If you are following the anti-aging media news, you’ve heard about the alleged benefits of calorie restriction (also known as food restriction or diet restriction). Studies in numerous species have demonstrated that reduction of calories 30-50% below ad libitum levels of a nutritious diet slows the aging process, increases lifespan, reduces the incidence and delays the onset of age-related diseases, improves stress resistance, and decelerates functional decline.
In a previous article http://www.brinkzone.com/general-health/calorie-restriction-vs-the-bodybuilding-lifestyle/ Will pointed out that practicing calorie restriction counters the bodybuilding lifestyle. Here I will explain that it not only counters the bodybuilding lifestyle, but also is makes it impossible to implement and reap the benefits of other healthy lifestyle habits, and in addition brings along several pitfalls and negative health consequences in humans.
While animal studies can and do shed light on what’s going on at mechanistic level, we have to be very careful and resist the temptation to extrapolate results from animal experiments to humans. Here I will make the case for that we can age gracefully and successfully and increase our health span and “youngevity” without having to starve ourselves for life.
While the news on the anti-aging effects of calorie restriction are relatively recent in popular media, calorie restriction has been studied scientifically since the 1930s 1, 2. Results of many subsequent studies different species have demonstrated that substantial reductions of food intake to 30–60% below spontaneous intake levels decreases the incidence and age of onset of many age-related diseases, and increases both average and maximum 3, 4.
How does it work?
The exact mechanisms underlying the aging retardation, prevention of aging-related diseases and extension of average and/ or maximum lifespan with calorie restriction are today under intense scientific scrutiny. While new findings are constantly emerging, calorie restriction causes significant alterations in energy metabolism, oxidative damage, insulin sensitivity, and functional changes in both the neuroendocrine and sympathetic nervous systems 5. On a molecular level, some identified mechanisms underlying the pro-longevity effects of calorie restriction include the following:
(i) reduced oxidative stress and damage 6;
(ii) reduced glycation of macromolecules and lowered accumulation of AGEs (Advanced Glycation End-products) 7-11;
(iii) reduced DNA damage and increased repair 12;
(iv) reduced inflammation and autoimmunity 13;
(v) increased mitochondrial metabolic efficiency to protect the plasma membrane 14;
(vi) reduced damage to cellular components 15;
(vii) enhanced maintenance of age-related patterns of gene expression 16;
(viii) enhanced protection against stress 17, 18
While these molecular level effects are beneficial, they have only been demonstrated in laboratory animals. Calorie restriction in humans has many other effects (some of which have no equivalence in animals) which are not conductive to health (more on this later). Thus, we have to look at all the joint effects of caloric restriction, separately for each species, before we can draw conclusions about its final outcome.
Calorie restriction will obviously benefit anybody who is carrying around excess body fat. Nothing new here; go on a diet (restrict your caloric intake and exercise), lose the flab, reduce your risk factors (like insulin resistance, high blood pressure, etc) and you will live longer. So don’t let advocates of calorie restriction fool you when they support their arguments by referring to studies on overweight (e.g. “overfat”) and obese subjects 19-22. The focus in this article is on the effects of calorie restriction in non-obese folks.
Drum roll… does it work in non-obese humans?
This is a controversial question even among researchers who are actively studying calorie restriction. The opinions as split; roughly half of them taking the position that yes, calorie restriction can be applicable and confer health benefits to humans, while the other half argue that calorie restriction isn’t applicable to non-obese humans and instead poses a risk for detrimental health effects 23 (more on that later).
Why wouldn’t calorie restriction have the same beneficial anti-aging effects in non-obese humans as in non-obese animals?
Humans differ in many ways from rodents and non-human primates. Firstly, laboratory animals live in artificial environments and often are “metabolically morbid”24, 25. It is noteworthy that calorie restriction increases life span most in rodents with large spontaneous food intake, but has a minor effect on lean litter mates 26.
Secondly, rodents and non-human primates (even rhesus monkeys) have much shorter life spans than humans, and have been selected under very different evolutionary pressures 27-30. This will cause them to respond differently to food restriction and other environmental situations 23, 29. This is especially true when it comes to aging, because aging is not a programmed process in the sense that no genes have evolved specifically to cause damage and aging 31. Prominent gerontologists all agree that aging is a result of evolutionary neglect, not evolutionary intent 32-35. Mechanisms of aging might therefore not be expected to be as highly conserved between distantly related organisms as are mechanisms of development and metabolism 31.
Thirdly, in comparison to humans, exercise appears to have only minor benefits in terms of lifespan in rodents 36-39. But even so, exercise does improve average lifespan of rats independent of calorie restriction 40, and increases in food intake is not harmful when balanced by an increase in exercise induced energy expenditure 40.
We all know about the health promoting and anti-aging effects of exercise (see below) and that the majority of us don’t exercise enough. An important consequence of calorie restriction in humans is a reduced spontaneous physical activity level 41-44. Because rodents are not as troubled by heart disease as humans, they don’t derive as much benefit as we do from elevated exercise 38. And they are less negatively affected by reduced exercise and physical inactivity 38. For us, a reduced activity level will have major detrimental health effects that most likely would offset any purported benefits of caloric restriction.
Calorie restriction is not the only example of animal experimental results that don’t directly apply to humans. Other examples are CLA 45, leptin 46, 47 and torcetrapib 48, 49 (a drug use to elevate HDL “good cholesterol” levels) which all show a lot of promise in rodents, but failed to replicate their beneficial effects in humans, and actually ended up causing more harm than good in humans 45, 48, 49. Another prime example that results from animal experiments cannot be directly extrapolated to humans is growth hormone (GH) and IGF-1. In animals, GH/IGF-1 deficiency confers longevity 50, 51. However, in humans, GH/ IGF-1 deficiency is a risk factor for cardiovascular disease and, therefore, early death 52. I will cover this in much more depth in an upcoming article on hormone replacement therapy (HRT).
Adverse health effects of calorie restriction in humans, and especially in non-obese humans
Calorie restriction in non-obese people induces the following detrimental effects:
– Decreases muscle mass and strength 53 and exercise intolerance 54.
– Reduces spontaneous physical activity levels 41, 43, 44 and energy expenditure 42, 44, 55, 56.
– Lowers testosterone 57, IGF-1 58-60 and thyroid hormone 61 levels.
– Increases cortisol levels 62.
– Lightheadedness and dizziness 54.
– Negative psychological effects; constant hunger, preoccupation with food, binge eating, emotional deadening and/or depression, mood swings, irritability, anxiety, and social isolation 54, 63.
By reducing spontaneous physical activity and energy expenditure, calorie restriction lowers energy flux. Energy flux refers to the absolute level of energy intake and expenditure under conditions of energy balance (that is, when caloric intake equals caloric output) 64, 65. A high energy flux is a key mechanism contributing to the elevated resting metabolic rate seen in habitually exercising people 66, which in turn can help in the fight against obesity 67. A low relative resting metabolic rate (RMR), expressed in relation to fat-free mass, is a risk factor for subsequent fat gain 68. After 4 years of follow-up, the risk of gaining 10 kg was approximately seven times greater in those subjects with the lowest relative RMR than in those with the highest RMR. The subjects who gained more than 10 kg had a relative RMR that was only 70 calories lower per day (24 hour period) than those who didn’t gain. The rate of relative total (24-hour) energy expenditure was estimated to be responsible for up to 40% of the weight change68. This points to the importance of RMR in obesity prevention, in addition to total energy expenditure. Further support for the importance of keeping a high energy flux comes from a study showing that the age-related decline in RMR is related to age-associated reductions in exercise volume and energy intake, and does not occur in those who maintain exercise volume and/or energy intake at a level similar to that of younger peers 69. A high energy flux also increases RMR in younger adults 64, and is therefore has benefits regardless of age.
A notable finding that totally counters the proposed benefits of calorie restriction is that physical activity energy expenditure (which caloric restriction counteracts) is strongly associated with a lower risk of mortality 70, a reduced rate of death and preserved health 71 (more in this below).
The cortisol elevation seen with calorie restriction has dual negative effects in that it not only adds bite to your appetite 72 and thereby makes calorie restriction hard to maintain for longer periods of time, but also breaks down muscle tissue 73. It’s notable that a lower physical activity, which as mentioned above is a consequence of calorie restriction, amplifies the catabolic response of muscle to cortisol 73. Thus, long-term calorie restriction not only elevates cortisol, but also contributes to making the muscles more susceptible to its catabolic effects. The muscle catabolic effect seen with calorie restriction will further exacerbate sarcopenia (age related muscle loss) and its consequences 74-79.
More info on the risks associated with calorie restriction can be found on the website of the calorie restriction (CR) society: http://www.crsociety.org/resources/risks
Considering these side-effects, it is not surprising that there is no evidence showing that calorie restriction extends maximum life span or life expectancy in lean humans 19, 80. And there probably never will be. Thus, it is ironc that the (CR) society’s goal is to “help people of all ages live longer and healthier lives by eating fewer calories with adequate nutrition (ie, providing enough essential nutrients to cover survival needs)”.
I also want to comment on the CR society statement of adequate nutrition. There are two important issues here:
First, adequate nutrition as defined by “covering survival needs” is not optimal. It is well known that several nutrients (eg omega-3 fats, protein, vitamin D, vitamin K2, vitamin E. vitamin C, calcium etc) have major health promoting effects when ingested in larger amounts than necessary to cover just survival needs.
Second, adequate nutrition cannot make up for the serious side effects of calorie restriction listed above.
The negative psychological and social consequences induced by chronic calorie restriction in humans have no equivalent in animals. I want to point out that even researchers who are advocates of calorie restriction have expressed their concern and concluded that calorie restriction would be harmful in lean people 19.
What about the Okinawans?
The Okinawan population is renowned for their reduced morbidity and mortality having the greatest percentage of centenarians anywhere in the world 81, 82. Compared to Americans, the mortality rate of Okinawans between the age of 60 and 64 years is 50% lower. The death rates due to heart disease, stroke, and cancer is approximately 30–40% lower compared to the rest of Japan and even more so compared to the United States. Why do Okinawans have the longest disability-free life expectancy in the world?
Calorie restriction proponents believe the answer is their diet. The Okinawans consume a diet lower in calories compared to the rest of Japan by 20% and the United States by 40%. Their diet mimics the amount of caloric restriction imposed on experimental animals, and appears to also mimic the effects of the calorie restricted diet in animals. However, the Okinawan diet provides more than just “adequate nutrition”. It consists mainly of vegetables, legumes, fruits, seaweed, fish, and unique vegetable varieties (eg konnyaku, shiitake Mushroom, hechima, gobo, tofu) and herbs/spices (Ucchin, Fuchiba, Hihatsu, Ichoba), which are well-known for the health promoting effects 83-85 (the Okinawan longevity foods deserve an article in its own right). In contrast to the Western diet, the Okinawan longevity foods are highly anti-inflammatory and anti-acidogenic 85. The Okinawans also have a very different stress-free ancestral lifestyle and culture that the Western world 86. Thus, attributing their healthiness to their calorie restriction is a major flaw. Another fact to bear in mind when calorie restriction proponents bring up the Okinawans as evidence is that none of the Okinawans have achieved the maximum life-span recorded by the French woman Jeanne Calment (122 years).
Living Fast, Dying When?
More than 100 years ago it was documented that energy expenditure expressed in relation to body size and lifespan was relatively fixed 87. This led to the conclusion that energy used up faster will shorten lifespan, and the rate of living theory of aging. Based on this theory, things wear out with use and the faster they are used, the sooner they wear out. In line with this reasoning, the reduced energy expenditure seen calorie restriction has been proposed to be one mechanism behind its longevity extending effects in different organism and animals 88.
However, this has been refuted by inconsistencies among birds and bats which live several fold longer than do mammals of comparable body size and resting metabolic rate 89. Additionally, rats exposed to long duration cold exposure increased their energy expenditure, but did not have a shortened lifespan 90. These studies and others 91, 92, together with falsification of the original pretenses that gave rise to the rate of living theory 93, have completely refuted the concept that an increased energy expenditure decreases longevity. Further support comes from a study showing that retardation of the aging process can occur without the restriction of calories or any other nutrient per unit of lean body mass 91.
Energy expenditure data in humans also boldly refute the rate of living theory of aging. An increase in free-living activity energy expenditure of approx. 300 calories/day has been associated with a 32% lower risk of mortality, even after adjusting for age, gender, race, weight, height, percentage of body fat, and sleep duration, health status, education, prevalent health conditions, and smoking behavior 70. This study also found that individuals expending higher levels of physical activity energy were more likely to work for pay and climb stairs. This indicates that elderly who engage in physical activity (which calorie restriction would counteract) are functionally independent, which is a very important outcome and goal for anti-aging interventions 70. This was confirmed in a follow-up study which reported that activity energy expenditure is strongly associated with reduced mobility impairment and preserved physical function 94. A growing body of evidence confirms that activity energy expenditure might be an important determinant of lifespan 95, 96. Fitness enhancement and muscle gain is a well documented anti-aging strategy 96, and both fitness muscle growth can only be achieved via an increased energy flux. Thus, the importance for physical activity for human health and longevity is a major counter argument against calorie restriction in humans.
Calorie restriction mimetics – the best of two worlds
While evidence is accumulating that long-term calorie restriction in non-obese humans falls short of the expectations as the ‘‘fountain of youth’’ as seen in lower organisms and animals, research has identified substances that activate some the same molecular and signaling pathways as calorie restriction does. These so called calorie restriction mimetics have potential to confer health benefits without imposing calorie restriction and risking its side effects, and is an emerging research field 97-101. The focus of calorie restriction mimetic research is to discover nutrient sensors and their upstream effectors leading to the anti-aging and life-extending effects of calorie restriction seen in animals 102. I will cover this in an upcoming article.
The answers to a scientific debate started with the question “‘Do you think that calorie restriction can increase longevity in all species, particularly in human beings?’’ neatly summarizes the contrasting views and ambiguity regarding calorie restriction for anti-aging in humans 23, 103:
(1) We do not know for sure;
(2) It’s too early to decide;
(3) Currently we think so (based on incomplete monkey data);
(4) It cannot work in humans;
(5) We will never know for sure;
The truth is, there is direct experimental evidence that you will live longer from practicing calorie restriction. Instead of prolongation of life, calorie restriction can more appropriately be regarded as way to prevent life shortening caused by obesity.
The key to health and anti-aging in humans is a high energy flux. While some animals can benefit from calorie restriction, we will be better off getting up from our chairs and putting on our sneakers. Keeping a high energy flux via regular exercise and non-exercise activities is an effective strategy for maintaining energy expenditure and regulating appetite, and thereby preventing obesity, sarcopenia and cardiovascular diseases which plague humans as we get older (but not rodents, in whom most the benefits of calorie restriction are seen). Ironically, in humans long-term calorie restriction induces hormonal and metabolic effects that actually increase the risk for obesity and its consequences, and thus is a recipe for becoming a miserable couch potato.
In humans, exercise, physical fitness and body composition is more important for health, anti-aging and vital longevity than the caloric intake per see. If you implement regular exercise training and non-exercise activities into your lifestyle, you can physiologically “afford” to eat more, and get to be healthier and happier while you live longer.
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