Caloric Restriction: Difference between revisions

'''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}}.

 

[[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}}]]

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}}

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.

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}}

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}}

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}}

[[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}}

 

=== 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.

* [[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}}

* [[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}}