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.

Eggs: To consume with moderation

Eggs: To consume with moderation

The old debate over whether egg consumption is detrimental to cardiovascular health has been revived since the recent publication of a study that finds a significant, albeit modest, association between egg or dietary cholesterol consumption and the incidence of cardiovascular disease (CVD) and all-cause mortality. Eggs are an important food source of cholesterol: a large egg (≈50 g) contains approximately 186 mg of cholesterol. The effect of eggs and dietary cholesterol on health has been the subject of much research over the last five decades, but recently it has been assumed that this effect is less important than previously thought. For example, the guidelines of medical and public health organizations have in recent years minimized the association between dietary cholesterol and CVD (see the 2013 AHA/ACC Lifestyle Guidelines and the 2015–2020 Dietary Guidelines for Americans). In 2010, the American guidelines recommended consuming less than 300 mg of cholesterol per day; however, the most recent recommendations (2014–2015) do not specify a daily limit. This change stems from the fact that cholesterol intake from eggs or other foods has not been shown to increase blood levels of LDL-cholesterol or the risk of CVD, as opposed to the dietary intake of saturated fat that significantly increases LDL cholesterol levels, a significant risk of CVD.

Some studies have reported that dietary cholesterol increases the risk of CVD, while others reported a decrease in risk or no effect with high cholesterol consumption. In 2015, a systematic review and meta-analysis of prospective studies was unable to draw conclusions about the risk of CVD associated with dietary cholesterol, mainly because of heterogeneity and lack of methodological rigour in the studies. The authors suggested that new carefully adjusted and rigorously conducted cohort studies would be useful in assessing the relative effects of dietary cholesterol on the risk of CVD.

What distinguishes the study recently published in JAMA from those published previously is its great methodological rigour, in particular a more rigorous categorization of the components of the diet, which makes it possible to isolateindependent relationships between the consumption of eggs or cholesterol from other sources and the incidence of CVD. The cohorts were also carefully harmonized, and several fine analyses were performed. The data came from six U.S. cohorts with a total of 29,615 participants who were followed for an average of 17.5 years.

The main finding of the study is that greater consumption of eggs or dietary cholesterol (including eggs and meat) is significantly associated with a higher risk of CVD and premature mortality. This association has a dose-response relationship: for every additional 300 mg of cholesterol consumed daily, the risk of CVD increases by 17% and that of all-cause mortality increases by 18%. Each serving of ½ egg consumed daily is associated with an increased risk of CVD of 6% and an increased risk of all-cause mortality of 8%. On average, an American consumes 295 mg of cholesterol every day, including 3 to 4 eggs per week. The model used to achieve these results took into account the following factors: age, gender, race/ethnicity, educational attainment, daily energy intake, smoking, alcohol consumption, level of physical activity, use of hormone therapy. These adjustments are very important when you consider that egg consumption is commonly associated with unhealthy behaviours such as smoking, physical inactivity and unhealthy eating. These associations remain significant after additional adjustments to account for CVD risk factors (e.g. body mass index, diabetes, blood pressure, lipidemia), consumption of fat, animal protein, fibre and sodium.

A review of this study suggests that the association between cholesterol and the incidence of CVD and mortality may be due in part to residual confounding factors. The authors of this review believe that health-conscious people reported eating fewer eggs and cholesterol-containing foods than they actually did. Future studies should include “falsification tests” to determine whether a “health consciousness” factor is the cause of the apparent association between dietary cholesterol and CVD risk.

Eggs, TMAO and atherosclerosis
A few years ago, a metabolomic approach identified a compound in the blood, trimethylamine-N-oxide (TMAO), which is associated with increased cardiovascular risks. TMAO is formed from molecules from the diet: choline, phosphatidylcholine (lecithin) and carnitine. Bacteria present in the intestinal flora convert these molecules into trimethylamine (TMA), then the TMA is oxidized to TMAO by liver enzymes called flavin monooxygenases. The main dietary sources of choline and carnitine are red meat, poultry, fish, dairy products and eggs (yolks). Eggs are an important source of choline (147 mg/large egg), an essential nutrient for the liver, muscles and normal foetal development, among others.

A prospective study indicated that elevated plasma concentrations of TMAO were associated with a risk of major cardiac events (myocardial infarction, stroke, death), independent of traditional risk factors for cardiovascular disease, markers of inflammation, and renal function. It has been proposed that TMAO promotes atherosclerosis by increasing the number of macrophage scavenger receptors, which carry oxidized LDL (LDLox) to be degraded within the cell, and by stimulating macrophage foam cells (i.e. filled with LDLox fat droplets), which would lead to increased inflammation and oxidation of cholesterol that is deposited on the atheroma plaques. A randomized controlled study indicates that the consumption of 2 or more eggs significantly increases the TMAO in blood and urine, with a choline conversion rate to TMAO of approximately 14%. However, this study found no difference in the blood levels of two markers of inflammation, LDLox and C-reactive protein (hsCRP).

Not all experts are convinced that TMAO contributes to the development of CVD. A major criticism is focused on fish and seafood, foods that may contain significant amounts of TMAO, but are associated with better cardiovascular health. For example, muscle tissue in cod contains 45–50 mmol TMAO/kg. For comparison, the levels of choline, a precursor of TMAO, are 24 mmol/kg in eggs and 10 mmol/kg in red meat. The only sources of choline that are equivalent to that in TMAO in marine species are beef and chicken liver. TMAO contained in fish and seafood is therefore significantly more important quantitatively than TMAO that can be generated by the intestinal flora from choline and carnitine from red meat and eggs. This was also measured: plasma levels of TMAO are much higher in people who have a fish-based diet (> 5000 μmol / L) than in people who eat mostly meat and eggs (139 μmol / L). In their response to this criticism, the authors of the article point out that not all fish contain the same amounts of TMAO and that many (e.g. sea bass, trout, catfish, walleye) do not contain any. Fish that contain a lot of TMAO are mainly deep-sea varieties (cod, haddock, halibut). The TMAO content of other fish, including salmon, depends on the environment and when they are caught.

Other experts believe this could be a case of reverse causality: the reduction in renal function associated with atherosclerosis could lead to an accumulation of TMAO, which would mean that this metabolite is a marker and not the cause of atherosclerosis. To which the authors of the hypothesis counter that the high concentration of TMAO is associated with a higher risk of cardiovascular events even when people have completely normal kidney function.

Diabetes and insulin resistance
People who are overweight (BMI> 25) and obese (BMI> 50) are at higher risk of becoming insulin resistant and having type 2 diabetes and metabolic syndrome, conditions that can, independently or in combination, lead to the development of cardiovascular disease. There is evidence that dietary cholesterol may be more harmful to diabetics. Intestinal absorption of cholesterol is impaired in diabetics, i.e. it is increased. However, in a randomized controlled trial, when diabetic patients consumed 2 eggs per day, 6 times per week, their lipid profile was not altered when their diet contained mono- and polyunsaturated fatty acids. Other studies (mostly subsidized by the egg industry) suggest that eggs are safe for diabetics.

Dr. J. David Spence of the Stroke Prevention & Atherosclerosis Research Center believes that people at risk for CVD, including diabetics, should avoid eating eggs (see also this more detailed article). This expert in prevention argues that it is the effects of lipids after a meal that matter, not fasting lipid levels. Four hours after a meal high in fat and cholesterol, harmful phenomena such as endothelial dysfunction, vascular inflammation and oxidative stress are observed. While egg whites are unquestionably a source of high-quality protein, egg yolks should not be eaten by people with cardiovascular risks or genetic predispositions to heart disease.

The association between the consumption of eggs or foods containing cholesterol and the risk of CVD is modest. But since this risk increases with the amount consumed, people who eat a lot of eggs or foods containing cholesterol have a significant risk of harming their cardiovascular health. For example, according to the study published in JAMA, people who consume two eggs per day instead of 3 or 4 per week have a 27% higher risk of CVD and a 34% higher risk of premature mortality. It is therefore prudent to minimize the consumption of eggs (less than 3 or 4 eggs per week) and meat in order to limit the high intake of cholesterol and choline and avoid promoting atherosclerosis.

Hypertension and hypercholesterolemia in young adults increase cardiovascular risk after the age of 40

Hypertension and hypercholesterolemia in young adults increase cardiovascular risk after the age of 40

Numerous epidemiological studies carried out over the last decades have shown a link between exposure to cardiovascular risk factors early in life and cardiovascular events at a later age. High blood pressure and high cholesterol are important modifiable risk factors for cardiovascular disease (CVD) and major components of risk prediction algorithms.

In prospective studies, childhood obesity, which subsides in adulthood, appears to cause only a slight increase in the risk of developing cardiovascular disease (CVD) over the course of life. Similarly, a few years after quitting smoking, the cardiovascular risk associated with smoking seems very low, even if smoking is stopped in adulthood. The same is not true for hypertension and hypercholesterolemia. Treatment of hypertension with medication does not reverse the damage done earlier in life, mainly to the heart, blood vessels and kidneys. For example, people who are hypertensive, but whose blood pressure is normalized by medication, have an increased risk of CVD after age 40. Treatment of familial hypercholesterolemia by statins significantly reduces the risk of CVD in young adults, but these people have more atherosclerotic CVD.

Until recently, we did not know whether exposure to these risk factors in early adulthood independently contributed to the risk of CVD, i.e. regardless of exposure to these same risk factors later in life. A study on the long-term effects of hypercholesterolemia and hypertension experienced at a young age, including a large amount of data and therefore of great statistical power, was recently published in the Journal of the American College of Cardiology (JACC). The data included in this study came from 6 U.S. cohorts, including 36,030 participants, who were followed for an average of 17 years.

The study found a strong association between having high blood pressure (BP) or high LDL-cholesterol at a young age (18–39 years), and the development of cardiovascular disease later in life (≥40 years). Specifically, young adults with LDL-cholesterol> 2.6 mmol/L had a 64% higher risk of coronary heart disease than those with a level of <2.6 mmol/L, regardless of cholesterol-LDL levels later in life. Similarly, young adults with systolic BP ≥130 mmHg had a 37% higher risk of heart failure than those with systolic BP <120 mmHg, and young adults with diastolic BP ≥80 mmHg had a 21% higher risk of heart failure than those with diastolic BP <80 mmHg. With respect to the risk of stroke after age 40, they are not affected by elevated cholesterol levels or increased systolic or diastolic BP at a younger age (18–39 years).

Even slightly elevated LDL-cholesterol levels of 2.6-3.3 mmol/L during early adulthood significantly increase the risk of coronary heart disease (28%) compared to <2.6 mmol / L. However, LDL cholesterol levels of 2.6-3.3 mmol/L are generally considered acceptable for healthy individuals who have no known CVD or other cardiovascular risk factors.

In an editorial published in the same journal, Gidding and Robinson suggest that the impacts of high cholesterol and hypertension in young people on cardiovascular risks later in life could be underestimated since: 1) the data from this study come from old cohorts, and we know that today’s young adults are more likely to be obese and have diabetes at a younger age; 2) there is probably a “survivor bias” in this type of study, i.e. it is possible that some young adults with particularly high blood pressure or cholesterol may have had a cardiovascular accident (an exclusion criteria) or that they have died before reaching the age at which the participants in these studies are recruited.

The increase in cardiovascular accidents before the age of 65 and the results of the study described above make it urgentto take action on prevention. Young adults, particularly women and non-Caucasians, did not benefit from the overall reduction of cardiovascular disease rates in the general population. This is probably due to three factors: the epidemic of obesity and diabetes; the lack of treatment for young adults who would benefit; the lack of clinical trials focusing on this age group, which would lead to better guidelines.

Drs. Gidding and Robinson believe that the first response of the medical community to the results of the study recently published in JACC and other similar analyses should be to become aware and recognize that there is a prevention deficit among young adults. In the United States, less than one third of adults under the age of 50 who should be treated for hypertension according to the guidelines receive treatment, and less than half of the participants in the NHANES study (National Health and Nutrition Examination Survey) who had a diagnostic criterion for familial hypercholesterolemia were treated with a statin.

The current trend is to treat hypercholesterolemia at a later age when the burden of the disease is already high and only a modest reduction in cardiovascular risk has been demonstrated. However, by lowering cholesterol earlier in life, mainly through a change in lifestyle, it is possible to avoid cardiovascular events in old age. By focusing more on young adults with less advanced disease and therefore more likely to be treated successfully, prevention and future clinical trials will reduce the burden of cardiovascular disease for future generations.

Saturated fats, coconut oil and cardiovascular disease

Saturated fats, coconut oil and cardiovascular disease

The American Heart Association (AHA) recently published a review of current knowledge on the association between dietary fats and cardiovascular disease. By taking into consideration the entirety of the available scientific evidence, the committee concluded that a lower intake in saturated fat and replacing it with unsaturated fat represents the optimal combination to reduce the incidence of heart disease in the population, especially if it is accompanied by a transition toward an overall healthy diet, such as the Mediterranean diet.

The positive impact of substituting saturated fat with unsaturated fat can mainly by explained by the opposite effects of these two types of fat on the LDL cholesterol level, a well-established risk factor for cardiovascular disease. Whereas saturated fat is associated with an increase of this cholesterol, and thus an increase in the risk of cardiovascular events, unsaturated fat leads to a decrease in LDL cholesterol levels in the blood and is associated with a significant decrease in mortality.  Since animal-based protein sources (meat, dairy products, eggs) are the main sources of saturated fat in diets, whereas plant-based fats are mainly unsaturated, the mere act of reducing consumption of animal products while simultaneously increasing the consumption of plant-based foods is a very easy way to improve the quality of dietary fats, and thus reduce the risk of heart disease. In fact, it is interesting to note that several regions of the world known for their low incidence of cardiovascular disease (Okinawa, Japan; Ikaria, Greece; Sardinia; and the Tsimané people of the Amazon) all share one commonality: a diet high in plant-based foods with a low intake of animal protein and saturated fat.

Plant-based saturated fat
Whereas almost all plant-based fats mainly contain unsaturated fat, there is nevertheless one notable exception: tropical palm and coconut oils (see the Table). Indeed, palm oil (extracted from the fruit pulp) and palm kernel oil (derived from the kernels) contain very high levels of saturated fat (50% for palm oil and 82% for palm kernel oil), which gives them a semi-solid texture at room temperature. This property is used in the food industry to improve the texture of cookies, cakes and other products, and the high level of saturated fat also ensures that these oils are much more resistant to oxidation and considerably improves the shelf life of these foods. However, like all sources of saturated fat, these oils increase blood cholesterol levels and thus are not recommended for cardiovascular health. Not to mention the devastating environmental impact of the intensive cultivation of oil palm, in particular in Indonesia: almost two million hectares of tropical forest are destroyed every year for this crop, a deforestation that has disastrous environmental consequences and threatens animals such as tigers and orangutans from Sumatra and Borneo with extinction.

Table.  Proportion of saturated, monounsaturated and polyunsaturated fat in different animal and plant-based fats.

Source of fatSaturated fat
(g/100g)
Monounsaturated fat
(g/100g)
Polyunsaturated fat
(g/100g)
Butter63264
Canola oil76328
Coconut oil8262
Corn oil132855
Olive oil147310
Palm oil49379
Palm kernel oil82112
Lard394511
Soybean oil162358
Sunflower oil10844

Coconut oil: saturated fat with positive effects?
Coconut oil is another plant-based source that contains a very high proportion of saturated fat (82%), but that, curiously, has gained a good reputation over the years. In fact, a recent survey reported that 72% of Americans consider coconut oil a “healthy” food! Two main characteristics of coconut oil, frequently mentioned in mainstream press, explain this popularity:

1) Population studies. Epidemiological studies conducted among populations that consume large quantities of coconut, such as the inhabitants of Polynesian islands like Tokelau or those of the Melanesian island Kitava, revealed a low incidence of heart disease, despite a high intake of saturated fat from this fruit. It should be noted, however, that it is the coconut meat, very high in fibre, that is consumed by these populations, so the lack of effect on cardiovascular disease cannot be extrapolated to that associated with adding purified coconut oil to Western diets, which contain a large proportion of processed foods.

2) Impact on cholesterol. The saturated fat in coconut oil has shorter chains than that found in palm oil or in butter, and, in theory, has less harmful effects on cholesterol levels. About half of saturated fat contained in coconut oil is in the form of lauric acid (12 carbon atoms), and studies show that the effect of this fatty acid on LDL cholesterol is half that of palmitic acid (16 carbon atoms). In practice, however, a systematic review of the studies conducted to date indicates that coconut oil increases LDL cholesterol levels in a similar way to other sources of saturated fat (butter, palm oil) and in a more significant way than unsaturated fat, such as olive oil for example.

Overall, these observations suggest that coconut oil is a source of saturated fat like any other, and that it should be used sparingly to prevent an increase in the risk of heart disease. For everyday cooking, virgin olive oil is a much better choice because of its very well documented positive effects on cardiovascular health. Among other plant-based oils, the use of canola oil is recommended, as it contains the highest proportion of omega-3 polyunsaturated fats, known for their anti-inflammatory effects.