Dr Martin Juneau, M.D., FRCPCardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.12 August 2022
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.
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.
|Duration of the study||Participants||Key results||Source
|13 h (6 a.m.-7 p.m.)||2 weeks||29 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 weeks||5 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 weeks||34 M |
| ←→ weight|
|Moro et al. (2016)
|TRE: 6 h (8 a.m.-2 p.m.)|
Ctl: 12 h (8 a.m.-8 p.m.)
|5 weeks||8 M (avg. 56 years)|
BMI>25 and prediabetes
↓appetite in the evening
|Sutton et al. (2018)
|8 h (10 a.m.-6 p.m.)||12 weeks||41 W, 5 M (avg. 50 years)|
|↓ 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 weeks||12 W, 1 M (29–57 years)|
| ←→ weight|
|Antoni et al. (2018)
Early: 8 a.m.-5 p.m.
Late: 12 p.m.-9 p.m.
|1 week||15 M (avg. 55 years)|
|↓ weight (-0.8 kg)|
↓ postprandial blood glucose
↓ 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
|70 M, 46 W (avg. 47 years)|
|↓ weight (1.2%) for TRE (not significant)||Lowe et al. (2020)
|10 h (time of the participant’s choice)||12 weeks||13 M, 6 W (avg. 59 years)|
(with metabolic syndrome)
|Wilkinson et al. (2020)
|4 h (3 p.m.-7 p.m.)|
6 h (1 p.m.-7 p.m.)
|8 weeks||53 W, 5 M|
(-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 weeks||53 W, 7 M|
|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 weeks||32 W|
|↓weight (-4 kg)|
↓CV risk (Framingham score)
|Schroder et al. (2021)
|8 h (time of the participant’s choice)||12 weeks||37 W, 13 M|
|↓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 weeks||71 M, 68 W (avg. 30 years)|
|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 weeks||64 W, 18 M|
↓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 weeks||69 W, 12 M (avg. 38 years)|
|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 weeks||72 W, 18 M (avg. 43 years)|
|higher weight loss for TRE vs. ctl|
(-6.3 kg vs. -4.0 kg)
|Jamshed et al. (2022)
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.
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.
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.
Dr Martin Juneau, M.D., FRCPCardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.12 May 2022
- 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 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 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 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
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).
Dr Martin Juneau, M.D., FRCPCardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.30 October 2017
Updated on September 11, 2018
The dramatic increase in population body weight over the past 40 years is becoming the major public health problem of our generation. Once a very rare phenomenon, the prevalence of obesity is rising sharply in most countries worldwide, reaching 5% among children (108 million) and 12% among adults (604 million) in 2015. In Canada, the situation is even worse, with no less than 62% of the adult population being overweight, including 27% who are obese. Moreover, this is not improving, as we are also among the top countries with the highest rates of overweight children and adolescents, with 15% of young boys and 10% of young girls who are obese.
These statistics are truly alarming, as overweight, and more specifically obesity, is an important risk factor for a wide range of chronic diseases, including cardiovascular disease, type 2 diabetes, at least 13 types of cancer, and various musculoskeletal disorders. The negative impacts of having an overweight population are already beginning to appear: in the United States, where the prevalence of obesity is one of the highest in the world, a report by the Center for Disease Control and Prevention (CDC) recently showed a decrease in life expectancy due in part to the effects of obesity on cardiovascular disease. In other words, the dramatic increase in the number of overweight people is counteracting the benefits of decreased tobacco use in recent years, with disastrous consequences for both the population’s life expectancy and quality.
Losing weight is hard
Overweight is basically the result of an imbalance caused by the consumption of calories in excess of the body’s energy needs. In theory, the treatment of obesity is therefore relatively simple: it is a matter of restoring a balance between caloric intake and expenditure, for example by eating less and moving more, which causes an energy deficit that leads over time to the dissipation of excess calories accumulated in the form of fat, and, therefore, to weight loss.
In reality, losing weight, and especially maintaining weight loss in the long term, is an extremely difficult task that the majority of overweight people are unable to successfully achieve. For example, in a randomized study on the impact of four popular diets (Atkins, Zone, Weight Watchers and Ornish), researchers noted that the weight loss achieved by each of these diets was relatively modest (in the order of 2-3 kg), a failure that can be explained in large part by the very high attrition rate among participants. Greater weight loss, in the order of 20 kg, can be achieved in the short term with even more severely calorie-deficient diets, but again, adherence to these extreme diets is very low, and weight loss is quickly followed by weight gain. This is a major problem, as obesity is a chronic condition that requires sustained weight loss over a long period of time to significantly reduce the risk of developing the range of problems resulting from being overweight.
This difficulty in losing weight is due to the fact that caloric intake and caloric expenditure are interrelated phenomena that exert a mutual influence in order to maintain a stable body weight. In practical terms, this means that changes in energy balance, whether due to decreased caloric intake and/or increased physical activity levels, are countered by a series of physiological adaptations that resist weight loss, for example by decreasing basal metabolic rate. As a result, even if a person manages to create an energy deficit by eating less or being more active, it is usually offset by a corresponding decrease in the energy expended by the body or by an increase in appetite to compensate for missing calories. The difficulty in losing weight is therefore not due to a lack of willpower, as still too many people think, but rather a consequence of our metabolism’s fierce resistance to anything that is likely to cause weight loss.
In recent years, it has been proposed that low-carbohydrate but high-fat diets (“low-carb, high-fat”, or LCHF) may be a solution to bypass the body’s “defense” mechanisms and increase weight loss (see box for a summary of the scientific aspects of this approach). Since carbohydrates cause a marked increase in insulin levels, which is the hormone involved in the conservation of energy stored in the form of fat, it is proposed that a low-carbohydrate diet could reduce insulin levels, thus allowing the body to mobilize fat stored in adipose tissue and to use it as a source of energy. According to the model, this increased use of fat would result in an increase in metabolism (around 500 kcal/day), and should therefore allow significant weight loss.
In Canada, the food guide recommends consuming about 300 g of carbohydrates per day, which corresponds to 1,200 calories, or 60% of the total calorie consumption of an average adult (2,000 calories). In a low-carbohydrate diet, this proportion is around 20% of total calories (100 g of carbohydrates) and can even decrease to 5% of calories (20 g of carbohydrates, equivalent to a single slice of bread) in ketogenic diets
The principle behind low-carb diets is that calories from carbohydrates favour more accumulation of excess weight than calories from fat. In other words, it is not so much the quantity, but especially the type of calories consumed that are important for weight loss. This hypothesis is based on two well-documented effects of insulin on metabolism:
1) In carbohydrate-rich diets, the insulin secreted by the pancreas allows fat cells to capture the sugars released into the blood and to turn them into fat for future use.
2) Simultaneously, insulin blocks the use of calories accumulated in fat tissue, thus preventing weight loss. These actions of insulin ensure that fat tissue not only accumulates excess calories, but that these calories cannot even be used to support the body’s energy needs.
In other words, even if there is a surplus of stored energy, the body is in famine mode! In response to this deficiency, it reduces its basal metabolic rate to save energy (which helps prevent the use of excess calories) and simultaneously increases appetite to obtain the calories needed to maintain these functions. There is therefore a vicious circle in which excess carbohydrates lead to overweight, and overweight leads to an increase in food consumption. This model would explain the increase in body weight observed in a large number of people with diabetes who are treated with insulin.
The impact of low-carb diets on body weight has been the subject of a very large number of randomized clinical studies over the past two decades. In general, these studies show that in the short term (3 to 6 months), obese or morbidly obese people experience significant weight loss on these diets compared to traditional low-calorie diets (low-fat diets, for example). In most cases, however, weight loss is temporary and decreases considerably over time: the difference in kilos lost 2 years into various diets is minimal and insufficient to have a significant clinical impact (Figure 1).
Figure 1. Comparison of the weight loss achieved with low-carbohydrate or low-fat diets over a 2-year period. Adapted from Foster (2010).
Several meta-analyses of randomized clinical trials comparing weight loss for low-fat and low-carb diets confirm the slight advantage of low-carb diets, but show that additional weight loss from these diets is relatively modest, at around 1-2 kg (Table 1).
Table 1. Summary of meta-analyses comparing weight loss obtained with low-carbohydrate (low-carb) or low-fat diets.
To explain these disappointing results, it should first be mentioned that the theory on which low-carb diets are based, i.e., a decrease in insulin increases the body’s energy expenditure and fat metabolism, seems inaccurate. When researchers rigorously measured energy expenditure in response to diets containing either low amounts of fat or carbohydrates, they observed that the increase in metabolism from low-carb diets is very low and has no major impact on weight loss. In fact, the opposite is true: for equal calories, weight loss is slightly higher for people on a low-fat diet compared to a low-carbohydrate diet.
Hence, there does not seem to be any major advantage to preferentially restricting carbohydrate intake to promote weight loss. Although sometimes significant, the weight loss that occurs in the first few months of these diets tends to diminish over time, becoming similar to results obtained for low-calorie diets. The most important factor is limiting total calories, whether from carbohydrates or fat. In fact, studies show that people who diligently follow low-calorie diets for at least 2 years manage to achieve significant weight loss, whether or not these diets are rich in carbohydrates, fats or proteins.
Impact on cardiovascular health
Several studies have examined the impact of low-carb diets on cardiovascular risk factors and, again, the results do not seem to show significant advantages over conventional low-calorie diets. In the short term, studies indicate that low-carb diets increase HDL cholesterol levels and decrease triglycerides, which is positive, but simultaneously increase LDL cholesterol levels (due to a higher intake of saturated fat), which is negative. However, since these effects disappear over time, they likely do not have major clinical implications. It should be noted that the increase in HDL cholesterol levels observed in response to low-carb diets is maintained over the longer term and remains about twice as high as for people on a low-fat diet. An increase in HDL levels is generally considered beneficial to cardiovascular health, but its real impact in a context where saturated fat intake is high (as with low-carb diets) is yet to be established. Overall, it can be argued that weight loss is the most important factor in improving the cardiovascular health of people who are obese, regardless of the diet used.
It is important to note that the results of the studies mentioned here indicate the average weight loss observed in a population on a given weight loss diet. However, in each of these groups, there are major differences in the response to these diets, with some people losing a lot of weight, others losing less, and some even gaining weight. This phenomenon is observed for all diets, whether they are low in carbohydrates or fat (Figure 2).
Figure 2. Distribution of weight changes for each participant in a study comparing the effectiveness of low-carbohydrate (Atkins) and low-fat (Ornish) diets. Adapted from Gardner (2012).
All of the factors responsible for these significant variations are not yet known, but they likely reflect the heterogeneity of the human metabolism and its very different responses to food. For example, it is known that postprandial glucose responses (a risk factor for cardiovascular disease and premature death) vary considerably from person to person, even when they eat exactly the same meal. A host of factors have been proposed to explain this phenomenon (sleep-wake cycle, mealtime, level of physical activity, composition of the intestinal microbiome), but the degree of insulin sensitivity is certainly among the most important. Several studies have reported that insulin-resistant (diabetic and prediabetic) people lose more weight on a low-carbohydrate diet than on a low-fat diet, whereas, conversely, low-fat diets may work better for people with greater insulin sensitivity. The advantages of a low-carb diet in this population do not seem to be limited to weight loss: a recent study showed that compared to a low-fat diet, a low-carb diet with mainly unsaturated fat resulted in a greater improvement in lipid profile and blood sugar levels, and a reduction in medication in obese and diabetic patients, despite similar weight loss. Low-carbohydrate diets may therefore be a promising approach for the optimal treatment of type 2 diabetes.
It is also possible that a low-carbohydrate diet may have additional positive effects. For example, it has been suggested that the high consumption of carbohydrate-rich foods preferentially increases the accumulation of fat in the viscera and liver, which in turn increases the risk of cardiovascular disease and type 2 diabetes. It has also been suggested that a very low-carbohydrate diet could reduce appetite by increasing blood ketone levels. Low-carb diets are also often associated with higher protein consumption, which could contribute to an increased sense of satiety, thus lowering total caloric intake.
In short, there is no universal solution to weight loss, and low-carbohydrate diets can be an interesting tool to help some people lose weight. One advantage of these diets is the elimination of sources of simple sugars (sweets, soft drinks, foods made with refined flour), which do not provide any useful benefits for health and are known to promote overweight and the development of several chronic diseases. However, a major disadvantage is that these diets limit the intake of certain plant-based foods known to have very positive impacts on the prevention of cardiovascular disease and overall health, such as fruits, legumes and whole grain products.
Another negative aspect of low-carb diets is that they often recommend a high intake of saturated animal fats (red meat, cured meats, dairy products), which increase LDL cholesterol levels, an important risk factor for cardiovascular disease. Recent results indicate that this type of diet can be harmful to health: for example, one study showed that people whose carbohydrate intake was less than 40% of total calories had a 20% higher risk of premature death than those whose carbohydrate intake was 50-55% of total calories. However, this increased risk is only observed in people who replace carbohydrates with animal proteins and fats; when carbohydrates are replaced by foods of plant origin, on the contrary, there is a decrease (18%) in the risk of premature death.
These observations are consistent with several studies showing that the substitution of saturated fat with unsaturated fat is associated with a marked decrease in the risk of cardiovascular events and mortality (Figure 3). People who wish to adopt a low-carb approach are therefore well advised to limit the consumption of saturated fats and instead turn to polyunsaturated fats (avocados, fatty fish, nuts, flaxseed, etc.) as a primary source, due to the well-documented cardioprotective effect of these fats.
Figure 3. Variation in the risk of premature mortality according to the proportion of different types of fat in the diet. Adapted from Wang et al. JAMA Intern. Med. 2016; 176: 1134-1145.
Dr Martin Juneau, M.D., FRCPCardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.19 September 2017
Updated on March 15, 2019
Life expectancy at birth in Canada in 2015 was 84.1 years for women and 80.2 years for men. It has been steadily rising for half a century: in 1960 life expectancy was 74.1 years for women and 71.1 for men. However, it is far from the exceptional longevity observed in specific areas of our planet where we find a large proportion of centenarians. These regions, named “Blue Zones”, have been identified by two demographers, Gianni Pes and Michel Poulain, and journalist Dan Buettner, author of the article The Secrets of Long Life in National Geographic magazine and the book The Blue Zones.
The five Blue Zones identified in the world.
By studying the longevity of the inhabitants of Sardinia, an Italian island in the Mediterranean Sea, the demographers Gianni Pes and Michel Poulain and their collaborators have located the areas where morecentenarianslive. These longevity hot spots, or Blue Zones (the researchers initially used a blue marker to delineate these areas on a map), are located in a mountainous area of the island, the Barbagia, which was still difficult to access a few decades ago. This geographical situation discouraged immigration and promoted consanguinity, reducing the diversity of the genetic heritage. In the area of exceptional longevity, in the southeast of the Province of Nuoro, 91 people have become centenarians among the 18,000 people who were born in the region between 1880 and 1900. In one village in particular, Seulo, 20 centenarians were identified between 1996 and 2016. In comparison, according to Statistics Canada, there were 17.4 centenarians per 100,000 inhabitants in Canada in 2011.
The analysis of genes involved in inflammation, cancer and heart disease did not reveal any significant difference that could be related to the exceptional longevity of the Sardinians. Researchers therefore suspect that environmental characteristics, lifestyle and diet are much more important than genetic predispositions for a long and healthy life. Many of these Sardinian centenarians are shepherds or farmers who have been doing a great deal of outdoor physical activity throughout their lives. The Sardinian diet, which is part of the Mediterranean diet, could play an important role in the longevity of the inhabitants of this Blue Zone. Indeed, the Sardinian diet consists of homegrown vegetables (mainly beans, tomatoes, eggplants), whole-grain bread, Pecorino cheese made from whole milk from grass-fed sheep, and local red wine particularly rich in polyphenols. The traditional Sardinian diet included meat once a week at most.
When journalist Dan Buettner asked some of these centenarians the reason for their exceptional longevity, many mentioned the importance of family and social ties; in Sardinia, elderly people live with their family rather than in retirement homes. The elderly who live in the Sardinian Blue Zone believe they have excellent mental well-being and report few symptoms of depression. An Italian study of 160 elders of the Sardinian Blue Zone reports that the trait of resilience was significantly associated with markers of good mental health. For these seniors, resilience and satisfaction derived from social ties are predictors of all markers of good mental health.
Japan has one of the largest concentrations of centenarians in the world, more than 34.7 per 100,000 inhabitants in 2010. The inhabitants of the islands of the Okinawa archipelago in southwestern Japan have a particularly high life expectancy, and 66.7 centenarians per 100,000 inhabitants have been recorded in this prefecture. Women living in Okinawa are 3 times more likely to live to age 100 than North Americans. The Okinawa diet is plant-based, and includes many leafy green vegetables, sweet potatoes, fish and seafood. The majority of Okinawa’s centenarians maintained a vegetable garden during their lifetime and moderate physical activity, which helps reduce stress and stay in shape. The people of Okinawa traditionally practice self-restraint when it comes to food, by following the Confucian teaching hara hachi bu, which recommends eating so as to be 80% satiated at the end of a meal. Older people in Okinawa are very active and maintain strong family and social ties, for example through regular meetings called moai. It is very important for them to make sense of their life. To have an ikigaiis to have a reason to get up every morning.
Nicoya, Costa Rica
Life expectancy is relatively high in Costa Rica (82.1 for women and 77.4 for men), especially in the region of the Nicoya Peninsula where men aged 60 are 7 times more likely to become centenarians than other Costa Ricans. Like Sardinia, Nicoya is a region that has been relatively isolated for hundreds of years. The cancer mortality rate is 23% lower than in the rest of the country, and Nicoya residents have a plant-based diet (squash, black beans, corn tortillas, plenty of local fruits), but that also includes eggs and meat (chicken and pork). The centenarians of Nicoya are very physically active, have strong family ties as well as strong religious faith, and like to work. Their stress level is low and they are generally very positive and happy.
Loma Linda, United States
The only identified Blue Zone in North America is located in Loma Linda, a city in Southern California, located 100 km east of Los Angeles, where there is a community of 9,000 members of the Seventh-day Adventist Church. In California, a 30-year-old Adventist man will live on average 7.3 years longer than a white Californian of the same age. A 30-year-old Adventist woman will live on average 4.4 years longer than a Californian of the same age. Knowing that about two thirds of Americans die from cardiovascular disease or cancer, it is not surprising that Adventists are living longer as their way of life means they are less at risk of developing these diseases. About half of Adventists are vegetarians or rarely eat meat, and non-vegetarian Adventists are twice as likely to develop cardiovascular disease. The majority of Adventists are non-smokers and do not drink alcohol. As a result, they have a lower incidence of lung cancer than Americans in general. Adventists are physically active and have a very developed community spirit, as they are very religious and their church encourages its members to help one another.
Icaria is a Greek island in the Eastern Aegean Sea where one in three inhabitants will reach the age of 90. The incidence of cancer, cardiovascular disease, diabetes and dementia is significantly lower than the rest of the world. As in Sardinia, Okinawa and other Blue Zones, Icarians maintain a vegetable garden at home and lead a low-stress life. Their diet, of the Mediterranean type, is composed of vegetables (potatoes, peas, lentils, green leafy vegetables), fruits, olive oil, fish, goat milk, dairy products, and a little meat. Icarians eat little sugar and drink coffee, red wine and herbal teas made from rosemary, sage, oregano and artemisia daily. Icarians who observe the calendar of the Greek Orthodox Church must fast regularly, and caloric restriction is known to slow down the aging process in mammals.
The inhabitants of the Blue Zones, Okinawa, Sardinia, Nicoya, Icaria and Loma Linda, share characteristics in their lifestyle that contribute to their longevity. In his book The Blue Zones, Dan Buettner lists 9 common features:
- Moderate and regular physical activity, throughout life.
- Caloric restriction.
- Semi-vegetarianism, food largely sourced from plants.
- Moderate alcohol consumption (especially red wine).
- Give meaning and purpose to life.
- Reduced stress.
- Engagement in spirituality or religion.
- Family is at the centre of life.
- Social commitment, integration in the community.
Dr Martin Juneau, M.D., FRCPCardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.12 July 2017
The excessive accumulation of body fat, particularly when concentrated in the abdomen, is an important risk factor for several diseases, including heart disease, type 2 diabetes, dementia as well as several types of cancer. Consequently, for people who are overweight or obese, weight loss is a very important way to reduce the incidence and progression of several of these diseases.
Many studies show that weight loss is indeed associated with a significant improvement of several aspects of the metabolism. For example, an American study showed that among overweight individuals with diabetes, a 5-10% loss of body weight was associated with a notable improvement of several risk factors for heart disease (glycemia, blood pressure, triglycerides, HDL cholesterol) after one year. These positive effects are even more pronounced when weight loss is more significant, in particular with regard to sugar metabolism, but the key takeaway is that weight loss, even when relatively modest, has a very positive impact on health.
Unfortunately, losing weight is not a “small” matter, since it entails significantly reducing calorie intake for long periods. However, the results of the CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) study show that it is possible: in this study, conducted over two years, participants successfully reduced their calorie intake by 12%, which translated into a 10% weight loss and a significant improvement of several cardiometabolic risk factors. However, this decrease in calorie intake was well below what researchers wanted (25%), even though participants were closely monitored and could ask for advice from several specialists in the research team. Significantly reducing food consumption, namely by 500 to 600 calories daily, thus represents a difficult objective to achieve for most people, which explains the well-documented difficulty of adhering, in the long term, to popular weight loss diets developed over the last few years. Generally, these diets are associated with relatively significant short-term weight loss, but it is very difficult to maintain this loss in the longer term and the majority of people regain the lost pounds (and sometimes even more) after a certain time. When these diets are repeatedly attempted, they cause what is known as the “yo-yo” effect, which is not only discouraging but can also be harmful to health: in fact, a recent study showed that in patients with a history of cardiovascular events, frequent body-weight fluctuations were associated with a marked increase in the risk of myocardial infarction (117%), stroke (136%), diabetes (78%), and premature death (124%).
Strict but brief restriction
To overcome these limitations, more and more researchers have focused on fasting as a way to take advantage of the benefits associated with caloric restriction. Instead of consistently reducing the number of calories consumed every day, which seems virtually impossible for the majority of people, this approach involves alternating periods of normal calorie intake with more or less prolonged fasting periods. What we refer to as “intermittent fasting”, for example, consists of fasting or drastically reducing calorie intake (500 calories a day) intermittently, for example, 1 or 2 days a week. These fasting periods can be consecutive, as in the 5:2 diet (5 days of normal diet followed by two days of fasting), or alternating (one out of two days, for example). In both cases, studies show that intermittent fasting is associated with weight loss and an improvement of several cardiometabolic markers, similar to the results obtained following continuous caloric restriction, and could therefore present an interesting alternative.
Nevertheless, an inherent limit to this type of strict fasting is that it remains very difficult for many people to completely deprive themselves of food for 2-3 days. Not to mention that the complete elimination of calories can lead to severe complications in some people, in particular in elderly or frail subjects.
It is in this context that Dr. Valter Longo’s team (University of South California) came up with the idea of developing a diet that reproduces the positive effects of fasting on the body, but without completely forgoing food. Their research conducted on mice showed that a less strict caloric restriction (calories reduced by half), achieved through a plant-based diet high in polyunsaturated fats but low in protein and carbohydrates, could mimic the effects of very strict fasting on several cardiometabolic risk factors and was associated with a significant improvement on health (fewer cancers, reduction in bone-density loss, improvement of cognitive performance) as well as of the life expectancy of the animals. Referred to as the “fasting mimicking diet” (FMD), this new type of caloric restriction could thus represent a new approach to not only lose weight but also improve health in general.
This strategy’s potential is clearly illustrated by the results of a phase 2 clinical study recently published in Science Translational Medicine. The 100 study participants were divided into a control group that followed their usual diet, and a study group that were prescribed the FMD for 5 consecutive days every month, for a period of three months. Afterward, the groups were switched, meaning that the participants from the first control group tested the FMD, whereas the volunteers in the study group reverted to their usually dietary habits.
The results obtained are extremely interesting. One week following the end of the third caloric restriction cycle using the FMD, participants had lost on average 3 kilos (6.6 lb.), had a smaller waistline (3 cm), and showed an improvement in their blood pressure compared to the control group (- 4 mm Hg). Positive effects of caloric restriction on fasting glucose, the lipid profile (triglycerides, cholesterol), inflammatory protein levels (C-reactive protein), and certain growth factors such as IGF-1 (implicated in the development of cancer) were also observed, in particular in individuals who presented anomalies in these markers at the start of the study. For example, the blood sugar level of participants who were prediabetic at the beginning of the study returned to normal after the intervention.
Caloric restriction using the FMD is still at the experimental stage and further research is necessary to better evaluate its effects in the longer term. In the meantime, one thing is certain: most chronic diseases currently affecting the population are a consequence of the overconsumption of food, and there are only advantages to eating less, even if only a few days a month.
Pr. Normand Mousseau, Ph.D.Professeur de physique à l’Université de Montréal, titulaire de la Chaire de recherche de l’UdeM sur les matériaux complexes, l’énergie et les ressources naturelles et directeur académique de l’Institut de l’énergie Trottier.20 April 2017
Type 2 diabetes is without question one of the most serious consequences of being overweight. With the steady increase in obesity worldwide, the International Diabetes Federation estimates that 415 million adults have diabetes, and that 318 million are “pre-diabetic,” i.e., have chronic glucose intolerance, which puts them at high risk of eventually developing the disease. This is a major concern, as diabetes causes premature aging of the blood vessels and significantly increases the risk of cardiovascular disease.
Type 2 diabetes is generally considered to be a chronic, irreversible and incurable disease, for which the only therapeutic option is to limit the damage caused by hyperglycemia. In this testimonial, Normand Mousseau, Professor of Physics at Université de Montréal, demonstrates that this is not the case, and that drastic lifestyle changes leading to significant weight loss may be sufficient to restore blood glucose levels and to completely eliminate diabetes without medical or pharmacological intervention. This is a spectacular example of the immense potential of lifestyle to not only prevent but also cure certain diseases resulting from being overweight.
I was diagnosed with type 2 diabetes four years ago, in May 2013. Seeking treatment for an infection that would not heal, I consulted a doctor. I was 46, I didn’t have a family physician and hadn’t had a medical examination in a long time. Indeed, despite being very overweight – at the time, I weighed 230 pounds (104 kg) at 5’11” (180 cm) – I thought I was in good health.
A few days after the blood test recommended by my doctor, he gave me the bad news: my fasting blood sugar exceeded 14 mmol/l, double the threshold for diabetes. When I asked him what I could do to heal, he replied that type 2 diabetes is a chronic and degenerative disease. All I could do was slow its progression and limit its effects by combining medication with weight loss, better nutrition, and a little physical exercise.
The news hit me hard: type 2 diabetes is a terrible and insidious disease that affects quality of life, and even causes death.
As soon as I was diagnosed, I decided to change my lifestyle. While taking 500 then 850 mg of metformin twice a day, I cut sugar, added a lot of vegetables to my diet, and started running. I also learned to use a blood glucose meter to monitor the daily fluctuations in my blood sugar, in constant fear that it might exceed acceptable thresholds.
As a result of these lifestyle changes, I quite rapidly lost about 30 pounds. By the end of 2013, I was running 5 to 7 km two or three times a week and weighed around 195 pounds. My diabetes was still there, however, as was the certainty that the disease would progress and that all of my efforts would be in vain.
Finally, almost a year after my diagnosis, in April 2014, I decided to redouble my efforts and checked for myself whether type 2 diabetes was really a chronic disease. After a few days of research in medical journals and on the Internet, among the false promises and half-truths, I found news that seemed credible and confirmed that yes, type 2 diabetes can be cured!
The treatment proposed by Professor Roy Taylor of Lancaster University in the United Kingdom is alarmingly simple: you have to lose weight, usually a lot, and probably quickly.
Taylor’s approach is based on three sets of results, some of which date back more than 50 years:
- First, it has been known since the mid-1970s that a large percentage of people with type 2 diabetes who undergo bariatric surgery to reduce stomach size and facilitate weight loss recover from diabetes, so the disease is not irreversible;
- Second, it has been known for about 20 years that the beta cells of the pancreas, which are responsible for the production of insulin, are very sensitive to the presence of fat molecules;
- Finally, thanks to magnetic imaging, it has been observed that, even in a group of people with a healthy weight, some individuals with diabetes show an above-average presence of fat in their internal organs.
Based on this work, Taylor concluded that the presence of fat in internal organs is toxic to the pancreas, and that reducing it can allow the organ to function normally again. He then developed an approach that he tested on 13 diabetic and overweight individuals: for two months, they adopted a very low-calorie diet of 600 to 700 calories a day. Despite the small study size, the results, published in 2011, are staggering: the majority of participants reached blood glucose levels below the diabetes threshold and maintained normal blood glucose levels for three months after the end of the study. In a journal article published shortly afterwards, Taylor stated that his approach also worked for people on insulin.
I was astounded when I read this research. Could the solution be that simple?
Since I had little to lose by testing the approach, except for a little weight, I started on a very low-calorie diet, adopting an alternating two-phase approach:
- a 600-calorie diet for 8 to 10 days, eating a minimum of 200 g of vegetables, and drinking 2 litres of water a day
- three weeks on a more reasonable 1,500-calorie diet.
By the end of my third 600-calorie round in August 2014, I weighed 165 pounds, had lost about 30 pounds, and was completely cured, with fasting blood glucose levels of about 5.8 mmol/l, without any medication. One year later, in October 2015, my weight had stabilized around 170 pounds, my HbA1c was 5.1%, and my blood sugar was 5.7 mmol/l.
Almost three years after the end of my treatment, I am eating normally while monitoring my weight, I run 8 to 10 km 3 times a week, and I maintain my fasting blood sugar levels around 5.7 mmol/l. Of course, I am still at risk of developing type 2 diabetes – my genetic predisposition hasn’t disappeared! – and if I regain the weight, it is very likely that after some time my pancreas will start to fail again. However, I am no longer diabetic, and that is a great relief.
Since the publication of my book last year, I’ve received many testimonials from people of all ages reporting their success in beating their type 2 diabetes by following this diet. Some of them shared that their doctors were simply amazed. All of them told me that their lives had been changed as a result.
Despite its simplicity, this treatment isn’t easy: losing weight demands significant effort; keeping it off requires iron will and a profound lifestyle change. However, it is worth the effort, as type 2 diabetes is a devastating disease that greatly reduces our quality of life. So, there is no reason not to start today!
Professor of Physics, Université de Montréal
Author of the book “Comment se débarrasser du diabète de type 2 sans chirurgie ni médicament”, Éditions du Boréal (2016).
Lim, E. L., K. G. Hollingsworth, B. S. Aribisala, M. J. Chen, J. C. Mathers and R. Taylor (2011). “Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol.” Diabetologia 54(10): 2506-2514.
Taylor, R. (2013). “Banting Memorial lecture 2012: reversing the twin cycles of type 2 diabetes.” Diabet Med 30(3): 267-275.
Tham, C. J., N. Howes and C. W. le Roux (2014). “The role of bariatric surgery in the treatment of diabetes.” Therapeutic Advances in Chronic Disease T5: 149-157.