Anti-aging supplements: A new fountain of youth?

Anti-aging supplements: A new fountain of youth?

OVERVIEW

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

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

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

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

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

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

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

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

Figure 1. Structures of berberine and metformin.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Brisk walking associated with a slowing down of the aging process

Brisk walking associated with a slowing down of the aging process

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

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.