Time-restricted eating, a promising approach for chronic disease prevention

Time-restricted eating, a promising approach for chronic disease prevention

Over the past few years, we have repeatedly commented (here, here, and here) on the research that has looked at the benefits associated with intermittent fasting and calorie restriction in general. In this article, we approach this subject from a more general angle: how can we explain that the simple fact of restricting caloric intake to a shorter window of time can lead to such benefits?

It is now clearly established that what we eat daily has a huge influence on the development of all chronic diseases. As we have mentioned several times, many studies have indeed shown that a high intake of plants (fruits, vegetables, whole grains, legumes, nuts and seeds) is associated with a significant reduction in the risk of these diseases, while conversely, the risk of overweight, cardiovascular disease, type 2 diabetes, several types of cancer and premature mortality is increased by excessive consumption of animal products (meat and deli meats in particular) as well as ultra-processed industrial foods.

However, diet quality does not seem to be the only parameter that can modulate the risk of these chronic diseases; indeed, many studies carried out in recent years suggest that the period of time during which food is consumed also plays a very important role. For example, preclinical studies have revealed that rodents that have continuous access to food rich in sugar and fat develop excess weight and several metabolic disturbances implicated in the genesis of chronic diseases (insulin resistance, in particular), while those who eat the same amount of food, but in a shorter amount of time, do not show these metabolic abnormalities and do not accumulate excess weight.

In other words, it would not only be the amount of calories that matters, but also the window of time during which these calories are consumed. This new concept of time-restricted eating (TRE) is truly revolutionary and is currently attracting enormous interest from the scientific and medical communities.

Intermittent fasting
Strictly speaking, time-restricted eating is a form of intermittent fasting since calorie intake is restricted to relatively short periods of the day (e.g., 6–8 h), alternating with periods of fasting ranging from 16 to 18 h (a popular formula is the 16:8 diet, i.e. a 16 h fast followed by an 8 h eating window). This type of intermittent fasting is generally easier to adopt than other more restrictive types of fasting such as the 5:2 diet, in which 5 days of normal eating is interspersed with 2 days (consecutive or not) where the calorie intake is zero or very low, or alternate day fasting (one day out of two of fasting, alternating). Since TRE is simply eating an early dinner or a late lunch to achieve a 16–18 h period of not eating, this type of intermittent fasting usually does not cause major lifestyle changes and is therefore within reach of most people.

Eating too much and too often
The interest in TRE and other forms of intermittent fasting can be seen, to some extent, as a reaction to the sharp increase in the number of overweight people observed in recent decades. Statistics show that 2/3 of Canadians are currently overweight (BMI>25), including a third who are obese (BMI>30), and this overweight has become so much the norm that we forget how much our collective waist circumference has skyrocketed over the past 50 years.

For example, statistics published by the US Centers for Disease Control and Prevention (CDC) indicate that between 1960 and 2010, the average weight of an American man increased from 166 pounds to 196 pounds (75 to 89 kg), while that of women increased from 140 pounds to 166 pounds (63 to 75 kg) (Figure 1). In other words, on average, a woman currently weighs the same as a man who lived during the ’60s! No wonder people are much thinner than they are today in family photos or movies from that era.

Figure 1. Increase in average body weight of the US population over the past decades. Adapted from data from the CDC. Note that the average weight of women in 2010 was identical to that of men in 1960 (red circles). A similar trend, as measured by the increase in the body mass index, has been observed in several regions of the world, including Quebec.

The overconsumption of calories, especially those from ultra-processed industrial foods, is certainly one of the main factors that have contributed to this rapid increase in the body weight of the population. The environment in which we live strongly encourages this excessive intake of energy (aggressive advertising, processed foods overloaded with sugar and fat, almost unlimited availability of food products), so that collectively we eat not only too much, but also too often. For example, a study carried out in the United States showed that what is generally considered to be the standard diet, i.e. the consumption of three meals a day spread over a period of 12 hours, is on the contrary a fairly marginal phenomenon (less than 10% of the population). In fact, the study showed that most people eat multiple times throughout the day (and evening), with an average interval of only 3 hours between calorie consumption periods. According to this study, more than half of the population consumes its food over a period of 15 hours or more per day, which obviously increases the risks of excessive energy intake. It should also be noted that these researchers observed that for the vast majority of participants, all the food consumed after 6:30 p.m. exceeded their energy needs.

Weight (and metabolism) control
Several studies suggest that intermittent fasting, including TRE, represents a valid approach to correct these excesses and restore the caloric balance essential for maintaining a normal body weight. Obviously, this is particularly true for obese people who eat more than 15 hours a day. For these people, simply reducing their eating window to 10–12 hours, without necessarily making special efforts to restrict their calorie intake, is associated with a reduction in body weight.

Most studies that have looked at the effect of TRE on body weight find similar results, namely that in overweight people, simply restricting the eating period to a window of 8–10 h generally leads to weight loss in the following weeks (Table 1). This loss is quite modest overall (2–4% of body weight), but can, however, become more significant when TRE is combined with a low-calorie diet.

It would, however, be reductionist to see TRE simply as an approach for controlling body weight. In practice, studies indicate that even in the absence of weight loss (or when the loss is very modest), TRE improves certain key aspects of metabolism. For example, in overweight, prediabetic men, reducing the eating window from 12 to 6 h for 5 weeks did not result in significant weight loss, but was nonetheless associated with lower resistance to insulin and fasting blood glucose. These results were confirmed by a subsequent study; in the latter case, however, the TRE-induced decrease in blood sugar only seems to occur when the eating window is in the first portion of the day (8 a.m.-5 p.m.) and is not observed for longer late windows (12 p.m.-9 p.m.). This superiority of TRE performed at the start of the day in reducing fasting blood glucose has been observed in other studies, but remains unexplained to date.

It should also be noted that these positive impacts of TRE on glucose metabolism are also observed in people of normal weight (BMI=22), which underlines how the benefits of TRE go far beyond simple weight loss.

Table 1. Examples of studies investigating the effects of TRE on body weight and metabolism.

Eating
window
Duration of the studyParticipantsKey resultsSource
13 h (6 a.m.-7 p.m.)2 weeks29 M (avg. 21 years) BMI=25
↓ weight (-0.4 kg)
↓ caloric intake

LeCheminant et al. (2013)
10–12 h (time at the choice of the participant)16 weeks5 M, 8 W (24–30 years) BMI>30
↓ weight (-3.3 kg)
↑ sleep quality
Gill and Panda (2015)
TRE: 8 h (1 p.m.-9 p.m.)
Ctl: 13 h (8 a.m.-9 p.m.)
8 weeks34 M
BMI=30
←→ weight
↓IGF-1
↓body fat
Moro et al. (2016)
TRE: 6 h (8 a.m.-2 p.m.)
Ctl: 12 h (8 a.m.-8 p.m.)

5 weeks8 M (avg. 56 years)
BMI>25 and prediabetes

←→ weight
↓insulin resistance
↓postprandial insulin
↓blood pressure
↓appetite in the evening
Sutton et al. (2018)
8 h (10 a.m.-6 p.m.)12 weeks41 W, 5 M (avg. 50 years)
BMI=35
↓ weight (-2.6%)
↓ caloric intake
↓ blood pressure
Gabel et al. (2018)
3 h less than usual
(breakfast 1.5 hours later; dinner 1.5 hours earlier)
10 weeks12 W, 1 M (29–57 years)
BMI=20-39
←→ weight
↓caloric intake
↓body fat
Antoni et al. (2018)
9 h
Early: 8 a.m.-5 p.m.
Late: 12 p.m.-9 p.m.
1 week15 M (avg. 55 years)
BMI>25
↓ weight (-0.8 kg)
↓ postprandial blood glucose
↓ TG
↓ fasting blood glucose (only for early TRE)
Hutchison et al. (2019)
TRE: 8 h (12 p.m.-8 p.m.)
Ctl: 3 meals at fixed times
12 weeks
70 M, 46 W (avg. 47 years)
BMI>25
↓ weight (1.2%) for TRE (not significant)Lowe et al. (2020)
10 h (time of the participant’s choice)12 weeks13 M, 6 W (avg. 59 years)
(with metabolic syndrome)
↓weight
↓waist circumference
↓blood pressure
↓LDL cholesterol
↓HbA1C
Wilkinson et al. (2020)
4 h (3 p.m.-7 p.m.)
6 h (1 p.m.-7 p.m.)
8 weeks53 W, 5 M
BMI>30
↓weight (3%)
↓insulin resistance
↓oxidative stress
↓caloric intake
(-500 kCal/d on average)
(no diff. between 4 h and 6 h)
Cienfuegos et al. (2020)
TRE: 10 h
Ctl: 12 h
(calorie deficit of 1000 kCal/d in both cases)
8 weeks53 W, 7 M
BMI>35
higher weight loss for TRE vs. ctl
(-8.5% vs. -7.1%)
↓ fasting blood glucose (only for TRE)
Peeke et al. (2021)
8 h (12 p.m.-8 p.m.)12 weeks32 W
BMI>32
↓weight (-4 kg)
↓CV risk (Framingham score)
Schroder et al. (2021)
8 h (time of the participant’s choice)12 weeks37 W, 13 M
BMI=35
↓weight (-5%)Przulj et al. (2021)
TRE: 8 h (8 a.m.-4 p.m.)
Ctl: 10 h
(In both cases, calorie reduction to 1800 kCal/d for men and 1500 kCal/d for women)
52 weeks71 M, 68 W (avg. 30 years)
BMI>30
higher weight loss for TRE vs. ctl
(-8 kg vs. -6.3 kg)
Liu et al. (2022)
TRE: 8 h
Early: 6 a.m.-2 p.m.
Late: 11 a.m.-7 p.m.
5 weeks64 W, 18 M
BMI=22
↓caloric intake
↓insulin resistance (early TRE)
↓fasting blood glucose (early TRE)
Xie et al. (2022)
TRE: 10 h (from breakfast)
Ctl: no time limit
(calorie reduction of 35% in both cases)
12 weeks69 W, 12 M (avg. 38 years)
BMI=34
higher weight loss for TRE vs. ctl
(-6.2 kg vs. -5.1 kg)
Thomas et al. (2022)
ART: 8h (7h-15h)
Ctl : ≥12h
TRE: 8 h (7 a.m.-3 p.m.)
Ctl: ≥12 h
(calorie reduction of 500kCal/d in both cases)
14 weeks72 W, 18 M (avg. 43 years)
BMI>30
higher weight loss for TRE vs. ctl
(-6.3 kg vs. -4.0 kg)
Jamshed et al. (2022)

Metabolic rhythms
The reasons for the positive impact of time-restricted eating are both very simple and eminently complex. First of all, simple in that we can intuitively understand that metabolism, like any job, requires periods of rest to optimize performance and avoid overheating and exhaustion.

During evolution, these metabolic work-rest cycles have developed in response to the Earth’s day-night cycle, which roughly corresponds to our sleep-wake cycle (Figure 2). During the day, we are in active mode and the main function of metabolism is to extract the energy contained in food (glucose, fatty acids, proteins) to meet the needs of the day. On the other hand, the metabolism is also predictable and economical, and a portion of this energy is not used immediately, but is rather stored in the form of glucose polymers (glycogen) or transformed into fat and stored at the level of adipose tissue to be used during more or less prolonged periods of fasting.

Figure 2. Rhythm of metabolic processes according to time of day. Most organisms, including humans, have evolved to have circadian rhythms (close to 24 hours) that create optimal time windows for rest, activity, and nutrient intake. This molecular clock coordinates appropriate metabolic responses with the light/dark cycle and improves energy efficiency through the temporal separation of anabolic (insulin secretion, glycogen synthesis, lipogenesis) and catabolic (lipolysis, glycogen breakdown) reactions in peripheral tissues. Disruptions in this cycle, for example following nutritional intake outside of the preferred time window, compromise organ functions and increase the risk of chronic disease. Adapted from Sassi and Sassone-Corsi (2018).

 

In this maintenance mode, which generally corresponds to the rest period (evening, night and beginning of the day), the function of the metabolism is to ensure that the energy supply to our cells remains adequate, even in the absence of food. Glucose stored as glycogen is first used to maintain blood sugar at a constant level, followed by a gradual transition in metabolism to the use of fat as the primary energy source. When the fasting period is prolonged, blood glucose levels become insufficient to keep the brain functioning (neurons are not able to use fatty acids as an energy source) and part of the fat is then used to produce ketone bodies. These ketone bodies can be metabolized by nerve cells (as well as cells in other organs, including muscles and the heart), allowing the body to not only survive a food deficiency, but also maintain physical and mental health needed to obtain this food (people who fast for longer periods of time (≥ 24 h) frequently report a noticeable improvement in their mental acuity). From an evolutionary perspective, this segmentation of metabolism into two distinct phases therefore developed to maximize energy extraction when food is available, while ensuring survival when it is not, during frequent periods of scarcity.

At the molecular level, this metabolic shift from glucose to fat therefore creates the equivalent of “work shifts” where the various enzymes and metabolic hormones active during the day are at rest during the night, while conversely, those which come into action during the night become inactive during the day.

One of the best examples of this finely orchestrated molecular choreography is the cycle governing the production of insulin. During the day, the cessation of melatonin secretion after waking allows the pancreas to produce insulin in response to carbohydrate ingestion, and the ensuing uptake of glucose from the bloodstream is used by cells to keep them functioning. At the same time, insulin also promotes the transformation of glucose into fatty acids in adipose tissue and the creation of an energy reserve for future use. In the evening, therefore at the start of the metabolic maintenance period, the secretion of melatonin (to promote sleep) interferes with that of insulin and the subsequent decrease in the entry of sugar into the cells facilitates the transition to the use of fat as the main source of energy during the rest period.

One of the immediate consequences of eating repeatedly over a long period of time during the day, for example 15 h or more as in the study mentioned earlier, is therefore to completely disrupt this insulin cycle. This is especially true for late evening calorie intake, when melatonin secretion normally signals the metabolism that energy extraction is complete for the day (insulin inhibition) and it is time to place oneself in the maintenance period. The ingestion of calories at this time then falls at a very bad moment, because both components of the metabolism are solicited at the same time and the ensuing cacophony simultaneously disrupts the normal functioning of each of them. For example, it has long been known that late caloric intake is associated with a higher increase in postprandial (post-meal) blood glucose.

Extended rest period
Limiting calorie intake to only 6–8 h of the waking period obviously has the immediate consequence of increasing the duration of the rest and maintenance period of the metabolism. It may not seem like much, but those few extra hours without caloric intake will force into motion a series of metabolic adaptations that are extremely important for the beneficial effects of TRE. This is where it gets complicated, but we can still try to simplify everything by separating these adaptations into two main categories:

  • Optimizing the metabolic transition. As mentioned earlier, the fasting period is associated with the shift from a metabolism focused on glucose as the main source of energy towards fatty acids. On the other hand, when the fasting period is relatively short, around 12 h (for example, the end of dinner around 6 p.m. followed by breakfast at 6 a.m. the next day), this metabolic transition towards fat remains incomplete: the decrease in postprandial glucose levels is correlated with a slight increase in free fatty acids in circulation, but this increase is transient and cancelled upon ingestion of the first meal of the day (Figure 3, left graph). In addition, this time frame is not sufficient to generate significant levels of ketone bodies.

Figure 3. The impact of TRE on the metabolic transition to the use of fat as the main source of energy. After each meal, the blood glucose concentration rises rapidly within 15 minutes, peaking 30–60 minutes after the start of the meal, while the absorption of dietary triglycerides is much slower with a peak that occurs 3 to 5 hours later. This rapid rise in glucose results in a drastic increase in systemic insulin (~400–500 pmol/L) to allow glucose uptake and, simultaneously, acts on adipose tissue to inhibit the release of free fatty acids and block the production of ketone bodies. Therefore, the utilization of carbohydrates accounts for 70–75% of energy expenditure after the consumption of a meal. Hepatic glycogen metabolism then shifts from breakdown (glycogenolysis) to synthesis (glycogenesis) and muscle metabolism shifts from oxidation of fatty acids and amino acids to oxidation of glucose and storage of glycogen. This finely tuned response results in a decrease in blood glucose to <7.8 mmol/L two hours after a meal. During a standard fasting period (12 h) (left figure), blood glucose is maintained at a constant level (about 4.0-5.5 mmol/L), and it is the oxidation of fatty acids that becomes the main source of energy (about 45%, against 35% for glucose and 20% for proteins). When the fasting period exceeds 12 h (right figure), the concentration of glucose and insulin continues to slowly decrease, while that of free fatty acids increases to ensure the metabolic transition to fat oxidation. This transition is also associated with the production of ketone bodies in response to the influx of free fatty acids into the liver. Adapted from Dote-Monterro et al. (2022).

By postponing this first meal for a few hours (or by eating the last meal of the previous day earlier) in order to fast a little longer (16 h, for example), the absence of new food sources of sugar and triglycerides forces the metabolism to turn to the reserves of fatty acids as a source of energy as well as to begin the transformation of a part of these fats into ketone bodies to compensate for the scarcity of glucose (Figure 3, graph on the right).

In other words, by spreading caloric intake over an extended period of time (12+ hours), the excess energy stored as fat is almost never used. For people who regularly consume more calories than they need, there may therefore be a gradual accumulation of fat over time. On the other hand, by restricting this caloric intake over a shorter period of time (less than 12 h), the greater metabolic transition towards fats makes it possible to use these reserves and thus avoid the accumulation of a surplus of energy that can lead to overweight.

  • Saving what you have gained. Another consequence of a prolonged period of fasting is to create a “climate of uncertainty” for the cells as to their future energy supply. If this shortage is prolonged, they then have no other choice but to adopt a cautious approach and to focus on maintaining their gains rather than considering continuing their expansion. To make a simple analogy, when times are tough, we devote our energies to maintaining the house and not to undertaking expansion work. This is exactly the approach favoured by the cells during a fast. In the absence of new sources of energy, the mechanisms involved in growth are put on hold and the residual energy is devoted instead to maintaining and repairing constituents essential to cellular integrity (DNA, mitochondria, proteins, etc.). This “rejuvenation cure” ensures that the general state of health of the cells is improved during a fast, which allows optimal functioning when the energy supply is restored.

Metabolic overheating
To better understand the impact of this adaptation to fasting on the metabolism, it may be useful to first visualize the extent to which the current standard diet, rich in foods of animal origin and ultra-processed foods (which alone currently account for nearly half of the daily calories consumed in Canada), is a perfect growth “cocktail” to create metabolic overheating and encourage the development of various pathologies.

This overheating is mainly caused by the simultaneous presence of two powerful activators of the signalling pathways involved in cell growth: free sugars and animal proteins (Figure 4). In particular, diets rich in protein and certain amino acids (methionine and branched-chain amino acids (BCAAs), mainly found in animal products) are the most effective in activating the GH/IGF-1 pathway involved in cell growth and premature aging. Under normal conditions, the activation of these growth pathways is obviously essential for survival, but when it becomes excessive, for example as a result of overconsumption of calories and/or too frequent food intake (for example over a period of 15 h, as observed in the study mentioned earlier), excess energy that is stored as fat can promote the development of resistance to the action of insulin (see our article on this subject). This insulin signalling disorder is truly problematic, as it catalyzes the onset of a series of metabolic upheavals that will create chronic inflammation and oxidative stress that are damaging to the entire body. These conditions can directly promote the development of the main chronic diseases (cardiovascular, type 2 diabetes, cancer, neurodegeneration) or even indirectly, by accelerating the aging process, one of the main risk factors for these diseases.

Figure 4. Effects of the standard Western diet on metabolism and the risk of chronic diseases. Prolonged daily caloric intake (≥12 h), combined with the presence of simple sugars and animal proteins, strongly activates the pathways involved in growth cells (GH/IGF-1, insulin) and promotes the development of metabolic abnormalities such as overweight and insulin resistance. The ensuing metabolic disturbances create a climate conducive to the development of conditions of chronic oxidative stress and inflammation that damage the cells (glucotoxicity, lipotoxicity, DNA damage, lipid damage and protein damage), accelerate biological aging, and increase the risk of several diseases.

Avoiding overheating
To simplify, we can see intermittent fasting, including TRE, as a way to minimize these risks of metabolic overheating and instead stimulate cellular preservation mechanisms (Figure 5). By restricting caloric intake to a shorter window of time, growth hormones like insulin and IGF-1 are activated, but to a lesser extent, reducing the risk of overweight, insulin resistance and, consequently, metabolic alterations favouring aging and the development of chronic diseases. Additionally, as mentioned before, the longer period of fasting forces the cells to enter maintenance mode and prioritize repairing and maintaining its structures over growth at all costs. At the molecular level, this results in the activation of sensors of the decrease in available energy (AMPK and sirtuins, in particular) and the entry into play of conservation processes such as the repair of proteins and DNA, the synthesis of new mitochondria (mitogenesis), the recycling of damaged components (known as the process of autophagy), and the renewal of stem cells.

It is important to mention that the benefits associated with intermittent fasting will be all the more evident if the energy consumed during the period of caloric intake comes mainly from plants. It has long been known that a plant-based diet (fruits, vegetables, legumes, nuts, seeds, etc.) provides a high intake of vitamins, minerals and certain bioactive compounds (polyphenols, for example), which have anti-inflammatory properties while being excellent sources of complex carbohydrates and unsaturated fats, nutrients that are essential for significantly reducing the risk of chronic diseases, especially cardiovascular diseases. It should also be mentioned that plant-based proteins, being less rich in methionine and branched-chain amino acids (BCAAs), activate GH/IGF-1 and insulin production less strongly than animal proteins and thus reduce the risk of insulin resistance and type 2 diabetes. Since the GH/IGF-1 pathway also represents a potent activator of mTOR (involved in protein synthesis and cell growth), the reduction of GH/IGF-1 by vegetable proteins helps to reduce the activity of this mTOR and thus stimulate autophagy, the recycling of cellular components essential to maintaining cell health.

Figure 5. Metabolic and physiological impacts of time-restricted eating and a predominantly plant-based diet. A caloric intake restricted to a time window of less than 8 hours and composed of plant-based nutrients (complex carbohydrates, unsaturated fats, proteins low in methionine and branched-chain amino acids (BCAAs)) promotes low resistance to insulin, low adiposity, moderate levels of GH/IGF-1 activities, reduced mTOR signalling, and increased autophagy. The combination of these effects improves metabolic functioning, reduces inflammation and oxidative stress, and promotes the maintenance and repair of cellular functions, which can lead to a slowing of the aging process and a decrease in the incidence of several chronic diseases, including diabetes, certain cancers, cardiovascular diseases and neurodegeneration. Adapted from Longo and Anderson (2022).

In short, we can see TRE (and intermittent fasting as a whole) as a simple way to use evolutionarily selected mechanisms to our advantage to optimize the functioning of our metabolism and thus create conditions incompatible with the development of chronic diseases. We must realize that we are currently living in an era of unprecedented food abundance, for which our physiology, which has evolved to deal with the scarcity of food, is completely unsuited. Controlling caloric intake in such an environment is not easy, especially for people who are overweight and who are trying to lose weight by eating less. Indeed,  low-calorie diets are most of the time ineffective in the long term, because caloric restriction is extremely difficult to sustain over long periods of time.

Restricting daily calorie intake to time windows shorter than 12 h, as with TRE, represents an attractive alternative to calorie restriction. On the one hand, it is not necessary to decrease the total amount of calories consumed to control weight, which makes this approach much more accessible for most people (in practice, studies indicate that people who adhere to TRE still decrease their calorie intake, but unintentionally). Additionally, intermittent fasting does not increase appetite hormones like ghrelin (unlike calorie restriction), which makes people less hungry and therefore less likely to “cheat” and abandon this approach.

In sum, TRE can be considered a form of “food self-defence” against the overabundance of calories present in our environment. By minimizing caloric excesses, this moderate and cautious approach helps to better control body weight and thus reduce the risk of all chronic diseases that result from being overweight.

 

 

 

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

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.

Choosing the right sources of carbohydrates is essential for preventing cardiovascular disease

Choosing the right sources of carbohydrates is essential for preventing cardiovascular disease

OVERVIEW

  • Recent studies show that people who regularly consume foods containing low-quality carbohydrates (simple sugars, refined flours) have an increased risk of cardiovascular events and premature mortality.
  • Conversely, a high dietary intake of complex carbohydrates, such as resistant starches and dietary fibre, is associated with a lower risk of cardiovascular disease and improved overall health.
  • Favouring the regular consumption of foods rich in complex carbohydrates (whole grains, legumes, nuts, fruits and vegetables) while reducing that of foods containing simple carbohydrates (processed foods, sugary drinks, etc.) is therefore a simple way to improve cardiovascular health.

It is now well established that a good quality diet is essential for the prevention of cardiovascular disease and the maintenance of good health in general. This link is particularly well documented with regard to dietary fat: several epidemiological studies have indeed reported that too high a dietary intake of saturated fat increases LDL cholesterol levels, an important contributor to the development of atherosclerosis, and is associated with an increased risk of cardiovascular disease. As a result, most experts agree that we should limit the intake of foods containing significant amounts of saturated fat, such as red meat, and instead focus on sources of unsaturated fat, such as vegetable oils (especially extra virgin olive oil and those rich in omega-3s such as canola), as well as nuts, certain seeds (flax, chia, hemp) and fish (see our article on this subject). This roughly corresponds to the Mediterranean diet, a diet that has repeatedly been associated with a lower risk of several chronic diseases, especially cardiovascular disease.

On the carbohydrate side, the consensus that has emerged in recent years is to favour sources of complex carbohydrates such as whole grains, legumes and plants in general while reducing the intake of simple carbohydrates from refined flour and added sugars. Following this recommendation, however, can be much more difficult than one might think, as many available food products contain these low-quality carbohydrates, especially the entire range of ultra-processed products, which account for almost half of the calories consumed by the population. It is therefore very important to learn to distinguish between good and bad carbohydrates, especially since these nutrients are the main source of calories consumed daily by the majority of people. To achieve this, we believe it is useful to recall where carbohydrates come from and how industrial processing of foods can affect their properties and impacts on health.

Sugar polymers
All of the carbohydrates in our diet come from, in one way or another, plants. During the photosynthetic reaction, in addition to forming oxygen (O2) from carbon dioxide in the air (CO2), plants also simultaneously transform the energy contained in solar radiation into chemical energy, in the form of sugar:

6 CO2 + 12 H2O + light → C6H12O6 (glucose) + 6 O2 + 6 H2O

In the vast majority of cases, this sugar made by plants does not remain in this simple sugar form, but is rather used to make complex polymers, i.e., chains containing several hundred (and in some cases thousands) sugar molecules chemically bonded to one another. An important consequence of this arrangement is that the sugar contained in these complex carbohydrates is not immediately accessible and must be extracted by digestion before reaching the bloodstream and serving as a source of energy for the body’s cells. This prerequisite helps prevent sugar from entering the blood too rapidly, which would unbalance the control systems responsible for maintaining the concentration of this molecule at levels just sufficient enough to meet the needs of the body. And these levels are much lower than one might think; on average, the blood of a healthy person contains a maximum of 4 to 5 g of sugar in total, or barely the equivalent of a teaspoon. Dietary intake of complex carbohydrates therefore provides enough energy to support our metabolism, while avoiding excessive fluctuations in blood sugar that could lead to health problems.

Figure 1 illustrates the distribution of the two main types of sugar polymers in the plant cell: starches and fibres.

Figure 1. The physicochemical characteristics and physiological impacts of starches and dietary fibres from plant cells. Adapted from Gill et al. (2021).

Starches. Starches are glucose polymers that the plant stores as an energy reserve in granules (amyloplasts) located inside plant cells. This source of dietary carbohydrates has been part of the human diet since the dawn of time, as evidenced by the recent discovery of genes from bacteria specializing in the digestion of starches in the dental plaque of individuals of the genus Homo who lived more than 100,000 years ago. Even today, a very large number of plants commonly eaten are rich in starch, in particular tubers (potatoes, etc.), cereals (wheat, rice, barley, corn, etc.), pseudocereals (quinoa, chia, etc.), legumes, and fruits.

Digestion of the starches present in these plants releases units of glucose into the bloodstream and thus provides the energy necessary to support cell metabolism. However, several factors can influence the degree and speed of digestion of these starches (and the resulting rise in blood sugar). This is particularly the case with “resistant starches” which are not at all (or very little) digested during gastrointestinal transit and therefore remain intact until they reach the colon. Depending on the factors responsible for their resistance to digestion, three main types of these resistant starches (RS) can be identified:

  • RS-1: These starches are physically inaccessible for digestion because they are trapped inside unbroken plant cells, such as whole grains.
  • RS-2: The sensitivity of starches to digestion can also vary considerably depending on the source and the degree of organization of the glucose chains within the granules. For example, the most common form of starch in the plant kingdom is amylopectin (70–80% of total starch), a polymer made up of several branches of glucose chains. This branched structure increases the contact surface with enzymes specialized in the digestion of starches (amylases) and allows better extraction of the glucose units present in the polymer. The other constituent of starch, amylose, has a much more linear structure which reduces the efficiency of enzymes to extract the glucose present in the polymer. As a result, foods with a higher proportion of amylose are more resistant to breakdown, release less glucose, and therefore cause lower blood sugar levels. This is the case, for example, with legumes, which contain up to 50% of their starch in the form of amylose, which is much more than other commonly consumed sources of starches, such as tubers and grains.
  • RS-3: These resistant starches are formed when starch granules are heated and subsequently cooled. The resulting starch crystallization, a phenomenon called retrogradation, creates a rigid structure that protects the starch from digestive enzymes. Pasta salads, potato salads, and sushi rice are all examples of foods containing resistant starches of this type.

An immediate consequence of this resistance of digestion-resistant starches is that these glucose polymers can be considered dietary fibre from a functional point of view. This is important because, as discussed below, the fermentation of fibre by the hundreds of billions of bacteria (microbiota) present in the colon generates several metabolites that play extremely important roles in the maintenance of good health.

Dietary fibre. Fibres are polymers of glucose present in large quantities in the wall of plant cells where they play an important role in maintaining the structure and rigidity of plants. The structure of these fibres makes them completely resistant to digestion and the sugar they contain does not contribute to energy supply. Traditionally, there are two main types of dietary fibre, soluble and insoluble, each with its own physicochemical properties and physiological effects. Everyone has heard of insoluble fibre (in wheat bran, for example), which increases stool volume and speeds up gastrointestinal transit (the famous “regularity”). This mechanical role of insoluble fibres is important, but from a physiological point of view, it is mainly soluble fibres that deserve special attention because of the many positive effects they have on health.

By capturing water, these soluble fibres increase the viscosity of the digestive contents, which helps to reduce the absorption of sugar and dietary fats and thus to avoid excessive increases in blood sugar and blood lipid levels that can contribute to atherosclerosis (LDL cholesterol, triglycerides). The presence of soluble fibre also slows down gastric emptying and can therefore decrease calorie intake by increasing feelings of satiety. Finally, the bacterial community that resides in the colon (the microbiota) loves soluble fibres (and resistant starches), and this bacterial fermentation generates several bioactive substances, in particular the short chain fatty acids (SCFA) acetate, propionate and butyrate. Several studies carried out in recent years have shown that these molecules exert a myriad of positive effects on the body, whether by reducing chronic inflammation, improving insulin resistance, lowering blood pressure and the risk of cardiovascular disease, or promoting the establishment of a diversified microbiota, optimal for colon health (Table 1).

A compilation of many studies carried out in recent years (185 observational studies and 58 randomized trials, which equates to 135 million person-years) indicates that consuming 25 to 30 g of fibre per day seems optimal to benefit from these protective effects, approximately double the current average consumption.

Table 1. Main physiological effects of dietary fibre. Adapted from Barber (2020).

Physiological effectsBeneficial health impacts
MetabolismImproved insulin sensitivity
Reduced risk of type 2 diabetes
Improved blood sugar and lipid profile
Body weight control
Gut microbiotaPromotes a diversified microbiota
Production of short-chain fatty acids
Cardiovascular systemDecrease in chronic inflammation
Reduced risk of cardiovascular events
Reduction of cardiovascular mortality
Digestive systemDecreased risk of colorectal cancer

Overall, we can therefore see that the consumption of complex carbohydrates is optimal for our metabolism, not only because it ensures an adequate supply of energy in the form of sugar, without causing large fluctuations in blood sugar, but also because it provides the intestinal microbiota with the elements necessary for the production of metabolites essential for the prevention of several chronic diseases and for the maintenance of good health in general.

Modern sugars
The situation is quite different, however, for several sources of carbohydrates in modern diets, especially those found in processed industrial foods. Three main problems are associated with processing:

Simple sugars. Simple sugars (glucose, fructose, galactose, etc.) are the molecules responsible for the sweet taste: the interaction of these sugars with receptors present in the tongue sends a signal to the brain warning it of the presence of an energy source. The brain, which alone consumes no less than 120 g of sugar per day, loves sugar and responds positively to this information, which explains our innate attraction to foods with a sweet taste. On the other hand, since the vast majority of carbohydrates produced by plants are in the form of polymers (starches and fibres), simple sugars are actually quite rare in nature, being mainly found in fruits, vegetables such as beets, or even some grasses (sugar cane). It is therefore only with the industrial production of sugar from sugar cane and beets that consumers’ “sweet tooth” could be satisfied on a large scale and that simple sugars became commonly consumed. For example, data collected in the United States shows that between 1820 and 2016, the intake of simple sugars increased from 6 lb (2.7 kg) to 95 lb (43 kg) per person per year, an increase of about 15 times in just under 200 years (Figure 2).

 

 

Figure 2. Consumption of simple sugars in the United States between 1820 and 2016.  From Guyenet (2018).

Our metabolism is obviously not adapted to this very high intake of simple sugars, far beyond what is normally found in nature. Unlike the sugars found in complex carbohydrates, these simple sugars are absorbed very quickly into the bloodstream and cause very rapid and significant increases in blood sugar. Several studies have shown that people who frequently consume foods containing these simple sugars are more likely to suffer from obesity, type 2 diabetes and cardiovascular disease. For example, studies have found that consuming 2 servings of sugary drinks daily was associated with a 35% increase in the risk of coronary heart disease. When the amount of added sugars consumed represents 25% of daily calories, the risk of heart disease nearly triples. Factors that contribute to this detrimental effect of simple sugars on cardiovascular health include increased blood pressure and triglyceride levels, lowered HDL cholesterol, and increased LDL cholesterol (specifically small, very dense LDLs, which are more harmful to the arteries), as well as an increase in inflammation and oxidative stress.

It is therefore necessary to restrict as much as possible the intake of simple sugars, which should not exceed 10% of the daily energy intake according to the World Health Organization. For the average adult who consumes 2,000 calories per day, that’s just 200 calories, or about 12 teaspoons of sugar or the equivalent of a single can of soft drink.

Refined flour.  Cereals are a major source of carbohydrates (and calories) in most food cultures around the world. When they are in whole form, i.e., they retain the outer shell rich in fibre and the germ containing several vitamins and minerals, cereals are a source of complex carbohydrates (starches) of high quality and beneficial to health. This positive impact of whole grains is well illustrated by the reduced risk of coronary heart disease and mortality observed in a large number of population studies. For example, recent meta-analyses have shown that the consumption of about 50 g of whole grains perday is associated with a 22–30% reduction in cardiovascular disease mortality, a 14–18% reduction in cancer-relatedmortality, and a 19–22% reduction in total mortality.

On the other hand, these positive effects are completely eliminated when the grains are refined with modern industrial metal mills to produce the flour used in the manufacture of a very large number of commonly consumed products (breads, pastries, pasta, desserts, etc.). By removing the outer shell of the grain and its germ, this process improves the texture and shelf life of the flour (the unsaturated fatty acids in the germ are sensitive to rancidity), but at the cost of the almost total elimination of fibres and a marked depletion of several nutrients (minerals, vitamins, unsaturated fatty acids, etc.). Refined flours therefore essentially only contain sugar in the form of starch, this sugar being much easier to assimilate due to the absence of fibres that normally slow down the digestion of starch and the absorption of released sugar (Figure 3).

Figure 3. Schematic representation of a whole and refined grain of wheat.

Fibre deficiency. Fortification processes partially compensate for the losses of certain nutrients (e.g., folic acid) that occur during the refining of cereal grains. On the other hand, the loss of fibre during grain refining is irreversible and is directly responsible for one of the most serious modern dietary deficiencies given the many positive effects of fibre on the prevention of several chronic diseases.

Poor-quality carbohydrates
Low-quality carbohydrate sources with a negative impact on health are therefore foods containing a high amount of simple sugars, having a higher content of refined grains than whole grains, or containing a low amount of fibre (or several of these characteristics simultaneously). A common way to describe these poor-quality carbohydrates is to compare the rise in blood sugar they produce to that of pure glucose, called the glycemic index (GI) (see box). The consumption of food with a high glycemic index causes a rapid and dramatic rise in blood sugar levels, which causes the pancreas to secrete a large amount of insulin to get glucose into the cells. This hyperinsulinemia can cause glucose to drop to too low levels, and the resulting hypoglycemia can ironically stimulate appetite, despite ingesting a large amount of sugar a few hours earlier. Conversely, a food with a low glycemic index produces lower, but sustained, blood sugar levels, which reduces the demand for insulin and helps prevent the fluctuations in blood glucose levels often seen with foods with a high glycemic index. Potatoes, breakfast cereals, white bread, and pastries are all examples of high glycemic index foods, while legumes, vegetables, and nuts are conversely foods with a low glycemic index.

Glycemic index and load
The glycemic index (GI) is calculated by comparing the increase in blood sugar levels produced by the absorption of a given food with that of pure glucose. For example, a food that has a glycemic index of 50 (lentils, for example) produces a blood sugar half as important as glucose (which has a glycemic index of 100). As a general rule, values below 50 are considered to correspond to a low GI, while those above 70 are considered high. The glycemic index, however, does not take into account the amount of carbohydrate in foods, so it is often more appropriate to use the concept of glycemic load (GL). For example, although watermelon and breakfast cereals both have high GIs (75), the low-carbohydrate content of melon (11 g per 100 g) equates to a glycemic load of 8, while 26 g of carbohydrates present in breakfast cereals result in a load of 22, which is three times more. GLs ≥ 20 are considered high, intermediate when between 11 and 19, and low when ≤ 10.

PURE study
Results from the PURE (Prospective Urban and Rural Epidemiology) epidemiological study conducted by Canadian cardiologist Salim Yusuf have confirmed the link between low-quality carbohydrates and the risk of cardiovascular disease. In the first of these studies, published in the prestigious New England Journal of Medicine, researchers examined the association between the glycemic index and the total glycemic load of the diet and the incidence of major cardiovascular events (heart attack, stroke, sudden death, heart failure) in more than 130,000 participants aged 35 to 70, spread across all five continents. The study finds that a diet with a high glycemic index is associated with a significant (25%) increase in the risk of having a major cardiovascular event in people without cardiovascular disease, an increase that reaches 51% in those with pre-existing cardiovascular disease (Figure 4). A similar trend is observed for the glycemic load, but in the latter case, the increased risk seems to affect only those with cardiovascular disease at the start of the study.

Figure 4. Comparison of the risk of cardiovascular events according to the glycemic index or the glycemic load of the diet of healthy people (blue) or with a history of cardiovascular disease (red). The median glycemic index values were 76 for quintile 1 and 91 for quintile 5. For glycemic load, the mean values were 136 g of carbohydrates per day for Q1 and 468 g per day for Q5. Note that the increased risk of cardiovascular events associated with a high glycemic index or load is primarily seen in participants with pre-existing cardiovascular disease. From Jenkins et al. (2021).

The impact of the glycemic index appears to be particularly pronounced in overweight people (Figure 5). Thus, while the increase in the risk of major cardiovascular events is 14% in thin people with a BMI less than 25, it reaches 38% in those who are overweight (BMI over 25).

 

Figure 5. Impact of overweight on the increased risk of cardiovascular events related to the glycemic index of the diet. The values shown represent the increased risk of cardiovascular events observed for each category (quintiles 2 to 5) of the glycemic index compared to the category with the lowest index (quintile 1). The median values of the glycemic indices were 76 for quintile 1; 81 for quintile 2; 86 for quintile 3; 89 for quintile 4; and 91 for quintile 5. Taken from Jenkins et al. (2021).

This result is not so surprising, since it has long been known that excess fat disrupts sugar metabolism, especially by producing insulin resistance. A diet with a high glycemic index therefore exacerbates the rise in postprandial blood sugar already in place due to excess weight, which leads to a greater increase in the risk of cardiovascular disease. The message to be drawn from this study is therefore very clear: a diet containing too many easily assimilated sugars, as measured using the glycemic index, is associated with a significant increase in the risk of suffering a major cardiovascular event. The risk of these events is particularly pronounced for people with less than optimal health, either due to the presence of excess fat or pre-existing cardiovascular disease (or both). Reducing the glycemic index of the diet by consuming more foods containing complex carbohydrates (fruits, vegetables, legumes, nuts) and fewer products containing added sugars or refined flour is therefore an essential prerequisite for preventing the development of cardiovascular disease.

Refined flours
Another part of the PURE study looked more specifically at refined flours as a source of easily assimilated sugars that can abnormally increase blood sugar levels and increase the risk of cardiovascular disease. Researchers observed that a high intake (350 g per day, or 7 servings) of products containing refined flours (white bread, breakfast cereals, cookies, crackers, pastries) was associated with a 33% increase in the risk of coronary heart disease, 47% in the risk of stroke, and 27% in the risk of premature death. These observations therefore confirm the negative impact of refined flours on health and the importance of including as much as possible foods containing whole grains in the diet. The preventive potential of this simple dietary change is enormous since the consumption of whole grains remains extremely low, with the majority of the population of industrialized countries consuming less than 1 serving of whole grains daily, well below the recommended minimum (half of all grain products consumed, or about 5 servings per day).

Wholemeal breads are still a great way to boost the whole-grain intake. However, special attention must be paid to the list of ingredients. In Canada, the law allows up to 5% of the grain to be removed when making whole wheat flour, and the part removed contains most of the germ and a fraction of the bran (fibres). This type of bread is superior to white bread, but it is preferable to choose products made from whole-grain flour which contains all the parts of the grain. Note also that multigrain breads (7-14 grains) always contain 80% wheat flour and a maximum of 20% of a mixture of other grains (otherwise the bread does not rise), so the number of grains does not matter, but what does matter is whether the flour is whole wheat or ideally integral, which is not always the case.

In short, a simple way to reduce the risk of cardiovascular events and improve health in general is to replace as much as possible the intake of foods rich in simple sugars and refined flour with plant-based foods containing complex carbohydrates. In addition to carbohydrates, this simple change alone will influence the nature of the proteins and lipids ingested as well as, at the same time, all the phenomena that promote the appearance and progression of atherosclerotic plaques.

Why do the Japanese have the highest life expectancy in the world?

Why do the Japanese have the highest life expectancy in the world?

OVERVIEW

  • The Japanese have the highest life expectancy at birth among the G7 countries.
  • The higher life expectancy of the Japanese is mainly due to fewer deaths from ischemic heart disease, including myocardial infarction, and cancer (especially breast and prostate).
  • This exceptional longevity is explained by a low rate of obesity and a unique diet, characterized by a low consumption of red meat and a high consumption of fish and plant foods such as soybeans and tea.

Several diets are conducive to the maintenance of good health and to the prevention of cardiovascular disease, for example, the Mediterranean diet, the DASH diet (Dietary Approaches to Stop Hypertension), the vegetarian diet, and the Japanese diet. We often refer to the Mediterranean Diet in these pages, because it is well established scientifically that this diet is particularly beneficial for cardiovascular health. Knowing that the Japanese have the highest life expectancy among the G7 countries, the special diet in Japan has also captured the attention of experts and an informed public in recent years.

Japanese life expectancy
Among the G7 countries, Japan has the highest life expectancy at birth according to 2016 OECD data, particularly for women. Japanese men have a slightly higher life expectancy (81.1 years) than that of Canadian men (80.9 years), while the life expectancy of Japanese women (87.1 years) is significantly higher (2.4 years) than that of Canadian women (84.7 years). The healthy life expectancy of the Japanese, 74.8 years, is also higher than in Canada (73.2 years).

The higher life expectancy of Japanese people is mainly due to fewer deaths from ischemic heart disease and cancers, particularly breast and prostate cancer. This low mortality is mainly attributable to a low rate of obesity, low consumption of red meat, and high consumption of fish and plant foods such as soybeans and tea. In Japan, the obesity rate is low (4.8% for men and 3.7% for women). By comparison, in Canada 24.6% of adult men and 26.2% of adult women were obese (BMI ≥ 30) in 2016. Obesity is an important risk factor for both ischemic heart disease and several types of cancers.

Yet in the early 1960s, Japanese life expectancy was the lowest of any G7 country, mainly due to high mortality from cerebrovascular disease and stomach cancer. The decrease in salt and salty food intake is partly responsible for the decrease in mortality from cerebrovascular disease and stomach cancer. The Japanese consumed an average of 14.5 g of salt/day in 1973 and probably more before that. They eat less salt these days (9.5 g/day in 2017), but it’s still too much. Canadians now consume on average about 7 g of salt/day (2.76 g of sodium/day), almost double the intake recommended by Health Canada.

The Japanese diet
Compared to Canadians, the French, Italians and Americans, the Japanese consume much less meat (especially beef), dairy products, sugar and sweeteners, fruits and potatoes, but much more fish and seafood, rice, soybeans and tea (Table 1). In 2017, the Japanese consumed an average of 2,697 kilocalories per day according to the FAO, significantly less than in Canada (3492 kcal per day), France (3558 kcal per day), Italy (3522 kcal per day), and the United States (3766 kcal per day).

Table 1. Food supply quantity (kg/capita/year) in selected countries in 2013a.

              aAdapted from Tsugane, 2020. FAO data: FAOSTAT (Food and agriculture data) (http://www.fao.org/).

Less red meat, more fish and seafood
The Japanese eat on average almost half as much meat as Canadians (46% less), but twice as much fish and seafood. This considerable difference translates into a reduced dietary intake of saturated fatty acids, which is associated with a lower risk of ischemic heart disease, but an increased risk of stroke. On the contrary, dietary intake of omega-3 fatty acids found in fish and seafood is associated with a reduced risk of ischemic heart disease. The lower consumption of red meat and higher consumption of fish and seafood by the Japanese could therefore explain the lower mortality from ischemic heart disease and the higher mortality from cerebrovascular disease in Japan. Experts believe that the decline in death from cerebrovascular disease is associated with changes in the Japanese diet, specifically increased consumption of animal products and dairy products, and consequently of saturated fat and calcium (a consumption which remains moderate), combined with a decrease in salt consumption. Indeed, contrary to what is observed in the West, the consumption of saturated fat in Japan is associated with a reduction in the risk of hemorrhagic stroke and to a lesser extent of ischemic stroke, according to a meta-analysis of prospective studies. The cause of this difference is not known, but it could be attributable to genetic susceptibility or confounding factors according to the authors of the meta-analysis.

Soybeans
Soy is a food mainly consumed in Asia, including Japan where it is consumed as is after cooking (edamame) and especially in processed form, by fermentation (soy sauce, miso paste, nattō) or by coagulation of soy milk (tofu). It is an important source of isoflavones, molecules that have anticancer properties and are beneficial for good cardiovascular health. Consumption of isoflavones by Asians has been linked to a lower risk of breast and prostate cancer (see our article on the subject).

Sugar
The Japanese consume relatively few sugars and starches, which partly explains the low prevalence of obesity-associated diseases such as ischemic heart disease and breast cancer.

Green tea
The Japanese generally consume green tea with no added sugar. Prospective studies from Japan show that green tea consumption is associated with a lower risk of all-cause mortality and cardiac death.

Westernization of Japanese eating habits
The westernization of the Japanese diet after World War II allowed the inhabitants of this country to be healthier and to reduce mortality caused by infectious diseases, pneumonia and cerebrovascular diseases, thereby considerably increasing their life expectancy. A survey of the eating habits of 88,527 Japanese from 2003 to 2015 indicates that this westernization continues. Based on the daily consumption of 31 food groups, the researchers identified three main types of eating habits:

1- Plant foods and fish
High intakes of vegetables, fruits, legumes, potatoes, mushrooms, seaweed, pickled vegetables, rice, fish, sugar, salt-based seasonings and tea.

2- Bread and dairy
High intakes of bread, dairy products, fruits and sugar. Low intake of rice.

3- Animal foods and oils
High intakes of red and processed meat, eggs, vegetable oils.

A downward trend in the “plant foods and fish” group (the staple of the traditional Japanese diet or washoku) was observed in all age groups. An increase in the “bread and dairy” group was observed in the 50–64 and ≥65 years age groups, but not among the youngest. For the “animal foods and oils” group, an increasing trend was observed during the thirteen years of the study in all age groups except the youngest (20–34 years). The Japanese are eating more and more like Westerners. Will this have an adverse effect on their health and life expectancy? It is too early to know, only the next few decades will tell.

Contribution of genes and lifestyle to the health of the Japanese
Some risk factors for cardiovascular disease and cancer are hereditary, while others are associated with lifestyle (diet, smoking, exercise, etc.). At the turn of the 20th century, there was significant Japanese immigration to the United States (especially California and Hawaii) and South America (Brazil, Peru). After a few generations, the descendants of Japanese migrants adopted the way of life of the host countries. While Japan has one of the lowest incidences of cardiovascular disease in the world, this incidence doubled among the Japanese who migrated to Hawaii and quadrupled among those who chose to live in California according to a 1975 study. What is surprising is that this increase has been observed regardless of blood pressure or cholesterol levels, and seems rather directly related to the abandonment of the traditional Japanese way of life by migrants.

Since the 1970s, the average cholesterol level of the Japanese has nonetheless increased, but despite this and the high rate of smoking in this country, the incidence of coronary heart disease remains substantially lower in Japan than in the West. To better understand these differences, a 2003 study compared the risk factors and diets of Japanese living in Japan with third- and fourth-generation Japanese migrants living in Hawaii in the United States. Men’s blood pressure was significantly higher among Japanese than among Japanese-Americans, while there was no significant difference for women. Far fewer Japanese were treated for hypertension than in Hawaii. More Japanese people (especially men) smoked than Japanese-Americans. Body mass index, blood levels of LDL cholesterol, total cholesterol, glycated hemoglobin (an indicator for diabetes), and fibrinogen (a marker of inflammation) were significantly lower in Japan than in Hawaii. HDL cholesterol (the “good” cholesterol) was higher in the Japanese than in the Japanese-Americans. The dietary intake of total fat and saturated fatty acids (harmful to cardiovascular health) was lower in Japan than in Hawaii. In contrast, the intake of polyunsaturated fatty acids and omega-3 fatty acids (beneficial for good cardiovascular health) was higher in Japan than in Hawaii. These differences may partly explain the lower incidence of coronary heart disease in Japan than in Western industrialized countries.

In other words, even if these migrants have the same basic risk as their compatriots who have remained in the country of origin (age, sex and heredity), the simple fact of adopting the lifestyle of their host country is enough to significantly increase their risk of cardiovascular disease.

Although the Japanese diet is different from those of Western countries, it has similar characteristics to the Mediterranean diet. Why not prepare delicious Japanese soy dishes from time to time (for example, tofu, edamame, miso soup), drink green tea, eat less meat, sugar and starch and more fish? Not only will your meals be more varied, but you could enjoy the health benefits of the Japanese diet.