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Caloric Restriction: Difference between revisions
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''' | [[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}}. | 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}}. | ||
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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}} | 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== | ==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, 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}} | 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 === | === Longevity === | ||
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=== Reduction of Oxidative Stress === | === Reduction of Oxidative Stress === | ||
There are indications that 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}} | 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=== | ===Hormesis=== | ||
According to a contrary hypothesis, 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}} | 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}} | 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}} | ||
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=== Increased Autophagy === | === 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. | [[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 [[ | 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}} | A comparable effect was observed in plants whose lighting was reduced.{{pmid|20021367}} | ||
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* [[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}} | * [[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}} | * [[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 == | ||
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* {{pmid text|24691430}} | * {{pmid text|24691430}} | ||
* {{pmid text|37118425}} | * {{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]] | |||