Anti-aging supplements: A new fountain of youth?

Anti-aging supplements: A new fountain of youth?

OVERVIEW

  • Berberine, like the antidiabetic drug metformin, is an activator of an enzyme (AMPK) that is involved in some beneficial anti-aging effects of calorie restriction.
  • Resveratrol and pterostilbene reduce inflammation, the risk of heart disease, cancer and neurodegeneration, in addition to protecting the integrity of the genome through the activation of enzymes called “sirtuins”.
  • Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) supplements are effective in increasing levels of nicotinamide adenine dinucleotide (NAD) which decline with age.
  • Some of these supplements extend the life of several living organisms (yeast, worms, flies) and laboratory animals (mice, rats), but there is no evidence in humans to this effect yet.

For millennia, man has sought to slow aging and prolong life using elixirs, miraculous waters, pills and other supplements. Yet we know today that in communities where people live longer (the “blue zones”), it seems that the “secret” of longevity consists in a lifestyle characterized by sustained physical activity throughout life, a healthy diet composed mainly of plants, and very strong social and family ties.

There is however this idea that certain molecules have anti-aging properties, i.e., that they are able to delay normal aging and therefore prolong life, despite a suboptimal lifestyle. This question is also of interest to scientists who have identified and studied the anti-aging effects of certain molecules, especially on cultured cells and laboratory animals. Several “anti-aging” supplements are commercially available, but are they really effective?

Metformin
Metformin has been a widely prescribed drug for over 60 years to treat type 2 diabetes. Metformin is a synthetic, non-toxic analog of galegine, an active compound extracted from the Galega officinalis (Goat’s rue) plant that was used as early as the 17th century as a remedy for the excessive emission of urine caused by diabetes. It normalizes blood sugar by increasing the insulin sensitivity of the main tissues that use glucose, such as the liver and adipose tissue.

Metformin causes energy stress in the cell by inhibiting complex I of the mitochondrial respiratory chain (energy powerhouse in the cell), which in turn inhibits the enzyme mTORC1 (mechanistic target of rapamycin complex 1) by mechanisms depending or not on the activation of the enzyme AMPK. The mTORC1 complex, composed of the enzyme mTOR (a serine/threonine kinase) and regulatory proteins, is involved in the regulation of several cellular activities (protein synthesis, transcription of DNA into RNA, cell proliferation, growth, motility, and survival) in response to nutrient sensing. It is also involved in the many changes that occur during the slowing down of aging caused by caloric restriction, at the level of mitochondrial function and cellular senescence. Adenosine monophosphate kinase (AMPK) is an enzyme that functions as a central sensor of metabolic signals.

Metformin attenuates the signs of aging and increases the lifespan of several living organisms, including several animal species. In humans, diabetics who take metformin live longer than those who do not take this drug. Undesirable side effects associated with taking metformin include short-term diarrhea, flatulence, stomach pain, and long-term reduced absorption of vitamin B12.

Could metformin delay aging in the general population, as appears to be the case for diabetics? To answer this question, a controlled clinical trial is underway, the TAME (Targeting Aging with Metformin) study, which will be carried out with 3,000 participants aged 65 to 79, recruited from 14 pilot sites in the United States. The six-year study aims to establish whether taking metformin can delay the development or progression of chronic diseases associated with aging, such as cardiovascular disease, cancer and dementia. This study is generating a lot of interest because metformin is an inexpensive drug with a well-established safety profile. If the results are positive, metformin could become the first drug prescribed to treat aging and potentially increase the healthy life expectancy of the elderly.

Berberine
Berberine is an isoquinoline alkaloid that is found in several species of plants: Chinese Coptis (Coptis chinensis), goldenseal (Hydrastis canadensis), and barberry (Berberis vulgaris). Chinese Coptis is one of the 50 fundamental herbs of the traditional Chinese pharmacopoeia and is used primarily to prevent or alleviate symptoms associated with digestive diseases, such as diarrhea. Berberine has many scientifically well-documented biological effects (see these review articles here and here), including anti-inflammatory, anti-tumour, and antiarrhythmic activities, and favourable effects on the regulation of blood sugar and blood lipids. Berberine prolongs the lifespan of Drosophila (fruit flies) and stimulates their locomotor activity.

Figure 1. Structures of berberine and metformin.

Metformin and berberine: Mimetic compounds of calorie restriction
Berberine acts similarly to metformin, although their structures are very different (see Figure 1). Both molecules are activators of an enzyme, AMPK, which functions as a central sensor of metabolic signals. AMPK activation is implicated in some health benefits of long-term calorie restriction. Because of this common mechanism, it has been suggested that metformin and berberine may act as calorie restriction mimetics and increase healthy lifespan. Here are the main potential benefits of AMPK activators that have been identified:

  • reduced risk of atherosclerosis
  • reduced risk of myocardial infarction
  • reduced risk of stroke
  • improvement in metabolic syndrome
  • reduced risk of type 2 diabetes
  • glycemic control in diabetics
  • reduced risk of weight gain
  • reduced risk of certain cancers
  • reduced risk of dementia and other neurodegenerative diseases

It should be noted that no randomized controlled study has yet been published to demonstrate such positive effects in humans.

Resveratrol, pterostilbene
Resveratrol and pterostilbene are natural polyphenolic compounds of the stilbenoid class that are found in small amounts in the skin of grapes (resveratrol), almonds, blueberries and other plants (pterostilbene). Studies have shown (see this review article) that resveratrol can reduce inflammation, the risk of heart disease, cancer, and neurodegenerative disease. Resveratrol activates sirtuin genes, enzymes that protect the integrity of DNA and the epigenome (the set of modifications that are not encoded by the DNA sequence, which regulate the activity of genes in facilitating or preventing their expression). It seems that pterostilbene is a better alternative to resveratrol because it is better absorbed in the intestine and is more stable in the human body. Additionally, some studies indicate that pterostilbene is superior to resveratrol in cardioprotective, anticancer, and antidiabetic effects.

Resveratrol prolongs the life of living organisms such as yeast (+70%), the worm C. elegans (+10-18%), bees (+33-38%), and some fish (+19-56%). However, resveratrol supplementation does not prolong the life of healthy mice or rats. In addition, resveratrol prolonged the life (+31%) of mice whose metabolism was weakened by a high-calorie diet. Resveratrol appears to protect obese mice against fatty liver disease by decreasing inflammation and lipogenesis. Resveratrol is a molecule with high potential to improve health and longevity in humans, but it will not be easy to demonstrate the effectiveness of this molecule on longevity in large-scale clinical trials because of the enormous costs and compliance issues associated with this kind of long-term trial.

Can NAD precursor supplements prevent aging?
Nicotinamide adenine dinucleotide (NAD) plays an essential role in cellular metabolism, as a cofactor or coenzyme in redox reactions (see Figure 2) and as a signalling molecule in various metabolic pathways and other biological processes. NAD is involved in more than 500 distinct enzymatic reactions and is one of the most abundant molecules in the human body (approx. 3 g/person). Biochemistry textbooks still describe the metabolism of NAD in a static way and mainly insist on the conversion reactions (redox) between the oxidized form “NAD+” and the reduced form “NADH” (see Figure 2 below).

Figure 2. Nicotinamide adenine dinucleotide is a coenzyme involved in many redox reactions at the cellular level. The equation at the top of the figure shows the exchange of two electrons in this reaction. Differences in the structures of NAD+ (oxidized form) and NADH (reduced form) are shown in red.

Yet recent research results show that NAD is involved in a host of reactions other than oxidation-reduction. NAD and its metabolites serve as substrates for a wide variety of enzymes that are involved in several aspects of maintaining cellular balance (homeostasis). For example, sirtuins, a family of enzymes that metabolize NAD, have impacts on inflammation, cell growth, circadian rhythm, energy metabolism, neuronal function, and resistance to stress.

Human cells, with the exception of neurons, cannot import NAD. They must therefore synthesize it from the amino acid tryptophan or from one of the forms of vitamin B3, such as nicotinamide (NAM, also known as niacinamide) or nicotinic acid (niacin, NA). The concentration of NAD in the body decreases with age, a decrease that has been associated with metabolic and neurodegenerative pathologies. It was therefore questioned whether it would be possible to delay aging by compensating for the decline with supplements.

There are three approaches to increasing NAD levels in the body:

  • Supplementation with NAD precursors
  • Activation of enzymes involved in the biosynthesis of NAD
  • Inhibition of NAD degradation

NAD precursors
An intake of 15 mg of niacin via the diet maintains homeostatic (constant) levels of NAD. It was long believed that this niacin intake was optimal for the entire population; however, it has been shown that the levels of NAD decrease with age and that supplementation which brings the levels of NAD to a normal value, or slightly above, has benefits for the health of living organisms, from yeast to rodents.

Nicotinic acid (niacin) supplementation at very high doses (250-1000 mg/day for 4 months) is effective in increasing the concentration of NAD in the body according to a clinical study, but its use is limited by unpleasant side effects, including flushing and itchy skin caused by prostaglandin release (>50 mg niacin/day), fatigue and gastrointestinal effects (>500 mg/day). The other form of vitamin B3, nicotinamide (NAM), has the disadvantage of inhibiting certain enzymes such as PARP and sirtuins, so researchers believe that other precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are more promising since they do not inhibit these same enzymes. NMN is found in nature, particularly in fruits and vegetables (broccoli, cabbage, cucumber, avocado, edamame), but the dietary intake of NMN is too low to help maintain constant levels of NAD in the body.

NR is well tolerated and a daily oral dose of 1000 mg results in a substantial increase in blood and muscle NAD levels, stimulation of mitochondrial energy activity and a decrease in inflammatory cytokines in the bloodstream. Studies in animals or cells in culture indicate that NR supplementation has positive health effects and neuroprotective effects in models of Cockayne syndrome (inherited disease due to a defect in DNA repair), noise-induced injuries, amyotrophic lateral sclerosis, Alzheimer’s and Parkinson’s diseases.

Figure 3. Structures of four forms of vitamin B3, precursors of NAD. The similarity between the structures of these molecules is indicated in blue and black, the differences in red. These four molecules are all precursors of NAD (see text).

Effect of NAD supplementation on neurodegeneration
A phase I controlled clinical trial (NADPARK study) was carried out in order to establish whether oral NR supplementation can actually increase the levels of NAD in the brain and have impacts on the cerebral metabolism of patients suffering from Parkinson’s disease. Thirty newly diagnosed patients were treated daily for 30 days with 1000 mg of NR or a placebo. Supplementation was well tolerated and significantly, albeit variably, increased brain levels of NAD and its metabolites as measured by 31phosphorus nuclear magnetic resonance. In patients who received NR and had an increase in NAD in the brain, changes in brain metabolism were observed, associated with slight clinical improvements. These results, published in 2022, are considered promising by researchers who are in the process of conducting a phase II clinical trial (NOPARK study), which aims to establish whether or not NR supplementation can delay the degeneration of dopaminergic neurons of the nigrostriatal region of the brain and clinical disease progression in patients with early-stage Parkinson’s disease.

Effect of NAD supplementation on aging
Studies show that NR and MNM supplementation increases NAD levels in mice, and slightly increases the lifespan of these animals. Other beneficial effects reported in mice include improved muscle endurance, protection against complications of diabetes, slowed progression of neurodegeneration, and improvements in the heart, liver and kidneys. In humans, few well-done studies have been carried out to date and these were of short duration and produced mostly disappointing results, unlike the data obtained in animals. The relatively short lifespan of mice (2 to 3 years) makes it possible to test the effect of supplements on their longevity, but this type of experiment cannot be considered in humans who have a much longer life expectancy.

NNM and NR supplements are available over-the-counter and the U.S. Food and Drug Administration (FDA) has determined that, based on available data, they are safe to consume (it should be noted that unlike medications, the US FDA does not evaluate the therapeutic efficacy of supplements). Not all over-the-counter supplements are of equal quality, so it is recommended to choose products that are GMP certified (Good Manufacturing Practice, a regulation promulgated by the FDA). Please note that, given the state of knowledge on the subject, we do not encourage the use of NMN or NR supplements.

Fortunately, it is possible to do something to maintain a normal level of NAD as you age without having to consume supplements: exercise! A recent study indicates that the decrease in NAD in elderly people who do little or no exercise is not observed in those who do regular physical activity (at least 3 structured physical exercise sessions of at least one hour each per week). These very active older adults (walking an average of 13,000 steps per day) had NAD levels comparable to younger adult participants. NAD levels and mitochondrial and muscle function increase with the amount of exercise, as estimated by the number of steps walked daily.

Some supplements are promising and the results of well-conducted studies that are ongoing or to come will need to be carefully monitored. Taking supplements on a daily basis is expensive, their quality is very variable, and some can have side effects (intestinal discomfort for example). In the current state of knowledge, it appears that most of the potential benefits associated with taking these supplements, including longevity, can be achieved simply by combining regular exercise, a healthy plant-based diet, maintenance of a healthy weight (BMI between 18.5 and 25 kg/m2), and caloric restriction (for example by practising intermittent fasting once a week).

The cardiovascular benefits of avocado

The cardiovascular benefits of avocado

OVERVIEW

  • Avocado is an exceptional source of monounsaturated fat, with content similar to that of olive oil.
  • These monounsaturated fats improve the lipid profile, in particular by raising HDL-cholesterol levels, a phenomenon associated with a reduced risk of cardiovascular disease.
  • A recent study confirms this cardioprotective potential of avocado, with a 20% reduction in the risk of coronary heart disease observed in regular consumers (2 or more servings per week).

There is currently a consensus in the scientific community on the importance of favouring dietary sources of unsaturated fats (especially monounsaturated and omega-3 polyunsaturated fats) to significantly reduce the risk of cardiovascular disease and premature mortality (see our article on this subject). With the exception of fatty fish rich in omega-3 (salmon, sardines, mackerel), plant-based foods are the main sources of these unsaturated fats, particularly oils (olive oil and those rich in omega-3 like canola oil), nuts, certain seeds (flax, chia, hemp) as well as fruits such as avocado. Regular consumption of these foods high in unsaturated fats has repeatedly been associated with a marked decrease in the risk of cardiovascular events, a cardioprotective effect that is particularly well documented for extra-virgin olive oil and nuts.

A unique nutritional profile
Although the impact of avocado consumption has been less studied than that of other plant sources of unsaturated fat, it has been suspected for several years that this fruit also exerts positive effects on cardiovascular health. On the one hand, avocado stands out from other fruits for its exceptionally high monounsaturated fat content, with a content (per serving) similar to that of olive oil (Table 1). On the other hand, a serving of avocado contains very high amounts of fibre (4 g), potassium (350 mg), folate (60 µg), and several other vitamins and minerals known to participate in the prevention of cardiovascular disease.

Table 1. Comparison of the lipid profile of avocado and olive oil. The data corresponds to the amount of fatty acids contained in half of a Haas avocado, the main variety consumed in the world, or olive oil (1 tablespoon or 15 mL). Taken from USDA. FoodData Central.

Fatty acidsAvocado (68 g)Olive oil (15 mL)
Total10 g12.7 g
Monounsaturated6.7 g9.4 g
Polyunsaturated1.2 g1.2 g
Saturated1.4 g2.1 g

This positive impact on the heart is also suggested by the results of intervention studies that examined the impact of avocado on certain markers of good cardiovascular health. For example, a meta-analysis of 7 studies (202 participants) indicates that the consumption of avocado is associated with an increase in HDL cholesterol and a decrease in the ratio of total cholesterol to HDL cholesterol, a parameter which is considered to be a good predictor of coronary heart disease mortality. A decrease in triglycerides, total cholesterol and LDL cholesterol levels associated with the consumption of avocado has also been reported, but is, however, not observed in all studies. Nevertheless, the increase in HDL cholesterol observed in all the studies is very encouraging and strongly suggests that avocado could contribute to the prevention of cardiovascular disease.

A cardioprotective fruit
This cardioprotective potential of avocado has just been confirmed by the results of a large-scale epidemiological studycarried out among people enrolled in two large cohorts headed by Harvard University, namely the Nurses’ Health Study (68,786 women) and the Health Professionals Follow-up Study (41,701 men). Over a period of 30 years, researchers periodically collected information on the dietary habits of participants in both studies and subsequently examined the association between avocado consumption and the risk of cardiovascular disease.

The results obtained are very interesting: compared to people who never or very rarely eat them, regular avocado consumers have a risk of coronary heart disease reduced by 16% (1 serving per week) and 21% (2 servings or more per week) (Figure 1).

Figure 1. Association between the frequency of avocado consumption and the risk of coronary heart disease. The quantities indicated refer to one serving of avocado, corresponding to approximately half of the fruit. Taken from Pacheco et al. (2022).

There are therefore only benefits to integrating avocado into our eating habits, especially if its monounsaturated fats replace other sources of fats that are less beneficial to health. According to the researchers’ calculations, replacing half a serving of foods rich in saturated fat (butter, cheese, deli meats) with an equivalent quantity of avocado would reduce the risk of cardiovascular disease by approximately 20%.

Avocados are increasingly popular, especially among young people, and are even predicted to become the 2nd most traded tropical fruit by 2030 globally, just behind bananas. In light of the positive effects of these fruits on cardiovascular health, we can only welcome this new trend.

Obviously, the high demand for avocado creates strong pressures on the fruit’s production systems, particularly in terms of deforestation for the establishment of new crops and increased demand for water. However, it is important to note that the water footprint (the amount of water required for production) of avocado is much lower than that of all animal products, especially beef (Table 2). In addition, as is the case for all plants, the carbon footprint of avocado is also much lower than that of animal products, the production of an avocado generating approximately 0.2 kg of CO2-eq compared to 4 kg for beef.

Table 2. Comparison of the water footprint of avocado and different foods of animal origin. Taken from UNESCO-IHE Institute for Water Education (2010) 

FoodWater footprint
(m3/ton)
Beef15,400
Lamb and sheep10,400
Porc6,000
Chicken4,300
Eggs3,300
Avocado1,981

A pro-inflammatory diet increases the risk of dementia

A pro-inflammatory diet increases the risk of dementia

OVERVIEW

  • In a study on aging and diet conducted in Greece, 1,059 older people reported in detail what they ate for three years.
  • At the end of the study, people with the most inflammatory diet had a 3-fold higher risk of developing dementia compared to those whose diet had a low-inflammatory index.
  • The main anti-inflammatory foods are vegetables, fruits, whole grains, tea, and coffee. The main pro-inflammatory foods that should be avoided or eaten infrequently and in small amounts are red meat, deli meats, refined flours, added sugars, and ultra-processed foods.

Dietary Inflammatory Index
Several studies suggest that the nature of the foods we eat can greatly influence the degree of chronic inflammation and, in turn, the risk of chronic disease, including cardiovascular disease. For example, a pro-inflammatory diet has been associated with an increased risk of cardiovascular disease, with a 40% increase in risk in people with the highest index (see our article on the subject).

Pro-inflammatory diet and risk of dementia
In order to see if there is an association between a diet that promotes systemic inflammation and the risk of developing dementia, 1,059 elderly people residing in Greece were recruited as part of the study Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). Only people without a diagnosis of dementia at the start of the study were included in the cohort. The inflammatory potential of the participants’ diet was estimated using the Dietary Inflammatory Index (DII) based on the known effect of various foods on the blood levels of inflammatory markers . The main pro-inflammatory foods are red meat, deli meats, refined flour, added sugars, and ultra-processed foods. Some of the main anti-inflammatory foods are vegetables, fruits, whole grains, tea, coffee, and red wine.

After a follow-up of 3 years on average, 62 people were diagnosed with dementia. Participants who had the diet with the highest inflammatory index had a three-fold higher risk of developing dementia at the end of the study, compared to those with the least inflammatory index. In addition, there appears to be a dose-response relationship, with an increased risk of dementia that increases by 21% for each unit of the inflammatory index.

Inflammation, interleukin-6, and cognitive decline
The study in Greece is not the first to be conducted on the impact of a pro-inflammatory diet on the incidence of dementia. In a Polish study of 222 postmenopausal women, those with cognitive deficits had significantly higher blood levels of interleukin-6 (IL-6; a marker of inflammation), were less educated, and were less physically active, compared to women with normal cognitive functions. Postmenopausal women who had a pro-inflammatory diet were much more likely to have cognitive impairment compared to those who had an anti-inflammatory diet, even after adjusting for age, height, body mass index, level of education, and levels of physical activity. Each one-point increase in the dietary inflammatory index was associated with a 1.55-fold increase in the risk of cognitive impairment.

In addition to these studies, it is interesting to see that a meta-analysis of 7 prospective studies including 15,828 participants showed that there is an association between the concentration of IL-6 in the blood and the overall cognitive decline in the elderly. Participants who had the most circulating IL-6 had a 42% higher risk of suffering cognitive decline than those with low blood IL-6 levels.

Several studies have suggested that systemic inflammation (i.e., outside the central nervous system) may play a role in neurodegeneration, Alzheimer’s disease, and cognitive decline in older adults. People with Alzheimer’s disease and mild cognitive impairment tend to have high blood levels of markers of inflammation (IL-6, TNF-α, CRP). In addition, a study indicates that people who have elevated levels of markers of inflammation during midlife have an increased risk of cognitive decline in subsequent decades.

Since the studies described above are observational, they do not establish a causal link between inflammatory diet and dementia. They only show that there is an association. Further studies are needed in the future to establish a cause and effect relationship and identify the underlying molecular mechanisms.

Evidence from recent studies should encourage experts to more often recommend diets high in flavonoids that decrease systemic inflammation and are conducive to the maintenance of good cognitive health. Mediterranean-type diets or the hybrid MIND diet (Mediterranean-DASH Intervention for Neurodegenerative Delay) with an abundance of plants are particularly effective in reducing or delaying cognitive decline.

Childhood obesity, a ticking time bomb for cardiometabolic diseases

Childhood obesity, a ticking time bomb for cardiometabolic diseases

OVERVIEW

  • Obesity rates among Canadian children and teens have more than tripled over the past 40 years.
  • Childhood obesity is associated with a marked increase in the risk of type 2 diabetes and cardiovascular disease in adulthood, which can significantly reduce healthy life expectancy.
  • Policies to improve the diet of young people are key to reversing this trend and preventing an epidemic ofcardiometabolic diseases affecting young adults in the coming years.

One of the most dramatic changes to have occurred in recent years is undoubtedly the marked increase in the number of overweight children. For example, obesity rates among Canadian children and adolescents have more than tripled over the past 40 years. Whereas in 1975, obesity was a fairly rare problem affecting less than 3% of children aged 5–19, the prevalence of obesity has made a gigantic leap since that time, affecting nearly 14% of boys and 10% of girls in 2016 (Figure 1). If data on overweight is added to these figures, then approximately 25% of young Canadians are overweight (a similar trend is observed in Quebec). This prevalence of obesity appears to have plateaued in recent years, but recent US surveys suggest that the COVID-19 pandemic may have caused an upsurge in the number of overweight young people, particularly among 5-11-year-olds.

Figure 1. Increase in the prevalence of obesity among Canadian children over the past 40 years. From NCD Risk Factor Collaboration (2017).

Measuring childhood obesity
Although not perfect, the most common measure used to determine the presence of overweight in young people under the age of 19 is the body mass index (BMI), calculated by dividing the weight by the square of height (kg/m²). However, the values obtained must be adjusted according to age and sex to take into account changes in body composition during growth, as shown in Figure 2.

Figure 2. WHO growth standards for boys aged 5–19 living in Canada. Data comes from WHO (2007).

Note that a wide range of BMI on either side of the median (50th percentile) is considered normal. Overweight children have a BMI higher than that of 85–95% of the population of the same age (85th-95th percentile), while the BMI of obese children is higher than that of 97% of the population of the same age (97th percentile and above). Using z-scores is another way to visualize childhood overweight and obesity. This measurement expresses the deviation of the BMI from the mean value, in standard deviation. For example, a z-score of 1 means that the BMI is one standard deviation above normal (corresponding to overweight), while z-scores of 2 and 3 indicate, respectively, the presence of obesity and severe obesity.

This marked increase in the proportion of overweight children, and particularly obese children, is a worrying trend that bodes very badly for the health of future generations of adults. On the one hand, it is well established that obesity during childhood (and especially during adolescence) represents a very high risk factor for obesity in adulthood, with more than 80% of obese adults who were already obese during their childhood. This obesity in adulthood is associated with an increased risk of a host of health problems, both from a cardiovascular point of view (hypertension, dyslipidemia, ischemic diseases) and the development of metabolic abnormalities (hyperglycemia, resistance to insulin, type 2 diabetes) and certain types of cancer. Obesity can also cause discrimination and social stigma and therefore have devastating consequences on the quality of life, both physically and mentally.

Another very damaging aspect of childhood obesity, which is rarely mentioned, is the dramatic acceleration of the development of all the diseases associated with overweight. In other words, obese children are not only at higher risk of suffering from the various pathologies caused by obesity in adulthood, but these diseases can also affect them at an early age, sometimes even before reaching adulthood, and thus considerably reduce their healthy life expectancy. These early impacts of childhood obesity on the development of diseases associated with overweight are well illustrated by the results of several recent studies on type 2 diabetes and cardiovascular disease.

Early diabetes
Traditionally, type 2 diabetes was an extremely rare disease among young people (it was even called “adult diabetes” at one time), but its incidence has increased dramatically with the rise in the proportion of obese young people. For example, recent US statistics show that the prevalence of type 2 diabetes in children aged 10–19 has increased from 0.34 per 1000 children in 2001 to 0.67 in 2017, an increase of almost 100% since the beginning of the millennium.

The main risk factors for early diabetes are obesity, especially severe obesity (BMI greater than 35) or when the excess fat is mainly located in the abdomen, a family history of the disease, and belonging to certain ethnic groups. However, obesity remains the main risk factor for type 2 diabetes: in obese children (4–10 years) and adolescents (11–18 years), glucose intolerance is frequently observed during induced hyperglycemia tests, a phenomenon caused by the early development of insulin resistance. A characteristic of type 2 diabetes in young people is its rapid development. Whereas in adults, the transition from a prediabetic state to clearly defined diabetes is generally a gradual process, occurring over a period of 5–10 years, this transition can occur very quickly in young people, in less than 2 years. This means that the disease is much more aggressive in young people than in older people and can cause the early onset of various complications, particularly at the cardiovascular level.

A recent study, published in the prestigious New England Journal of Medicine, clearly illustrates the dangers that arise from early-onset type 2 diabetes, appearing during childhood or adolescence. In this study, the researchers recruited extremely obese children (BMI ≥ 35) who had been diagnosed with type 2 diabetes in adolescence and subsequently examined for ten years the evolution of different risk factors and pathologies associated with this disease.

The results are very worrying, because the vast majority of patients in the study developed one or more complications during follow-up that significantly increased their risk of developing serious health problems (Figure 3). Of particular note is the high incidence of hypertension, dyslipidemia (LDL-cholesterol and triglyceride levels too high), and kidney (nephropathies) and nerve damage (neuropathies) in this population, which, it should be remembered, is only 26 years on average. Worse still, almost a third of these young adults had 2 or more complications, which obviously increases the risk of deterioration of their health even more. Moreover, it should be noted that 17 serious cardiovascular accidents (infarction, heart failure, stroke) occurred during the follow-up period, which is abnormally high given the young age of the patients and the relatively small number of people who participated in the study (500 patients).

Figure 3. Incidence of different complications associated with type 2 diabetes in adolescents. From TODAY Study Group (2021).

It should also be noted that these complications occurred despite the fact that the majority of these patients were treated with antidiabetic drugs such as metformin or insulin. This is consistent with several studies showing that type 2 diabetes is much harder to control in young people than in middle-aged people. The mechanisms responsible for this difference are still poorly understood, but it seems that the development of insulin resistance and the deterioration of the pancreatic cells that produce this hormone progress much faster in young people than in older people, which complicates blood sugar control and increases the risk of complications.

This difficulty in effectively treating early type 2 diabetes means that young diabetics are much more at risk of dying prematurely than non-diabetics (Figure 4). For example, young people who develop early diabetes, before the age of 30, have a mortality rate 3 times higher than the population of the same age who is not diabetic. This increase remains significant, although less pronounced, until about age 50, while cases of diabetes that appear at older ages (60 years and over) do not have a major impact on mortality compared to the general population. It should be noted that this increase in mortality affecting the youngest diabetics is particularly pronounced at a young age, around 40 years of age.

These results therefore show how early type 2 diabetes can lead to a rapid deterioration in health and take decades off life, including years that are often considered the most productive of life (forties and fifties). For all these reasons, type 2 diabetes must be considered one of the main collateral damages of childhood obesity.

Figure 4. Age-standardized mortality rates for diagnosis of type 2 diabetes. Standardized mortality rates represent the ratio of mortality observed in individuals with diabetes to anticipated mortality for each age group. From Al-Saeed et al. (2016).

Cardiovascular disease
In recent years, there has been an upsurge in the incidence of cardiovascular disease in young adults. This new trend is surprising given that mortality from cardiovascular diseases has been in constant decline for several years in the general population (thanks in particular to a reduction in the number of smokers and improved treatments), and one might have expected that young people would also benefit from these positive developments.

The data collected so far strongly suggests that the increase in the prevalence of obesity among young people contributes to this upsurge of premature cardiovascular diseases, before the age of 55. On the one hand, it has been shown that a genetic predisposition to develop overweight during childhood is associated with an increased risk of coronary heart disease (and type 2 diabetes) in adulthood. On the other hand, this increased risk has also been observed in long-term studies examining the association between the weight of individuals during childhood and the incidence of cardiovascular events once they have reached adulthood. For example, a large Danish study of over 275,000 school-aged children (7–13 years old) showed that each one-unit increase in BMI z-score at these ages (see legend to Figure 2 for the definition of the z-score) was associated with an increased risk of cardiovascular disease in adulthood, after 25 years (Figure 5).

This increased risk is directly proportional to the age at which children are overweight, i.e., the more a high BMI is present at older ages, the greater the risk of suffering a cardiovascular event later in adulthood. For example, an increase of 1 in the z -score of 13-year-old children is associated with twice as much of an increase in risk in adulthood as a similar increase in a 7-year-old child (Figure 5). Similar results are observed for girls, but the increased risk of cardiovascular disease is lower than for boys.


Figure 5. Relationship between body mass index in childhood and the risk of cardiovascular disease in adulthood. The values represent the risks associated with a 1-unit increase in BMI z-score at each age. From Baker et al. (2007).

Early atherosclerosis
Several studies suggest that the increased risk of cardiovascular disease in adulthood observed in overweight children is a consequence of the early development of several risk factors that accelerate the process of atherosclerosis. Autopsy studies of obese adolescents who died of non-cardiovascular causes (e.g., accidents) revealed that fibrous atherosclerotic plaques were already present in the aorta and coronary arteries, indicating an abnormally rapid progression of atherosclerosis.

As mentioned earlier, type 2 diabetes is certainly the worst risk factor that can generate this premature progression, because the vast majority of diabetic children and adolescents very quickly develop several abnormalities that considerably increase the risk of serious damage to blood vessels (Figure 3). But even without the presence of early diabetes, studies show that several risk factors for cardiovascular disease are already present in overweight children, such as hypertension, dyslipidemia, chronic inflammation, glucose intolerance or even vascular abnormalities (thickening of the internal wall of the carotid artery, for example). Exposure to these factors that begins in childhood therefore creates favourable conditions for the premature development of atherosclerosis, thereby increasing the risk of cardiovascular events in adulthood.

It should be noted, however, that the negative impact of childhood obesity on health in adulthood is not irreversible. Indeed, studies show that people who were overweight or obese during childhood, but who had a normal weight in adulthood, have a risk of cardiovascular disease similar to that of people who have been thin all their lives. However, obesity is extremely difficult to treat, both in childhood and in adulthood, and the best way to avoid prolonged chronic exposure to excess fat and damage to cardiovascular health (and health in general) which results from it is obviously to prevent the problem at the source by modifying lifestyle factors, which are closely associated with an increased risk of developing overweight, in particular the nature of the diet and physical activity (psychosocial stress may also play a role). Given the catastrophic effects of childhood obesity on health, cardiovascular health in particular, the potential for this early preventive approach (called “primordial prevention”) is immense and could help halt the current rise in diabetes and premature mortality affecting young adults.

Ideal cardiovascular health
A recent study shows how this primordial prevention approach can have an extraordinary impact on cardiovascular health. In this study, researchers determined the ideal cardiovascular health score, as defined by the American Heart Association (Table 1), of more than 3 million South Koreans with an average age of 20–39 years. Excess weight is a very important element of this score because of its influence on other risk factors also used in the score such as hypertension, fasting hyperglycemia and cholesterol.

Participants were followed for a period of approximately 16 years, and the incidence of premature cardiovascular disease (before age 55) was assessed using as the primary endpoint a combination of hospitalization for infarction, stroke, cardiac insufficiency, or sudden cardiac death.

Table 1. Parameters used to define the ideal cardiovascular health score. Since there is 1 point for each target reached, a score of 6 reflects optimal cardiovascular health. Adapted from Lloyd-Jones et al. (2010), excluding dietary factors that were not assessed in the Korean study.

As shown in Figure 6, cardiovascular health in early adulthood has a decisive influence on the risk of cardiovascular events that occur prematurely, before the age of 55. Compared to participants in very poor cardiovascular health at the start (score of 0), each additional target reached reduces the risk of cardiovascular events, with maximum protection of approximately 85% in people whose lifestyle allows achieving 5 or more ideal heart health targets (scores of 5 and 6). Similar results were obtained in the United States and show how early health, from childhood through young adulthood, plays a key role in preventing the development of cardiovascular disease during aging.

Figure 6. Influence of cardiovascular health in young adults on the risk of premature cardiovascular events. From Lee et al. (2021).

Yet our society remains strangely passive in the face of the rise in childhood obesity, as if the increase in body weight of children and adolescents has become the norm and that nothing can be done to reverse this trend. This lack of interest is really difficult to understand, because the current situation is a ticking time bomb that risks causing a tsunami of premature chronic diseases in the near future, affecting young adults. This is an extremely worrying scenario if we consider that our healthcare system, in addition to having to contend with diseases that affect an aging population (1 out of 4 Quebecers will be over 65 in 2030), will also have to deal with younger patients suffering from cardiometabolic diseases caused by overweight. Needless to say, this will be a significant burden on healthcare systems.

This situation is not inevitable, however, as governments have concrete legislative means that can be used to try to reverse this trend. Several policies aimed at improving diet quality to prevent disease can be quickly implemented:

  • Taxing sugary drinks. A simple and straightforward approach that has been adopted by several countries is to introduce a tax on industrial food products, especially soft drinks. The principle is the same as for all taxes affecting other products harmful to health such as alcohol and tobacco, i.e., an increase in prices is generally associated with a reduction in consumption. Studies that have examined the impact of this approach for soft drinks indicate that this is indeed the case, with reductions in consumption observed (among others) in Mexico, Berkeley (California) and Barbados. This approach therefore represents a promising tool, especially if the amounts collected are reinvested in order to improve the diet of the population (subsidies for the purchase of fruit and vegetables, for example).
  • Requiring clear nutrition labels on packaging. We can help consumers make informed choices by clearly indicating on the front of the product whether it is high in sugar, fat or salt, as is the case in Chile (see our article on this subject).
  • Eliminating the marketing of unhealthy foods for children. The example of Chile also shows that severe restrictions can be imposed on the marketing of junk food products by prohibiting the advertising of these products in programs or websites aimed at young people as well as by prohibiting their sale in schools. The United Kingdom plans to take such an approach very soon by eliminating all advertising online and on television of products high in sugar, salt and fat before 9 p.m., while Mexico has gone even further by banning all sales of junk food products to children.

There is no reason Canada should not adopt such approaches to protect the health of young people.

Lignans: Compounds of plant origin that promote good cardiovascular health

Lignans: Compounds of plant origin that promote good cardiovascular health

OVERVIEW

  • Dietary lignans are phenolic compounds that come mainly from plant-based foods, especially seeds, whole grains, fruits, vegetables, wine, tea and coffee.
  • Consumption of lignans is associated with a reduced risk of developing cardiovascular disease, according to several well-conducted studies.

There are over 8,000 phenolic and polyphenolic compounds found in plants. These compounds are not nutrients, but they have various beneficial biological activities in the human body. They are generally grouped into 4 classes: phenolic acids, flavonoids, stilbenes (e.g., resveratrol), and lignans. Lignans are dimers of monolignols, which can also be used in the synthesis of a long branched polymer, lignin, found in the walls of the conductive vessels of plants. From a nutritional standpoint, lignins are considered to be a component of insoluble dietary fibre.

Figure 1. Structures of the main dietary lignans

Dietary lignans, the most important of which are matairesinol, secoisolariciresinol, pinoresinol and lariciresinol, come mainly from plant-based foods, particularly seeds, whole grains, fruits, vegetables, wine, tea and coffee (see Table 1). Other lignans are found only in certain types of food, such as medioresinol (sesame seeds, rye, lemon), syringaresinol (grains), sesamin (sesame seeds). Lignans are converted into enterolignans by the gut microbiota, which are then absorbed into the bloodstream and distributed throughout the body.

Table 1. Lignan content of commonly consumed foods.
Adapted from Peterson et al., 2010 and Rodriguez-Garcia et al., 2019.

Several studies indicate that lignans can prevent cardiovascular disease and other chronic diseases, including cancer, and improve cardiovascular health, through its anti-inflammatory and estrogenic properties (the ability to bind to estrogen receptors).

A recently published US study indicates that there is a significant association between dietary intake of lignans and the incidence of coronary heart disease. Among the 214,108 people from 3 cohorts of healthcare professionals, those who consumed the most lignans (total) had a 15% lower risk of developing coronary heart disease than those who consumed little. Considering each lignan separately, the association was particularly favourable for matairesinol (-24%), compared to secoisolariciresinol (-13%), pinoresinol (-11%), and lariciresinol (-11%). There is a nonlinear dose-response relationship for total lignans, matairesinol, and secoisolariciresinol with a plateau (maximum effect) at approximately 300 µg/day, 10 µg/day, and 100 µg/day, respectively. Canadians consume an average of 857 µg of lignans per day, enough to benefit from the positive effects on cardiovascular health, but residents of some Western countries such as the United Kingdom, the United States and Germany do not have an optimal intake of lignans (Table 2).

The favourable association for lignans was especially apparent among participants who had a high dietary fibre intake. The authors of the study suggest that fibre, by supporting a healthy microbiota, may promote the production of enterolignans in the gut.

Table 2. Daily intake of lignans in Western countries.
Adapted from Peterson et al., 2010.

PREDIMED (Prevención con Dieta Mediterránea), a recognized study conducted among over 7,000 Spaniards (55–80 years old) at high risk of developing cardiovascular disease, compared the Mediterranean diet (supplemented with nuts and extra virgin olive) to a low-fat diet advocated by the American Heart Association for the prevention of cardiovascular disease (CVD). In this study, the Mediterranean diet was clearly superior to the low-fat diet in preventing CVD, so the study was stopped after 4.8 years for ethical reasons. Further analysis of the PREDIMED data showed that there is a very favourable association between a high dietary intake of polyphenols and the risk of CVD. Participants who consumed the most total polyphenols had a 46% lower risk of CVD than those who consumed the least. The polyphenols that were most strongly associated with reduced risk of CVD were flavanols (-60%), hydroxybenzoic acids (-53%), and lignans (-49%). It should be noted that the nuts and extra virgin olive oil that were consumed daily by participants in the PREDIMED study contain appreciable amounts of lignans.

Another analysis  of data from the PREDIMED study showed a favourable association between total polyphenol intake and the risk of death from any cause. A high intake of total polyphenols, compared to a low intake, was associated with a 37% reduction in the risk of premature mortality. Stilbenes and lignans were the most favourable polyphenols for reducing the risk of mortality, by 52% and 40%, respectively. In this case, flavonoids and phenolic acids were not associated with a significant reduction in mortality risk.

No randomized controlled studies on phenolic compounds and the risk of CVD have been performed to date. There is therefore no direct evidence that lignans protect the cardiovascular system, but all the data from population studies suggests that it is beneficial for health to increase the dietary intake of lignans and therefore to eat more fruits, vegetables, whole grains, legumes, nuts and extra virgin olive oil, which are excellent sources of these still too little known plant-based compounds.

Will cultured meat soon be on our plates?

Will cultured meat soon be on our plates?

OVERVIEW

  • To preserve the planet’s environment and produce enough food to meet growing global demand, experts believe that in the future there will be a need to reduce livestock farming and conventional meat consumption.
  • Cultured meat is presented as a sustainable alternative to farmed meat for those who want to protect the environment but do not want to become vegetarians.
  • For cultured meat to be consumed on a large scale, production techniques and social acceptability will have to make significant progress.

Today there are 7.3 billion human beings on our planet, and it is expected that there will be 9 billion by 2050. The Food and Agriculture Organization (FAO) estimates that in 2050, 70% more food will be required to meet the demand of the growing population. This poses a great challenge because of limited resources and arable land. Meat production (especially beef and pork) is the most resource-intensive, and experts believe it would not be responsible, or even possible, to continue to produce more and more of these foods. Even though meat consumption is declining in developed countries, it is increasing globally because consumers in developing countries are getting richer and meat is seen by the new middle class in these countries as a desirable luxury food.

Among the solutions proposed to get out of this impasse is cultured meat (or lab-grown meat), which is presented as a sustainable alternative to farmed meat for those who want to protect the environment, but who do not wish to become vegetarians. It should be noted that some experts consider that cultured meat poses certain problems and that it would not be a viable alternative to conventional meat (see here and here). We will come back to this a little later in the text.

How is meat grown?
To grow meat, you must first obtain a muscle sample from a live adult animal (by biopsy, under anesthesia) and isolate a subpopulation of cells called “stem” or “satellite” cells. These stem cells participate in muscle regeneration and have the ability to differentiate into muscle cells themselves. The muscle stem cells are then cultured in bioreactors in the presence of a nutrient medium containing growth factors that induce rapid proliferation. The cells are then transformed into muscle cells that form structures called “myotubes” no larger than 0.3 mm in length and mechanically assembled into muscle tissue and ultimately into ground meat or artificial “steak”.

Problematic use of fetal calf serum and growth promoters
The best culture medium for growing cells contains fetal calf serum, obtained from fetal blood after slaughtering a pregnant cow. The procedure usually used (cardiac puncture of the still alive calf fetus) is considered cruel and inhumane by many. This is a problem since large numbers of calves would have to be produced to meet the demand for large-scale meat cultivation, and this use is unacceptable to vegetarians and those who follow a vegan diet or lifestyle. Fortunately, it is now possible, on a laboratory scale, to grow muscle cells without the use of fetal calf serum. However, the serum-free culture will need to be adopted on an industrial scale. To replace fetal calf serum, the industry will need to use growth factors and hormones that will need to be produced on an industrial scale. The use of growth promoters is prohibited in the European Union for conventional meat production; however, you cannot grow meat without using these growth factors and hormones. Overexposure to certain growth promoters can have harmful effects on human health, but this is a subject of debate and several countries approve the supervised use of stimulators in animal production.

From cell to steak
Real muscle (meat) is made up of muscle fibres organized into bundles, blood vessels, nerves, connective tissues, and adipocytes (fat cells). Simply producing animal muscle cells is therefore not enough to recreate meat. This is why in 2013 the first dish prepared from cultivated meat was a simple burger-type patty. Industries that develop cultured meat must now attempt to recreate a 3D structure that will resemble real meat as much as possible, a task that is proving difficult. It’s about recreating the taste experience associated with eating a steak, chicken thigh or shrimp.

Researchers have recently made progress and successfully created small samples of cultured meat that mimic real meat. Using a new approach, a Japanese research group succeeded in growing beef muscle cells in long filaments aligned in a single direction, a structure that closely resembles muscle fibres. When these cultured cells were stimulated by an electric current, the filaments contracted, similar to muscle fibres. Researchers at the University of Tokyo have so far managed to produce pieces of cultured meat weighing a few grams at most. The next challenge will be to successfully produce larger pieces of cultured meat, up to 100 g, and introduce other tissues (blood vessels, fat cells) to mimic meat more convincingly. It should be noted that the culture medium used in this study contained fetal calf serum, an ingredient that cannot be used industrially for ethical and economic reasons, as mentioned above.

Cultured chicken meat
Singapore’s food regulatory agency approved the sale of meat grown by the US company Eat Just in 2020. It was the first time that the sale of cultured meat had been permitted by a state. Eat Just grows chicken meat using a process that does not require antibiotics. This cultured meat is safe because it contains very low levels of bacteria, much less than conventional chicken meat. Cultured chicken meat contains a little more protein, has a more varied amino acid composition, and contains more monounsaturated fat than conventional meat. The muscle cells are grown in 1200-litre bioreactors and then combined with plant ingredients to make chicken nuggets. The Singapore-approved process uses fetal calf serum, but Eat Just plans to use a serum-free culture medium in their future productions.

Estimation of the environmental cost of cultured meat
Cultivated meat production offers many environmental advantages compared to conventional meat, according to a study published in 2011. It would reduce greenhouse gas (GHG) emissions by 78 to 96%, use 7 to 45% less energy and 82 to 96% less water, depending on the type of product. In contrast, a more recent and rigorous study suggests that in the long term, the impact of cultured meat on the environment may be greater than that associated with livestock farming. Cultivated meat production will certainly reduce global warming in the short term since less GHGs will be emitted compared to cattle farming. In the very long term however (i.e., several hundred years), models predict that this would not necessarily be the case, because the main GHG generated by livestock, methane (CH4), does not accumulate in the atmosphere, unlike CO2 which is practically the only GHG generated by cultivated meat. Another study based on data from 15 companies involved in the production of cultured meat concludes that it is less harmful to the environment than the production of beef, but that it has a greater impact on the environment than the production of chicken, pork and plant-based “meat”. In order for the environmental score of cultivated meat to be better than that of conventional products, the industry would have to use only sustainable energy.

Cost of cultured meat
The first cultivated beef burger was produced in 2013 by a Dutch laboratory at an estimated cost of US $416,000. In 2015, the cost of production (on an industrial scale) was reduced to around $12, and it is expected that the price could be the same as conventional meat within ten years. The cultured chicken nuggets produced by Just Eat each cost $63 to produce in 2019, so industries still have some way to go for cultured meat to become affordable enough for consumers to consume on a regular basis.

Cultured meat: an alternative for Canadians?
According to a 2018 Dalhousie University survey of 1,027 Canadians, 32.2% of respondents planned to reduce their meat consumption in the next 6 months. However, cultured meat is not very popular with Canadians as only 18.3% of those consulted said that this new type of “meat” represented an alternative to real meat for them. There is hope, however, as younger consumers (40 and under) seem more likely (34%) to view cultured meat as an alternative.

Will cultured meat one day replace conventional meat on our plates? Although there is still progress to be made before this is possible, both in terms of production and social acceptability, we can hope that the important efforts made will lead to results within a decade. Ideally, for our health and that of the planet, we should reduce our consumption of meat (of all kinds) and eat mainly plants, as is the case with the Mediterranean diet and other traditional diets.