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Caloric Restriction for anti-aging and longevity - does it work in non-obese humans?

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If you are following the anti-aging news, you’ve heard about the supposed benefits of chronic calorie restriction for increasing longevity. These claims are based on research done in various species such as flies, worms and mice.
 
Here I will explain that chronic calorie restriction makes it impossible to implement and reap the health benefits of an active lifestyle with regular exercise, and causes severe health consequences for 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 that chronic calorie restriction actually counteracts the prospects of a healthy vital long life.
 

Background

 
While the news on the anti-aging effects of calorie restriction are relatively recent in popular media, calorie restriction has been studied scientifically in different species (worms, spiders, rodents, dogs, cows and monkeys) since the 1930s.[1, 2] Results of most studies 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 lifespan.[3, 4]
 

How does it work?

 
The exact mechanisms by which calorie restriction slows down the aging process, prevents development of aging-related diseases and extends of average and/or maximum lifespan, are currently under intense scientific scrutiny. 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:
 
- reduced oxidative stress and damage [6]; 
 
- reduced glycation of macromolecules and less accumulation of  AGEs (Advanced Glycation End-products) [7-11]; 
 
- reduced DNA damage and increased repair.[12]
 
- reduced inflammation and autoimmunity.[13]
 
- increased mitochondrial metabolic efficiency.[14]
 
- reduced damage to cellular components.[15]
 
- maintenance of youthful patterns of gene expression.[16]
 
- enhanced protection against stress.[17, 18]
 
However, these molecular level effects have mainly been demonstrated in laboratory animals. Calorie restriction in humans has many other effects (some of which have no equivalent in animals) that 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 for that particular species.
 

Calorie restriction – just another fancy name for dieting?

 
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 (such as insulin resistance, high blood pressure, triglycerides (blood fat) 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]. Here I am focusing on the effects of calorie restriction in non-obese folks.
 

Drum roll… does chronic calorie restriction 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 this 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. First, 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 that have a large spontaneous food intake, but has a minor effect on lean litter mates.[26]
 
Second, 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]
 
Third, 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 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 humans, a reduced physical activity level will have major detrimental health effects that most likely would offset any - if possible - 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). These all showed a lot of promise in rodents but failed to replicate their beneficial effects in humans, and torcetrapib and CLA actually ended up causing more harm than good in humans.[45, 48, 49] Another prime example that results from animal experiments cannot be 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 early death (I will cover this in much more depth in an upcoming article).[52] 
 

Adverse health effects of chronic calorie restriction in humans

 
Chronic calorie restriction in non-obese people results in the following detrimental effects:
 
- Decreased muscle mass and strength [53] and exercise intolerance.[54]
 
- Reduced spontaneous physical activity levels [41, 43, 44] and energy expenditure.[42, 44, 55, 56]
 
- Reduced testosterone [57] and thyroid hormone [58] levels, as well as IGF-1 levels if protein intake is restricted.[59-63]
 
- Increased cortisol levels.[64]
 
- 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, 65]
 
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).[66, 67] A high energy flux is a key mechanism contributing to the elevated resting metabolic rate seen in habitually exercising people [68], which contributes to protection against obesity.[69] For example, a low resting metabolic rate (RMR), expressed in relation to fat-free mass, is a risk factor for subsequent fat gain.[70] After 4 years of follow-up, the risk of gaining 10 kg was approximately 7 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 total daily (24-hour) energy expenditure was estimated to be responsible for up to 40% of the weight change.[70] 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.[71] A high energy flux also increases RMR in younger adults [66], and is therefore has benefits regardless of age. 
A notable finding that totally counters the proposed benefits of calorie restriction is that a high physical activity energy expenditure  - which is reduced by caloric restriction [41-44, 55, 56] - is strongly associated with a lower risk of mortality [72], less deaths and preserved health [73] (more in this below).
 
The cortisol elevation seen with calorie restriction has dual negative effects in that it not only adds a bite to your appetite [74] and thereby makes calorie restriction hard to maintain for longer periods of time, but also breaks down muscle tissue.[75] It's notable that a reduced physical activity level, which as mentioned above is a consequence of calorie restriction, amplifies the catabolic effect of cortisol on muscle.[75] Thus, long-term calorie restriction not only elevates cortisol, but also contributes to making 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 [76-81], which plagues humans but not worms, fruit flies and mice.
 
Considering these side-effects, it is not surprising that there is no evidence showing that calorie restriction life span in lean humans.[19, 82]  And there probably never will be. Thus, it is ironic 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)". 
 
More info on the risks associated with calorie restriction can be found on the website of the Calorie Restriction (CR) Society: www.crsociety.org/resources/risks
 
I want to comment on the CR society statement of adequate nutrition. There are two important issues here:
 
First, adequate nutrition, defined as "covering survival needs" is not optimal nutrition. It is well known that several nutrients (e.g. omega-3 fats, protein, vitamin D, vitamin K2, calcium, vitamin E, vitamin C, choline 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 chronic 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.[83, 84] Compared to Americans, the mortality rate of Okinawans between the age of 60 and 64 years is half that of the American population. 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.[85-87] In contrast to the Western diet, the Okinawan longevity foods are highly anti-inflammatory and anti-acidogenic [87]. The Okinawans also have a very different stress-free ancestral lifestyle and culture that the Western world.[88] Thus, attributing their healthiness and longevity to their calorie restriction is a major flaw. Another fact to bear in mind when calorie restriction proponents bring up the Okinawans as evidence for their position 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.[89] 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 with calorie restriction has been proposed to be one mechanism behind its longevity extending effects in different organism and animals.[90]
 
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.[91] Additionally, rats exposed to long duration cold exposure increased their energy expenditure, but did not have a shortened lifespan.[92] These studies and others [93, 94], together with falsification of the original assumptions that gave rise to the rate of living theory [95], 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.[93]
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% reduced risk of mortality among elderly, even after adjusting for age, gender, race, weight, height, percent body fat, sleep duration, health status, education, prevalent health conditions, and smoking behavior [72]. 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.[96] A growing body of evidence confirms that activity energy expenditure might be an important determinant of lifespan in humans.[97, 98] Regular exercise that improving fitness and increases muscle mass is a well documented anti-aging strategy [98], and fitness and 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. This is supported by data showing that exercise may promote longevity through pathways common to effects of caloric restriction.[99] This further reduces the potential of caloric restriction as a viable strategy for humans.
 

Does calorie restriction work by reducing intra-abdominal “belly” fat?

 
A research group at the Institute for Aging Research, Albert Einstein College of Medicine have hypothesized that the ability of calorie restriction to improve longevity is by reducing visceral fat, i.e. intra-abdominal “belly” fat.[100] Surgical removal of visceral fat, but not subcutaneous fat removal, closely resembles the effects of prolonged calorie restriction. [101] This suggests that decreased visceral fat could largely account for the beneficial effects of a reduction in food intake. Additionally, earlier studies have a shown a causal role for visceral fat in age-related metabolic decline, impaired glucose metabolism (similar to rodents), and for the development of cancer (similar to rodents) and atherosclerotic vascular disease (in humans).[72] 
 
This is good news, as exercise dose-dependently reduces visceral fat in humans [102, 103] and results in fat loss with a smaller degree of calorie restriction.[104] And importantly, exercise also improves aerobic fitness, which has other important cardiovascular and metabolic implications that cannot be achieved by calorie restriction alone.
 

What about calorie restriction mimetics?

 
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 – called calorie restriction mimetics - that activate some the same molecular and signaling pathways as calorie restriction does.[105, 106]
 
A  called calorie restriction mimetic is a compound, either naturally occurring or a manmade drug, that mimics metabolic, hormonal, and physiological effects of calorie restriction, activates stress response pathways observed in calorie restriction and enhances stress protection, produces calorie restriction-like effects on longevity, reduces age-related disease, and maintains more youthful function, all without significantly reducing food intake.[105]
 
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.[107-112] The focus of calorie restriction mimetic research is to discover and activate nutrient sensors, to achieve at least some of the anti-aging and life-extending effects of calorie restriction that have been seen in animals.[113]. Some examples are the polyphenols resveratrol and EGCG (epigallocatechin-3-gallate), and the drug metformin (which I will cover separately in an upcoming article).[105, 106]
 
However, although currently researched calorie restriction mimetics appear to confer life and healthspan extending impacts across numerous cell types and model organisms via for example SIRT1/AMPK interaction, the downstream impact on genome function (gene expression) is varied across cell-type, organism-type, and compound-type, in addition to variations in experimental details (such as exposure times, drug concentrations).[106] This suggests that although mechanisms mediating health and lifespan in response to calorie restriction and calorie restriction mimetics are similar, the effects on gene expression (which is of paramount importance for human longevity) mean that these compounds may not be direct mimetics of calorie restriction across the board.
 

Exercise as a “human calorie restriction strategy”

 
Considering the downsides of chronic calorie restriction for humans, and the vast amount of research proving the health promoting effects of regular exercise in humans, including increased longevity and vitality [114-117], one may wonder if exercise could be a “human calorie restriction strategy”? 
 
Even though exercise and caloric restriction affect energy metabolism in a diametrically opposite manner, many of the effects of calorie restriction that have been seen in animal experiments are the same as those that occur in humans in response to exercise, such as improved mitochondrial function, oxidative metabolism, autophagy, ROS detoxification, genomic stability, see figure 1.[112] This can explain the similar health benefits of calorie restriction in animals and exercise in humans. However, as indicated in figure 1, while calorie restriction only causes weight loss, exercise not only improves body composition (by reducing body fat and increasing muscle mass) but also improves muscle and cardiovascular function.
 
Figure 1. Common and distinct effects of exercise and caloric restriction.[112]
 

Figure modified from Handschin, C., Caloric restriction and exercise "mimetics'': Ready for prime time? Pharmacol Res, 2016. 103: p. 158-66

Figure 1 also shows the benefits to humans conferred by exercise but not by calorie restriction, and how these benefits improve healthspan. Lifespan and healthspan are different things, and improvement in one does not necessarily lead to improvement in the other (as indicated in the figure with a separation line). Most people probably prefer to add life to their years, than merely years to their life. 
 
Interestingly, because calorie restriction and calorie restriction mimetics affect many of the same molecular pathways as exercise, several compounds that are investigated as calorie restriction mimetics can also be classified as exercise mimetics.[112] I will cover both exercise mimetics in-depth in an upcoming article.
 

Restricting calories vs. carbs

 
Most of the research on calorie restriction has reduced calories from all macronutrients (protein, fat and carbs). However, the role of each nutritional component in the regulation of lifespan is not well established.[118] Human data shows that a low carbohydrate diet may delay aging in humans by preventing metabolic diseases and improving general health [118], and glucose (the main carbohydrate) has been suggested to speed up aging processed via several mechanisms.[119]
 
Reduction in aging related metabolic deterioration can be achieved with an energy composition of 20% carbohydrate, 20% protein and 60% fat - without imposed calorie restriction - and nutritional supplements.[120] In this study, daily nutritional supplements to enhance insulin sensitivity were: L-carnitine 2000 mg, alpha-lipoic acid 400 mg, coenzyme Q-10 100 mg, 1 tbsp cod liver oil, magnesium 300mg, potassium 300mg, vitamin C 1000 mg, vitamin E 800 mg, and a multivitamin providing all essential B vitamins and minerals.[120]
 
Thus, for humans is seems that restricting carbs is more important than restricting total calories per see. Further support for this comes for research on calorie restriction mimetics. One class of calorie restriction mimetics work by glycolytic inhibition, i.e. by inhibiting glycolysis, which is the biochemical process that breaks down glucose to cellular energy (ATP).[105] Glycolysis can also be reduced by simply eating less carbs, as that causes a metabolic shift that makes the body burn more fat for energy, as opposed to glucose (via glycolysis).
 

Conclusion

 
The answers to the scientific debate in response to 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 as a strategy for anti-aging in humans [23, 121]:
 
(1) We do not know for sure.
 
(2) It is too early to say.
 
(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 no 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 premature death caused by obesity. 
 
The key to health and anti-aging in humans is a high energy flux, achieved by regular exercise and nutrient dense unprocessed foods. This will prevent sarcopenia as well as heart disease, which is the number one killer in humans (but not rodents and other species). 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 regulating appetite [122-125] and thereby preventing obesity, sarcopenia and cardiovascular disease, 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. By implement regular exercise training and non-exercise activities (i.e. reduce your daily sitting time) into your lifestyle, you can physiologically “afford” to eat more while reaping all health benefits and happily enjoying a longer life.
 

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Last modified on Sunday, 18 September 2016 03:31
Monica

Medical Writer & Nutritionist

MSc Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

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