Calorie restriction

Caloric restriction (CR), 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.

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

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

Cardiovascular risks reduced
Some research has shown CR to reduce atherosclerosis risk factors.

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

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


 * The calorie-restricted group also fared much better than the control group in terms of average blood pressure (100/60 vs. 130/80 mm Hg), fasting glucose, fasting insulin (65% reduction), body mass index (19.6 ± 1.9 vs. 25.9 ± 3.2 kg/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 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

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 insulin 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 longevity 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, 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.

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 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."

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."

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

Not for the young, or those 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 loss, several studies have shown that the body adjusts to the new diet in more or less half a year. 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.

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

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

Excessive calorie restriction may result in starvation, 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."

Primates
A study on rhesus macaques, funded by the National Institute on Aging, was started in 1989 at the University of Wisconsin–Madison and is still ongoing. 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.

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 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 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.

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 elegans 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.

Mechanism of Action
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 hormesis.

Hormesis
Research has pointed toward hormesis as an explanation. Southam and Ehrlich (1943) reported that a bark extract that was known to inhibit fungal growth, actually stimulated growth when given at very low concentrations. They coined the term "hormesis" to describe such beneficial actions resulting from the response of an organism to a low-intensity biological stressor. The word "hormesis" is derived from the Greek word "hormaein" which means "to excite". The (Mito)hormesis hypothesis of CR proposes that the diet imposes a low-intensity biological stress on the organism, which elicits a 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 Ristow'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.

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 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.

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

Free radicals and glycation
Two very prominent proposed explanations of aging which 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 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.

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, MIT biologist Leonard Guarente cautioned that "(treatment) won't be a substitute for a healthy lifestyle. You'll still need to go to the gym". Sir2 or "silent information regulator 2" is a sirtuin, discovered in baker's yeast cells, 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.

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

No benefit to houseflies, overfed model organisms
One set of experiments shows that CR has no benefits in the housefly. The authors hypothesize that the widely purported effects of CR may be because a diet containing more calories can increase bacterial proliferation, or 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 libitum group. This view, however, is disputed by Spindler, Dhahbi, and colleagues who showed that in late adulthood, acute CR partially or completely reversed age-related alterations of liver, brain and heart proteins and that mice placed on CR at 19 months of age 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 sclerosis (ALS). Research on a transgenic mouse model of ALS demonstrates that CR may hasten the onset of death in ALS. Hamadeh et al. therefore concluded: "These results suggest that CR diet is not a protective strategy for patients with amyotrophic lateral sclerosis (ALS) and hence is contraindicated." Hamadeh et al. also note two human studies that they indicate show "low energy intake correlates with death in people with ALS." However, in the first study, Slowie, Paige, and Antel state: "The reduction in energy intake by ALS patients did not correlate with the proximity of death but rather was a consistent aspect of the illness." They 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.

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 Aging's (NIA) Laboratory of Neurosciences, and colleagues have found that intermittent fasting and calorie restriction affect the progression of diseases similar to Huntington's disease, Parkinson's disease, and Alzheimer's disease in mice (PMID 11119686). In one study, rats and mice ate a low-calorie diet or were deprived of food for 24 hours every other day. Both methods improved glucose metabolism, increased insulin sensitivity, and increased stress resistance. Researchers have long been aware that calorie restriction extends 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 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 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.