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Caloric restriction (CR), or calorie restriction, is a dietary regimen that is based on low calorie intake. "Low" can be defined relative to the subject's previous intake before intentionally restricting calories, or relative to an average person of similar body type. CR without malnutrition has been shown to work in a variety of species, among them yeast, fish, rodents and dogs to decelerate the biological aging process, resulting in longer maintenance of youthful health and an increase in both median and maximum lifespan.

No clinical trial has been performed involving humans. Two trials have been performed involving primates, but have not demonstrated increases in median lifespan. A study of rhesus monkeys begun in 1987 by the National Institute on Aging published results in August 2012 that found evidence of health benefits, but did not demonstrate increased median lifespan. A study by the University of Wisconsin beginning in 1989 is still ongoing. Research on maximum life span in that study is still ongoing.

Calorie restriction is a feature of several dietary regimens, including the Okinawa diet and the CRON-diet. Sometimes calorie restriction is called calorie restriction with adequate nutrition (or CRAN) to clarify that this is done while still keeping healthy levels of protein, vitamins and minerals while lowering calories.

Research history

In 1934, Mary Crowell and Clive McCay of Cornell University observed that laboratory rats fed a severely reduced calorie diet while maintaining micronutrient levels resulted in life spans of up to twice as long as otherwise expected. These findings were explored in detail by a series of experiments with mice conducted by Roy Walford and his student Richard Weindruch. In 1986, Weindruch reported that restricting the calorie intake of laboratory mice proportionally increased their life span compared to a group of mice with a normal diet. The calorie-restricted mice also maintained youthful appearances and activity levels longer and showed delays in age-related diseases. The results of the many experiments by Walford and Weindruch were summarized in their book The Retardation of Aging and Disease by Dietary Restriction (1988) (ISBN 0-398-05496-7).

The findings have since been accepted and generalized to a range of other animals. Researchers are investigating the possibility of parallel physiological links in humans. In the meantime, many people have independently adopted the practice of calorie restriction in some form.

In 1989, scientists at University of Wisconsin started a study of 20 adult male rhesus monkeys; 9 of them were put on a normal diet and 11 were subjected to a 30% reduction in dietary intake. Results are being periodically published.

A study at UCSF called "CRONA" was started in December 2010, and studied 28 long-term CR practitioners over a few months. The study was completed on September 20, 2011. As of August 2012 the results had not yet been published.

Effects on humans

Positive effects

Cardiovascular risks reduced

Some research has shown CR to reduce atherosclerosis risk factors.

A small study of long-term CR practitioners studied the effects of a diet with 10–25% less calorie intake than the average "Western" diet. Mean Body mass index (BMI) was 19.6 in the CR group; the matched group's mean BMI was 25.9, comparable to the BMI for middle-aged people in the US.

The mean BMI in the CR group dropped from 24 (range of 19.4 to 29.6) to 19.5 (range of 16.5 to 22.8) over periods of 3–15 years. Nearly all the decrease in both BMI and cardiovascular risk factors occurred in the first year. Adjusting for age, the average total cholesterol and LDL (bad) cholesterol levels in the CR group were below those seen in all but the lowest 10% of the population. The average HDL (good) cholesterol levels were in the 85th to 90th percentile range for normal middle-aged US men.

The calorie-restricted group also fared much better than the control group in terms of average blood pressure (100/60 vs. 130/80 mm Hg), fasting glucose, fasting insulin (65% reduction), body mass index (19.6 ± 1.9 vs. 25.9 ± 3.2 kg/m), body fat percentage (8.7% ± 7% vs. 24% ± 8%), C-reactive protein, carotid IMT (40% reduction), and platelet-derived growth factor AB.

The CR group had triglyceride levels as low as the lowest 5% of Americans in their 20s. (The CR group's age range was 35–82.) Systolic and diastolic blood pressure levels in the CR group were about 100/60, a level more typical of 10-year-olds. Fasting plasma insulin concentration was 65% lower. Fasting plasma glucose concentration was also lower.

The principal investigator in this study noted an apparent lower rate of cardiovascular aging, with arteriosclerosis progress indicators particularly slowed.

The comparison group's statistics aligned approximately with the US national average on the dimensions considered. Fasting plasma insulin levels and fasting plasma glucose levels are used as tests to predict diabetes.

The American CALERIE study began in 2007 and investigates the effects of a 25% reduction in caloric intake on healthy adults over a period of two years.

The effect of CR on IGF-1 serum levels seen in rodents appears to only manifest in humans when protein intake is not much higher than the Recommended Dietary Allowance.

Improved memory

A 2009 research paper compared results of a group of normal to overweight elderly people who were given no intervention, who were given fish oil, or who were placed on a CR diet: the CR subjects "were instructed to reduce caloric intake aiming at a 30% reduction relative to previous habits, over a period of 3 months". Memory tests were done at baseline and three months after the study started (in other words, just when they had actually reduced their intake to 30% of baseline). The study found that the CR group lost the most weight; this group also had an improvement in memory. The study did not show whether the memory improvement was due to weight loss or specifically due to the CR intervention.

Reacting to this study, a spokesman for the British Dietetic Association said that people, particularly for those already at normal or low weight, should be "extremely careful" about attempting such a diet. She said, "There is other evidence that, far from enhancing memory, dieting or removing meals can interfere with memory and brain function." Another study found that while people who were underweight or of normal weight from midlife onward were at reduced risk of dementia, for people older than 65, those who were underweight had a higher dementia risk than normal or overweight people. Such findings are often interpreted as evidence of "reverse causation," with disease leading to weight loss late in life rather than low weight leading to disease.

Negative effects

The long-term effects of CR on humans are still unknown.

Musculoskeletal losses

Short-term studies in humans report loss of muscle mass and strength and reduced bone mineral density. This is to be expected as part of the weight loss that accompanies CR. Beyond using lean tissue as an energy source, the presence of catabolic hormones, such as cortisol, and the lack of anabolic ones, such as insulin, disrupts protein synthesis, amino acid uptake, and immune response.

People who lose weight as a result of CR but who are sedentary have a reduced capacity to perform exercise compared with those who lost similar amounts of weight from exercise alone, emphasizing the need for strength training in CR practitioners.

A study of long-term CR practitioners "who had been eating a CR diet (approximately 35% less calories than controls) for an average of 6.8 ± 5.2 years (mean age 52.7 ± 10.3 years)" found that they had reduced bone mineral density at the level of hip and spine, in accordance with a previous one-year weight-loss trial, but that after initial weight loss they had achieved a stable, normal level of bone turnover and that the microarchitectural structure of their bones was healthy; the researchers concluded that "These findings suggest that markedly reduced BMD is not associated with significantly reduced bone quality in middle-aged men and women practicing long-term calorie restriction with adequate nutrition." Some specialists say that minor mineral losses can be minimized with regular physical activity and vitamin D and calcium supplements.

The authors of a 2007 review of the CR literature warned that "t is possible that even moderate calorie restriction may be harmful in specific patient populations, such as lean persons who have minimal amounts of body fat."

Low BMI, high mortality

CR diets typically lead to reduced body weight, and in some studies, low body weight has been associated with increased mortality, particularly in late middle-aged or elderly subjects. One of the more famous of such studies linked a body mass index (BMI) lower than 18 in women with increased mortality from noncancer, non−cardiovascular disease causes. The authors attempted to adjust for confounding factors (cigarette smoking, failure to exclude pre-existing disease); others argued that the adjustments were inadequate.

"epidemiologists from the ACS (American Cancer Society), American Heart Association, Harvard School of Public Health, and other organizations raised specific methodologic questions about the recent Centers for Disease Control and Prevention (CDC) study and presented analyses of other data sets. The main concern ... is that it did not adequately account for weight loss from serious illnesses such as cancer and heart disease ... failed to account adequately for the effect of smoking on weight ... As a result, the Flegal study underestimated the risks from obesity and overestimated the risks of leanness."

While low body weight in the elderly can be caused by conditions associated with aging (such as cancer, chronic obstructive pulmonary disorder, or depression) or of the cachexia (wasting syndrome) and sarcopenia (loss of muscle mass, structure, and function), the results of a large epidemiological study published in the fall of 2011 show that among the Japanese, an association between a BMI under 21 (under 65 kg for a 1.75 m tall individual (or in imperial units, under 140 lb for a 5'-9" tall individual)) and increased mortality persists even when confounders like age, smoking, and disease are carefully controlled for.

Such epidemiological studies of body weight are not about CR as used in anti-aging studies; they are not about caloric intake to begin with, as body weight is influenced by many factors other than energy intake. Moreover, "the quality of the diets consumed by the low-BMI individuals are difficult to assess, and may lack nutrients important to longevity." Typical low-calorie diets rarely provide the high nutrient intakes that are a necessary feature of an anti-aging calorie restriction diet. As well, "The lower-weight individuals in the studies are not CR because their caloric intake reflects their individual ad libitum set-points, and not a reduction from that set-point."

Triggering eating disorders

Concerns are sometimes raised that CR can make people feel hungry all the time and may lead to obsessing about food, causing eating disorders. However, a controlled study of human CR found no increase in eating disorder symptoms or other harmful psychological effects, in line with extensive earlier research. In those who already suffer from a binge-eating disorder, calorie restriction can precipitate an episode of binge eating, but it does not seem to pose any such risk otherwise.

Not for the young or those seeking to become pregnant

Long-term calorie restriction at a level sufficient for slowing the aging process is generally not recommended in children, adolescents, and young adults (under the age of approximately 21), because this type of diet may interfere with natural physical growth, as has been observed in laboratory animals. In addition, mental development and physical changes to the brain take place in late adolescence and early adulthood that could be negatively affected by severe calorie restriction. Pregnant women and women trying to become pregnant are advised not to practice calorie restriction, because low BMI may result in ovulatory dysfunction (infertility), and underweight mothers are more prone to preterm delivery.

Miscellaneous concerns

It has also been noted that people losing weight on such diets risk developing cold sensitivity, menstrual irregularities, and even infertility and hormonal changes.

Moreover, calorie restriction has been reported in mice to hinder their ability to fight infection, and some evidence suggests that in patients with amyotrophic lateral sclerosis, calorie restriction accelerates the onset of the disease.

Excessive calorie restriction may result in starvation.

Effects of CR on life span in different organisms

Primates

A study on rhesus macaques funded by the National Institute on Aging was started in 1989 at the University of Wisconsin–Madison and is still ongoing. Monkeys were enrolled in the study at ages of between 7 and 14 years. Preliminary results published in 2000 showed lower fasting insulin and glucose levels as well as higher insulin sensitivity and LDL profiles, associated with lower risk of atherogenesis in dietary-restricted animals. Results published in 2008 showed that CR attenuated age-related sarcopenia in these primates. Results published in 2009 showed that caloric restriction in rhesus monkeys blunts aging and significantly delays the onset of age-related disorders such as cancer, diabetes, cardiovascular disease, and brain atrophy. 80% of the calorie-restricted monkeys were still alive, compared to only half of the controls. Results to date have also found a trend toward a reduced overall death rate, which has not yet reached statistical significance. An additional analysis, restricted to causes of death related to aging, did find a significant reduction in age-related deaths. However, the interpretation of this finding is uncertain, as it is hypothetically possible that the exclusion of deaths due to non-aging causes may somehow mask an involvement of CR in such deaths, although the sample size is too low to say for certain. A study published in 2011 examined the effect of stress on various brain functions in these monkeys. In the control group, stress reactivity was associated with less volume and tissue density in areas important for emotional regulation and the endocrine axis, including prefrontal cortices, hippocampus, amygdala, and hypothalamus. CR reduced these relationships.

In contrast to the conclusions reached by the University of Wisconsin–Madison (WNPRC) study, a 2012 National Institute on Aging (NIA) study published in the journal Nature, concluded that a calorie restriction regimen did not improve survival outcomes whether implemented in young or older age rhesus monkeys. A key difference between the WNPRC and the NIA studies is that the monkeys in the WNPRC study were fed a more unhealthy diet.

In 2006, researchers at New York's Mount Sinai School of Medicine reported results comparing the brains of 3 monkeys fed a normal diet and 3 monkeys on a CR diet for their entire lives. The normal diet group "consisted of three male Squirrel monkeys (20–27 years old), who died from congestive heart failure, liver failure or complications of intestinal bleeding, respectively; the weight at the time of death of the CON group ranged 526–866 g. The CR group consisted of 3 male Squirrel monkeys (15–20 years old) on CR diet for 14 to 18 years, who died from inanition, complications of bleeding or by complications from liver necrosis, respectively; the weight at the time of death of CR group ranged 526–813." The squirrel monkeys on a lifelong calorie-restrictive diet were less likely to develop Alzheimer's-like changes in their brains.

Rodents

Seventy years ago, C. M. McCay et al. discovered that reducing the amount of calories fed to rodents nearly doubled their life spans. The life extension varied for each species, but on average there was a 30–40% increase in life span in both mice and rats. CR preserves a range of structural and functional parameters in aging rodents. For example, studies in female mice have shown that estrogen receptor-alpha declines in the aging pre-optic hypothalamus. The female mice that were given a calorically restricted diet during the majority of their lives maintained higher levels of ERα in the pre-optic hypothalamus than did their non–calorically restricted counterparts.

Studies in female mice have shown that both the Supraoptic nucleus (SON) and Paraventricular nucleus (PVN) lose about one-third of IGF-1R immunoreactivity with normal aging. Old calorically restricted mice lose higher numbers of IGF-1R non-immunoreactive cells while maintaining similar counts of IGF-1R immunoreactive cells in comparison to Old-Al mice. Consequently, Old-CR mice show a higher percentage of IGF-1R immunoreactive cells, reflecting increased hypothalamic sensitivity to IGF-1, in comparison to normally aging mice.

Yeast

Fungi models are very easy to manipulate, and many crucial steps toward the understanding of aging have been made with them. Many studies were undertaken on budding yeast and fission yeast to analyze the cellular mechanisms behind increased longevity due to calorie restriction. First, calorie restriction is often called dietary restriction because the same effects on life span can be achieved by only changing the nutrient quality without changing the amount of calories. Data from Dr Guarente, Dr Kennedy, Dr Jazwinski, Dr Kaeberlein, Dr Longo, Dr Shadel, Dr Nyström, Dr Piper, and others showed that genetic manipulations in nutrient-signaling pathways could mimic the effects of dietary restriction. In some cases, dietary restriction requires mitochondrial respiration to increase longevity (chronological aging), and in some other cases not (replicative aging). Nutrient sensing in yeast controls stress defense, mitochondrial functions, Sir2, and others. These functions are all known to regulate aging. Genes involved in these mechanisms are TOR, PKA, SCH9, MSN2/4, RIM15, SIR2, etc.

Drosophila

Research in 2003 by Mair et al. showed that dietary restriction extends the life of fruit flies of any age, with instantaneous effects on death rates. Two years later, the same group showed that calories do not explain the extension of life span by dietary restriction in the fruit fly.

Caenorhabditis elegans

Recent work on Caenorhabditis elegans, a free-living, transparent nematode (roundworm), has shown that restriction of glucose metabolism extends life span by primarily increasing oxidative stress to exert an ultimately increased resistance against oxidative stress, a process called (mito)hormesis.

Effects of CR on animal behavior

Activity level

Laboratory rodents placed on a CR diet tend to exhibit increased activity levels (particularly when provided with exercise equipment) at feeding time. In one study, animals on a conventional diet "showed little activity" by early middle age, while those on CR "were observed to run around the cage and climb onto and hang from the wire cage tops throughout their life spans. In fact, the longest surviving mouse was observed hanging from the top of his cage only 3 days before he became moribund." Monkeys undergoing CR also appear more restless immediately before and after meals.

Stereotyped behavior

Observations in some accounts of animals undergoing CR have noted an increase in stereotyped behaviors. For example, monkeys on CR have demonstrated an increase in licking, sucking, and rocking behavior.

Food-related behavior

Unlike rodents with normal access to food, rats on CR exhibit longer periods of eating, higher food consumption, and hoarding of food. Studies of nonhuman primates on CR noted cooing, pacing, and intense eating.

Aggression

A CR regimen may also lead to increased aggressive behavior in animals. For example, rats on CR are prone to attack strangers more fiercely and are more likely to kill other rats than are controls, while monkeys have been observed to demonstrate threat displays at meal times.

Mechanisms

Even though there has been research on CR for over 70 years, the mechanism by which CR works is still not well understood. Some explanations include reduced cellular divisions, lower metabolic rates, reduced production of free radicals, reduced DNA damage and hormesis.

Hormesis

Research has pointed toward hormesis as an explanation. Southam and Ehrlich (1943) reported that a bark extract that was known to inhibit fungal growth actually stimulated growth when given at very low concentrations. They coined the term "hormesis" to describe such beneficial actions resulting from the response of an organism to a low-intensity biological stressor. The word "hormesis" is derived from the Greek word "hormaein", which means "to excite". The (mito)hormesis hypothesis of CR proposes that the diet imposes a low-intensity biological stress on the organism, which elicits a defensive response that helps protect it against the causes of aging. In other words, CR places the organism in a defensive state so that it can survive adversity, resulting in improved health and longer life. This switch to a defensive state may be controlled by longevity genes (see below).

Mitochondrial hormesis

Mitochondrial hormesis was a purely hypothetical concept until late 2007, when work by Michael Ristow's group on a small worm named Caenorhabditis elegans suggested that the restriction of glucose metabolism extends life span primarily by increasing oxidative stress to stimulate the organism into having an ultimately increased resistance to further oxidative stress. This is probably the first experimental evidence for hormesis being the reason for extended life span following CR.

Although aging can be conceptualized as the accumulation of damage, the more recent determination that free radicals participate in intracellular signaling has made the categorical equation of their effects with "damage" more problematic than was commonly appreciated in the past. It was previously proposed on a hypothetical basis that free radicals may induce an endogenous response culminating in more effective adaptations that protect against exogenous radicals (and possibly other toxic compounds). Recent experimental evidence strongly suggests that this is indeed the case, and that such induction of endogenous free-radical production extends the life span of a model organism and mitohormetically exerts life-extending and health-promoting effects. Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction.

Evolution

It has been recently argued that during years of famine, it may be evolutionarily desirable for an organism to avoid reproduction and to up-regulate protective and repair enzyme mechanisms to try to ensure that it is fit for reproduction in future years. This argument seems to be supported by recent work studying hormones. A study on male mice found that CR generally feminizes gene expression, and that many of the most significantly changed individual genes are involved in aging, hormone signaling, and p53-associated regulation of the cell cycle and apoptosis; it concluded that the life-extending effects of CR may arise partly from a shift toward a gene expression profile more typical of females. Prolonged severe CR lowers total serum and free testosterone while increasing SHBG concentrations in humans; these effects are independent of adiposity.

Lowering of the concentration of insulin and substances related to insulin, such as insulin-like growth factor 1 and growth hormone, has been shown to up-regulate autophagy, the repair mechanism of the cell. A related hypothesis suggests that CR works by decreasing insulin levels and thereby up-regulating autophagy, but CR affects many other health indicators, and it is still undecided whether insulin is the main concern. Calorie restriction has been shown to increase DHEA in primates, but it has not been shown to increase DHEA in post-pubescent primates. The extent to which these findings apply to humans is still under investigation.

Chromatin and PHA-4

Evidence suggests that the biological effects of CR are closely related to chromatin function. A study conducted by the Salk Institute for Biological Studies and published in the journal Nature in May 2007 determined that the gene PHA-4 is responsible for the longevity behind calorie restriction in roundworms, "with similar results expected in humans".

Free radicals and glycation

Two very prominent proposed explanations of aging that have a bearing on calorie restriction are the free radical theory and the glycation theory. With high amounts of energy available, mitochondria do not operate very efficiently and generate more superoxide. With CR, energy is conserved and there is less free radical generation. A CR organism will have less fat and require less energy to support the weight, which also means that there does not need to be as much glucose in the bloodstream.

Less blood glucose means less glycation of adjacent proteins and less fat to oxidize in the bloodstream to cause sticky blocks resulting in atherosclerosis. Type 2 diabetics are people with insulin insensitivity caused by long-term exposure to high blood glucose. Obesity leads to type 2 diabetes. Type 2 diabetes and uncontrolled type 1 diabetes are much like "accelerated aging", due to the above effects. There may even be a continuum between CR and the metabolic syndrome.

Caloric restriction with optimal nutrition has not been tested in comparison to caloric excess with optimal nutrition. It may be that with extra calories, nutrition must be similarly increased to ratios comparable to that of calorie restriction in order to provide similar anti-aging benefits. Stated levels of calorie needs may be biased towards sedentary individuals. Calorie restriction may be nothing other than adapting the diet to the body's needs.

Reduced DNA damage

Calorie restriction reduces production of reactive oxygen species (ROS). ROS cause several types of DNA damage including 8-hydroxy-2’-deoxyguanosine (8-OHdG). The level of 8-OHdG is often used as an indicator of the general level of oxidative damage in DNA.

Sohal et al. observed that caloric restriction decreased 8-OHdG damages in the DNA of mouse, heart, skeletal muscle, brain, liver and kidney. The levels of 8-OHdG in the DNA of these organs in 15 month old mice were reduced to an average of 81% of that in the DNA of mice fed an unrestricted diet. Kaneko et al. observed that, in rats, dietary restriction retarded the onset of age-related increases in 8-OHdG in nuclear DNA of brain, heart, liver and kidney. The level of 8-OHdG in these organs of the calorie restricted rats at 30 months averaged 65% of the level in rats fed an unrestricted diet. Hamilton et al. found that dietary restriction in both mice and rats reduced the age-related levels of 8-OHdG. In rats aged 24–26 months that had been fed a calorie restricted diet, the level of 8-OHdG in heart, skeletal muscle, brain and kidney DNA was, on average, 62% of the level in rats fed an unrestricted diet. In mice, after a calorie restricted diet for 24–26 months, the level of 8-OHdG in heart, brain, liver and kidney DNA averaged 71% of the level in mice fed an unrestricted diet. Also, Wolf et al. observed that, in the rat, calorie restriction reduced 8-OHdG in the DNA of heart, skeletal muscle, brain and liver. After 24 months, the levels of 8-OHdG in these organs averaged 64% of those in the rats fed an unrestricted diet.

Thus in rodents, calorie restriction slows aging, decreases ROS production and reduces the accumulation of oxidative DNA damage in multiple organs. These results link reduced oxidative DNA damage to slower aging. The consistent observation that calorie restriction reduces oxidative DNA damage lends support to the proposal of Holmes et al. that oxidative DNA damages are a prominent cause of aging. This is also discussed in detail by Bernstein et al.

Caloric restriction mimetics

Work on the mechanisms of CR has given hope to the synthesizing of future drugs to increase the human life span by simulating the effects of calorie restriction. In particular, the large number of genes and pathways reported to regulate the actions of CR in model organisms represent attractive targets for developing drugs that mimic the benefits of CR without its side effects. However, MIT biologist Leonard Guarente cautioned that "(treatment) won't be a substitute for a healthy lifestyle. You'll still need to go to the gym."

Sir2, or "silent information regulator 2", is a sirtuin, discovered in baker's yeast cells, that is hypothesized to suppress DNA instability. In mammals, Sir2 is known as SIRT1. David Sinclair at Harvard Medical School in Boston is a leading proponent of the view that the gene Sir2 may underlie the effect of calorie restriction in mammals by protecting cells from dying under stress. It is suggested that a low-calorie diet that requires less Nicotinamide adenine dinucleotide to metabolize may allow SIRT1 to be more active in its life-extending processes. An article in the June 2004 issue of the journal Nature showed that SIRT1 releases fat from storage cells.

Sir2/SIRT1 and resveratrol

Attempts are being made to develop CR mimetics interventions. Resveratrol has been reported to activate Sir2/SIRT1 and extend the lifespan of yeast, nematode worms, fruit flies, and mice consuming a high-caloric diet. Resveratrol does not extend life span in normal mice.

The effect of resveratrol on lifespan in C. elegans and Drosophila was reinvestigated by D. Gems and L. Partridge. They concluded that previously reported life-span increases were in fact due to natural variability in the life spans of C. elegans. A recent study found resveratrol extends the lifespan of a vertebrate fish by 59%. In the yeast, worm, and fly studies, resveratrol did not extend life span if the Sir2 gene was mutated. A 2010 study concluded that SRT1720 and resveratrol are not direct activators of SIRT1.

Matt Kaeberlein and Brian Kennedy at the University of Washington believe that Sinclair's work on resveratrol is an artifact and that the Sir2 gene has no relevance to CR. They have proposed that caloric restriction increases life span by decreasing the activity of the Target of Rapamycin (TOR) kinase.

Gurarente has recently published that behavior associated with caloric restriction did not occur when Sirt1 knockout mice were put on a calorie-restricted diet, the implication being that Sirt1 is necessary for mediating the effects of caloric restriction. However, the same paper also reported that the biochemical parameters thought to mediate the life span–extending effects of calorie restriction (reduced insulin, IGF-1, and fasting glucose) were no different in normal mice and mice lacking Sirt1. Whether the life span–extending effect of CR was still evident in Sirt1 knockout mice was not reported in that study. According to Sinclair's data, Sirtuins (SirT1, Sir2, ...) are behind the putative effect of calorie restriction on longevity, although some research has cast doubt on this claim. A clinical trial of the resveratrol formulation SRT501 was suspended.

CR extends the life span and prevents aging. It has been found that these effects are modulated by SIRT3, a member of the sirtuins, a class of protein deacetylases. SIRT3 is mitochondrial. SIRT3-knockout mice did not live longer when calorically restricted, but wild-type mice did live longer when calorically restricted.

Objections

No benefit to houseflies, overfed model organisms

One set of experiments shows that CR has no benefits in the housefly. The authors hypothesize that the widely purported effects of CR may be because a diet containing more calories can increase bacterial proliferation, or because the type of high-calorie diets used in past experiments have a stickiness, general composition, or texture that reduces longevity.

At one time, some researchers suggested that some of the effects of CR are artifacts because the laboratory model organisms are kept on non-physiological high-calorie diets. This would mean that calorie restriction simply means mimicking the energy supply of a natural environment. However, many modern CR studies restrict the control animals by 10–20% below their ad libitum intake in order to avoid confounding by obesity. Additionally, "at least some laboratory mice under a caloric restriction regimen that maximizes longevity have been reported to cease estrous cycling. Because all existing wild mice populations must reproduce or become extinct, presumably they are eating relatively more than restricted laboratory mice during at least part of the year." A study designed to evaluate the energy intake, expenditure, and balance of mice in the wild, ad libitum–fed laboratory mice, and calorie-restricted mice concluded that "CR experiments do in fact restrict energy consumption beyond that typically experienced by mice in nature. Therefore, the retarded aging observed with CR is not due to eliminating the detrimental effects of overeating."

Physical activity testing biases

While some tests of calorie restriction have shown increased muscle tissue in the calorie-restricted test subjects, how this has occurred is unknown. Muscle tissue grows when stimulated, so it is possible that the calorie-restricted test animals exercised more than their companions on higher calories. The reason behind this may be that animals enter a foraging state during calorie restriction. To control for this variable, tests would need to be monitored to ensure that levels of physical activity are equal between groups.

Insufficient calories and amino acids for exercise

Exercise has also been shown to increase health and life span and lower the incidence of several diseases (relative to sedentary and obese controls, but not to energy-restricted sedentary controls of matching body weight). Calorie restriction comes into conflict with the high caloric needs of athletes, and may not provide them sufficient energy levels or amino acids for repair, although this is not a criticism of CR per se, since it is certainly possible to be an unhealthy athlete or an athlete destined to die at a young age due to poor diet, stresses, etc. Moreover, in experiments comparing CR to exercise, CR animals lived much longer than exercised animals.

Does calorie restriction only benefit the young?

There is some evidence suggesting that the benefit of CR in rats might only be reaped in early years. A study on rats that were gradually introduced to a CR lifestyle at 18 months showed no improvement over the average life span of the ad libitum group. This view, however, is disputed by Spindler, Dhahbi, and colleagues, who showed that in late adulthood, acute CR partially or completely reversed age-related alterations of liver, brain and heart proteins, and that mice placed on CR at 19 months of age showed increases in life span. The Wisconsin rhesus monkey study showed increased survival rates and decreased diseases of aging from caloric restriction even though the study started with adult monkeys.

Possible contraindications

Both animal and human research suggest that CR may be contraindicated for people with amyotrophic lateral sclerosis (ALS). Research on a transgenic mouse model of ALS demonstrates that CR may hasten the onset of death in ALS. Hamadeh et al. therefore concluded, "These results suggest that CR diet is not a protective strategy for patients with amyotrophic lateral sclerosis (ALS) and hence is contraindicated." Hamadeh et al. also note two human studies that, they indicate, show "low energy intake correlates with death in people with ALS." However, in the first study, Slowie, Paige, and Antel state, "The reduction in energy intake by ALS patients did not correlate with the proximity of death but rather was a consistent aspect of the illness." They conclude, "ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake."

Previously, Pedersen and Mattson also found that in the ALS mouse model, CR "accelerates the clinical course" of the disease and had no benefits. Suggesting that a calorically dense diet may slow ALS, a ketogenic diet in the ALS mouse model has been shown to slow the progress of disease. More recently, Mattson et al. opine that the death by ALS of Roy Walford, a pioneer in CR research and its antiaging effects, may have been a result of his own practice of CR. However, as Mattson et al. acknowledge, Walford's single case is an anecdote that by itself is insufficient to establish the proposed cause-effect relation.

Negligible effect on larger organisms

Another objection to CR as an advisable lifestyle for humans is the claim that the physiological mechanisms that determine longevity are very complex, and that the effect would be small to negligible in our species.

Intermittent fasting as an alternative approach

Studies by Dr. Mark P. Mattson, chief of the National Institute on Aging's (NIA) Laboratory of Neurosciences, and colleagues have found that intermittent fasting and calorie restriction affect the progression of diseases similar to Huntington's disease, Parkinson's disease, and Alzheimer's disease in mice (PMID 11119686). In one study, rats and mice ate a low-calorie diet or were deprived of food for 24 hours every other day. Both methods improved glucose metabolism, increased insulin sensitivity, and increased stress resistance. Researchers have long been aware that calorie restriction extends life span, but this study showed that improved glucose metabolism also protects neurons in experimental models of Parkinson's and stroke.

Another NIA study found that intermittent fasting and calorie restriction delay the onset of Huntington's disease–like symptoms in mice and prolongs their lives. Huntington's disease (HD), a genetic disorder, results from neuronal degeneration in the striatum. This neurodegeneration results in difficulties with movements that include walking, speaking, eating, and swallowing. People with Huntington's also exhibit an abnormal, diabetes-like metabolism that causes them to lose weight progressively.

This NIA study compared adult HD mice who ate as much as they wanted with HD mice who were kept on an intermittent fasting diet during adulthood. HD mice possess the abnormal human gene huntingtin and exhibit clinical signs of the disease, including abnormal metabolism and neurodegeneration in the striatum. The mice on the fasting program developed clinical signs of the disease about 12 days later and lived 10–15% longer than the free-fed mice. The brains of the fasting mice also showed less degeneration. Those on the fasting program also regulated their glucose levels better and did not lose weight as quickly as the other mice. Researchers found that fasting mice had higher brain-derived neurotrophic factor (BDNF) levels. BDNF protects neurons and stimulates their growth. Fasting mice also had high levels of heat-shock protein-70 (Hsp70), which increases cellular resistance to stress.

Another NIA study compared intermittent fasting with cutting caloric intake. Researchers let a control group of mice eat freely (ad libitum). Another group was fed 60% of the calories that the control group consumed. A third group was fasted for 24 hours, then permitted to free-feed. The fasting mice did not cut total calories at the beginning and end of the observation period, and only slightly cut calories in between. A fourth group was fed the average daily intake of the fasting mice every day. Both the fasting mice and those on a restricted diet had significantly lower blood sugar and insulin levels than the free-fed controls. Kainic acid, a toxin that damages neurons, was injected into the dorsal hippocampus of all mice. Hippocampal damage is associated with Alzheimer's. Interestingly, the scientists found less damage in the brains of the fasting mice than in those on a restricted diet, and most damage in mice with an unrestricted diet. But the control group that ate the average daily intake of the fasting mice (~10% restriction) also showed less damage than the mice on the restricted diet.

Another Mattson study in which overweight adult asthmatics followed alternate day calorie restriction (ADCR) for eight weeks showed a marked improvement in oxidative stress, inflammation, and the severity of the disease. Evidence from the medical literature suggests that ADCR in the absence of weight loss prolongs life span in humans.

Intermittent fasting has also been shown to increase the resistance of neurons in the brain to excitotoxic stress.

See also

Notes

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External links

• Calorie Restriction and Longevity - Gerontology, 2011

• Articles with inconsistent citation formats
• Diets
• Eating behaviors
• Gerontology
• Life extension
• Senescence