Calorie restriction

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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. Caloric restriction 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.[1]

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.[2] A study by the University of Wisconsin beginning in 1989 is still ongoing.[1][3][4] Research on maximum life span in that study is still ongoing.

Calorie restriction is a feature of several dietary regimens, including the Okinawa diet[5] and the CRON-diet. Sometimes calorie restriction is called calorie restriction with adequate nutrition (CRAN) to clarify that this is done while still keeping healthy levels of protein, vitamins and minerals while lowering calories.

Research history[edit]

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 non-human and human primates. In the meantime, many people have independently adopted the practice of calorie restriction in some form.

Currently there are 2 ongoing randomized control studies on the effects of CR in non-human primates: the Wisconsin National Primate Research Center and the National Institute on Aging CR monkey studies. In 1989, scientists at University of Wisconsin started a study involving 46 adult male and 30 female rhesus monkeys.[1][3] The National Institute on Aging CR monkeys study, started in 1987, involves 60 male and 60 female rhesus monkeys. Monkeys in both studies have been randomized with a 1:1 ratio to 30% CR or to a control diet. Results are being periodically published.

A group of scientists at Washington University in St.Louis have studied long-term physiologic, metabolic and molecular effects of CR in a small group of healthy lean men and women.[6]

In May 2007 a multi-center clinical trial called the CALERIE ( Comprehensive Assessment of the Long-term Effects of Reducing Energy Intake) study was begun, to examine the effect of 2 years of sustained 25% CR on: a) slowing aging as assessed by proxy indicators and b) protecting against age-related disease processes. 220 healthy volunteers across 3 sites (Tufts University, Pennington Biomedical Research Center, and Washington University School of Medicine) were recruited.[7]

A study at UCSF called "CRONA" was started in December 2010, and studied 28 long-term CR practitioners over a few months.[8] The study was completed on September 20, 2011.[9] As of August 2012 the results had not yet been published.

Effects on humans[edit]

Positive effects[edit]

Biomarkers for cardiovascular risk[edit]

In 2004, Fontana et al. published data from a study of 18 individuals who had been on CR for an average of 6 years and 18 age-matched healthy individuals on typical American diets. The study took one set of measurements of risk factors for atherosclerosis from each group and compared them and found that "it appears that long-term CR has a powerful protective effect against atherosclerosis."[10] The study noted that the high quality diets consumed by the CR practitioners may be responsible for some of these beneficial effects.[10]

Data from the NIA-funded CALERIE phase 1 randomized clinical trials show that 20% CR for 12 months in overweight individuals results in a significant reduction in visceral fat mass, LDL-cholesterol, triglycerides, and C-reactive protein, and improves insulin sensitivity.[11]

Biomarkers for cancer risk[edit]

Long-term CR in humans results in a reduction of several metabolic and hormonal factors that have been associated with increased risk of some of the most common type of cancer in developed countries.[12] Individuals practicing CR without malnutrition have lower levels of total and abdominal fat, circulating insulin, testosterone, estradiol and inflammatory citokines.[13][14][15] However, unlike in rodents, long-term CR does not reduce serum IGF-1 levels in humans, unless protein intake is also reduced.[16][17]

Negative effects[edit]

The long-term effects of moderate CR with adequate intake of nutrients on humans are still unknown.[18] However, severe or extreme CR may result in serious deleterious effects, as it has been shown in the “Minnesota Starvation Experiment”.[19] This study was conducted during World War II on a group of lean men (they were conscientious objectors), who restricted their calorie intake by 45% for 6 months.[19] As expected, this severe degree of CR resulted in many positive metabolic adaptations (e.g. decreased body fat, blood pressure, improved lipid profile, low serum T3 concentration, and decreased resting heart rate and whole-body resting energy expenditure), but also caused a wide range of negative effects, such as anemia, lower extremity edema, muscle wasting, weakness, neurological deficits, dizziness, irritability, lethargy, and depression.[19]

Musculoskeletal losses[edit]

Short-term studies in humans report loss of muscle mass and strength and reduced bone mineral density.[20] 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,[21] 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,[22] 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."[23] Some specialists say that minor mineral losses can be minimized with regular physical activity and vitamin D and calcium supplements.[24]

Similarly, despite acute reductions in muscle mass at onset, CR retards the age-related loss of muscle structure and function (sarcopenia) in nonhuman primates[25][26] and rodents;[27][28] however, no longitudinal data are available on this subject in humans.

The authors of a 2007 review of the CR literature warned that "[i]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."[29]

Low BMI, high mortality[edit]

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.[30] The authors attempted to adjust for confounding factors (cigarette smoking, failure to exclude pre-existing disease); others argued that the adjustments were inadequate.[31]

"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 ... [and] 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."[32]

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),[33] 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.[34]

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."[18] Typical low-calorie diets rarely provide the high nutrient intakes that are a necessary feature of an anti-aging calorie restriction diet.[35][36][37] 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."[18]

Triggering eating disorders[edit]

Concerns are sometimes raised that CR can make people feel hungry all the time and may lead to obsessing about food, causing eating disorders.[21] 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.[38] 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.[39]

Not for the young or those seeking to become pregnant[edit]

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.[40] 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.[40]

Miscellaneous concerns[edit]

It has also been noted that people losing weight on such diets risk developing cold sensitivity, menstrual irregularities, and even infertility and hormonal changes.[41]

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.[42]

Excessive calorie restriction may result in starvation.

Effects of CR on life span in different organisms[edit]


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.[43] CR also attenuated age-related loss of muscle mass and function (sarcopenia) in these primates.[25][26] 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.[44] [45] 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.[1][3] A study published in 2011 examined the effect of stress on various brain functions in these monkeys.[46] 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.[47] A key difference between the WNPRC and the NIA studies is that the monkeys in the WNPRC study were fed a more unhealthy diet.[48]

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."[49] The squirrel monkeys on a lifelong calorie-restrictive diet were less likely to develop Alzheimer's-like changes in their brains.[49]


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.[50] 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.[51]

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.[52][53]


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.[54][55][56][57][58]


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.[59] Two years later, the same group showed that calories do not explain the extension of life span by dietary restriction in the fruit fly.[60]

Caenorhabditis elegans[edit]

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.[61]

Effects of CR on animal behavior[edit]

Activity level[edit]

Laboratory rodents placed on a CR diet tend to exhibit increased activity levels (particularly when provided with exercise equipment) at feeding time. Monkeys undergoing CR also appear more restless immediately before and after meals.[62] Despite this brief daily period of increased activity overall activity is no higher in CR than AL animals in youth after an initial period of adaptation to the diet.[63] On the other hand, CR has been found to retard the decline in activity that occurs during normal aging: 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 [CR] mouse was observed hanging from the top of his cage only 3 days before he became moribund."[64]

Stereotyped behavior[edit]

Observations in some accounts of animals undergoing CR have noted an increase in stereotyped behaviors.[62] For example, monkeys on CR have demonstrated an increase in licking, sucking, and rocking behavior.[65]

Food-related behavior[edit]

Unlike rodents with normal access to food, rats on CR exhibit longer periods of eating, higher food consumption,[66] and hoarding of food.[67] Studies of nonhuman primates on CR noted cooing, pacing, and intense eating.[68]


A CR regimen may also lead to increased aggressive behavior in animals.[62] For example, rats on CR are prone to attack strangers more fiercely and are more likely to kill other rats than are controls,[67] while monkeys have been observed to demonstrate threat displays at meal times.[68]


Even though there has been research on CR for over 70 years, the mechanism by which CR works is still not well understood.[1] Some explanations include reduced cellular divisions, lower metabolic rates, reduced production of free radicals,[69] reduced DNA damage[70][71] and hormesis.[72]


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).[73]

Mitochondrial hormesis[edit]

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.[61] 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).[74] 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.[75][76][77]


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.[78] 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.[79] Prolonged severe CR lowers total serum and free testosterone while increasing SHBG concentrations in humans; these effects are independent of adiposity.[80]

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.[81] A related hypothesis suggests that CR works by decreasing insulin levels and thereby up-regulating autophagy,[81][82] but CR affects many other health indicators, and it is still undecided whether insulin is the main concern.[50] Calorie restriction has been shown to increase DHEA in primates, but it has not been shown to increase DHEA in post-pubescent primates.[83][84] The extent to which these findings apply to humans is still under investigation.

Chromatin and PHA-4[edit]

Evidence suggests that the biological effects of CR are closely related to chromatin function.[85] 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".[86]

Free radicals and glycation[edit]

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[edit]

Calorie restriction reduces production of reactive oxygen species (ROS).[69][87] 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.[88] 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.[89] 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.[90] 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.[91]

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.[71] This is also discussed in detail by Bernstein et al.[92]

Caloric restriction mimetics[edit]

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.[93][94][95] 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."[96]

Sir2, or "silent information regulator 2", is a sirtuin, discovered in baker's yeast cells, that is hypothesized to suppress DNA instability.[97] 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.[98] 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.[99]


Attempts are being made to develop drugs that act as CR mimetics, and much of that work has focused on a class of proteins called sirtuins.[100] Resveratrol has been reported to activate SIRT1 and extend the lifespan of yeast,[101] nematode worms, fruit flies,[102] vertebrate fish,[103] and mice consuming a high-caloric diet.[104] However, resveratrol does not extend life span in normal mice[105] and the effect of resveratrol on lifespan in nematodes and fruit flies has been disputed.[106]

There are studies that indicate that resveratrol may not function through SIRT1[107][108] but may work through other targets.[109][110] A clinical trial of the resveratrol formulation SRT501 was suspended.[111]

There is some evidence from mice that caloric restriction may be mediated through SIRT3[112] or SIRT6.[113]


No benefit to houseflies, overfed model organisms[edit]

One set of experiments shows that CR has no benefits in the housefly.[114] 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.[115] 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."[116] 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."[117]

Hypothesized Confounding by Activity Levels[edit]

Calorie restriction preserves muscle tissue in nonhuman primates[25][26] and rodents.[27][28] Mechanisms include reduced muscle cell apoptosis and inflammation;[27] protection against[28] or adaptation to[25] age-related mitochondrial abnormalities; and preserved muscle stem cell function.[118] Muscle tissue grows when stimulated, so it has been suggested that the calorie-restricted test animals exercised more than their companions on higher calories, perhaps because animals enter a foraging state during calorie restriction. However, studies show that overall activity levels are no higher in CR than AL animals in youth,[63] while CR animals are more active at middle age and beyond due to a protective effect against the decline in activity observed in middle-aged and older animals.[64]

Insufficient calories and amino acids for exercise[edit]

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).[119] 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.[120]

Does calorie restriction only benefit the young?[edit]

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.[121] 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.[122] 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.[45]

Possible contraindications[edit]

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."[123] Hamadeh et al. also note two human studies[124][125] 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."[124]

Previously, Pedersen and Mattson also found that in the ALS mouse model, CR "accelerates the clinical course" of the disease and had no benefits.[126] 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.[127] 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.[128] 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[edit]

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.[129]

Intermittent fasting as an alternative approach[edit]

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.[130] 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.[131] 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.[130]

Another Mattson study[132] 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.[133]

Intermittent fasting has also been shown to increase the resistance of neurons in the brain to excitotoxic stress.[130]

See also[edit]


  1. ^ a b c d e Anderson, R. M.; Shanmuganayagam, D.; Weindruch, R. (2009). "Caloric Restriction and Aging: Studies in Mice and Monkeys". Toxicologic Pathology 37 (1): 47–51. doi:10.1177/0192623308329476. PMID 19075044. 
  2. ^ Kolata, Gina (2012-09-29). "Severe Diet Doesn’t Prolong Life, at Least in Monkeys". The New York Times. 
  3. ^ a b c Rezzi, Serge; Martin, François-Pierre J.; Shanmuganayagam, Dhanansayan; Colman, Ricki J.; Nicholson, Jeremy K.; Weindruch, Richard (2009). "Metabolic shifts due to long-term caloric restriction revealed in nonhuman primates". Experimental Gerontology 44 (5): 356–62. doi:10.1016/j.exger.2009.02.008. PMC 2822382. PMID 19264119. 
  4. ^ Colman RJ, Anderson RM, Johnson SC, et al. (2009). "Caloric restriction delays disease onset and mortality in rhesus monkeys.". Science 325 (5937): 201–4. Bibcode:2009Sci...325..201C. doi:10.1126/science.1173635. PMC 2812811. PMID 19590001. 
  5. ^ The Anti-Aging Plan: Strategies and Recipes for Extending Your Healthy Years by Roy Walford (page 26)
  6. ^ Cava E et al. Will calorie restriction work in humans? Aging (Albany NY).2013 Jul;5(7):507-14.
  7. ^ Rickman AD et al. The CALERIE Study: Design and methods of an innovative 25% caloric restriction intervention Contemp Clin Trials. 2011 November; 32(6): 874–881.
  8. ^ Fernandez, Elizabeth (18 April 2011). "Extreme Dieting: Does It Lead to Longer Lives?". UCSF News Center. UCSF. Retrieved 2011-09-02. 
  9. ^ "Long-term Caloric Restriction and Cellular Aging Markers - Full Text View". Retrieved 2012-11-10. 
  10. ^ a b Fontana, L. (2004). "Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans". Proceedings of the National Academy of Sciences 101 (17): 6659–63. Bibcode:2004PNAS..101.6659F. doi:10.1073/pnas.0308291101. 
  11. ^ Fontana L, et al. Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial. Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E197-202
  12. ^ Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004 Aug;4(8):579-91
  13. ^ Cangemi R, Friedmann AJ, Holloszy JO, Fontana L. Long-term effects of calorie restriction on serum sex-hormone concentrations in men. Aging Cell. 2010 Apr;9(2):236-42
  14. ^ Fontana L, Klein S, Holloszy JO. Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production. Age (Dordr). 2010 Mar;32(1):97-108
  15. ^ Meyer TE, Kovács SJ, Ehsani AA, Klein S, Holloszy JO, Fontana L. Long-term caloric restriction ameliorates the decline in diastolic function in humans. J Am Coll Cardiol. 2006 Jan 17;47(2):398-402
  16. ^ Fontana, Luigi; Weiss, Edward P.; Villareal, Dennis T.; Klein, Samuel; Holloszy, John O. (2008). "Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans". Aging Cell 7 (5): 681–7. doi:10.1111/j.1474-9726.2008.00417.x. PMC 2673798. PMID 18843793. 
  17. ^ Redman LM, Veldhuis JD, Rood J, Smith SR, Williamson D, Ravussin E; Pennington CALERIE Team. The effect of caloric restriction interventions on growth hormone secretion in nonobese men and women. Aging Cell. 2010 Feb;9(1):32-9.
  18. ^ a b c Spindler, Stephen R. (2010). "Biological Effects of Calorie Restriction: Implications for Modification of Human Aging". The Future of Aging. pp. 367–438. doi:10.1007/978-90-481-3999-6_12. ISBN 978-90-481-3998-9. 
  19. ^ a b c Keys A, Brozek J, Henschels A & Mickelsen O & Taylor H. The Biology of Human Starvation, 1950, Vol. 2, p. 1133. University of Minnesota Press, Minneapolis
  20. ^ Morley, John E; Chahla, Elie; Alkaade, Saad (2010). "Antiaging, longevity and calorie restriction". Current Opinion in Clinical Nutrition and Metabolic Care 13 (1): 40–5. doi:10.1097/MCO.0b013e3283331384. PMID 19851100. 
  21. ^ a b "Some try extreme calorie restriction for long life". Retrieved 2010-07-28. 
  22. ^ Villareal, Dennis T.; Fontana, Luigi; Weiss, Edward P.; Racette, Susan B.; Steger-May, Karen; Schechtman, Kenneth B.; Klein, Samuel; Holloszy, John O. (2006). "Bone mineral density response to caloric restriction-induced weight loss or exercise-induced weight loss: a randomized controlled trial". Archives of Internal Medicine 166 (22): 2502–10. doi:10.1001/archinte.166.22.2502. PMID 17159017. 
  23. ^ Villareal, Dennis T.; Kotyk, John J.; Armamento-Villareal, Reina C.; Kenguva, Venkata; Seaman, Pamela; Shahar, Allon; Wald, Michael J.; Kleerekoper, Michael; Fontana, Luigi (February 2011). "Reduced bone mineral density is not associated with significantly reduced bone quality in men and women practicing long-term calorie restriction with adequate nutrition". Aging Cell 10 (1): 96–102. doi:10.1111/j.1474-9726.2010.00643.x. PMID 20969721. Retrieved 22 August 2012. 
  24. ^
  25. ^ a b c d McKiernan, SH; Colman, RJ; Aiken, E; Evans, TD; Beasley, TM; Aiken, JM; Weindruch, R; Anderson, RM (2012 Mar). "Cellular adaptation contributes to calorie restriction-induced preservation of skeletal muscle in aged rhesus monkeys". Exp Gerontol 47 (3): 229–36. doi:10.1016/j.exger.2011.12.009. PMID 22226624. 
  26. ^ a b c Colman, RJ; Beasley, TM; Allison, DB; Weindruch, R (2008). "Attenuation of Sarcopenia by Dietary Restriction in Rhesus Monkeys". The journals of gerontology. Series A, Biological sciences and medical sciences 63 (6): 556–9. doi:10.1093/gerona/63.6.556. PMC 2812805. PMID 18559628. 
  27. ^ a b c Dirks Naylor, AJ; Leeuwenburgh, C (2008 Jan). "Sarcopenia: the role of apoptosis and modulation by caloric restriction". Exerc Sport Sci Rev 36 (1): 19–24. doi:10.1097/jes.0b013e31815ddd9d. PMID 18156949. 
  28. ^ a b c Bua, E; McKiernan, SH; Aiken, JM (2004 Mar). "Calorie restriction limits the generation but not the progression of mitochondrial abnormalities in aging skeletal muscle". FASEB J 18 (3): 582–4. doi:10.1096/fj.03-0668fje. PMID 14734641. 
  29. ^ Fontana, L.; Klein, S. (2007). "Aging, Adiposity, and Calorie Restriction". JAMA 297 (9): 986–94. doi:10.1001/jama.297.9.986. PMID 17341713. 
  30. ^ Flegal, K. M.; Graubard, B. I.; Williamson, D. F.; Gail, M. H. (2007). "Cause-Specific Excess Deaths Associated With Underweight, Overweight, and Obesity". JAMA 298 (17): 2028–37. doi:10.1001/jama.298.17.2028. PMID 17986696. 
  31. ^ Holzman, Donald (2005-05-27). "Panel Suggests Methodology Flawed of Recent CDC Obesity Study". Medscape Medical News. Retrieved 2011-02-21. 
  32. ^ "RESEARCHERS WEIGH RISKS DUE TO OVERWEIGHT". CA 55 (5): 268–9. 2005. doi:10.3322/canjclin.55.5.268. 
  33. ^ Hu, Frank (2008). "Interpreting Epidemiologic Evidence and Causal Inference in Obesity Research". In Frank B. Hu. Obesity Epidemiology. New York, NY: Oxford University Press. pp. 38–52. ISBN 0-19-531291-0. Retrieved 2011-02-20. 
  34. ^ USA (2012-10-19). "Body mass index and mortality from all causes an... [J Epidemiol. 2011] - PubMed - NCBI". Retrieved 2012-11-10. 
  35. ^ St. Jeor, S. T.; Howard, B. V.; Prewitt, T. E.; Bovee, V.; Bazzarre, T.; Eckel, R. H.; Nutrition Committee Of The Council On Nutrition (2001). "Dietary Protein and Weight Reduction: A Statement for Healthcare Professionals From the Nutrition Committee of the Council on Nutrition, Physical Activity, and Metabolism of the American Heart Association". Circulation 104 (15): 1869–74. doi:10.1161/hc4001.096152. PMID 11591629. 
  36. ^ De Souza, RJ; Swain, JF; Appel, LJ; Sacks, FM (2008). "Alternatives for macronutrient intake and chronic disease: a comparison of the OmniHeart diets with popular diets and with dietary recommendations". The American journal of clinical nutrition 88 (1): 1–11. PMC 2674146. PMID 18614716. 
  37. ^ Ma, Y; Pagoto, S; Griffith, J; Merriam, P; Ockene, I; Hafner, A; Olendzki, B (2007). "A Dietary Quality Comparison of Popular Weight-Loss Plans". Journal of the American Dietetic Association 107 (10): 1786–91. doi:10.1016/j.jada.2007.07.013. PMC 2040023. PMID 17904938. 
  38. ^ Williamson, Donald A.; Martin, Corby K.; Anton, Stephen D.; York-Crowe, Emily; Han, Hongmei; Redman, Leanne; Ravussin, Eric; Pennington Calerie, Team (2008). "Is caloric restriction associated with development of eating-disorder symptoms? Results from the CALERIE trial". Health Psychology 27 (1 Suppl): S32–42. doi:10.1037/0278-6133.27.1.S32. PMID 18248104. 
  39. ^ Binge-Eating Disorder: Clinical Foundations and Treatment (1 ed.). The Guilford Press. 2007. p. 15. ISBN 978-1-59385-594-9. "It can be concluded that caloric restriction does not appear to be associated with the development of binge eating in individuals who have never reported problems with binge eating." 
  40. ^ a b "Risks". Retrieved 2010-07-28. 
  41. ^ USA (2012-10-19). "Cellular mechanisms of cardioprotection by calorie restriction: state of the science and future perspectives". Retrieved 2012-11-10. 
  42. ^ "Caloric Restriction". Retrieved 2010-07-28. 
  43. ^ Ramsey, J; Colman, RJ; Binkley, NC; Christensen, JD; Gresl, TA; Kemnitz, JW; Weindruch, R (2000). "Dietary restriction and aging in rhesus monkeys: the University of Wisconsin study". Experimental Gerontology 35 (9–10): 1131–49. doi:10.1016/S0531-5565(00)00166-2. PMID 11113597. 
  44. ^ Wade, Nicholas (10 July 2009). "Dieting Moneys Offer Hope for Living Longer". New York Times. Retrieved 2009-09-10. 
  45. ^ a b Reduced Diet Thwarts Aging, Disease In Monkeys Science Daily, July 10, 2009
  46. ^ Willette, Auriel A.; Coe, Christopher L.; Colman, Ricki J.; Bendlin, Barbara B.; Kastman, Erik K.; Field, Aaron S.; Alexander, Andrew L.; Allison, David B.; Weindruch, Richard H.; Johnson, Sterling C. (2011). "Calorie restriction reduces psychological stress reactivity and its association with brain volume and microstructure in aged rhesus monkeys". Psychoneuroendocrinology 37 (7): 903–916. doi:10.1016/j.psyneuen.2011.10.006. 
  47. ^ Mattison, Julie A.; et al. (2012). "Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study". Nature 489: 318–321. Bibcode:2012Natur.489..318M. doi:10.1038/nature11432. 
  48. ^ Calorie restriction falters in the long run Nature News, August 29, 2012
  49. ^ a b Qin, W; Chachich, M; Lane, M; Roth, G; Bryant, M; De Cabo, R; Ottinger, MA; Mattison, J et al. (2006). "Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus)". Journal of Alzheimer's disease 10 (4): 417–22. PMID 17183154. 
  50. ^ a b Mattson, Mark P. (2005). "ENERGY INTAKE, MEAL FREQUENCY, AND HEALTH: A Neurobiological Perspective*". Annual Review of Nutrition 25: 237–60. doi:10.1146/annurev.nutr.25.050304.092526. PMID 16011467. 
  51. ^ Yaghmaie, F; Saeed, O; Garan, SA; Freitag, W; Timiras, PS; Sternberg, H (2005). "Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice". Neuro endocrinology letters 26 (3): 197–203. PMID 15990721. 
  52. ^ Saeed, O; Yaghmaie, F; Garan, S; Gouw, A; Voelker, M; Sternberg, H; Timiras, P (2007). "Insulin-like growth factor-1 receptor immunoreactive cells are selectively maintained in the paraventricular hypothalamus of calorically restricted mice". International Journal of Developmental Neuroscience 25 (1): 23–8. doi:10.1016/j.ijdevneu.2006.11.004. PMID 17194562. 
  53. ^ Yaghmaie, F; Saeed, O; Garan, S; Voelker, M; Gouw, A; Freitag, W; Sternberg, H; Timiras, P (2006). "Age-dependent loss of insulin-like growth factor-1 receptor immunoreactive cells in the supraoptic hypothalamus is reduced in calorically restricted mice". International Journal of Developmental Neuroscience 24 (7): 431–6. doi:10.1016/j.ijdevneu.2006.08.008. PMID 17034982. 
  54. ^ Kaeberlein, Matt; Burtner, Christopher R.; Kennedy, Brian K. (2007). "Recent Developments in Yeast Aging". PLoS Genetics 3 (5): e84. doi:10.1371/journal.pgen.0030084. PMC 1877880. PMID 17530929. 
  55. ^ Dilova, I.; Easlon, E.; Lin, S. -J. (2007). "Calorie restriction and the nutrient sensing signaling pathways". Cellular and Molecular Life Sciences 64 (6): 752–67. doi:10.1007/s00018-007-6381-y. PMID 17260088. 
  56. ^ Chen, D; Guarente, L (2007). "SIR2: a potential target for calorie restriction mimetics". Trends in Molecular Medicine 13 (2): 64–71. doi:10.1016/j.molmed.2006.12.004. PMID 17207661. 
  57. ^ Piper, Peter W. (2006). "Long-lived yeast as a model for ageing research". Yeast 23 (3): 215–26. doi:10.1002/yea.1354. PMID 16498698. 
  58. ^ Longo, V (2009). "Linking sirtuins, IGF-I signaling, and starvation". Experimental Gerontology 44 (1–2): 70–4. doi:10.1016/j.exger.2008.06.005. PMID 18638538. 
  59. ^ Mair, W.; Goymer, P; Pletcher, SD; Partridge, L (2003). "Demography of Dietary Restriction and Death in Drosophila". Science 301 (5640): 1731–3. Bibcode:2003Sci...301.1731M. doi:10.1126/science.1086016. PMID 14500985. 
  60. ^ Mair, W.; Piper, M. D. W; Partridge, L (2005). "Calories Do Not Explain Extension of Life Span by Dietary Restriction in Drosophila". PLOS 3 (7): e223. doi:10.1371/journal.pbio.0030223.st001. 
  61. ^ a b Schulz, Tim J.; Zarse, Kim; Voigt, Anja; Urban, Nadine; Birringer, Marc; Ristow, Michael (2007). "Glucose Restriction Extends Caenorhabditis elegans Life Span by Inducing Mitochondrial Respiration and Increasing Oxidative Stress". Cell Metabolism 6 (4): 280–293. doi:10.1016/j.cmet.2007.08.011. PMID 17908557. 
  62. ^ a b c Vitousek, K. M., Manke, F. P., Gray, J. A., & Vitousek, M. N. (2004). Caloric Restriction for Longevity: II--The Systematic Neglect of Behavioural and Psychological Outcomes in Animal Research. European Eating Disorders Review, 12(6), 338-360.
  63. ^ a b Faulks, SC; Turner, N; Else, PL; Hulbert, AJ (2006 Aug). "Calorie restriction in mice: effects on body composition, daily activity, metabolic rate, mitochondrial reactive oxygen species production, and membrane fatty acid composition". J Gerontol A Biol Sci Med Sci 61 (8): 781–94. PMID 16912094. 
  64. ^ a b Means, L. W., Higgins, J. L., & Fernandez, T. J. (1993). Mid-life onset of dietary restriction extends life and prolongs cognitive functioning. Physiology & Behavior, 54, 503–508.
  65. ^ Weed, J. L., Lane, M. A., Roth, G. S., Speer, D. L., & Ingram, D. K. (1997). Activity measures in rhesus monkeys on long-term calorie restriction. Physiology & Behavior, 62, 97–103.
  66. ^ Duffy, P. H., Feuers, R., Leakey, J. E. A., & Hart, R. W. (1991). Chronic caloric restriction in old female mice: Changes in the circadian rhythms of physiological and behavioral variables. In L. Fishbein (Ed.), Biological effects of dietary restriction (ILSI Monographs) (pp. 245– 263). London: Springer-Verlag.
  67. ^ a b Lore R., Gottdiener C., Delahunty M. J. (1986). "Lean and mean rats: Some effects of acute changes in the food supply upon territorial aggression". Aggressive Behavior 12: 409–415. 
  68. ^ a b Ramsey J. J., Colman R. J., Binkley N. C., Christensen J. D., Gresl T. A., Kemnitz J. W. et al. (2000). "Dietary restriction and aging in rhesus monkeys: The University of Wisconsin study". Experimental Gerontology 35: 1131–1149. doi:10.1016/S0531-5565(00)00166-2. PMID 11113597. 
  69. ^ a b Sohal RS, Ku HH, Agarwal S, Forster MJ, Lal H. (1994). Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse. Mech Ageing Dev 74(1-2) 121-133. PMID 7934203
  70. ^ Sohal RS, Agarwal S, Candas M, Forster MJ, Lal H. (1994). Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech Ageing Dev 76(2-3) 215-224. PMID 7885066
  71. ^ a b Holmes GE, Bernstein C, Bernstein H. (1992). Oxidative and other DNA damages as the basis of aging: a review. Mutat Res 275(3-6) 305-315. PMID 1383772
  72. ^ Hormesis: A Revolution in Biology, Toxicology and Medicine By Mark P. Mattson, Edward J. Calabrese
  73. ^ Mattson, M (2008). "Dietary Factors, Hormesis and Health". Ageing Research Reviews 7 (1): 43–8. doi:10.1016/j.arr.2007.08.004. PMC 2253665. PMID 17913594. 
  74. ^ Tapia, P (2006). "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, intermittent fasting, exercise and dietary phytonutrients: "Mitohormesis" for health and vitality". Medical Hypotheses 66 (4): 832–43. doi:10.1016/j.mehy.2005.09.009. PMID 16242247. 
  75. ^ Schulz, Tim J.; Zarse, Kim; Voigt, Anja; Urban, Nadine; Birringer, Marc; Ristow, Michael (2007). "Glucose Restriction Extends Caenorhabditis elegans Life Span by Inducing Mitochondrial Respiration and Increasing Oxidative Stress". Cell Metabolism 6 (4): 280–93. doi:10.1016/j.cmet.2007.08.011. PMID 17908557. 
  76. ^ Bjelakovic, G.; Nikolova, D.; Gluud, L. L.; Simonetti, R. G.; Gluud, C. (2007). "Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis". JAMA 297 (8): 842–57. doi:10.1001/jama.297.8.842. PMID 17327526. 
  77. ^ Ristow, M; Zarse, K (2010). "How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis)". Experimental Gerontology 45 (6): 410–8. doi:10.1016/j.exger.2010.03.014. PMID 20350594. 
  78. ^ [Charlie Rose- Calorie restriction]
  79. ^ Estep, Preston Wayne; Warner, Jason B.; Bulyk, Martha L. (2009). "Short-Term Calorie Restriction in Male Mice Feminizes Gene Expression and Alters Key Regulators of Conserved Aging Regulatory Pathways". In Orban, Laszlo. PLoS ONE 4 (4): e5242. Bibcode:2009PLoSO...4.5242E. doi:10.1371/journal.pone.0005242. PMC 2667255. PMID 19370158. 
  80. ^ Cangemi, Roberto; Friedmann, Alberto J.; Holloszy, John O.; Fontana, Luigi (2010). "Long-term effects of calorie restriction on serum sex-hormone concentrations in men". Aging Cell 9 (2): 236–42. doi:10.1111/j.1474-9726.2010.00553.x. PMID 20096034. 
  81. ^ a b Bergamini, E; Cavallini, G; Donati, A; Gori, Z (2003). "The anti-ageing effects of caloric restriction may involve stimulation of macroautophagy and lysosomal degradation, and can be intensified pharmacologically". Biomedecine & Pharmacotherapy 57 (5–6): 203–8. doi:10.1016/S0753-3322(03)00048-9. 
  82. ^ Cuervo, Ana Maria; Bergamini, Ettore; Brunk, Ulf T; Dröge, Wulf; Ffrench, Martine; Terman, Alexei (2005). "Autophagy and Aging: the Importance of Maintaining "Clean" Cells". Autophagy 1 (3): 131–40. doi:10.4161/auto.1.3.2017. PMID 16874025. 
  83. ^ Mattison, J; Lane, MA; Roth, GS; Ingram, DK (2003). "Calorie restriction in rhesus monkeys". Experimental Gerontology 38 (1–2): 35–46. doi:10.1016/S0531-5565(02)00146-8. PMID 12543259. 
  84. ^ Urbanski, H F.; Downs, J L; Garyfallou, V T; Mattison, J A; Lane, M A; Roth, G S; Ingram, D K (2004). "Effect of Caloric Restriction on the 24-Hour Plasma DHEAS and Cortisol Profiles of Young and Old Male Rhesus Macaques". Annals of the New York Academy of Sciences 1019: 443–7. doi:10.1196/annals.1297.081. PMID 15247063. 
  85. ^ Vaquero, A.; Reinberg, D. (2009). "Calorie restriction and the exercise of chromatin". Genes & Development 23 (16): 1849–69. doi:10.1101/gad.1807009. PMC 2725938. PMID 19608767. 
  86. ^ "The gene for longevity, if you're a worm". ABC News. 2007. Retrieved 2007-05-03. 
  87. ^ Gredilla R, Sanz A, Lopez-Torres M, Barja G. (2001). Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart" FASEB J 15(9) 1589-1591. PMID 11427495
  88. ^ Sohal RS, Agarwal S, Candas M, Forster MJ, Lal H. (1994). Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice" Mech Ageing Dev 76(2-3) 215-224. PMID 7885066
  89. ^ Kaneko T, Tahara S, Matsuo M. (1997). Retarding effect of dietary restriction on the accumulation of 8-hydroxy-2'-deoxyguanosine in organs of Fischer 344 rats during aging. Free Radic Biol Med 23(1) 76-81. PMID 9165299
  90. ^ Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K, Walter CA, Richardson A. (2001). Does oxidative damage to DNA increase with age?" Proc Natl Acad Sci U S A 98(18) 10469-10474. PMID 11517304
  91. ^ Wolf FI, Fasanella S, Tedesco B, Cavallini G, Donati A, Bergamini E, Cittadini A. (2005). Peripheral lymphocyte 8-OHdG levels correlate with age-associated increase of tissue oxidative DNA damage in Sprague-Dawley rats. Protective effects of caloric restriction. Exp Gerontol 40(3) 181-188. PMID 15763395
  92. ^ Bernstein, H., Payne, C.M., Bernstein, C., Garewal, H., Dvorak, K. (2008). Cancer and aging as consequences of un-repaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1-47.
  93. ^ Minor, RK; Allard, JS; Younts, CM; Ward, TM; de Cabo, R (July 2010). "Dietary interventions to extend life span and health span based on calorie restriction.". The journals of gerontology. Series A, Biological sciences and medical sciences 65 (7): 695–703. doi:10.1093/gerona/glq042. PMC 2884086. PMID 20371545. 
  94. ^ Contestabile, A (2009). "Benefits of caloric restriction on brain aging and related pathological States: understanding mechanisms to devise novel therapies.". Current medicinal chemistry 16 (3): 350–61. PMID 19149582. 
  95. ^ de Magalhaes JP, Wuttke D, Wood SH, Plank M, Vora C (2012). "Genome-environment interactions that modulate aging: powerful targets for drug discovery". Pharmacol Rev 64 (1): 88–101. doi:10.1124/pr.110.004499. PMID 22090473. 
  96. ^ Vergano, Dan (3 May 2007). "Longevity gene linked to low-calorie diets". USA Today. Retrieved 2007-05-03. 
  97. ^ Sinclair, David A; Guarente, Leonard (1997). "Extrachromosomal rDNA Circles— A Cause of Aging in Yeast". Cell 91 (7): 1033–1042. doi:10.1016/S0092-8674(00)80493-6. PMID 9428525. 
  98. ^ Cohen, H. Y.; Miller, C; Bitterman, KJ; Wall, NR; Hekking, B; Kessler, B; Howitz, KT; Gorospe, M et al. (2004). "Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase". Science 305 (5682): 390–2. Bibcode:2004Sci...305..390C. doi:10.1126/science.1099196. PMID 15205477. 
  99. ^ Picard, Frédéric; Kurtev, Martin; Chung, Namjin; Topark-Ngarm, Acharawan; Senawong, Thanaset; MacHado De Oliveira, Rita; Leid, Mark; McBurney, Michael W. et al. (2004). "Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ". Nature 429 (6993): 771–6. Bibcode:2004Natur.429..771P. doi:10.1038/nature02583. PMC 2820247. PMID 15175761. 
  100. ^ Corton, J. C.; Apte, U; Anderson, SP; Limaye, P; Yoon, L; Latendresse, J; Dunn, C; Everitt, JI et al. (2004). "Mimetics of Caloric Restriction Include Agonists of Lipid-activated Nuclear Receptors". Journal of Biological Chemistry 279 (44): 46204–12. doi:10.1074/jbc.M406739200. PMID 15302862. 
  101. ^ Howitz, Konrad T.; Bitterman, Kevin J.; Cohen, Haim Y.; Lamming, Dudley W.; Lavu, Siva; Wood, Jason G.; Zipkin, Robert E.; Chung, Phuong et al. (2003). "Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan". Nature 425 (6954): 191–6. Bibcode:2003Natur.425..191H. doi:10.1038/nature01960. PMID 12939617. 
  102. ^ Wood, Jason G.; Rogina, Blanka; Lavu, Siva; Howitz, Konrad; Helfand, Stephen L.; Tatar, Marc; Sinclair, David (2004). "Sirtuin activators mimic caloric restriction and delay ageing in metazoans". Nature 430 (7000): 686–9. Bibcode:2004Natur.430..686W. doi:10.1038/nature02789. PMID 15254550. 
  103. ^ Valenzano, Dario R.; Terzibasi, Eva; Genade, Tyrone; Cattaneo, Antonino; Domenici, Luciano; Cellerino, Alessandro (2006). "Resveratrol Prolongs Lifespan and Retards the Onset of Age-Related Markers in a Short-Lived Vertebrate". Current Biology 16 (3): 296–300. doi:10.1016/j.cub.2005.12.038. PMID 16461283. 
  104. ^ Baur, Joseph A.; Pearson, Kevin J.; Price, Nathan L.; Jamieson, Hamish A.; Lerin, Carles; Kalra, Avash; Prabhu, Vinayakumar V.; Allard, Joanne S. et al. (2006). "Resveratrol improves health and survival of mice on a high-calorie diet". Nature 444 (7117): 337–42. Bibcode:2006Natur.444..337B. doi:10.1038/nature05354. PMID 17086191. 
  105. ^ Pearson, Kevin J.; Baur, Joseph A.; Lewis, Kaitlyn N.; Peshkin, Leonid; Price, Nathan L.; Labinskyy, Nazar; Swindell, William R.; Kamara, Davida et al. (2008). "Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending lifespan". Cell Metabolism 8 (2): 157–68. doi:10.1016/j.cmet.2008.06.011. PMC 2538685. PMID 18599363. 
  106. ^ Bass, T; Weinkove, D; Houthoofd, K; Gems, D; Partridge, L (2007). "Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans". Mechanisms of Ageing and Development 128 (10): 546–52. doi:10.1016/j.mad.2007.07.007. PMID 17875315. 
  107. ^ Pacholec, M.; Bleasdale, J. E.; Chrunyk, B.; Cunningham, D.; Flynn, D.; Garofalo, R. S.; Griffith, D.; Griffor, M. et al. (2010). "SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1". Journal of Biological Chemistry 285 (11): 8340–51. doi:10.1074/jbc.M109.088682. PMC 2832984. PMID 20061378. 
  108. ^ Zarse, K.; Schmeisser, S.; Birringer, M.; Falk, E.; Schmoll, D.; Ristow, M. (2010). "Differential Effects of Resveratrol and SRT1720 on Lifespan of AdultCaenorhabditis elegans". Hormone and Metabolic Research 42 (12): 837–9. doi:10.1055/s-0030-1265225. PMID 20925017. 
  109. ^ Kaeberlein, Matt; Kirkland, Kathryn T.; Fields, Stanley; Kennedy, Brian K. (2004). "Sir2-Independent Life Span Extension by Calorie Restriction in Yeast". PLoS Biology 2 (9): e296. doi:10.1371/journal.pbio.0020296. PMC 514491. PMID 15328540. 
  110. ^ Kaeberlein, M; Powersiii, R (2007). "Sir2 and calorie restriction in yeast: A skeptical perspective". Ageing Research Reviews 6 (2): 128–40. doi:10.1016/j.arr.2007.04.001. PMID 17512264. 
  111. ^ Suspended Resveratrol Clinical Trial: More Details Emerge(May 6, 2010)
  112. ^ Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, Tanokura M, Denu JM, Prolla TA. et al. (Nov 2010). "Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction". Cell. 143 (5): 802–12. 
  113. ^ Heidi Ledford for Nature News. February 22, 2012 Sirtuin protein linked to longevity in mammals: Male mice overproducing the protein sirtuin 6 have an extended lifespan.
  114. ^ Cooper, T. M.; Mockett, RJ; Sohal, BH; Sohal, RS; Orr, WC (2004). "Effect of caloric restriction on life span of the housefly, Musca domestica". The FASEB Journal 18 (13): 1591–3. doi:10.1096/fj.03-1464fje. PMID 15319362. 
  115. ^ Hayflick, Leonard (1994). How and Why We Age. New York, NY: Ballantine Books. p. 285. ISBN 9780345401557. 
  116. ^ Austad, Steven N. (November 2001). "Does Caloric Restriction in the Laboratory Simply Prevent Overfeeding and Return House Mice to Their Natural Level of Food Intake?". SAGE KE 2001 (6): pe3. doi:10.1126/sageke.2001.6.pe3. PMID 14602968. Retrieved 10 June 2012. 
  117. ^ Austad, Steven N.; Kristan, Deborah N (August 2003). "Are mice calorically restricted in nature?". Aging Cell 2 (4): 201–7. doi:10.1046/j.1474-9728.2003.00053.x. PMID 12934713. Retrieved 10 June 2012. 
  118. ^ Cerletti, M; Jang, YC; Finley3=LW; Haigis 4=MC; Wagers 5=AJ (2012 May 4). "Short-term calorie restriction enhances skeletal muscle stem cell function". Cell Stem Cell 10 (5): 515–9. doi:10.1016/j.stem.2012.04.002. PMID 22560075. 
  119. ^ J. O. Holloszy and K. B. Schechtman (1991-04-01). "Interaction between exercise and food restriction: effects on longevity of male rats". Retrieved 2012-11-10. 
  120. ^ Washington University School of Medicine. "Calorie Restriction Appears Better Than Exercise At Slowing Primary Aging." ScienceDaily 31 May 2006. 24 April 2009 <>.
  121. ^ Lipman, RD; Smith, DE; Bronson, RT; Blumberg, J (1995). "Is late-life caloric restriction beneficial?". Aging (Milan, Italy) 7 (2): 136–9. PMID 7548264. 
  122. ^ Spindler, S (2005). "Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction". Mechanisms of Ageing and Development 126 (9): 960–6. doi:10.1016/j.mad.2005.03.016. PMID 15927235. 
  123. ^ Hamadeh, Mazen J.; Rodriguez, M. Christine; Kaczor, Jan J.; Tarnopolsky, Mark A. (2005). "Caloric restriction transiently improves motor performance but hastens clinical onset of disease in the Cu/Zn-superoxide dismutase mutant G93A mouse". Muscle & Nerve 31 (2): 214–20. doi:10.1002/mus.20255. PMID 15625688. 
  124. ^ a b Kasarskis, Edward J; Berryman, Susan; Vanderleest, Jennifer G; Schneider, Andrew R; McClain, Craig J (1996). "Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death". The American journal of clinical nutrition 63 (1): 130–7. PMID 8604660. 
  125. ^ Slowie, LA; Paige, MS; Antel, JP (1983). "Nutritional considerations in the management of patients with amyotrophic lateral sclerosis (ALS)". Journal of the American Dietetic Association 83 (1): 44–7. PMID 6863783. 
  126. ^ Pedersen, WA; Mattson, MP (1999). "No benefit of dietary restriction on disease onset or progression in amyotrophic lateral sclerosis Cu/Zn-superoxide dismutase mutant mice". Brain Research 833 (1): 117–20. doi:10.1016/S0006-8993(99)01471-7. PMID 10375685. 
  127. ^ Zhao, Zhong; Lange, Dale J; Voustianiouk, Andrei; MacGrogan, Donal; Ho, Lap; Suh, Jason; Humala, Nelson; Thiyagarajan, Meenakshisundaram et al. (2006). "A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis". BMC Neuroscience 7: 29. doi:10.1186/1471-2202-7-29. PMC 1488864. PMID 16584562. 
  128. ^ Mattson, MP; Cutler, RG; Camandola, S (2007). "Energy intake and amyotrophic lateral sclerosis". Neuromolecular medicine 9 (1): 17–20. doi:10.1385/NMM:9:1:17. PMID 17114821. 
  129. ^ Phelan, J; Rose, M (2005). "Why dietary restriction substantially increases longevity in animal models but won't in humans". Ageing Research Reviews 4 (3): 339–50. doi:10.1016/j.arr.2005.06.001. PMID 16046282. 
  130. ^ a b c Anson, R. M.; Guo, Z; De Cabo, R; Iyun, T; Rios, M; Hagepanos, A; Ingram, DK; Lane, MA et al. (2003). "Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake". Proceedings of the National Academy of Sciences 100 (10): 6216–20. Bibcode:2003PNAS..100.6216A. doi:10.1073/pnas.1035720100. PMC 156352. PMID 12724520. 
  131. ^ Duan, W.; Guo, Z; Jiang, H; Ware, M; Li, XJ; Mattson, MP (2003). "Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice". Proceedings of the National Academy of Sciences 100 (5): 2911–6. Bibcode:2003PNAS..100.2911D. doi:10.1073/pnas.0536856100. PMC 151440. PMID 12589027. 
  132. ^ Johnson, James B.; Summer, Warren; Cutler, Roy G.; Martin, Bronwen; Hyun, Dong-Hoon; Dixit, Vishwa D.; Pearson, Michelle; Nassar, Matthew et al. (2007). "Alternate Day Calorie Restriction Improves Clinical Findings and Reduces Markers of Oxidative Stress and Inflammation in Overweight Adults with Moderate Asthma". Free Radical Biology and Medicine 42 (5): 665–74. doi:10.1016/j.freeradbiomed.2006.12.005. PMC 1859864. PMID 17291990. 
  133. ^ Johnson, J; Laub, D; John, S (2006). "The effect on health of alternate day calorie restriction: Eating less and more than needed on alternate days prolongs life". Medical Hypotheses 67 (2): 209–11. doi:10.1016/j.mehy.2006.01.030. PMID 16529878. 


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