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

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

Cardiologue 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.

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?

Cardiologue 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

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).

Brisk walking associated with a slowing down of the aging process

Brisk walking associated with a slowing down of the aging process

Cardiologue 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.26 April 2022

OVERVIEW

  • According to a study of more than 400,000 participants, walking pace is associated with telomere length, a genetic marker of biological age.
  • Among the participants, aged 56.5 years on average, those who walked the fastest had telomeres whose length was equivalent to a biological age 16 years younger.
  • This association depended on the intensity of walking (speed) and not on the total amount of physical activity.

Telomeres are repetitive DNA structures found at both ends of chromosomes that ensure the integrity of the genome during cell division (see also our article on the subject). Each time a cell divides, the telomeres shorten, until they become too short and the cell can no longer divide; it becomes senescent and eventually dies. The accumulation of senescent cells in the organs of the human body contributes to the development of diseases related to aging and frailty. Researchers consider telomere length to be a marker of “biological age”, independent of an individual’s date of birth.

The benefits of walking on physical and mental health are well documented, but researchers wanted to know if brisk walking could also be associated with slowing biological aging, as estimated by telomere length. In the UK study, 405,981 participants with an average age of 56.5 years reported information on walking speed, either by self-report or by wearing an accelerometer-type recording device. Telomere length was assessed in leukocytes (white blood cells) by PCR from a blood sample from each of the participants. The results show that faster walking speed was associated with longer telomeres (younger biological age) regardless of the total amount of physical activity. Complex statistical analyses (bidirectional Mendelian randomization) suggest a causal link between walking speed and telomere length, but not the reverse, i.e., that the lengthening of the telomeres is not responsible for a greater walking speed. A causal link can only be established with certainty by well-controlled and well-conducted intervention studies.

The results of this study reinforce the importance of brisk walking for the maintenance of good health. An earlier study by the same researchers at the University of Leicester in the UK indicated that as little as 10 minutes of brisk walking was associated with longer life expectancy, up to 20 years longer when comparing fast walkers to slow walkers. Brisk walking can be done at any age, indoors or outdoors, and requires no special athletic skills or expensive equipment.

Anti-aging effect of a healthy lifestyle

Anti-aging effect of a healthy lifestyle

Cardiologue 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.21 January 2019

According to recent studies, adopting a healthy lifestyle, i.e., eating well, exercising, managing stress, and not smoking or drinking too much alcohol, has beneficial effects on the aging of our cells. One of the well-documented phenomena that occur during cellular aging is the degradation of telomeres, unique structures found at the ends of each of our chromosomes; however, a healthy lifestyle can slow down this process

Telomeres and aging
Telomeres are repetitive DNA structures, shaped like a “hairpin”, found at both ends of chromosomes and that ensure the integrity of the genome during cell division. At each division, the telomeres shorten until they become too short to fulfill their protective function: the cell can no longer divide and enters senescence, then dies. Telomere shortening is countered by the action of telomerase, an enzyme that lengthens telomeres during each DNA replication. Telomere shortening in peripheral blood mononuclear cells (lymphocytes and monocytes) is associated with aging and aging-related diseases such as cancer, stroke, dementia, cardiovascular disease, obesity, osteoporosis and type 2 diabetes. Leukocyte telomere length is significantly, albeit weakly, associated with mortality, but cannot predict survival as well as other variables (age, mobility, cognition, smoking, daily life activities).

Physical activity
Physical training improves many aspects of human health, including exercise capacity, blood pressure regulation, insulin sensitivity, lipid profile, reduction of abdominal fat and inflammation. These beneficial effects contribute to increased endothelial function, delay the progression of atherosclerotic lesions, and improve collateralization of blood vessels in people with type 2 diabetes, coronary artery disease and heart failure. The underlying mechanisms are known in part, but details at the molecular level are less well known and are the subject of much research.

The process of cellular aging can be slowed down by sustained exercise. A study published in 2009 showed that sustained physical training in young and middle-aged athletes was associated with higher telomerase activity, increased expression of telomere-stabilizing proteins, and longer telomeres, compared to sedentary people.

The same research group recently conducted a randomized controlled trial to demonstrate that exercise is the cause of increased telomerase activity and telomere length. The results of the study were published in 2018 in the European Heart Journal. The researchers recruited 124 middle-aged men and women (≈50 years) who were in good health, but did not exercise. During the six-month study, participants were randomly divided into four groups: a control group and three groups that did different types of exercise 3 times a week; one group did endurance training (walking/running, 45 min/day); another group exercised at high intensity intervals (4 min at high intensity/4 min rest, repeated 4 times); and the third group did resistance exercises (various weight machines). Blood samples were taken before, during, and at the end of the study to measure telomere length and telomerase activity in leukocytes (white blood cells).

At the end of the study, those who exercised, regardless of the type, had better cardiorespiratory capacity than at the beginning of the study. Telomerase activity was 2–3 times higher in the leukocytes of those who did endurance or interval exercises, compared to the control group. However, this effect was not observed in people who did resistance exercises (weight training). Similarly, telomere length was greater in those who did endurance or interval exercises, but not in those who did resistance exercise.

These results suggest that endurance exercises such as running, brisk walking or swimming are more effective than resistance exercises to keep longer telomeres and delay cellular aging. It should not be concluded, however, that resistance exercises are useless for healthy aging. Resistance exercises increase overall fitness, which is one of the most important indicators of longevity. The researchers suggest further study on the effects of various combinations of endurance and resistance exercises on cellular aging. The lead author concludes that the central message of his study is that it is never too late to start exercising and that it will have beneficial effects on aging.

Proteomic approach to the effects of exercise
Researchers have studied the effects of endurance exercise on the expression of 1,129 proteins in the blood plasma (plasma proteome), classified into 10 modules or patterns according to their level of interconnection. Exercise altered protein expression of four modules in young men, and five modules in older men. Modules affected by the exercise included proteins related to signalling pathways involved in wound healing, apoptosis (cell death) regulation, glucose, insulin and cellular stress signalling, as well as immune and inflammatory responses. In addition, several exercise-affected modules could be correlated with physiological and clinical indicators of a healthy life, including diastolic blood pressure, insulin resistance, maximal aerobic capacity, and vascular endothelial function.

Diet
According to a systematic review of studies published on the subject, five studies indicate that fruit and vegetable consumption is associated with longer telomeres, while eight other studies have not identified a significant association. For foods other than fruits and vegetables, including grains and meats, the data are inconclusive as a whole. Some studies, however, indicate unfavourable associations between certain food groups and the length of telomeres: grains, processed meats, sugary drinks, fats and oils. With regard to eating habits, only the Mediterranean diet has been associated with longer telomeres, but not in all the studies published to date. Future larger-scale observational studies and more focused randomized controlled trials could help to better identify which elements of the diet are beneficial for telomere maintenance and help slow the process of cellular aging.

Effect of stress
Several cross-sectional studies have reported associations between telomere stability and stress exposure (review articles here, here and here). The association lasts throughout life and has been observed in children whose mothers had been under significant stress. It seems that even prenatal stress indirectly experienced by the fœtus is associated with shorter telomeres after birth. Prolonged or repeated exposure to stress is associated with a shortening of telomeres and the development of age-related diseases such as type 2 diabetes, heart disease, dementia and osteoarthritis. According to some studies, people with bipolar disorder, schizophrenia, major depression and post-traumatic stress disorder have shorter telomeres. Stress and mental illnesses therefore have direct effects on the aging of our cells, with consequences for health over the course of life.

Global lifestyle
For men diagnosed with low-grade prostate cancer, adopting a completely different and healthy lifestyle (plant-based, low-fat diet, exercise, stress management, social support) has been associated with a 10% increase in telomere length in their lymphocytes and monocytes, five years after the start of the intervention. Participants in the control group (active surveillance only), on the contrary, saw the average length of their telomeres decrease slightly (-3%). This intervention study included only a small group of people (n = 30), so larger-scale randomized controlled trials are needed to confirm these findings.

There is growing evidence that physical activity has a significant influence on health and quality of life as people age. For example, older people who exercise regularly are often in better shape, they are more muscular, and they are less likely to develop chronic illnesses or physical disabilities than sedentary seniors. Adopting a lifestyle that combines healthy eating, regular exercise and stress management is certainly one of the best things one can do to prevent or fight age-related diseases.