Calorie restriction

from Wikipedia, the free encyclopedia

Calorie restriction , also called caloric restriction or calorie restriction , is the designation for a diet with a 10 to 50 percent reduction in energy from food (see: physiological calorific value ) via diet compared to diet ad libitum ("at will") . The aim is to achieve a longer life expectancy or at least delayed aging or a health-promoting effect without causing malnutrition . In the English-language specialist literature, the terms caloric restriction , calorie restriction or dietary restriction are used for calorie restriction.

In this way, a health-promoting and life-prolonging effect could be demonstrated in a number of model organisms . For some species or cultivars , however, no increase in life expectancy was found. The increase in life expectancy of some rodent strains by up to 50% depends , among other things, on genome and gender.

Reliable data on the life-prolonging effect of calorie restriction in humans are not available. While the effect is largely recognized in the animal model, the transferability to humans is controversial. The mechanisms of action are hypothetical and unexplained.

history

An engraving supposed to show the calorie restricted Luigi Cornaro.

In his autobiographical treatise Discorsi della vita sobria ( On the moderate life ), which he wrote at the age of 83, the Venetian Luigi Cornaro (1467–1565) attributed his old age and health to the fact that he was on a strict diet (calorie restriction ) followed. Cornaro ate just as much as was necessary to survive. He chose the food not according to his taste, but according to health aspects.

Francis Peyton Rous found in animal experiments in 1914 that reducing the food supply in rats could reduce the incidence of tumors and prolong the life of the animals. In the 1930s, after similar animal experiments , Clive McCay and colleagues hypothesized that the prolongation of life through calorie restriction in rats was due to a reduced growth rate. They had no molecular biological explanation for this.

The life-prolonging effect of calorie restriction was described in 1934 by the US biochemist Clive Maine McCay (1898-1967) and Mary F. Crowell (both Cornell University ). McCay and Crowell found in their experiments with rats that the permanent reduction in the amount of food - while ensuring adequate nutrition - significantly increases the life expectancy of the animals. Some of the test animals received 33 percent less food than the comparison group, which was fed ad libitum (" ad libitum "), which increased the life expectancy of the first-named animals by almost 50 percent.

Morris Ross carried out further experiments with rats in the 1960s and 1970s and was able to support McCay's hypothesis.

In his test series, Ross was able to determine that the composition of the food - compared to the calorie restriction - has a significantly lower effect on extending life. Richard Weindruch and Roy Walford showed in experiments with mice in the 1980s that calorie restriction, even if it is only initiated in adult animals , can prolong life. They concluded that delayed ripening is not the main cause of life extension, but that calorie restriction apparently positively mediates the process of aging itself. In the second half of the 20th century, the Soviet doctor Galina Schatalowa experimented with calorie restriction in combination with raw food .

During the 1980s and early 1990s, researchers began a serious discussion of human participation studies of calorie restriction studies . As a result, studies were carried out with rhesus monkeys ( Macaca mulatta ), among others , which showed that the positive results from other animal species can also be transferred to primates.

Intensive research into the effects of calorie restriction on the nematode Caenorhabditis elegans began in the 1990s . In 1998, Bernard Lakowski and Siegfried Hekimi published that mutations that alter the worm's throat and restrict food intake increase life expectancy by 50%.

In the Biosphere 2 experiment, the study participants were supposed to feed themselves completely from the inner cycle of materials in a closed building complex. Roy Walford participated in the experiment from 1991 to 1993. When the study participants discovered that they had overestimated their ability to produce food, Walford suggested a calorie restriction. During seven eighths of their two-year stay, the eight test subjects consumed a low-calorie (7300 to 8900 kJ per day) diet consisting primarily of vegetables , fruit , nuts , grains and legumes . Walford reported that the healthy, lean test participants reacted with physiological, hematological, hormonal and biochemical changes comparable to those of the test animals in calorie restriction studies.

Effect on various living things

Effects of calorie restriction on the survival rate of laboratory mice (KR = calorie restriction).
Calorie restriction can significantly increase the life expectancy of the black-bellied fruit fly ( Drosophila melanogaster ).

Experiments similar to those with mice have been carried out since 1934 with a wide variety of species and varied experimental conditions. In the case of many species, not only the mean lifespan of the test animals but also their maximum lifespan is increased. The frequency of age-related diseases decreases accordingly. The effect of the increase in maximum life expectancy occurs in rodents both when starting the diet in the early phase of life (1st to 3rd month) and in the middle phase of life (12th month). If, on the other hand, the calorie restriction is started at a later stage in the life of the test animals, for example in the 17th or 24th month of mice, the effect is reversed and the life span of the test animals is shortened.

The calorie restriction was investigated on baker's yeast ( Saccharomyces cerevisiae ), the nematode Caenorhabditis elegans , the fruit fly Drosophila melanogaster , mice , rats , dogs and non-human primates .

Both in a study with rhesus monkeys by the US National Institute on Aging , as well as in a study on Drosophila , it was assumed that the prolongation of life depends not only on the calorie restriction, but also on the composition of the diet.

General criticism

Various findings cast doubts on the idea that calorie restriction slows down the aging process, delays the age-related decline in physiological fitness, or extends the lifespan of organisms from different phylogenetic groups. The positive effects of calorie restriction are not universal:

In fruit flies, the positive effects of calorie restriction are not reproduced if the nutrient fractions are carefully controlled.

The increase in life expectancy caused by calorie restriction is in some cases not even reproducible among the different strains of the same species.

The calorie restriction does not extend the life span of all mice. In the graphic above, a significant effect can be observed in C57BL / 6 mice (“laboratory mice”), while this is not seen in the DBA / 2 mice (“wild type”) below (AL = ad libitum , KR = calorie restriction).

Thus, calorie restriction does not lead to a life extension in all mouse strains. In 19 to 27% of the examined mouse breeds, a calorie restriction of 40% was found to even reduce life expectancy.

The C57BL / 6 mouse, which is often used in experiments, has a tendency to become overweight if there is an unlimited supply of food ( ad libitum ). In these animals the effect of the calorie restriction is significant. DBA / 2 mice, on the other hand, stay slim even when fed ad libitum. In mice from this strain, the calorie restriction does not lead to an extension of life. DBA / 2 mice consume more oxygen than C57BL / 6 mice with the same energy supply, which means that their metabolic rate is increased - they are poorer "feed converters". In previous experiments it was found that the calorie restriction is most successful in mice that have put on weight in early adulthood. The results of these studies are interpreted to mean that the life span is more influenced by the balance of energy intake and energy consumption. The calorie restriction can only bring about a life extension in experimental animals with a tendency to overweight or obesity.

The above NIA study in rhesus monkeys found no life extension. In a long-term study carried out at the Wisconsin National Primate Research Center over a period of 20 years on rhesus monkeys, on the other hand, a significantly better state of health and a significantly increased life expectancy were found in the group of animals that received only a reduced food supply during this period . In this group, 80% of the animals were still alive, while it was only 50% in the normally fed comparison group. In addition, a significantly delayed occurrence ( late-onset ) of age-associated diseases such as diabetes, cancer and brain atrophy , as well as cardiovascular incidents, could be observed in the animals with calorie restriction . The authors of the study come to the conclusion that calorie restriction in this primate species delays the aging process.

Effect on humans

There is currently no scientific evidence that permanent calorie restriction - with adequate human nutrition - leads to an increase in life expectancy compared to a slim adult. It is undisputed that being very overweight , i.e. obese , leads to a shortening of the mean and maximum life expectancy.

The hormonal and metabolic effects of calorie restriction observed in the test animals , such as lower body temperature , reduced metabolic rate and lower oxidative stress , could also be demonstrated in humans. Furthermore, lower values ​​for basal insulin ("fasting insulin "), profibrotic proteins , various growth factors - such as PDGF and TGF-α - as well as cytokines such as tumor necrosis factor -α were detected in the serum . It is also confirmed that long-term calorie restriction is an effective prevention against type II diabetes mellitus , high blood pressure and arteriosclerosis , which together are the main causes of morbidity , disability and mortality in humans.

Evolutionary counter-arguments

There are evolutionary theoretical arguments for the fact that calorie restriction in primates, the order of which also includes great apes including humans, has little or no positive effect on lifespan:

According to the disposable soma theory on the evolution of aging , a drastic reduction in the supply of energy would have a negative effect on reproduction or the lifespan of an organism, since the energy consumed is either used for metabolism, reproduction or for repair and maintenance of the body (physical integrity). must be spent. According to the disposable soma theory, an organism that channels its energy in a state of deficiency to repair and maintenance while suppressing other characteristics such as reproductive effort can live longer at the expense of reproductive capacity.

This fact can also be explained evolutionarily, since a famine has a negative effect on the survival of offspring and it makes less sense to invest energy in offspring who would probably not survive to sexual maturity anyway than in repairing and maintaining your own body .

If rodents' caloric intake is restricted, it actually affects the reproductive system: the increased longevity that rodents result from caloric restriction is always accompanied by a dramatic decline in reproductive capacity. Usually rodents reach sexual maturity around one month of age, and females can produce their body weight in offspring about every month and a half. Rodents are exposed to strong natural selection with regard to early, intensive reproductive investments, accompanied by a short life expectancy .

Primates, on the other hand, experience slow individual development and a low rate of reproduction, combined with a long life span compared to rodents or even similarly sized non-primates. It is therefore assumed that the calorie restriction in humans does not work in the same way as invertebrates and small mammals, because in humans the reproductive investment is low, but the life span is high.

It could be that the absolute life extension through calorie restriction is about one year in all species and not roughly proportional to the life span. The reason for this could be that the variability in food availability depends particularly on the annual decline in plant biomass in winter and is therefore independent of the size of an organism, its phylogenesis or the absolute lifespan. [This thesis is occasionally referenced as weather hypothesis after the publication by Aubrey de Gray from 2005. ] The theory should therefore only lead to an expectation of a life extension of 5 to 14 months, which also agrees with studies on various model organisms.

Risks of calorie restriction in humans

In the USA in particular, the results of animal experiments have led to the fact that calorie restriction has found many practicing followers , especially in California . Some of the followers have joined forces to form the Calorie Restriction Society . Excessive calorie reduction always carries the risk of malnutrition, which can have negative effects on physical and mental health. There are repeated warnings about possible eating disorders associated with calorie restriction. On the other hand, one study showed that calorie restriction does not lead to anorexia or bulimia accumulation . The psychological effects of calorie restriction were rated as positive in this study.

Long-term malnutrition can not only have positive effects but also lead to various deficiency diseases . Developmental disorders can occur in minors. The sensitivity to cold may increase. The ovulation may be suspended in women with very low BMI, resulting in temporary infertility. In the Minnesota Starvation Experiment , anemia , lower extremity edema , muscle wasting, weakness, neurological impairment, dizziness, irritability, lethargy, and depression were observed when a 90% carbohydrate calorie restriction was performed in adult males for six months . Short-term calorie restriction can lead to muscle wasting and decreased bone density . Restricting calories can be harmful in people with low body fat.

mechanism

The causes of the prolongation of the life of model organisms through the caloric restriction have not yet been clarified. The mechanism underlying this effect is unknown. It is possible that the extension of the lifespan results from the improvement of the state of health through the absence of obesity and the later onset of age-related diseases of the metabolic syndrome such as cardiovascular diseases and type II diabetes mellitus .

Studies done in mice suggest that the increase in life that comes with calorie restriction is not simply a result of slimness brought about by the calorie restriction. The maximum lifespan of male rats that kept a low body fat mass through exercise did not increase, but it did that of mice that kept a low body weight simply by restricting calories in a sedentary lifestyle.

The calorie restriction in rats creates soluble factors in the blood serum that prolong life in human cell cultures . Different mechanisms are discussed:

Reduction of oxidative stress

There is evidence that oxidative stress is reduced by reduced food intake, thereby delaying primary aging. Primary aging is the process of cells and organs that - in the absence of disease - defines the maximum life span (inevitable aging). Secondary aging is determined by external factors such as illnesses, environmental factors, lifestyle and physical activity (preventable aging). The oxidative stress mainly takes place in the mitochondria , the power plants of the cells. By resveratrol , the effect of calorie restriction can be induced in certain strains of mice partially. In yeast, the protein Rim15 , a glucose- inhibited protein kinase , serves as a sensor for nutrient concentrations as well as the initiation of meiosis and is necessary for a lifetime extension in yeast. However, in a meta-analysis it was also reported that a calorie restriction - contrary to earlier results - does not lead to an extension of the lifespan in yeast, but that the results in yeast are partly based on methodological artifacts .

Hormesis

A contrary hypothesis is oxidative stress should Reactive oxygen species (Engl. Reactive oxygen species , ROS) cell metabolism positively stimulate ( hormesis ), which as well as the health benefit of calorie restriction by fasting , oxidative plant substances in cruciferous vegetables , and body workout explain.

In contrast to the theory of free radicals , it is assumed that an increased formation of reactive oxygen species in the mitochondria associated with calorie restriction causes an adaptive reaction that increases stress resistance.

Activation of sirtuin-1 and decreased expression of the mTOR receptor

The signal-regulating enzymes Sirtuin-1 (Sirt1) in mammals and Sirtuin Sir2 in yeasts could play a role. The cells of the calorically restrictive fed test animals produce Sirt1 in larger quantities. An increased production of Sirt1 in turn reduces the expression of the mTOR receptor ( mammalian target of rapamycin ), which is also related to the aging process. The life expectancy of mice can be significantly increased by administering rapamycin , which docks at the mTOR receptor. Melatonin is also being studied for sirtuin activation.

"Reprogramming" metabolism and gene expression

According to another theory, the long-term reduced food intake "reprogrammes" the metabolism. A change in gene expression was found in mice under caloric restriction . On the one hand, the genes that are involved in the energy metabolism are overexpressed, while on the other hand, over 50 pro-inflammatory genes are downregulated. The regeneration of some stem cells may be increased. By metformin , a similar effect can be induced in certain strains of mice.

Increased formation of ketone bodies

Both calorie restriction and the ketogenic diet have therapeutic potential in various animal models of neurological diseases. With calorie restriction, there is a transition from glucose metabolism to the use of ketone bodies . Ketone bodies can be used as an alternative source of energy for brain cells when glucose availability is inadequate.

Ketone bodies protect neurons against different types of neural injury. This is an explanatory approach for the beneficial effect of calorie restriction in the animal model of neurological diseases.

Increased autophagocytosis

Autophagocytosis or autophagy , also known as "cellular self-digestion", is a cellular signaling pathway that is involved in the breakdown of proteins and organelles and plays a role in various diseases. Autophagy malfunction has been linked to neurodegeneration , microbial infection, and aging .

Several pieces of evidence suggest that autophagy is important for the effects of calorie restriction: The efficiency of autophagy decreases with increasing age; the decrease in autophagy is associated with changes in the biomarkers of aging; the age-dependent change in autophagy is prevented in the experiment by calorie restriction; if a decrease in the efficiency of autophagy is prevented, the effects are similar to those of calorie restriction; a long-lasting inhibition of autophagy accelerates the aging process; Long-term stimulation of autophagy, on the other hand, delays the aging process in rats ; stimulation of autophagy can save older cells from the accumulation of altered mitochondrial DNA ; stimulation of autophagy alleviates age-related hypercholesterolemia in rodents.

A comparable effect was observed in plants whose exposure was reduced.

Decreased thyroid hormones

The plasma levels of the thyroid hormones triiodothyronine (T 3 ), thyroxine (T 4 ) and thyroid-stimulating hormone (TSH) were measured in rhesus monkeys ( Macaca mulatta ) that were subjected to a 30% CR diet. The T 3 value in the plasma decreased compared to the control group. Given the effects of the thyroid axis on metabolism, this could be one mechanism by which a CR diet communicates its health benefits.

Calorie Restriction Mimetics

Even if the results of human studies should prove a positive effect of calorie restriction on the life expectancy of people, the necessary reduction in the supply of food energy over the corresponding duration and with the corresponding degree is not practicable or desired for the majority of people. Therefore, so-called calorie restriction mimetics ( CR mimetics ) are also being researched. The aim of this strategy is to discover compounds that mimic the effects of calorie restriction in the human body, for example by acting on the same metabolic pathways without the need for actual calorie restriction.

However, more studies are needed to determine whether calorie restriction mimetics actually have an impact on people's life expectancy.

Selection of possible calorie restriction mimetics

According to Ingram, various substances can be used as substances to mimic the calorie restriction in the human body:

  • 2-Deoxy-D-glucose is a substance that can initiate ketogenesis , causes rats to gain slightly less body weight than control animals and leads to a significant reduction in body temperature and the fasting serum insulin level, which simulates certain effects of calorie restriction.
  • Metformin , an oral antidiabetic drug , reduces the incidence of cancer in rats and slows the progression of the disease. It also reduces the incidence of cardiovascular disease and extends life span.
  • Like metformin, glipizide is an oral anti-diabetic drug that helps control blood sugar levels. It works by partially blocking the potassium channels of the beta cells of the islets of Langerhans .
  • Rosiglitazone prevents fatty acid-induced insulin resistance by reducing the glucose infusion rate and improves the insulin-mediated suppression of hepatic glucose production. In addition, it improves the systemic elimination of non-esterified fatty acids.
  • Like rosiglitazone, pioglitazone belongs to the class of thiazolidinediones / glitazones.
  • Soy isoflavones appear to have cardioprotective effects similar to those of calorie restriction, such as a reduction in LDL cholesterol, an inhibition of proinflammatory cytokines , stimulation of nitric oxide production, potential reduction of LDL particles, inhibition of platelet aggregation and an improvement vascular reactivity.
  • Resveratrol increases the survival rate of obese mice compared to a control group of lean, untreated animals. However, adding resveratrol to the diet of lean mice does not result in any further increase in lifespan.
  • Rimonabant is one of the endocannabinoids , cannabis-like substances that can regulate appetite and the energy balance. Rimonabant is a cannabinoid 1 receptor blocker. By overstimulating the endocannabinoid receptor in the hypothalamus , it stimulates fatty acid synthesis (lipogenesis), presumably by increasing adiponectin levels. This lipogenesis reduces intra-abdominal fat. Rimonabant also improves lipid profile and glucose tolerance.
  • Adiponectin , a hormone secreted by fat cells, reduces insulin resistance in obese mice by reducing the levels of triglycerides in the muscles and liver.
  • Sirolimus / rapamycin inhibited the mTOR signaling pathway when fed to mice and resulted in a significantly increased lifespan compared to control mice.
  • Acipimox inhibits the release of fatty acids from adipose tissue and reduces the blood concentration of LDL particles, accompanied by a reduction in triglyceride and cholesterol levels.

Adverse drug effects of calorie restriction mimetics

Depending on their class of active ingredients, the above-mentioned CR mimetics have different side effects / adverse drug effects:

  • Sirolimus inhibits IL-2 and other cytokine receptor-dependent signal cascades and thus develops a strong immunosuppressive effect.
  • Metformin can rarely cause lactic acidosis.
  • Rimonabant can cause diarrhea, dizziness and nausea as well as promote respiratory infections. Other possible undesirable effects are suicidal ideation, memory disorders and probably also seizures.
  • Rosiglitazone - especially in combination with insulin - can cause weight gain and hypercholesterolemia, anemia and edema.
  • Pioglitazone can increase both body weight and the amount of water in the body, and it also increases the risk of fractures. It could also potentially increase your risk of bladder cancer.
  • In women with elevated plasma levels, adiponectin is associated with an increased risk of dementia.

See also

literature

Trade journals (reviews)

  • L. Fontana: Extending Healthy Life Span From Yeast to Humans. In: Science 328, 2010, pp. 321-326. PMID 20395504 .
  • JE Morley et al. a .: Antiaging, longevity and calorie restriction. In: Current Opinion in Clinical Nutrition and Metabolic Care 13, 2010, pp. 40-45. doi: 10.1097 / MCO.0b013e3283331384 PMID 19851100 .
  • J. Skrha: Effect of caloric restriction on oxidative markers. In: Adv Clin Chem 47, 2009, pp. 223-247. PMID 19634782 .
  • JV Smith et al. a .: Energy restriction and aging. In: Curr Opin Clin Nutr Metab Care 7, 2004, pp. 615-622. PMID 15534428 .

Reference books

  • EJ Masoro: Caloric Restriction: A Key to Understanding and Modulating Aging. Elsevier Health Sciences Verlag, 2002, ISBN 0-444-51162-8 .

Popular science articles

  • R. Weindruch: Living longer with poor food? In: Spectrum of Science Dossier 4, 2008, pp. 18–26.
  • J. Blech: healing power of hunger . In: Der Spiegel . No. 50 , 2006, p. 154 ( online ).
  • P. Bethge, L. Höflinger, J. Koch: The biology of hunger . In: Der Spiegel . No. 13 , 2011, p. 154 ( online ).

Web links

Individual evidence

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