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Caloric restriction (CR), a | [[File:Food level, fecundity and longevity.jpg|thumb|Food level, fecundity and longevity. Median life span and fecundity are negatively affected by a very low nutrient concentration in higher eukaryotes. However, life span but not fecundity is optimized by dietary restriction (DR).{{pmid|20395504}}]] | ||
'''Caloric restriction''' '''(CR)''', also known as '''calorie restriction''' or '''dietary restriction (DR)''', refers to a diet that reduces the intake of chemically bound energy from foods by 10 to 50 percent compared to ''ad libitum'' ("at will") nutrition. The goal is to achieve a higher life expectancy or at least delayed aging or health-promoting effects{{pmid|21663754}}{{pmid|19104499}}, without leading to malnutrition. | |||
In a number of [[Model Organisms|model organisms]], a health-promoting and life-extending effect has been demonstrated through this method. However, no extension of life expectancy has been observed in some species or breeds. The extension of life expectancy in some rodent strains by up to 50%{{pmid|21840335}} is dependent on the genome and sex among other factors{{pmid|25269675}}. | |||
==Effects in Model Organisms== | |||
=== Positive Effects === | === Positive Effects === | ||
[[File:Caloric restriction 02.png|thumb| | [[File:Caloric restriction 02.png|thumb|[[Kaplan–Meier Survival Curve]] on the effects of calorie restriction of laboratory mice (KR=Calorie Restriction, Überlebensrate=Cumulative survival, Alter=age, Monate=months).{{pmid|3958810}}]] | ||
Calorie restriction has been studied in [[Model Organism|model organisms]] such as [[Yeast (Saccharomyces Cerevisiae)]]{{pmid|11000115}}{{pmid|12124627}}, [[Nematodes (Caenorhabditis Elegans)]]{{pmid|9789046}}, [[Fruit Flies (Drosophila Melanogaster)]]{{pmid|16000018}}, [[Mice (Mus Musculus)]]{{pmid|3958810}}, [[Rats (Rattus Norvegicus)]]<ref>C. M. McCay und M. F. Crowell: ''Prolonging the Life Span''. In: ''The Scientific Monthly'' 39, 1934, S. 405–414; {{JSTOR|15813}}.</ref>, [[Domestic Dogs (Canis Familiaris)]]{{pmid|18062831}} and [[Non-Human Primates]].{{pmid|12424798}}{{pmid|10630588}}{{pmid|8994305}} | |||
Calorie restriction has been studied in [[Model Organism|model organisms]] such as [[Yeast (Saccharomyces Cerevisiae)]]{{pmid|11000115}}{{pmid|12124627}}, [[Nematodes (Caenorhabditis Elegans)]]{{pmid|9789046}}, [[Fruit Flies (Drosophila Melanogaster)]]{{pmid|16000018}}, [[Mice (Mus Musculus)]]{{pmid|3958810}}, [[Rats (Rattus Norvegicus)]]<ref>C. M. McCay und M. F. Crowell: ''Prolonging the Life Span''. In: ''The Scientific Monthly'' 39, 1934, S. 405–414; {{JSTOR|15813}}.</ref>, [[Domestic Dogs (Canis Familiaris)]]{{pmid|18062831}} and | |||
In many species, not only is the average lifespan of the test animals increased, but also their maximum lifespan. The frequency of age-related diseases correspondingly decreases.{{pmid|18729811}} The effect of an increase in maximum life expectancy occurs in rodents both when starting the diet in the early life phase (1st to 3rd month), and in the middle life phase (12th month).{{pmid|12424798}}{{pmid|10630588}} However, if calorie restriction is started in a later life phase of the test animals, such as in the 17th or 24th month of mice, the effect reverses and the lifespan of the test animals is shortened.{{pmid|12586746}} | In many species, not only is the average lifespan of the test animals increased, but also their maximum lifespan. The frequency of age-related diseases correspondingly decreases.{{pmid|18729811}} The effect of an increase in maximum life expectancy occurs in rodents both when starting the diet in the early life phase (1st to 3rd month), and in the middle life phase (12th month).{{pmid|12424798}}{{pmid|10630588}} However, if calorie restriction is started in a later life phase of the test animals, such as in the 17th or 24th month of mice, the effect reverses and the lifespan of the test animals is shortened.{{pmid|12586746}} | ||
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In fruit flies, positive effects of caloric restriction are not reproduced with careful control of nutrient fractions.{{pmid|18268352}} | In fruit flies, positive effects of caloric restriction are not reproduced with careful control of nutrient fractions.{{pmid|18268352}} | ||
The increase in lifespan caused by caloric restriction is not even reproducible among different strains of the same species.{{pmid|24941891}}[[File:Caloric restriction with different mice.png|thumb|Calorie restriction does not extend lifespan in all mice. In the top graph, a significant effect is observed in C57BL/6 mice ("laboratory mice"), while it is absent in DBA/2 mice ("wild type") below (AL=''ad libitum'', CR=Calorie Restriction).{{pmid|12586746}}]]Thus, calorie restriction does not lead to lifespan extension in all mouse strains.{{pmid|12586746}} In 19 to 27% of the mouse strains studied, a 40% caloric restriction even resulted in a shortened lifespan. | The increase in lifespan caused by caloric restriction is not even reproducible among different strains of the same species.{{pmid|24941891}}[[File:Caloric restriction with different mice.png|thumb|Calorie restriction does not extend lifespan in all mice. In the top graph, a significant effect is observed in C57BL/6 mice ("laboratory mice"), while it is absent in DBA/2 mice ("wild type") below (AL=''ad libitum'', CR=Calorie Restriction).{{pmid|12586746}}]]Thus, calorie restriction does not lead to lifespan extension in all mouse strains.{{pmid|12586746}} In 19 to 27% of the mouse strains studied, a 40% caloric restriction even resulted in a shortened lifespan.{{pmid|19878144}}{{pmid|20452416}} | ||
The frequently used [[C57BL/6 mice|C57BL/6]] mice tend to become overweight with unrestricted food access (''ad libitum''). In these animals, the effect of caloric restriction is significant. DBA/2 mice, on the other hand, remain lean even with ad-libitum feeding. In mice from this strain, caloric restriction does not lead to lifespan extension. DBA/2 mice consume more oxygen with the same energy intake than C57BL/6 mice, meaning their metabolic rate is increased – they are poorer "feed converters."{{pmid|19141702}} It was already observed in earlier experiments that caloric restriction is most successful in mice that gain significant weight in early adulthood.{{pmid|958413}} The results of these studies are interpreted to mean that lifespan is more influenced by the balance of energy intake and energy expenditure. Only in test animals prone to overweight or obesity can caloric restriction cause lifespan extension.<ref>{{Cite web|url=https://www.aerzteblatt.de/nachrichten/35192/Lebensverlaengerung-Mythos-der-Kalorienrestriktion-widerlegt|title=Life Extension: Myth of Caloric Restriction Refuted|website=[[Deutsches Ärzteblatt|aerzteblatt.de]]|date=2009-01-26|archive-url=https://web.archive.org/web/20150518230228/http://www.aerzteblatt.de/nachrichten/35192/Lebensverlaengerung-Mythos-der-Kalorienrestriktion-widerlegt|archive-date=2015-05-18|archive-bot=2019-09-14 14:53:42 InternetArchiveBot|access-date=2015-05-01}}</ref> | The frequently used [[C57BL/6 mice|C57BL/6]] mice tend to become overweight with unrestricted food access (''ad libitum''). In these animals, the effect of caloric restriction is significant. DBA/2 mice, on the other hand, remain lean even with ad-libitum feeding. In mice from this strain, caloric restriction does not lead to lifespan extension. DBA/2 mice consume more oxygen with the same energy intake than C57BL/6 mice, meaning their metabolic rate is increased – they are poorer "feed converters."{{pmid|19141702}} It was already observed in earlier experiments that caloric restriction is most successful in mice that gain significant weight in early adulthood.{{pmid|958413}} The results of these studies are interpreted to mean that lifespan is more influenced by the balance of energy intake and energy expenditure. Only in test animals prone to overweight or obesity can caloric restriction cause lifespan extension.<ref>{{Cite web|url=https://www.aerzteblatt.de/nachrichten/35192/Lebensverlaengerung-Mythos-der-Kalorienrestriktion-widerlegt|title=Life Extension: Myth of Caloric Restriction Refuted|website=[[Deutsches Ärzteblatt|aerzteblatt.de]]|date=2009-01-26|archive-url=https://web.archive.org/web/20150518230228/http://www.aerzteblatt.de/nachrichten/35192/Lebensverlaengerung-Mythos-der-Kalorienrestriktion-widerlegt|archive-date=2015-05-18|archive-bot=2019-09-14 14:53:42 InternetArchiveBot|access-date=2015-05-01}}</ref> | ||
The NIA study on rhesus monkeys found no lifespan extension.{{pmid|22932268}} In a long-term study conducted at the ''Wisconsin National Primate Research Center'' over a period of 20 years on rhesus monkeys, a significantly better health status and a significantly increased lifespan were observed in the group of animals that received a reduced food supply during this period. In this group, 80% of the animals were still alive, compared to only 50% in the normally fed control group. Furthermore, in the animals with calorie restriction, a significantly delayed onset | The NIA study on rhesus monkeys found no lifespan extension.{{pmid|22932268}} In a long-term study conducted at the ''Wisconsin National Primate Research Center'' over a period of 20 years on rhesus monkeys, a significantly better health status and a significantly increased lifespan were observed in the group of animals that received a reduced food supply during this period. In this group, 80% of the animals were still alive, compared to only 50% in the normally fed control group. Furthermore, in the animals with calorie restriction, a significantly delayed onset of age-associated diseases such as diabetes, cancer, and brain atrophy, as well as cardiovascular incidents, was observed. The authors of the study conclude that calorie restriction delays the aging process in this primate species.{{pmid|19590001}} | ||
== | === Genetic Variations === | ||
In animal models, some physiological and metabolic traits, especially lifespan, are strongly affected by genetic backgrounds and variations as well as non-genetic factors such as symbiotic microbiome and water balance{{pmid|28220799}}. The role of particular genes in the response of lifespan to caloric restriction has been investigated by determining if a genetic alteration alters this response. Lifespan rises to a maximum as the food intake is lowered, but can decline rapidly if the food supply is further reduced. Therefore, the effects of mutations should be examined over a broad range of food intakes, so that the degree of caloric restriction that maximizes life span can be determined and used in tests for genetic effects{{pmid|17465680}}. | |||
When a collection of recombinant inbred mouse strains were tested for lifespan under ad libitum diet and caloric restriction (40% reduction compared to ad libitum diet) diet, a wide range of lifespan responses were observed in both ad libitum and caloric restriction diets{{pmid|19878144}}{{pmid|23562825}}. For example, the mean lifespan of female mice on ad libitum diet varied from 407 to 1208 days. Strikingly, their lifespans on CR diet varied to a greater degree from 113 to 1225 days. Importantly, not only did CR fail in lifespan extension in some lines, but it even shortened lifespan in some lines too{{pmid|19878144}}. | |||
Similarly, a strong variation in lifespan response to diets was observed when a collection of nearly 200 genetically distinct lines of Drosophila (DGRP: Drosophila Genetic Reference Panel) tested for lifespan in ad libitum (5% Yeast) and caloric restriction (0.5% Yeast){{doi|10.2139/ssrn.3420829|Wilson, Kenneth Anthony and Beck, Jennifer and Nelson, Christopher S. and Hilsabeck, Tyler A. and Promislow, Daniel and Brem, Rachel B. and Kapahi, Pankaj, Genome-Wide Analyses for Lifespan and Healthspan in D. Melanogaster Reveal Decima as a Regulator of Insulin-Like Peptide Production (July 16, 2019)}}. In both cases, lifespan response also significantly varied between males and females{{pmid|19878144}}{{doi|10.2139/ssrn.3420829|Wilson, Kenneth Anthony and Beck, Jennifer and Nelson, Christopher S. and Hilsabeck, Tyler A. and Promislow, Daniel and Brem, Rachel B. and Kapahi, Pankaj, Genome-Wide Analyses for Lifespan and Healthspan in D. Melanogaster Reveal Decima as a Regulator of Insulin-Like Peptide Production (July 16, 2019)}}, generating a further layer of complication in understanding the mechanisms of caloric restriction. A simple interpretation of these animal studies would suggest that a certain type of caloric restriction may not be beneficial, but they can be even deleterious depending on genetic variations and sex{{pmid|30442801}}. Therefore, for human applications of caloric restriction, it is suggested that individualized genomics and medicine should be established first to take full advantage of caloric restriction.{{pmid|32344591}} | |||
== | |||
==Effects in Humans== | |||
The hormonal and metabolic effects of calorie restriction observed in experimental animals, such as lower body temperature, reduced metabolic rate, and decreased [[Oxidative Stress|oxidative stress]], have also been demonstrated in humans.{{pmid|18729811}}{{pmid|16595757}} Additionally, lower serum levels of basal insulin ("fasting insulin"), profibrotic proteins, various growth factors - such as PDGF and TGF-α - as well as cytokines like Tumor Necrosis Factor-α have been detected.{{pmid|15096581}}{{pmid|17389710}}{{pmid|17093155}}{{pmid|16732018}}{{pmid|16412867}} It is also established that long-term calorie restriction is an effective prevention against Type II Diabetes, high blood pressure, and Atherosclerosis, which together are the main causes of Morbidity, disabilities, and Mortality in humans.{{pmid|19262201}} | |||
=== Longevity === | |||
Currently, there is no scientific evidence that permanent calorie restriction – with adequate nutrition – leads to an extension of life expectancy compared to a lean adult.<ref>{{cite web |author=Stephan Schleim |url=https://www.heise.de/tp/features/Auf-der-Suche-nach-dem-Jungbrunnen-das-Beispiel-Kalorienreduktion-3395506.html |title=In Search of the Fountain of Youth: The Example of Calorie Restriction |website=[[Telepolis|heise.de]] |date=2012-08-31 |access-date=2015-05-11}}</ref> It is undisputed that severe overweight, i.e., obesity, leads to a reduction in average and maximum life expectancy. However, reviews have confirmed that calorie restriction (or [[Intermittent Fasting|Intermittent fasting]]) in healthy adults is likely to lead to similar life extension – extensions of health and lifespan – as observed in animal experiments. They describe the health effects and molecular mechanisms of such phases, including Autophagy. A problem with scientific studies on this is that the relatively long lifespan of humans makes it difficult to directly test such interventions.{{pmid|34518687}} Periods in which calorie intake is limited to a constant deficit can be combined with intermittent fasting (periods with intervals of consuming no food, only water, and tea/coffee, for example) and variants of the Mediterranean diet, which typically have long-term cardiovascular benefits and could also increase longevity.{{pmid|32943166}} Which protocols (such as duration and magnitude of the calorie deficit) and combinations (see, for example, Caloric restriction mimetic, effects of coffee, and AMPK) with calorie restriction are effective or most effective in humans in general and depending on the individual{{pmid|34555343}} is still unknown. | |||
== | |||
===Risks of Calorie Restriction in Humans=== | |||
Specifically in the USA, the results of animal experiments have led to many practitioners adopting calorie restriction, particularly in California. A group of these practitioners formed the ''Calorie Restriction Society''. Excessive calorie reduction always carries the risk of malnutrition, which can negatively affect physical and mental health. There are repeated warnings about potential eating disorders with calorie restriction. On the other hand, a study showed that calorie restriction does not lead to an increase in anorexia or bulimia. The psychological effects of calorie restriction were evaluated as positive in this study.{{pmid|18248104}} | |||
Long-term undernutrition can, besides positive effects, also lead to various deficiency diseases. Developmental disorders can occur in minors. Cold sensitivity may increase.{{pmid|19944269}} Ovulation can be suspended in women with very low BMI, resulting in temporary infertility.{{pmid|19944269}} In the ''Minnesota Starvation Experiment'', anemia, edema in the lower extremities, muscle wasting, weakness, neurological impairments, dizziness, irritability, lethargy, and depression were observed in adult males undergoing a six-month calorie restriction with a 90% carbohydrate diet.<ref>{{cite book|last1=Keys|first1=A.|last2=Brozek|first2=J.|last3=Henschels|first3=A.|last4=Mickelsen|first4=O.|last5=Taylor|first5=H.|title=The Biology of Human Starvation|year=1950|volume=2|publisher=University of Minnesota Press|location=Minneapolis|page=1133}}</ref> Short-term calorie restriction can lead to muscle wasting and reduced bone density.{{pmid|19851100}} In individuals with low body fat, calorie restriction can be harmful.{{pmid|17341713}} | |||
== | == Mechanism == | ||
The reasons for the lifespan extension in model organisms through caloric restriction are not yet fully understood. The underlying mechanism of this effect remains unknown. It's possible that the extension of lifespan results from improved health status due to the absence of obesity and the delayed onset of age-related diseases of the metabolic syndrome such as cardiovascular diseases and Type II Diabetes mellitus. | |||
Studies conducted with mice suggest that the lifespan extension associated with caloric restriction is not simply a result of leanness caused by calorie restriction. The maximum lifespan of male rats that maintained a low body fat mass through physical activity did not increase, but it did for mice that maintained a low body weight through caloric restriction alone, despite a sedentary lifestyle.{{pmid|17341713}} | |||
Caloric restriction in rats produces soluble factors in the blood serum that cause lifespan extension in human cell cultures.{{pmid|25855056}} Various mechanisms are being discussed: | |||
=== Reduction of Oxidative Stress === | |||
There are indications that [[Oxidative Stress|oxidative stress]] is reduced by decreased food intake, thereby delaying primary aging. Primary aging is the process in cells and organs that defines the maximum lifespan in the absence of diseases (inevitable aging). Secondary aging is determined by external factors such as diseases, environmental factors, lifestyle, and physical activity (avoidable aging).<ref name="Tostlebe2005">M. Tostlebe: [http://d-nb.info/978638670/34 ''Disproportionalität der Aktivitäten der mitochondrialen Atmungskettenkomplexe im Myokard und in der Skelettmuskulatur im Alter.''] Dissertation, Martin-Luther-Universität Halle-Wittenberg, 2005.</ref> Oxidative stress primarily occurs in the mitochondria, the powerhouses of the cells.{{pmid|19549533}}{{pmid|19634782}} In some mouse strains, the effect of calorie restriction can be partially induced by [[Resveratrol]].{{pmid|25824609}} In yeasts, the protein ''Rim15'', a glucose-inhibited protein kinase, acts as a sensor of nutrient concentrations as well as the initiator of Meiosis and is necessary for lifespan extension in yeasts.{{pmid|24706810}} However, a meta-analysis also reported that caloric restriction – contrary to previous results – does not lead to lifespan extension in yeasts, but the results in yeasts are partly based on methodological artifacts.{{pmid|25071164}} | |||
===Hormesis=== | |||
According to a contrary hypothesis, [[Oxidative Stress|oxidative stress]] from reactive oxygen species (ROS) is thought to positively stimulate cell metabolism (Hormesis), which may explain the health benefits of caloric restriction as well as Fasting, oxidative plant compounds in cabbage vegetables, and physical training.{{pmid|16242247}} | |||
In contrast to the free radical theory, it is assumed that an increased formation of reactive oxygen species in the mitochondria, associated with caloric restriction, causes an adaptive response that enhances stress resistance.{{pmid|20350594}} | |||
===Activation of Sirtuin-1 and Reduced Expression of the mTOR Receptor === | |||
Signal-regulating enzymes such as [[SIRT1|Sirtuin-1 (Sirt1)]] in mammals, or [[SIRT2|Sirtuin ''Sir2'']] in yeasts, may play a role.{{pmid|25349818}} The cells of calorically restricted test animals produce Sirt1 in larger quantities.{{pmid|19713122}} An increased production of Sirt1, in turn, reduces the expression of the mTOR receptor (''mammalian Target of Rapamycin''),{{pmid|20169165}} which is also associated with the aging process. The lifespan of mice can be significantly extended by administering [[Rapamycin]], which docks to the mTOR receptor.{{pmid|20331443}}{{pmid|19587680}} [[Melatonin]] is also being studied due to its activation of Sirtuin.{{pmid|25824609}} | |||
=== "Reprogramming" of Metabolism and Gene Expression === | |||
According to another theory, long-term reduced food intake "reprograms" the metabolism.{{pmid|17063031}} In mice under caloric restriction, a changed gene expression has been observed. On one hand, genes involved in energy metabolism are overexpressed,{{pmid|14688200}} while on the other hand, over 50 pro-inflammatory genes are downregulated.{{pmid|16424110}}{{pmid|19075044}} It's possible that the regeneration of some stem cells is enhanced.{{pmid|24211426}} In some strains of mice, a similar effect can be induced by [[Metformin]].{{pmid|25269675}} | |||
===Increased Formation of Ketone Bodies=== | |||
Both caloric restriction and the ketogenic diet have therapeutic potential in various animal models of neurological diseases.{{pmid|18845187}} Under caloric restriction, there is a transition from glucose metabolism to the use of ketone bodies. Ketone bodies can be used as an alternative energy source for brain cells when glucose availability is poor.{{pmid|25896951}} | |||
Ketone bodies protect neurons against various types of neuronal injuries. This is one explanation for the beneficial effect of caloric restriction in the animal model of neurological diseases.{{pmid|25896951}} | |||
=== Increased Autophagy === | |||
[[Autophagy]], also known as “cellular self-digestion”, is a cellular pathway involved in the breakdown of proteins and organelles, and plays a role in various diseases. Dysfunctions in autophagy are associated with neurodegenerative diseases, microbial infections, and aging. | |||
Several indications suggest that autophagy is important for the effects of calorie restriction: The efficiency of autophagy decreases with age; the decline in autophagy is associated with changes in aging biomarkers; the age-dependent change in autophagy is prevented experimentally by calorie restriction; preventing a decrease in autophagy efficiency mimics the effects of calorie restriction; prolonged inhibition of autophagy accelerates the aging process; conversely, prolonged stimulation of autophagy delays the aging process in [[Rats (Rattus Norvegicus)|rats]]; stimulating autophagy can protect older cells from accumulation of altered mitochondrial DNA; stimulating autophagy alleviates age-related hypercholesterolemia in rodents.{{pmid|23331488}} | |||
A comparable effect was observed in plants whose lighting was reduced.{{pmid|20021367}} | |||
=== Reduced Thyroid Hormones === | |||
Plasma levels of thyroid hormones Triiodothyronine (T<sub>3</sub>), Thyroxine (T<sub>4</sub>), and Thyroid-stimulating Hormone (TSH) were measured in Rhesus monkeys (''Macaca mulatta'') subjected to a 30% CR (caloric restriction) diet. The plasma T<sub>3</sub> level decreased compared to the control group. Given the impact of the thyroid axis on metabolism, this could be a mechanism through which a CR diet mediates its health benefits.{{pmid|12189585}} | |||
[[Category:Lifespan Extending]] | [[Category:Lifespan Extending]] | ||
== Calorie Restriction Mimetics == | |||
Even if human studies prove a positive effect of calorie restriction on human life expectancy, the necessary reduction in food energy intake over the corresponding duration and degree is not practical or desired for the majority of people. | |||
Therefore, so-called ''Calorie Restriction Mimetics'' (CR mimetics) are also being researched. The goal 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 restriction of food energy intake.{{pmid|24079773}} | |||
However, further studies are required to determine whether calorie restriction mimetics actually have an impact on human life expectancy.{{pmid|17341713}} | |||
=== Potential Calorie Restriction Mimetics === | |||
According to Ingram, various substances are considered as mimetics of calorie restriction in the human body:{{pmid|16626389}} | |||
* [[2-Deoxy-D-glucose|2-Deoxy-<small>D</small>-glucose]] can initiate [[Ketogenesis|ketogenesis]]{{pmid|21747957}}, makes rats gain slightly less body weight than control animals and leads to a significant reduction in body temperature and fasting serum insulin levels, thereby simulating certain effects of calorie restriction.{{doi|10.1089/rej.1.1998.1.327|MARK A. LANE, DONALD K. INGRAM, and GEORGE S. ROTH. | |||
2-Deoxy-D-Glucose Feeding in Rats Mimics Physiologic Effects of Calorie Restriction. | |||
Journal of Anti-Aging Medicine.Jan 1998.327-337.}} | |||
* [[Metformin]], an orally administered [[antidiabetic]], reduces cancer incidence in rats and slows the progression of the disease. It also reduces the occurrence of cardiovascular diseases and extends lifespan.{{pmid|20304770}} | |||
* [[Glipizide]], like Metformin, is an orally administered [[antidiabetic]] that helps control blood sugar levels. It works by partially blocking the potassium channels of the beta cells of the [[Islets of Langerhans]].{{pmid|6369967}} | |||
* [[Rosiglitazone]] prevents fatty acid-induced insulin resistance by reducing the glucose infusion rate and improves insulin-mediated suppression of hepatic glucose production. It also improves the systemic elimination of non-esterified fatty acids.{{pmid|15232684}} | |||
* [[Pioglitazone]], like Rosiglitazone, belongs to the class of substances known as Thiazolidinediones/Glitazones. | |||
* Soy [[Isoflavones]] appear to have cardioprotective effects similar to those of calorie restriction, such as reducing LDL cholesterol, inhibiting pro-inflammatory [[cytokines]], stimulating [[nitric oxide]] production, potentially reducing LDL particles, inhibiting platelet aggregation, and improving vascular reactivity.{{pmid|17689850}} | |||
* [[Resveratrol]] increases the survival rate of obese mice compared to a control group of lean, untreated animals. Adding Resveratrol to the diet of lean mice, however, does not further increase lifespan.{{pmid|21261652}} | |||
* [[Rimonabant]] belongs to the [[Cannabinoids|endocannabinoids]], cannabis-like substances that can regulate appetite and 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 the lipid profile and glucose tolerance.{{Citation needed}} | |||
* [[Adiponectin]], a hormone secreted by fat cells, reduces insulin resistance in obese mice by reducing triglyceride content in muscles and liver.{{pmid|11479627}} | |||
* [[Sirolimus]]/Rapamycin, when administered to mice with food, inhibits the mTOR pathway and resulted in a significantly increased lifespan compared to control mice.{{pmid|21629433}} | |||
* [[Acipimox]] inhibits the release of fatty acids from adipose tissue and reduces the blood concentration of LDL particles, along with a reduction in triglyceride and cholesterol levels.{{Citation needed}} | |||
== See Also == | |||
* [[Intermittent Fasting]] | |||
* [[Fasting-Mimicking Diet]] | |||
* [[Deregulated Nutrient Sensing]] | |||
* {{SeeWikipedia|Caloric restriction|}} | |||
== Further Reading == | |||
* {{pmid text|20395504}} | |||
* {{pmid text|32344591}} | |||
== Todo == | == Todo == | ||
* In fact, it has been shown that caloric restriction increases NAD+ bioavailability by activating the expression of NAMPT (nicotinamide phosphoribosyltransferase, which transforms nicotinamide [NAM] to NAD+ in the NAD+ salvage pathway) {{pmid|22190494}} | * In fact, it has been shown that caloric restriction increases NAD+ bioavailability by activating the expression of NAMPT (nicotinamide phosphoribosyltransferase, which transforms nicotinamide [NAM] to NAD+ in the NAD+ salvage pathway) {{pmid|22190494}} | ||
* {{pmid text|28094793}} | |||
* {{pmid text|24691430}} | |||
* {{pmid text|37118425}} | |||
* https://www.news-medical.net/news/20240417/Penn-State-study-examines-how-a-persons-telomeres-are-affected-by-caloric-restriction.aspx | |||
== References == | == References == | ||
<references /> | <references /> | ||
[[Category:Calorie Restriction Mimetic Compounds|!Caloric_Restriction]] | |||