abnormally high white blood cell count (leukocytosis) promote atherosclerosis, which can potentially cause myocardial infarction, stroke or heart failure.

To test whether regular exercise can modulate hematopoiesis, the researchers put mice in cages in the presence (or not for the control group) of an exercise wheel, where they could exercise at their will. Mice use these exercise wheels readily and with great zeal and are therefore not subjected to stress as when they are forced to exercise such as, for example, forced swimming that has already been used in other studies. After six weeks, mice that exercised voluntarily (doing about 20 times more physical activity than sedentary mice) reduced their body weight and increased their food intake.

Analyses have shown that exercise reduced the proliferation of hematopoietic stem and progenitor cells by 34%. The decrease in HSPC through exercise had the effect of reducing the number of inflammatory leukocytes (white blood cells) in the bloodstream. In addition, the mononuclear cells in the bone marrow of mice that exercised were less able to differentiate into granulocytes, macrophages, and pre-B cells. The researchers showed that the mechanism involves a decrease in the production of leptin (a hormone secreted during digestion to regulate fat stores and control the feeling of satiety) in fat tissues. The decrease in leptin in the bloodstream of mice had the effect of increasing the production of factors of quiescence and retention of hematopoietic stem cells in the bone marrow, and consequently of decreasing the number of leukocytes in the bloodstream (see figure below).

Figure. Schematic summary of the effects of exercise on leukocyte levels and the risk of cardiovascular disease. LepR+: expressing the leptin receptor. Adapted from Frodermann et al., 2019.

Leptin supplementation in mice that exercised (using subcutaneous micropumps) reversed the exercise-induced effects on hematopoiesis, proving that this digestive hormone is involved in this phenomenon.

The exercise wheel was removed from the mouse cage after six weeks. Three weeks later, the effect on leptin production faded, but the effects of exercise on hematopoiesis persisted, i.e. the leukocyte levels of exercise mice were still lower than that of sedentary mice. There is therefore a “memory” of the exercise, which was related to epigenetic changes, i.e. to a difference in the expression of certain genes without alteration of their DNA sequence.

A reduction in leukocyte levels in the blood can lead to an increased risk of infection, as has already been observed for high-intensity exercise. The researchers wanted to see if this was the case with the mice in their study. A component of the cell wall of bacteria (lipopolysaccharide) was injected into the stomachs of mice to induce an inflammatory response. The mice responded quickly by increasing the number of HSPC and defence cells (neutrophils, monocytes, B lymphocytes, T-cells) in the blood and at the site of infection. Mice who exercised reacted more than sedentary mice to lipopolysaccharide injection and had a lower mortality rate when real sepsis was provoked. It is therefore clear that regular voluntary exercise in mice does not decrease the emergency immune response to infection.

The researchers then wanted to find out if the decrease in leukocytes caused by exercise could reduce atherosclerosis and inflammation of atherosclerotic plaques. To do this they used a “knockout” mouse line in which the gene encoding apolipoprotein E was inactivated (Apoe–/–­­­­­). This protein carries lipids into the blood and is essential for their elimination. Inactivation of the Apoe gene causes hypercholesterolemia and atherosclerosis in mice. Apoe–/–­­­­­ mice that developed atherosclerosis were placed in cages containing an exercise wheel, which led to a decrease in leptin levels, a decrease in leukocytes, and a decrease in plaque size. The same beneficial effects of exercise on atherosclerosis were observed in a mouse line in which the gene encoding the leptin receptor was inactivated specifically at the level of stromal cells.

The researchers finally wanted to know if exercise could have beneficial effects on hematopoiesis in patients with cardiovascular disease. To do this, they checked whether there was an association between the amount of exercise and the blood levels of leptin or the number of leukocytes in 4,892 participants of the CANTOS study, who were all recruited after having a heart attack. Participants who exercised four or more times a week had significantly lower leptin blood levels. Another study (Athero-Express Study) also showed a favourable relationship between the amount of exercise and levels of leptin and leukocytes. The results of these two clinical studies, combined with those obtained in mice, indicate that physical activity has beneficial effects on leptin levels and leukocytosis in patients with cardiovascular disease.

This new study suggests that a sedentary lifestyle contributes to cardiovascular risk through an increased production of inflammatory leukocytes, and confirms the idea that physical activity reduces chronic inflammation. Let us recall the main recommendations of the World Health Organization’s (WHO) regarding physical activity for health:

“In order to improve cardiorespiratory and muscular fitness, bone health, reduce the risk of noncommunicable diseases and depression,

  1. Adults aged 18–64 should do at least 150 minutes of moderate-intensity aerobic physical activity throughout the week or do at least 75 minutes of vigorous-intensity aerobic physical activity throughout the week or an equivalent combination of moderate- and vigorous-intensity activity.
  2. Aerobic activity should be performed in bouts of at least 10 minutes duration.
  3. For additional health benefits, adults should increase their moderate-intensity aerobic physical activity to 300 minutes per week, or engage in 150 minutes of vigorous-intensity aerobic physical activity per week, or an equivalent combination of moderate- and vigorous-intensity activity.
  4. Muscle-strengthening activities should be done involving major muscle groups on 2 or more days a week.”

To learn more about the benefits, quantity and types of exercise, check out these articles:

How much exercise to live longer?

Exercise on an empty stomach to burn more fat

Can regular exercise compensate for long periods spent sitting?

Exercise benefits in cardiovascular disease: beyond attenuation of traditional risk factors

Exercise on an empty stomach to burn more fat

Exercise on an empty stomach to burn more fat

OVERVIEW

  • Sedentary men did supervised exercise 3 times a week for 6 weeks after ingesting either a sugary drink or a sugar-free placebo drink.
  • Participants who exercised on an empty stomach “burned” twice as much fat as those who consumed a sugary drink before exercise sessions.
  • Participants who exercised on an empty stomach also saw their insulin sensitivity improve more than those who ingested calories before the exercise sessions.

It is now well established that exercise in all its forms improves overall health. In addition to increasing cardiorespiratory capacity, regular exercise improves insulin sensitivity and reduces insulin secretion after meals. However, each individual’s response to similar exercises is very variable: some people become fitter or lose more weight or stabilize their blood sugar more than others. One of the factors that could be important is the timing of meals and exercise sessions. Muscles use energy in the form of sugars and fats, which can come from the last meal or from reserves in the body when fasting. The accumulation of too much fat in the muscles is problematic for health, because the fat-engorged muscles do not respond well to insulin, a hormone that stimulates the absorption of glucose by muscle, adipose and liver cells. Therefore, excess fat in the muscles can contribute to insulin resistance, hyperglycemia and increased risks of type 2 diabetes and other metabolic imbalances.

In a randomized controlled study, an international team tested the effect of the timing of meals on the metabolic benefits associated with exercise. Thirty sedentary and overweight or obese men were divided into three groups (see figure below): a control group that continued to live normally and two other groups that did supervised exercise in the morning (treadmill running), three times a week for six weeks, without breakfast; the second group ingested a vanilla-flavoured drink containing 20% sugar two hours before each exercise session, whereas the third group ingested a vanilla-flavoured placebo beverage containing water and no calories. After each morning exercise session, participants in both groups drank the beverage they had not received prior to the session. This means that all the runners ingested the same number of calories and did the same amount of exercise, only the timing of calorie consumption differed, i.e. before or after the exercise session.

Figure. Protocol schematic for the training study.  Adapted from Edinburgh et al., 2019.

The study was randomized and controlled, so participants did not know what type of drink they ingested before and after exercising. 83% of participants reported that they could not detect differences between the sugary and placebo drinks or were unable to identify which beverage contained sugar. It should be noted that the sugar used here, maltodextrin (partially hydrolyzed starch), has a very low sweetening power and is therefore difficult to detect.

Blood samples and biopsies of a muscle located in the thigh (vastus lateralis) were taken before and after the intervention in order to measure different metabolites and proteins of interest. Glucose, glycerol, triglycerides, HDL and LDL cholesterol, insulin, C-peptide, and fatty acids were measured in the blood, and phospholipid composition, protein content involved in glucose transport, insulin signalling and lipid metabolism were measured in the vastus lateralis muscle samples.

Not surprisingly, the control group did not improve their physical fitness or insulin sensitivity during these six weeks. On the contrary, the other two groups who exercised saw their fitness improved and their waistline decreased, although only a few of the participants lost weight.

The most striking finding of the study was that participants who exercised on an empty stomach “burned” twice as much fat as those who consumed a sugary drink before the exercise session. Yet participants in both groups who exercised expended the same number of calories.

Participants who ran on an empty stomach also saw their insulin sensitivity improve further and their muscles synthesized greater amounts of certain proteins (AMP-activated protein kinase, an energy sensor, and the glucose transporter GLUT4) involved in the response of muscle cells to insulin and the use of sugars.

Studies on exercise and metabolic health will need to consider the timing of meals in the future. Since it is not possible for everyone to exercise in the morning after the night fasting period, it will be interesting to check if it is possible to obtain the same metabolic benefits after a shorter daytime fasting period, for example, when exercising in the early evening after skipping lunch. However, it should not be forgotten that any physical activity (walking, housework, etc.), performed at any time of the day, is beneficial for health.

How much exercise to live longer?

How much exercise to live longer?

OVERVIEW

  • A meta-analysis published in October 2019 confirms that exercising reduces the risk of all-cause or cardiovascular mortality.
  • The decrease in risk is directly proportional to the amount of exercise up to about 2 hours of running per week. More than 4 hours of running per week or the equivalent do little to reduce the risk further.
  • Very high amounts of exercise (up to 8 times the amount of exercise recommended in public guidelines) do not reduce longevity, contrary to what some previous studies have suggested.

Exercise to live longer
Physical activity has many and varied beneficial effects on cardiovascular risk factors, including lower blood pressure and resting heart rate, improved blood sugar and lipidemia, normalizing body mass index, improved sleep and reduced stress. According to several long-term epidemiological studies, regular physical activity is one of the most effective lifestyle habits to increase life expectancy, up to 6 years.

Can too much exercise be detrimental to longevity?
This is an issue that is the subject of debate due to the conflicting data published to date. A meta-analysis published in October 2019 concludes that high amounts of exercise (up to 8 times the amount of exercise recommended by public guidelines) do not reduce longevity. This meta-analysis included 48 prospective studies, one of which included 6 distinct cohorts and another 9 distinct cohorts. Compared to the recommended level of physical activity (150 minutes of moderate to intense exercise per week), the mortality risk was lower for people who exercised more, at least up to 10 hours of running per week (Figure 1). This applies to all-cause mortality, and even more so to mortality from cardiovascular disease, including coronary heart disease. It should be noted that the reduction in mortality risk appears to be directly proportional to the amount of exercise up to about 2 hours of running per week and that more than 4 hours of running or the equivalent does little to reduce the risk further.

Figure 1. Dose-effect relationship between the amount of exercise and mortality from all causes, or mortality from cardiovascular disease, or mortality from coronary heart disease. The amount of exercise recommended in the public guidelines was used as a reference. Adapted from Blond et al., Br. J. Sports Med. 2019.

Some studies have suggested that a very large amount of exercise can decrease longevity. For example, a 15-year study of 55,137 participants (including 13,016 joggers) indicated that running reduced the risk of death from all causes by about 30% and the risk of cardiovascular mortality by 45%, with an increase in life expectancy of 3 years. A more detailed analysis of the results was made by the authors in an attempt to answer the question, “Is more exercise better for life expectancy?” The results show a so-called U-shaped curve (Figure 2) where hard runners (>49 MET-h/wk) appeared to have less benefit than light or moderate runners, but this difference was not statistically significant (P>0.05). One MET (Metabolic Equivalent of Task) corresponds to the amount of energy expended at rest, for walking it is 3.5 MET and for running it is approximately 7–8 MET.

Figure 2. Risk of mortality depending on the amount of running.
Adapted from Lee et al., Mayo Clinic Proc, 2016.

It should be noted that this is a single study, that the people who did >49 MET-h/wk represented only 1.6% of the study participants, and that the variation in the data collected was high. In contrast, the study described above, where very large amounts of exercise had no adverse effect on longevity, is a meta-analysis of 48 studies with a much higher total number of participants. This example illustrates why meta-analyses are so useful in epidemiology: they provide more accurate results (greater statistical power) and make it possible to draw global conclusions from a large number of studies and data.

Cardiorespiratory capacity and mortality risk
A recent study evaluated the association between cardiorespiratory capacity and all-cause mortality. The study population consisted of 122,007 patients who were followed for 8.4 years on average, during which time 13,637 patients died. At the beginning of the study, all patients did a treadmill stress test (limited by symptoms) to assess their cardiorespiratory capacity (CRC). For the analysis, participants were divided into 5 groups, according to the level of their CRC: low (<25th percentile), below average (25th–49th percentile), above average (50th–74th percentile), high (75th–97.6th percentile) and “Elite” (≥97.7th percentile). The results (Figure 3) clearly indicate that a greater CRC is associated with a decrease in mortality and that patients with very high CRC (Elite group) had the lowest risk of mortality.

Figure 3. Risk of all-cause mortality as a function of cardiorespiratory capacity.
Adapted from Mandsager et al., JAMA Network Open, 2018.

There is no U-curve in this study, but it must be noted that patients in the “Elite” group are not athletes and that it is not known whether or not they exercised regularly. The maximum cardiorespiratory capacity of the “Elite” group averaged 13.8 MET, which is considered excellent functional capacity, but slightly below the level of elite athletes (marathon runners, triathletes, cyclists) whose maximum cardiorespiratory capacity is about 17 to 20 MET. The fact remains thatcardiorespiratory capacity is a modifiable indicator of long-term mortality and that health care professionals should encourage their patients to achieve and maintain a high level of physical fitness.

Running a marathon puts a significant strain on the hearts of amateur runners
According to a Spanish study published in Circulation, amateur runners who complete a marathon event (42.2 km) see their levels of cardiac damage markers increase significantly. Cardiac markers [cardiac troponins I and T (TnIc and TnTc), the N-terminal truncated form of natriuretic brain peptide (NT-proBNP), creatine kinases (CK-MB and CK-MM), myoglobin] are proteins that are released into the blood when the heart muscle is damaged. In contrast, in half-marathon runners (21.1 km) and 10 km races there was no significant increase in markers of heart damage. A sudden increase in cardiac markers after exercise is generally considered benign because the normal values of these markers are restored after a few days. The authors of the study note that although the release of cardiac troponins into the blood is not an indicator of heart malfunction, higher concentrations after a marathon reflect greater cardiac stress than for shorter runs. The incidence of cardiac arrest during marathons is a fairly rare phenomenon, i.e. 1 in 50,000 runners who complete the race, but these accidents are highly publicized. Cardiorespiratory arrests during marathons occur especially in men aged 35 and over and are caused by coronary artery disease (obstruction of one of the coronary arteries that irrigates the heart muscle). When cardiorespiratory arrest occurs in a young person under the age of 35, the cause is usually congenital heart disease. Given the growing popularity of marathons and the lack of experience and adequate preparation of some amateur runners, this study suggests that shorter races (e.g. half marathons) would be more suited to reduce the stress placed on the hearts of these runners.

No U-curves for light to moderate intensity exercise
The Copenhagen City Heart Study recently reported that leisure time physical activity reduces both all-cause mortality and mortality from coronary heart disease. Compared to sedentary participants, the gains in life expectancy were: 2.8 years for those who did light physical activity, 4.5 years for moderate-intensity physical activity, and 5.5 years for high-intensity physical activity. There is no U-curve in this study, but it should be noted that participants who exercised intensely (4 hours per week or several hours per week of a competitive sport) in this study still did less than those of the other studies cited above. In several other studies of light to moderate intensity exercise during leisure time, a U-shaped relationship was not observed. In other words, it does not seem possible to do too much light to moderate physical activity, such as walking, housework, gardening, baseball or softball, bowling, volleyball, golf, doubles tennis (and other racket sports) and dance.

Humans have adapted to do a lot of physical activity during life. A recent study of the Hazda hunter-gatherer modern tribe in northern Tanzania shows that, on average, these people do 14 times more light-to-moderate physical activity than North Americans. Members of the Hazda tribe have few cardiovascular risk factors (low prevalence of hypertension throughout life, optimal levels for cardiovascular health biomarkers). The Chimanes, an indigenous people in the Bolivian Amazon who have a subsistence lifestyle based on hunting, fishing, gathering, and farming, also has excellent cardiovascular health. Chimanes are very active, travelling up to 18 km per day and it is estimated that less than 10% of waking hours are spent on sedentary activities, compared to more than 60% in North America.

On the contrary, North American adults today sit an average of about 10 hours a day out of 16 waking hours. Physical exercise on a regular basis is therefore necessary to maintain good cardiorespiratory capacity as well as good cardiovascular health and to be able to live longer in good health.

Aerobic fitness is associated with levels of blood metabolites that are good for your health

Aerobic fitness is associated with levels of blood metabolites that are good for your health

A large number of studies indicate that there is a positive association between exercise and good health, particularly good cardiovascular health. Researchers are now focusing their efforts on identifying the physiological and molecular mechanisms underlying these beneficial effects.

A study conducted among 580 young Finnish men shows that aerobic fitness (also known as cardiorespiratory capacity) is associated with levels of several metabolites that are beneficial to health. The approach used in this study is referred to as “metabolomics”, i.e. an approach that aims to identify metabolic differences, for example in the blood of people with a disease (diabetes, cancer) compared to people in good health. Most of the metabolomic studies conducted to date have focused on diseases, but this approach has also been applied recently to determine which metabolites are indicative of good health, particularly with regard to exercise.

Of the 66 metabolites selected in the Finnish study, 48 were at different levels between the group of participants who had the highest aerobic fitness and the one with the lowest aerobic fitness (see Figure 2 and Figure 3 of the original article). These differences include a 44% lower concentration of low-density lipoprotein (LDL, the “bad cholesterol”), an 81% higher concentration of high-density lipoprotein (HDL, the “good” cholesterol), a 52% lower total of triglycerides (Figure 1 below, orange bars). On the other hand, greater muscular strength of the participants was not associated with favourable levels for these same metabolites (Figure 1 below, blue bars).

Figure 1. Main differences in blood metabolites between the participants who had the highest aerobic fitness and those who had the lowest (orange bars) or between the participants who had the highest muscular strength and those who had the lowest (blue bars). * Significant difference (P <0.001 or P <0.002); NS: Not significant difference. From Kujala et al., 2019.

Cholesterol
The more detailed analysis (see Figure 2 in the original article) shows that all LDL and VLDL particles of different sizes (small, medium, large, very large, extremely large) are present in lower concentrations in the blood of participants who have a good aerobic capacity than in participants who have a lower aerobic capacity. On the contrary, all HDL particles (very large, large, or medium-sized), except for small ones, are present in higher concentrations in the group with the highest aerobic fitness. Large-size HDLs are particularly beneficial for good cardiovascular health.

Participants with good cardiorespiratory capacity had 80% less apolipoprotein B (ApoB) in their blood than those who were less fit. ApoB is a protein found in very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL). The measurement of the ApoB makes it possible to estimate the number of particles of cholesterol, which is a good indication of the risk of developing cardiovascular disease. High blood levels of ApoB are therefore a risk marker for cardiovascular disease, independently of the level of LDL-cholesterol.

Triglycerides
A high concentration of triglycerides in the blood is a risk marker for coronary heart disease and is associated with obesity and type 2 diabetes. Excessive consumption of sugars and alcohol (not fat) is generally the cause of a high level of triglycerides in the blood.

Other metabolites
Other important metabolites that are present in lower concentrations in individuals with good aerobic capacity include total fatty acids (-60%), glycerol (-64%), lactate (-34%), pyruvate (-36%), branched-chain amino acids (BCAA) isoleucine (-37%) and leucine (-55%), and amino acids phenylalanine (-54%) and tyrosine (-55%). Interestingly, theunsaturation degree of fatty acid of participants in better aerobic fitness was 59% higher than in less fit participants; asituation conducive to good cardiovascular health knowing that it is saturated fatty acids that, in excess, increase theconcentration of LDL-cholesterol and are atherogenic.

High levels of BCAA, phenylalanine and tyrosine are found in obese people and they have been associated with a 5-fold increased risk of developing type 2 diabetes in two separate cohorts. Lower levels of glycerol and ketone bodies (acetylacetate, 3-hydroxybutyrate) in individuals with a high aerobic capacity suggest an increase in fat degradation.

Several metabolites (19) remain associated with a high aerobic fitness after adjustments to account for age and percentageof body fat. After making the same adjustments, muscular strength was associated with only 8 measures of the “metabolome” and none of these associations related to cholesterol or other blood lipids.

This study found more favourable associations between aerobic fitness and certain metabolites that are risk factors for cardiovascular disease than for high muscular strength. It should not be concluded, however, that muscular endurance exercises are useless, quite the contrary. Indeed, muscle training increases aerobic fitness and is an important component of maintaining and improving the condition of people with chronic diseases and the elderly. It is therefore necessary to combine aerobic and muscular exercises to optimize the benefits for cardiovascular health and overall well-being.