Calorie restriction
Encyclopedia
Caloric restriction or calorie restriction, is a dietary regimen
that restricts calorie intake, where the baseline for the restriction varies, usually being the previous, unrestricted, intake of the subjects. Calorie restriction without malnutrition has been shown to improve age-related health and to slow the aging
process in a wide range of animals and some fungi.
CR is one of the few dietary interventions shown to increase both median and maximum lifespan in a variety of species, among them yeast, fish, rodents and dogs. There are ongoing studies on whether CR works in nonhuman primates, on its effects on human health, and on the metabolic parameters associated with CR in other species. The results so far are positive, but the studies are not yet complete, due to the long lifespan of the species. Among the current studies, one at UCSF, with Nobel laureate Elizabeth Blackburn
as part of the investigation team, is looking at long-term CR practitioners, including the psychological factors that keep them motivated to stay on a CR diet.
Calorie restriction is a feature of several dietary regimens
, including the Okinawa diet
and the CRON-diet.
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.
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 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 CR group had triglyceride
levels as low as the lowest 5% of Americans in their 20s. (The CR group 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 calorie 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
levels and reduced signs of inflammation. Scientists believe that memory improvement in this experiment was caused by the lower insulin levels, because high insulin levels are usually associated with lower memory and cognitive function. However, that relation seems to be age-specific since another study, when analyzing people older than 65, those who were underweight had a higher dementia risk than normal or overweight people.
and health in model organisms, and studies in humans demonstrate reduced risk factors for major diseases, the long-term effects on humans are still unknown.
Several studies revealed that dieters who restricted calories for 12 months had lower muscle mass and a reduced capacity to perform exercise compared with those who lost similar amounts of weight from exercise alone. Another study concluded that those who lost weight with the help of the CR diets are more prone to develop a loss of bone at the level of hip and spine
, the area most at risk for bone fractures. Some specialists say that minor mineral losses can be prevented with supplements of vitamin D
and calcium
.
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 the association between BMI<21 (under 140lbs for a 5'9" tall individual) and increased mortality persists even when confounders like age, smoking, and disease are carefully controlled for. To date, there are no human studies that have demonstrated a positive or even neutral association between low body weight and longevity.
In any case, epidemiological studies of body weight are not about CR as used in anti-aging studies; they are not about calorie 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."
, but it does not seem to pose any such risk otherwise.
, several studies have shown that the body adjusts to the new diet in about six months. Researchers argue that people who have little body fat should not use this method of losing weight but rather should exercise more because calorie restriction in this case can be harmful. The reason for this is that after the body's fat
reserves have been burned for energy, the proteins within muscle tissue will be consumed. In severe cases where individuals do not acknowledge the dangers they are exposing themselves to, they may suffer serious loss of the muscle mass.
Especially in children, adolescents and young adults
(under approximately 21), calorie restriction is not advised because this type of diet may interfere with the natural physical growth, as it 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 calorie restriction. Pregnant women are recommended not to try losing weight with this method. It has been shown that a low BMI is a risk factor in pregnancy as it may result in ovulatory dysfunction (infertility
), and mothers who are underweight are more prone to preterm delivery.
Individuals trying lose weight on a CR diet of less than 1,500 calories a day need to be monitored by a specialist in order to prevent potential side effects.
, 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, unless metabolism
is also slowed by some means. CR should not be confused with anorexia nervosa
or other eating disorders. If such a pattern is repeated for prolonged periods, the body may burn lean tissue (including but not limited to muscle and collagen
) along with its remaining fat reserves. The combination of starvation and the associated lethargy and decreased physical activity can result in muscular atrophy, reducing quality of life.
Beyond using lean tissue as energy source, the presence of catabolic hormones, such as cortisol, and lack of anabolic ones, such as insulin, disrupts protein synthesis, amino acid uptake and weakens the immune system. Commenting on a study where CR showed generally positive effects, one researcher 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."
s, funded by the National Institute on Aging, was started in 1989 at the University of Wisconsin–Madison
and is still ongoing. This study has so far shown 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. The monkeys were enrolled in the study at ages of between 7 and 14 years; at the 20 year point 80% of the calorically restricted monkeys were still alive, compared to only half of the controls. These results bore out earlier preliminary results that 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.
The most recent study conducted by Ricki J. Colman and Richard Weindruch at the University of Wisconsin used rhesus monkeys that live an average of 27 years and a maximum of 40, found that the dieting monkeys show many beneficial signs of caloric resistance, including significantly less diabetes, cancer, and heart and brain disease. However, as some of the monkeys are expected to live another 20 years, the findings are still inconclusive.
Results to date have 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 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.
Researchers at New York's Mount Sinai School of Medicine reported in 2006 that compared to monkeys fed a normal diet, squirrel monkeys on a life-long calorie-restrictive diet were less likely to develop Alzheimer's-like changes in their brains. Since squirrel monkeys are relatively long-lived, definitive conclusions regarding whether or not they are aging slower are not yet available.
Moderate CR attenuates age-related sarcopenia
in primates.
-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 their non-calorically restricted counterparts.
Studies in female mice have shown that both Supraoptic nucleus
(SON) and Paraventricular nucleus
(PVN) lose about one-third of IGF-1R immunoreactivity with normal aging. Old calorically restricted (CR) 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.
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
.
.
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 defense 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, and this results in improved health and longer life. This switch to a defensive state may be controlled by longevity genes (see below).
's group in a small worm named Caenorhabditis elegans
suggests that 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 years past. It was previously proposed on a hypothetical basis that free radicals may induce an endogenous response culminating in more effective adaptations which 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 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.
Lowering of the concentration of insulin
and substances which are related to insulin, e.g. Insulin-like growth factor 1
and Growth hormone
has been shown to upregulate autophagy
, the repair mechanism of the cell. A related hypothesis suggests that CR works by decreasing insulin
levels and thereby upregulating autophagy, but CR affects many other health indicators and whether insulin is the main concern is still undecided. Calorie restriction has been shown to increase DHEA in primates, however 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.
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".
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 II 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
.
Calorie Restriction with Optimal Nutrition has not been tested in comparison to Calorie Excess with Optimal Nutrition. It may be that with extra calories, nutrition must be similarly increased to ratios comparable to that of Calorie Restriction to provide similar antiaging benefits. Stated levels of calorie needs may be biased towards sedentary individuals. Calorie restriction may be no more than adapting the diet to the body's needs.
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, which is hypothesized to suppress DNA instability. In mammals Sir2 is known as SIRT1. David Sinclair at Harvard Medical School, 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 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.
s 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 lifespan in normal mice.
The effect of resveratrol on lifespan in C. elegans and Drosophila was re-investigated by D. Gems and L. Partridge. They concluded that previously reported lifespan increases were in fact due to natural variability in C. elegans lifespans 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 lifespan 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 Seattle believe that Sinclair's work on resveratrol is an artifact and that the Sir2 gene has no relevance to CR. They have proposed that the caloric restriction increases lifespan 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 lifespan extending effects of calorie restriction (reduced insulin, igf1 and fasting glucose), were no different in normal mice and mice lacking Sirt1. Whether the lifespan-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, however some research has cast doubt on this. A clinical trial of the resveratrol formulation SRT501 was suspended.
. The authors hypothesize that the widely purported effects of CR may be because a diet containing more calories can increase bacteria
l proliferation, or that the type of high calorie diets used in past experiments have a stickiness, general composition, or texture that reduces longevity.
Another related theory says that some of the calorie-restriction effects are artifacts, because the laboratory model organisms are kept at non-physiological high calorie diets. This would mean that calorie restriction simply means mimicking a natural environment energy supply.
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 show increases in lifespan. 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.
(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 go on to conclude: "We conclude that 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.
'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 lifespan, 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 delays 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 to 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 calorie 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 didn't cut total calories at the beginning and the 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 neuron
s, 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 that ate a restricted diet, and most damage in mice with an unrestricted diet. But the control group which ate the average daily intake of the fasting mice also showed less damage than the mice with restricted diet.
Another Mattson study in which overweight adult asthmatics followed alternate day calorie restriction (ADCR) for eight weeks showed marked improvement in oxidative stress, inflammation, and severity of the disease. Evidence from the medical literature suggests that ADCR in the absence of weight loss prolongs lifespan in humans.
Intermittent fasting has also been shown to increase the resistance of neurons in the brain to excitotoxic stress.
Diet (nutrition)
In nutrition, diet is the sum of food consumed by a person or other organism. Dietary habits are the habitual decisions an individual or culture makes when choosing what foods to eat. With the word diet, it is often implied the use of specific intake of nutrition for health or weight-management...
that restricts calorie intake, where the baseline for the restriction varies, usually being the previous, unrestricted, intake of the subjects. Calorie restriction without malnutrition has been shown to improve age-related health and to slow the aging
Senescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
process in a wide range of animals and some fungi.
CR is one of the few dietary interventions shown to increase both median and maximum lifespan in a variety of species, among them yeast, fish, rodents and dogs. There are ongoing studies on whether CR works in nonhuman primates, on its effects on human health, and on the metabolic parameters associated with CR in other species. The results so far are positive, but the studies are not yet complete, due to the long lifespan of the species. Among the current studies, one at UCSF, with Nobel laureate Elizabeth Blackburn
Elizabeth Blackburn
Elizabeth Helen Blackburn, AC, FRS is an Australian-born American biological researcher at the University of California, San Francisco, who studies the telomere, a structure at the end of chromosomes that protects the chromosome. Blackburn co-discovered telomerase, the enzyme that replenishes the...
as part of the investigation team, is looking at long-term CR practitioners, including the psychological factors that keep them motivated to stay on a CR diet.
Calorie restriction is a feature of several dietary regimens
Diet (nutrition)
In nutrition, diet is the sum of food consumed by a person or other organism. Dietary habits are the habitual decisions an individual or culture makes when choosing what foods to eat. With the word diet, it is often implied the use of specific intake of nutrition for health or weight-management...
, including the Okinawa diet
Okinawa diet
The Okinawa diet is a nutrient-rich, low-calorie dietfrom the indigenous people of the Ryūkyū Islands. In addition, a commercially promoted weight-loss diet has also been made based on this standard diet of the Islanders....
and the CRON-diet.
Research history
In 1934, Mary Crowell and Clive McCayClive McCay
Clive Maine, McCay was a biochemist, nutritionist, gerontologist, and professor of Animal Husbandry at Cornell University from 1927-1963. His main interest was the influence of nutrition on aging...
of Cornell University
Cornell University
Cornell University is an Ivy League university located in Ithaca, New York, United States. It is a private land-grant university, receiving annual funding from the State of New York for certain educational missions...
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
Roy Walford
Roy Lee Walford, M. D. was a pioneer in the field of caloric restriction. He died at age 79 of respiratory failure as a complication of amyotrophic lateral sclerosis...
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.
Cardiovascular risks reduced
Some research has shown CR to reduce atherosclerosisAtherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
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
Body mass index
The body mass index , or Quetelet index, is a heuristic proxy for human body fat based on an individual's weight and height. BMI does not actually measure the percentage of body fat. It was invented between 1830 and 1850 by the Belgian polymath Adolphe Quetelet during the course of developing...
(BMI) was 19.6 in the CR group; the matched group 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
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
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
High density lipoprotein
High-density lipoprotein is one of the five major groups of lipoproteins, which, in order of sizes, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, which enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream...
(good) cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
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/m2), 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
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
levels as low as the lowest 5% of Americans in their 20s. (The CR group age-range was 35-82.) Systolic
Systole (medicine)
Systole is the contraction of the heart. Used alone, it usually means the contraction of the left ventricle.In all mammals, the heart has 4 chambers. The left and right ventricles pump together. The atria and ventricles pump in sequence...
and diastolic blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
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
CALERIE
CALERIE is a trial currently underway in the U.S. to study the effects of prolonged calorie restriction on healthy human subjects....
study began in 2007 and investigates the effects of a 25% reduction in calorie intake on healthy adults over a period of two years.
The effect of CR on IGF-1
Insulin-like growth factor 1
Insulin-like growth factor 1 also known as somatomedin C is a protein that in humans is encoded by the IGF1 gene. IGF-1 has also been referred to as a "sulfation factor" and its effects were termed "nonsuppressible insulin-like activity" in the 1970s.IGF-1 is a hormone similar in molecular...
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 showed that a calorie restricted diet can improve memory in normal to overweight elderly. The diet also resulted in decreased insulinInsulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
levels and reduced signs of inflammation. Scientists believe that memory improvement in this experiment was caused by the lower insulin levels, because high insulin levels are usually associated with lower memory and cognitive function. However, that relation seems to be age-specific since another study, when analyzing people older than 65, those who were underweight had a higher dementia risk than normal or overweight people.
Health concerns
Although studies show that calorie restriction can improve longevityLongevity
The word "longevity" is sometimes used as a synonym for "life expectancy" in demography or known as "long life", especially when it concerns someone or something lasting longer than expected ....
and health in model organisms, and studies in humans demonstrate reduced risk factors for major diseases, the long-term effects on humans are still unknown.
Musculoskeletal losses
In addition to the benefits, short-term studies in humans report loss of muscle mass and muscle strength, and reduced bone mineral density.Several studies revealed that dieters who restricted calories for 12 months had lower muscle mass and a reduced capacity to perform exercise compared with those who lost similar amounts of weight from exercise alone. Another study concluded that those who lost weight with the help of the CR diets are more prone to develop a loss of bone at the level of hip and spine
Vertebral column
In human anatomy, the vertebral column is a column usually consisting of 24 articulating vertebrae, and 9 fused vertebrae in the sacrum and the coccyx. It is situated in the dorsal aspect of the torso, separated by intervertebral discs...
, the area most at risk for bone fractures. Some specialists say that minor mineral losses can be prevented with supplements of vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
and calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
.
Low BMI, high mortality: a non-issue?
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 BMI lower than 18, for 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 SocietyAmerican Cancer SocietyThe American Cancer Society is the "nationwide community-based voluntary health organization" dedicated, in their own words, "to eliminating cancer as a major health problem by preventing cancer, saving lives, and diminishing suffering from cancer, through research, education, advocacy, and...
), American Heart AssociationAmerican Heart AssociationThe American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...
, Harvard School of Public HealthHarvard School of Public HealthThe Harvard School of Public Health is one of the professional graduate schools of Harvard University, located in the Longwood Area of the Boston, Massachusetts neighborhood of Mission Hill, which is next to Harvard Medical School. HSPH is considered a significant school focusing on health in the...
, and other organizations raised specific methodologic questions about the recent Centers for Disease Control and PreventionCenters for Disease Control and PreventionThe Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...
(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."
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
Cachexia
Cachexia or wasting syndrome is loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite in someone who is not actively trying to lose weight...
(wasting syndrome) and sarcopenia
Sarcopenia
Sarcopenia is the degenerative loss of skeletal muscle mass and strength associated with aging...
(loss of muscle mass, structure, and function), the results of a large epidemiological study published in the fall of 2011 show that the association between BMI<21 (under 140lbs for a 5'9" tall individual) and increased mortality persists even when confounders like age, smoking, and disease are carefully controlled for. To date, there are no human studies that have demonstrated a positive or even neutral association between low body weight and longevity.
In any case, epidemiological studies of body weight are not about CR as used in anti-aging studies; they are not about calorie 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 eatingBinge eating
Binge eating is a pattern of disordered eating which consists of episodes of uncontrollable eating. It is sometimes as a symptom of binge eating disorder. During such binges, a person rapidly consumes an excessive amount of food...
, but it does not seem to pose any such risk otherwise.
Not for the young, or those with low body fat
The effect of these diets on people who want to lose weight is controversial. Although calorie restriction may provide quick weight lossWeight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
, several studies have shown that the body adjusts to the new diet in about six months. Researchers argue that people who have little body fat should not use this method of losing weight but rather should exercise more because calorie restriction in this case can be harmful. The reason for this is that after the body's fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...
reserves have been burned for energy, the proteins within muscle tissue will be consumed. In severe cases where individuals do not acknowledge the dangers they are exposing themselves to, they may suffer serious loss of the muscle mass.
Especially in children, adolescents and young adults
Youth
Youth is the time of life between childhood and adulthood . Definitions of the specific age range that constitutes youth vary. An individual's actual maturity may not correspond to their chronological age, as immature individuals could exist at all ages.-Usage:Around the world, the terms "youth",...
(under approximately 21), calorie restriction is not advised because this type of diet may interfere with the natural physical growth, as it has been observed in laboratory animals. In addition, mental development and physical changes to the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
take place in late adolescence and early adulthood that could be negatively affected by calorie restriction. Pregnant women are recommended not to try losing weight with this method. It has been shown that a low BMI is a risk factor in pregnancy as it may result in ovulatory dysfunction (infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
), and mothers who are underweight are more prone to preterm delivery.
Individuals trying lose weight on a CR diet of less than 1,500 calories a day need to be monitored by a specialist in order to prevent potential side effects.
Miscellaneous concerns
It has also been noted that people losing weight on such diets risk developing cold sensitivityCold sensitivity
Cold sensitivity or cold intolerance is unusual discomfort felt by some people when in a cool environment.There is much variation in the sensitivity to cold experienced by different people, with some putting on many layers of clothing while others in the same environment feel comfortable in one...
, menstrual irregularities and even infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
and hormonal changes.
Moreover, calorie restriction has been reported in mice to hinder their ability to fight infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
, and some evidence suggests that in patients with amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
calorie restriction accelerates the onset of the disease.
Excessive calorie restriction may result in starvation, unless metabolism
Basal metabolic rate
Basal Metabolic Rate , and the closely related resting metabolic rate , is the amount of daily energy expended by humans and other animals at rest. Rest is defined as existing in a neutrally temperate environment while in the post-absorptive state...
is also slowed by some means. CR should not be confused with anorexia nervosa
Anorexia nervosa
Anorexia nervosa is an eating disorder characterized by refusal to maintain a healthy body weight and an obsessive fear of gaining weight. Although commonly called "anorexia", that term on its own denotes any symptomatic loss of appetite and is not strictly accurate...
or other eating disorders. If such a pattern is repeated for prolonged periods, the body may burn lean tissue (including but not limited to muscle and collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
) along with its remaining fat reserves. The combination of starvation and the associated lethargy and decreased physical activity can result in muscular atrophy, reducing quality of life.
Beyond using lean tissue as energy source, the presence of catabolic hormones, such as cortisol, and lack of anabolic ones, such as insulin, disrupts protein synthesis, amino acid uptake and weakens the immune system. Commenting on a study where CR showed generally positive effects, one researcher 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."
Primates
A study on rhesus macaqueRhesus Macaque
The Rhesus macaque , also called the Rhesus monkey, is one of the best-known species of Old World monkeys. It is listed as Least Concern in the IUCN Red List of Threatened Species in view of its wide distribution, presumed large population, and its tolerance of a broad range of habitats...
s, funded by the National Institute on Aging, was started in 1989 at the University of Wisconsin–Madison
University of Wisconsin–Madison
The University of Wisconsin–Madison is a public research university located in Madison, Wisconsin, United States. Founded in 1848, UW–Madison is the flagship campus of the University of Wisconsin System. It became a land-grant institution in 1866...
and is still ongoing. This study has so far shown 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. The monkeys were enrolled in the study at ages of between 7 and 14 years; at the 20 year point 80% of the calorically restricted monkeys were still alive, compared to only half of the controls. These results bore out earlier preliminary results that 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.
The most recent study conducted by Ricki J. Colman and Richard Weindruch at the University of Wisconsin used rhesus monkeys that live an average of 27 years and a maximum of 40, found that the dieting monkeys show many beneficial signs of caloric resistance, including significantly less diabetes, cancer, and heart and brain disease. However, as some of the monkeys are expected to live another 20 years, the findings are still inconclusive.
Results to date have 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 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.
Researchers at New York's Mount Sinai School of Medicine reported in 2006 that compared to monkeys fed a normal diet, squirrel monkeys on a life-long calorie-restrictive diet were less likely to develop Alzheimer's-like changes in their brains. Since squirrel monkeys are relatively long-lived, definitive conclusions regarding whether or not they are aging slower are not yet available.
Moderate CR attenuates age-related sarcopenia
Sarcopenia
Sarcopenia is the degenerative loss of skeletal muscle mass and strength associated with aging...
in primates.
Rodents
Seventy years ago, McCay CM, et al., discovered that reducing the amount of calories fed to rodents nearly doubled their lifespans. The life extension was varied for each species but on average, there was a 30-40% increase in lifespan 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 receptorEstrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
-alpha declines in the aging pre-optic hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
. 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
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
hypothalamus than their non-calorically restricted counterparts.
Studies in female mice have shown that both Supraoptic nucleus
Supraoptic nucleus
The supraoptic nucleus is a nucleus of magnocellular neurosecretory cells in the hypothalamus of the mammalian brain. The nucleus is situated at the base of the brain, adjacent to the optic chiasm...
(SON) and Paraventricular nucleus
Paraventricular nucleus
The paraventricular nucleus is a neuronal nucleus in the hypothalamus. It contains multiple subpopulations of neurons that are activated by a variety of stressful and/or physiological changes. Many PVN neurons project directly to the posterior pituitary where they release oxytocin or vasopressin...
(PVN) lose about one-third of IGF-1R immunoreactivity with normal aging. Old calorically restricted (CR) 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 model are very easy to manipulate and many crucial steps toward the understanding of aging has been done with it. Many studies were published in budding yeast and fission yeast to analyse the cellular mechanisms behind the increased longevity due to calorie restriction. First, calorie restriction is often called dietary restriction because the same effects on life span can be reached by only changing the nutrient quality without changing the amount of calories. The 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 case dietary restriction needs mitochondrial respiration to increase longevity (chronological aging) and in some other case 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,...Drosophila
Research in 2003 by Mair et al. showed that calorie restriction extends the life of fruit flies of any age with instantaneous effects on death rates.Caenorhabditis elegans
Recent work in Caenorhabditis elegansCaenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
has shown that restriction of glucose metabolism extends life span by primarily increasing oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
to exert an ultimately increased resistance against oxidative stress, a process called (mito)hormesis
Hormesis
Hormesis is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses...
.
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 included reduced cellular divisions, lower metabolism rates, reduced production of free radicals and hormesisHormesis
Hormesis is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses...
.
Hormesis
Research has pointed toward hormesisHormesis
Hormesis is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses...
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
Hormesis
Hormesis is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses...
" 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
Hormesis
Hormesis is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses...
proposes that the diet imposes a low-intensity biological stress on the organism, which elicits a defense 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, and this results in improved health and longer life. This switch to a defensive state may be controlled by longevity genes (see below).
Mitochondrial hormesis
The mitochondrial hormesis was a purely hypothetical concept until late 2007 when work by Michael RistowMichael Ristow
Michael Ristow is a German medical researcher who has published influential articles on the metabolic basis of human diseases, including type 2 diabetes, obesity and cancer, as well as general aging processes...
's group in a small worm named Caenorhabditis elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
suggests that restriction of glucose metabolism extends life span primarily by increasing oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
to stimulate the organism into having an ultimately increased resistance to further oxidative stress. This is probably the first experimental evidence for hormesis
Hormesis
Hormesis is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses...
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 years past. It was previously proposed on a hypothetical basis that free radicals may induce an endogenous response culminating in more effective adaptations which 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 life span
Life expectancy
Life expectancy is the expected number of years of life remaining at a given age. It is denoted by ex, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...
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 upregulate protective and repair enzyme mechanisms to try to ensure that it is fit for reproduction in future years. This seems to be supported by recent work studying hormones. A study in male mice has found that CR generally feminizes gene expression and 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 CR's life-extension effects might 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
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
and substances which are related to insulin, e.g. Insulin-like growth factor 1
Insulin-like growth factor 1
Insulin-like growth factor 1 also known as somatomedin C is a protein that in humans is encoded by the IGF1 gene. IGF-1 has also been referred to as a "sulfation factor" and its effects were termed "nonsuppressible insulin-like activity" in the 1970s.IGF-1 is a hormone similar in molecular...
and Growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
has been shown to upregulate autophagy
Autophagy
In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance...
, the repair mechanism of the cell. A related hypothesis suggests that CR works by decreasing insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
levels and thereby upregulating autophagy, but CR affects many other health indicators and whether insulin is the main concern is still undecided. Calorie restriction has been shown to increase DHEA in primates, however 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 chromatinChromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
function.
A study conducted by the Salk Institute for Biological Studies
Salk Institute for Biological Studies
The Salk Institute for Biological Studies is a premier independent, non-profit, scientific research institute located in La Jolla, California. It was founded in 1960 by Jonas Salk, the developer of the polio vaccine; among the founding consultants were Jacob Bronowski and Francis Crick. Building...
and published in the journal Nature
Nature (journal)
Nature, first published on 4 November 1869, is ranked the world's most cited interdisciplinary scientific journal by the Science Edition of the 2010 Journal Citation Reports...
in May 2007 determined that the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
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 which have a bearing on calorie restriction are the free radical theoryFree-radical theory
The free-radical theory of aging states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most...
and the glycation
Glycation
Glycation is the result of the bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme. All blood sugars are reducing molecules. Glycation may occur either inside the body or outside the body...
theory. With high amounts of energy available, mitochondria do not operate very efficiently and generate more superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
. 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
Glycation
Glycation is the result of the bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme. All blood sugars are reducing molecules. Glycation may occur either inside the body or outside the body...
of adjacent proteins and less fat to oxidize in the bloodstream to cause sticky blocks resulting in atherosclerosis. Type II Diabetics
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
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
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
.
Calorie Restriction with Optimal Nutrition has not been tested in comparison to Calorie Excess with Optimal Nutrition. It may be that with extra calories, nutrition must be similarly increased to ratios comparable to that of Calorie Restriction to provide similar antiaging benefits. Stated levels of calorie needs may be biased towards sedentary individuals. Calorie restriction may be no more than adapting the diet to the body's needs.
Caloric restriction mimetics
Work on the mechanisms of CR has given hope to the synthesising of future drugs to increase the human lifespan by simulating the effects of calorie restriction. However, MITMassachusetts Institute of Technology
The Massachusetts Institute of Technology is a private research university located in Cambridge, Massachusetts. MIT has five schools and one college, containing a total of 32 academic departments, with a strong emphasis on scientific and technological education and research.Founded in 1861 in...
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
Sirtuin
Sirtuin or Sir2 proteins are a class of proteins that possess either histone deacetylase or mono-ribosyltransferase activity. Sirtuins regulate important biological pathways in bacteria, archaea and eukaryotes...
, discovered in baker's yeast
Baker's yeast
Baker's yeast is the common name for the strains of yeast commonly used as a leavening agent in baking bread and bakery products, where it converts the fermentable sugars present in the dough into carbon dioxide and ethanol...
cells, which is hypothesized to suppress DNA instability. In mammals Sir2 is known as SIRT1. David Sinclair at Harvard Medical School, Boston is a leading proponent of the view that the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
Sir2
Sir2
Sir2 was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied...
may underlie the effect of calorie restriction in mammals by protecting cells from dying under stress. It is suggested a low-calorie diet that requires less Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...
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
Nature (journal)
Nature, first published on 4 November 1869, is ranked the world's most cited interdisciplinary scientific journal by the Science Edition of the 2010 Journal Citation Reports...
showed that SIRT1 releases fat from storage cells.
Sir2/SIRT1 and resveratrol
Attempts are being made to develop CR mimeticCr mimetic
Caloric restriction mimetics try to mimic the substantial anti-aging effects caloric restriction has on many laboratory animals. In other words, the administration of a CRM results in the same physiological changes seen in CR itself...
s interventions. Resveratrol
Resveratrol
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
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 lifespan in normal mice.
The effect of resveratrol on lifespan in C. elegans and Drosophila was re-investigated by D. Gems and L. Partridge. They concluded that previously reported lifespan increases were in fact due to natural variability in C. elegans lifespans 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 lifespan if the Sir2 gene was mutated. A 2010 study concluded that SRT1720
SRT1720
SRT1720 is a drug developed by Sirtris Pharmaceuticals intended as a small-molecule activator of the sirtuin subtype SIRT1. It has similar activity in the body to the known SIRT1 activator resveratrol, but is 1000x more potent...
and resveratrol are not direct activators of SIRT1.
Matt Kaeberlein
Matt Kaeberlein
Dr. Matt Kaeberlein is an American biologist and biogerontologist best known for his research on evolutionarily conserved mechanisms of aging...
and Brian Kennedy at the University of Washington Seattle believe that Sinclair's work on resveratrol is an artifact and that the Sir2 gene has no relevance to CR. They have proposed that the caloric restriction increases lifespan by decreasing the activity of the Target of Rapamycin (TOR) kinase
Mammalian target of rapamycin
The mammalian target of rapamycin also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 is a protein which in humans is encoded by the FRAP1 gene...
.
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 lifespan extending effects of calorie restriction (reduced insulin, igf1 and fasting glucose), were no different in normal mice and mice lacking Sirt1. Whether the lifespan-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, however some research has cast doubt on this. A clinical trial of the resveratrol formulation SRT501 was suspended.
No benefit to houseflies, overfed model organisms
One set of experiments shows that CR has no benefits in the houseflyHousefly
The housefly , Musca domestica, is a fly of the suborder Cyclorrhapha...
. The authors hypothesize that the widely purported effects of CR may be because a diet containing more calories can increase bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
l proliferation, or that the type of high calorie diets used in past experiments have a stickiness, general composition, or texture that reduces longevity.
Another related theory says that some of the calorie-restriction effects are artifacts, because the laboratory model organisms are kept at non-physiological high calorie diets. This would mean that calorie restriction simply means mimicking a natural environment energy supply.
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 reasons behind this may be that animals enter a foraging state during calorie restriction. In order to control this variable, such tests would need to be monitored to make sure 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 lifespan and lower the incidence of several diseases. Calorie restriction comes into conflict with the high calorie needs of athletes, and may not provide them adequate levels of energy or sufficient 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 live much longer than exercised animals.Does Calorie Restriction only benefit the young?
There is some evidence to suggest that the benefit of CR in rats might only be reaped in early years. A study on rats which were gradually introduced to a CR lifestyle at 18 months showed no improvement over the average lifespan of the Ad libitumAd libitum
Ad libitum is Latin for "at one's pleasure"; it is often shortened to "ad lib" or "ad-lib"...
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 show increases in lifespan. 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.
Midlife Onset of Calorie Restriction as a Means of Prolonging Lifespan
This is a highly controversial topic of if and how to start such in Midlife in humans. See the books by lifetime calorie restriction researcher Roy Walford which offer inconclusive but supportive evidence for this thesis.Possible contraindications
Both animal and human research suggest BUD CR may be contraindicated for people with amyotrophic lateral sclerosisAmyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
(ALS). Research on a transgenic
Genetically modified organism
A genetically modified organism or genetically engineered organism is an organism whose genetic material has been altered using genetic engineering techniques. These techniques, generally known as recombinant DNA technology, use DNA molecules from different sources, which are combined into one...
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 go on to conclude: "We conclude that 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
Ketogenic diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...
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
Roy Walford
Roy Lee Walford, M. D. was a pioneer in the field of caloric restriction. He died at age 79 of respiratory failure as a complication of amyotrophic lateral sclerosis...
, 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
Anecdotal evidence
The expression anecdotal evidence refers to evidence from anecdotes. Because of the small sample, there is a larger chance that it may be true but unreliable due to cherry-picked or otherwise unrepresentative of typical cases....
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 Mark P. Mattson, Ph. D., chief of the National Institute on AgingNational Institute on Aging
The National Institute on Aging ' is a division of the U.S. National Institutes of Health , located in Baltimore, Maryland.The NIA leads a broad scientific effort to understand the nature of aging and to extend the healthy, active years of life...
's (NIA) Laboratory of Neurosciences, and colleagues have found that intermittent fasting
Intermittent fasting
Intermittent fasting is a pattern of eating that alternates between periods of fasting and non-fasting. A specific form of IF is alternate day fasting , which is a 48-hour routine typically composed of a 24-hour fast followed by a 24-hour non-fasting period...
and calorie restriction affect the progression of diseases similar to Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
, Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, and Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
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
Stress (medicine)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
resistance. Researchers have long been aware that calorie restriction extends lifespan, but this study showed that improved glucose metabolism also protects neurons in experimental models of Parkinson's and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
.
Another NIA study found that intermittent fasting and calorie restriction delays the onset of Huntington's disease-like symptoms in mice and prolongs their lives. Huntington's disease (HD), a genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
, results from neuronal degeneration in the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
. 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 to 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
Brain-derived neurotrophic factor
Brain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the "neurotrophin" family of growth factors, which are related to the canonical "Nerve Growth Factor", NGF...
(BDNF) levels. BDNF protects neurons and stimulates their growth. Fasting mice also had high levels of heat-shock protein-70 (Hsp70
Hsp70
The 70 kilodalton heat shock proteins are a family of ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms...
), which increases cellular resistance to stress.
Another NIA study compared intermittent fasting with cutting calorie 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 didn't cut total calories at the beginning and the 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
Kainic acid
Kainic acid is a natural marine acid present in some seaweed. It is a specific agonist for the kainate receptor used as an ionotropic glutamate receptor which mimics the effect of glutamate...
, a toxin that damages neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s, was injected into the dorsal hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
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 that ate a restricted diet, and most damage in mice with an unrestricted diet. But the control group which ate the average daily intake of the fasting mice also showed less damage than the mice with restricted diet.
Another Mattson study in which overweight adult asthmatics followed alternate day calorie restriction (ADCR) for eight weeks showed marked improvement in oxidative stress, inflammation, and severity of the disease. Evidence from the medical literature suggests that ADCR in the absence of weight loss prolongs lifespan in humans.
Intermittent fasting has also been shown to increase the resistance of neurons in the brain to excitotoxic stress.
See also
- CR Society InternationalCR Society InternationalThe CR Society International is a nonprofit 501 organization composed of several thousand people practicing, supporting, and conducting research into calorie restriction as a means of slowing the aging process. It was founded in 1994 by Brian M...
- Intermittent fastingIntermittent fastingIntermittent fasting is a pattern of eating that alternates between periods of fasting and non-fasting. A specific form of IF is alternate day fasting , which is a 48-hour routine typically composed of a 24-hour fast followed by a 24-hour non-fasting period...
- FastingFastingFasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. An absolute fast is normally defined as abstinence from all food and liquid for a defined period, usually a single day , or several days. Other fasts may be only partially restrictive,...
- ResveratrolResveratrolResveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
- StarvationStarvationStarvation is a severe deficiency in caloric energy, nutrient and vitamin intake. It is the most extreme form of malnutrition. In humans, prolonged starvation can cause permanent organ damage and eventually, death...
- Very Low Calorie DietVery Low Calorie DietVery low calorie diet is a diet with very or extremely low daily food energy consumption. It is defined as a diet of per day or less. VLCDs are formulated, nutritionally complete, liquid meals containing 800 kilocalories or less per day. VLCDs also contain the recommended daily requirements for...
- Okinawa dietOkinawa dietThe Okinawa diet is a nutrient-rich, low-calorie dietfrom the indigenous people of the Ryūkyū Islands. In addition, a commercially promoted weight-loss diet has also been made based on this standard diet of the Islanders....
- Mitohormesis
- Life extensionLife extensionLife extension science, also known as anti-aging medicine, experimental gerontology, and biomedical gerontology, is the study of slowing down or reversing the processes of aging to extend both the maximum and average lifespan...
- Lloyd DemetriusLloyd DemetriusLloyd A. Demetrius is a mathematician and theoretical biologist at the Max Planck Institute for Molecular Genetics at Berlin, Germany, and the Department of Organismic and Evolutionary biology, Harvard University...
- CRON-diet
- Luigi CornaroLuigi CornaroAlvise "Luigi" Cornaro was a Venetian nobleman who wrote treatises on dieting, including Discorsi della Vita Sobria . Finding himself near death at the age of 35, Cornaro modified his eating habits on the advice of his doctors and began to adhere on a calorie restriction diet...
- hara hachi buHara hachi bu, or hara hachi bunme , is a Confucian teaching that instructs people to eat until they are 80 percent full. Roughly, in English the Japanese phrase translates to, "Eat until you are eight parts full"...
External links
- Calorie Restriction and Longevity - Gerontology, 2011