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Caloric restriction (CR), a dietary regimen that reduces calorie intake without incurring malnutrition, has been a subject of scientific study in the context of aging and longevity. This practice is thought to extend lifespan and improve health outcomes in various species, including potentially humans.
==Science Behind Caloric Restriction==
===Mechanisms===
Caloric restriction is believed to impact aging through several biological pathways. These include reduced metabolic rate, decreased oxidative stress, improved insulin sensitivity, and activation of cellular maintenance mechanisms such as autophagy.
==Effects in Model Organisms==

=== Positive Effects ===
[[File:Caloric restriction 02.png|thumb|Effects of calorie restriction on the survival rate of laboratory mice (CR=Calorie Restriction).{{pmid|3958810}}]]
[[File:Drosophila melanogaster - side (aka).jpg|thumb|Calorie restriction can significantly increase the lifespan of the fruit fly (''Drosophila melanogaster'').]]
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.&nbsp;405–414; {{JSTOR|15813}}.</ref>, [[Domestic Dogs (Canis Familiaris)]]{{pmid|18062831}} and [[Non-Human Primates]].{{pmid|12424798}}{{pmid|10630588}}{{pmid|8994305}} 

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}}

Both in a study with rhesus monkeys{{pmid|22932268}} by the American National Institute on Aging, and in a study on ''Drosophila''{{pmid|16000018}}, it has been suggested that life extension depends not only on calorie restriction but also on the composition of the diet.

===General Criticism===
Various findings raise doubts about the notion that caloric restriction slows down the aging process, delays the age-related decline in physiological fitness, or extends the lifespan of organisms from different phylogenetic groups.{{pmid|24941891}} Positive effects of caloric restriction are not universal:

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.{{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 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}}<ref>rme: {{Webarchive |url=https://www.aerzteblatt.de/nachrichten/37311/Anti-Aging-Kalorienrestriktion-laesst-Affen-laenger-leben |title=Anti-Aging: Calorie Restriction Lets Monkeys Live Longer |wayback=20131015025849 |archive-bot=2019-09-14 14:53:42 InternetArchiveBot}} In: ''aerzteblatt.de'', July 10, 2009.</ref>

== 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|metabolic syndrome]] such as [[Cardiovascular disease]]s 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 culture]]s.{{pmid|25855056}} Various mechanisms are being discussed:

=== 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.<ref name="PMID19549533">A. Csiszar et al.: ''Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: role of circulating factors and SIRT1.'' In: ''Mech Ageing Dev'' 130, 2009, pp.&nbsp;518–527. PMID 19549533.</ref><ref name="PMID19634782">J. Skrha: ''Effect of caloric restriction on oxidative markers.'' In: ''Adv Clin Chem'' 47, 2009, pp.&nbsp;223–247. PMID 19634782.</ref> In some mouse strains, the effect of calorie restriction can be partially induced by [[Resveratrol]].<ref name="PMID 25824609">PMID 25824609.</ref> 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.<ref>S. Nagarajan, A. L. Kruckeberg, K. H. Schmidt, E. Kroll, M. Hamilton, K. McInnerney, R. Summers, T. Taylor, F. Rosenzweig: ''Uncoupling reproduction from metabolism extends chronological lifespan in yeast.'' In: ''PNAS.'' Volume 111, Number 15, April 2014, {{ISSN|1091-6490}}, pp.&nbsp;E1538–E1547, [[doi:10.1073/pnas.1323918111]], PMID 24706810, {{PMC|3992631}}.</ref> 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.<ref>25071164</ref>
===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.<ref>PMID 16242247.</ref>

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.<ref name="PMID20350594">PMID 20350594</ref>
===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}}

==Benefits of Caloric Restriction==
Research suggests that caloric restriction may offer several health benefits, including:
*Improved metabolic health
*Reduced risk of age-related diseases
*Enhanced brain function and protection against neurodegenerative diseases
*Possible extension of healthy lifespan

==Potential Risks and Concerns==
Caloric restriction, especially if not properly managed, can lead to:
*Nutritional deficiencies
*Loss of bone density
*Reduced muscle mass and strength
*Psychological challenges such as food obsession and social isolation
==Guidelines for Safe Practice==
Before starting caloric restriction, it is crucial to consult healthcare professionals. Some general guidelines include:
*Gradual reduction in calorie intake
*Emphasis on nutrient-dense foods
*Regular monitoring of health parameters
*Adjustment of diet based on individual health needs and lifestyle
==Conclusion==
While caloric restriction shows promise as a tool for extending healthspan and potentially lifespan, further research, especially in humans, is necessary. It is vital to approach this dietary regimen with caution and under medical supervision to avoid adverse effects.
[[Category:Lifespan Extending]]
== 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}}

== References ==
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