Calorie restriction

Health effects

In humans, the long-term health effects of moderate caloric restriction with sufficient nutrients are unknown. ^[4]

Risks of malnutrition

The term “calorie restriction” as used in gerontology refers to dietary regimens that reduce calorie intake without incurring malnutrition . ^[4] Malnutrition may be the result of poor nutrition , as shown in the Minnesota Starvation Experiment . ^[6] This study was conducted during World War II, a group of men who were restricted in their calorie intake by 45% for 6 months and approximately 90% of their diet with carbohydrates. ^[6] As expected, this malnutrition resulted in many positive metabolic adaptations (eg, decreased body fat, blood pressure, improved lipid profile, low serumT3 concentration, and decreased resting heart rate and whole-body resting energy expenditure), but also caused a wide range of negative effects, such as anemia , lower extremity edema , muscle wasting , weakness, neurological deficits, dizziness, irritability, lethargy, and depression. ^[7]

Musculoskeletal losses

Short-term studies in humans report a loss of muscle mass and strength and reduced bone mineral density . ^[8] However, it is unclear. ^[9] In a study in premenopausal women, bone mineral density after weight loss was higher when normalized for body weight; ^[9] Reduced nutrient uptake was also observed in humans undergoing long-term calorie restriction with adequate nutrition, but no fractures were reported ^[10] and the reduction in bone mineral density was not associated with deleterious changes in bone microarchitecture. ^[9]

The authors of a 2007 review of caloric restriction literature warned that “[i] t is possible that even moderate calorie restriction may be harmful in specific patient populations, such as lean persons who have minimal amounts of body fat.” ^[11]

Lower-than-normal body mass index, high mortality

Caloric restriction diets typically lead to reduced body weight, and reduced weight can be caused by other causes. In some studies, low body weight has been associated with increased mortality, particularly in late middle-aged or elderly subjects. Low body weight in the elderly can be caused by the pathologic conditions associated with aging and predisposing to higher mortality (such as cancer, chronic obstructive pulmonary disorder, or depression) or the cachexia (wasting syndrome) and sarcopenia (loss of muscle mass, structure , and function). ^[12] One of the most famous of such studies linked to a body mass indexless than 18 in women with increased mortality from noncancer, non-cardiovascular disease causes. ^[13] The authors attempted to adjust for confounding factors (cigarette smoking, failure to exclude pre-existing disease); others argued that the adjustments were inadequate. ^[14]

“Epidemiologists from the ACS ( American Cancer Society ), American Heart Association , Harvard School of Public Health , and other organizations raised specific methodological issues regarding the recent Centers for Disease Control and Prevention study and presented analyzes of other data sets. .. [and] failed to account for the effect of the condition of smoking on … risks from obesity and overestimated the risks of leanness. ” ^[15]

Such epidemiological studies of body weight are not about caloric restriction as used in anti-aging studies; they are not about intake, but they are also important because they are important to the diet. to longevity. ” ^[4] Such low-calorie diets provide high nutritional requirements that are necessary for an anti-aging calorie restriction diet. ^{[16] [17] [18]} As well, “The lower-weight individuals in the studies are not caloric restriction because their caloric intake reflects their individual ad libitum set-points and not a reduction from that set-point.” ^[4]

Triggering binge eating

In those who have a binge-eating disorder, calorie restriction can precipitate an episode of binge eating , but it does not seem to pose any such risk otherwise. ^[19]

Young or pregnant

Long-term caloric Has restriction level Sufficient for Slowing the aging process is Generally not recommended in children , teenagers , and young adults (under the age of Approximately 21) Because this kind of diet May interfere with natural physical growth, as has-been observed in laboratory animals . In addition, mental development and physical exchange to the brain take place in late adolescence and early adulthood That Could be Negatively affected by severe caloric restriction. ^[20] Pregnant women and women trying to get pregnant calorie restriction, because low BMI can result in ovulatory dysfunctioninfertility ), and underweight mothers are more prone to preterm delivery . ^[20]

Miscellaneous concerns

It has beens aussi Noted That People are losing weight diets Such risk Developing cold sensitivity , menstrual Irregularities , infertility , and hormonal changes. ^[21]

Mechanisms

Even though there is more research on caloric restriction for over 70 years, the mechanism by which caloric restriction works is still not understood. ^[2] Some explanations include reduced core body temperature, ^[22] reduced cellular damage , lower metabolic rates, reduced production of free radicals , ^[23] reduced DNA damage ^[24] [25] and hormesis . ^[26]

Temperature

Caloric restriction lowers the core body temperature, a phenomenon believed to be an adaptive response to reduce energy. Lowering the temperature may prolong the lifespan of cold blooded animals. Mice, which are warm blooded, have been engineered to a reduced core temperature which has increased independently of calorie restriction. ^[22]

Hormesis

Some research has pointed to the consequences of caloric restriction, and it may be helpful to reduce caloric intake to a low calorie intake. ^[27] As a potential role for caloric restriction, the diet imposes a low-intensity biological stress on the organism, eliciting a defensive response that can help protect against the disorders of aging. ^[28] In other words, caloric restriction places the organism in a defensive state so that it can survive adversity, resulting in improved health and longer life. ^[27] This switch to a defensive state can be controlled by longevity genes (see below). ^[29]

Mitochondrial hormesis

Mitochondrial hormesis was a purely hypothetical concept until late 2007, when Caenorhabditis elegans suggests that the restriction of glucose metabolism extends primarily through increasing oxidative stress to the organism by having an increased resistance to further oxidative stress. ^[30] This is probably the first experimental evidence for hormesis being the reason for extended life span following caloric restriction.

ALTHOUGH aging can be conceptualized as the accumulation of damage, the more recent determination That free radicals Participate in intracellular signaling HAS made the categorical equation of Their effects with “damage” more problematic than Commonly Was appreciated in the past. It has previously been proposed that the endogenous response can be more effective than other endogenous responses (eg, other potentially toxic compounds). ^[31] Sublethal mitochondrial stress with an increase in reactive oxygen species may precipitate many of the alterations in cellular physiology produced by caloric restriction. ^{[32] [33] [34]}

Evolution

It has been recently argued that it is possible to prevent it from becoming an organism and to prevent it from occurring in the future. This argument seems to be supported by recent work studying hormones. Prolonged severe CR lowers total serum and free testosterone while increasing sex hormone binding globulin concentrations in humans; these effects are independent of adiposity. ^[35]

Lowering of the concentration of insulin and substances related to insulin, Such As insulin-like growth factor 1 and growth hormone , has-been shown to up-Regulate autophagy , the repair mechanism of the cell. ^[36] A related hypothesis suggests that caloric restriction works by decreasing insulin levels and even up-regulating autophagy , ^[36] [37] goal caloric restriction affects many other health indicators, and it is still undecided whether insulin is the main concern. ^[38] Calorie restriction has been shown to increase DHEAIn primates, purpose It has not-been shown pour augmenter DHEA in post-pubescent primates. ^[39] [40] The extent to which these findings apply to humans is still under investigation.

Chromatin and PHA-4

Evidence suggests that the biological effects of caloric restriction are closely related to chromatin function. ^[41] One study determined that the PHA-4 gene is responsible for the longevity behind calorie restriction in roundworms, “with similar results expected in humans”. ^[42]

Reduced DNA damage

Calorie restriction reduces production of reactive oxygen species. ^[23] [43]

Sohal et al. observed that caloric restriction decreased 8-OHdG damages in the DNA of mice heart, muscle skeletal, brain, liver and kidney. The levels of 8-OHdG in the DNA of these organs were reduced to an average of 81% of that in the DNA of a fed unrestricted diet. ^[24] Kaneko et al. observed that, in rats, dietary restriction delayed the onset of age-related increases in 8-OHdG in nuclear DNA of brain, heart, liver and kidney. The level of 8-OHdG in these organs of the calorie restricted rats at 30 months averaged 65% of the level in the rats fed an unrestricted diet. ^[44]

In rodents, calorie restriction slows aging, ROS decreases production and reduces the accumulation of oxidative DNA damage in multiple organs. These results link reduced oxidative DNA damage to slower aging. The use of this method is consistent with the observation that calorie restriction reduces oxidative DNA damage. ^[25] [45]

Sirtuin-mediated mechanism

Sirtuins, specifically Sir2 (found in yeast) has been implicated in the aging of yeast ^[46] and is a highly conserved, NAD ⁺ – dependent histone deacetylase. ^[47] Sir2 homologs have been identified in a wide range of organisms from bacteria to humans. ^[48] Yeast has 3 SIR genes (SIR2, SIR3, and SIR4) that are responsible for silencing type loci, telomeres, and rDNA . ^[49] Although SID has been implicated in the silencing of rDNA . ^[50]In addition, SIR2 related genes also regulate the formation of some specialized survival forms, such as spores in yeast ^[51] and daher larvae in C. elegans . ^[52] A study done by Kaeberlein et al. (1999) in yeast found that deletions of sir2 decreased lifespan, and additional copies increased lifespan. ^[48]

In many calorie restriction studies, it is believed that mediates the effects of calorie restriction for several reasons. First, it was found that in yeast without SIR2, calorie restriction did not impart longevity in yeast; ^[53] second, in Sir2 mutant an abundance of extra-chromosomal ribosomal DNA circles (which typically limit lifespan) has been observed, and that mitigation of these circles restore regular life span, but still are resistant to calorie restriction-mediated longevity; ^[54] [55] Third, that caloric restriction increases the activity of Sir2 in vivo . ^[56] Although Sir2 has been implicated in calorie restriction-mediated longevity, the method is still under discussion.

Two hypotheses of Sir2 / caloric restriction-mediated longevity is the NADH mechanism and the NAD salvage pathway mechanism. In the NADH hypothesis, it is believed that caloric restriction causes an increase in respiration, ^[56]which in turn causes a reduction in the levels of NADH. ^[47] This decrease in the concentration of NADH would up regulate SIR2, since NADH functions as a competitive inhibitor of SIR2. ^[55]In addition, it has been shown that overexpression of NADH hydrogenase increased longevity and knocking out the electron transport chain blocked caloric restriction-mediated longevity. The NAD salvage pathway mechanism relates to a study by Anderson et al., In which they showed that caloric restriction causes an upregulation of PNC1 (a responsible enzyme for synthesizing NAD from nicotinamide and ADP-ribose) decreases the levels of nicotinamide, which in turn up shots SIR2 and thus increases lifespan. ^[57] Although these models are not mutually exclusive, ^[55]

Caloric restriction mimetics

Work on the mechanisms of caloric restriction has given hope to the synthesis of future drugs to increase the human lifespan by simulating the effects of calorie restriction. In particular, the subject of the present invention is of particular importance in the treatment of cancer. ^{[58] [59] [60]}

Sir2 , or “silent information regulator 2”, is a sirtuin , discovered in baker’s yeast cells, which is hypothesized to suppress DNA instability. ^[61] In mammals, Sir2 is known as SIRT1 . One proponent of the view that the gene Sir2 may underlie the effect of calorie restriction in mammals by protecting cells from stress dying. ^[62] It is suggested that a low-calorie diet that requires Nicotinamide adenine dinucleotide to metabolize may allow SIRT1 to be more active in its life-extending processes, possibly by a mechanism of SIRT1 releasing fat from storage cells. ^[63]

Sirtuins

Attempts are made to develop drugs that act as CR mimetics , and much of that work has focused on a class of proteins called sirtuins . ^[64] Resveratrol has been reported to activate SIRT1 and extend the lifespan of yeast, ^[65]nematode worms, fruit flies, ^[66] vertebrate fish, ^[67] and mice consuming a high-caloric diet. ^[68] However, resveratrol does not extend life span in normal mice ^[69] and the effect of resveratrol has been lifespan in nematodes and fruit flies has been disputed. ^[70]

There are studies that indicate that resveratrol may not function through SIRT1 ^[71] [72] but may work through other targets. ^[73] [74] A clinical trial of the resveratrol formulation SRT501 was suspended. ^[75]

History

Ancient medicine, the province of Hippocrates, and Galen after him, were taught that the fat is often slender. ^[76] Around 1000 AD, Avicenna taught the elderly to be less than when they were young. ^[76] Around the world, the Venetian nobleman Luigi Cornaro adopted a calorie restricted diet at age 35 and went on to live to be 102 years old. His very successful book Discorsi della vita sobria ^[77]Described His regimen, Restricting himself to 350 g (12 oz) of food daily (Including bread, egg yolk, meat, and soup) and 410 ml (14 US fl oz) of wine . ^[78][76]

In 1919, after observing starvation in Central Europe during World War I, Francis Benedict and his colleagues published the study of Human Vitality and Efficiency in Prolonged Restricted Diet ^[79]based on their experiment with 10% calorie reduction on male college students at the Carnegie Institution for Science . ^[80] Reduced rations had turned out to be “not necessarily cataclysmic.” Biomedical adaptation of Benedict is a metabolic adaptation of Benedict’s metabolic adaptation . ^[80]

Hoping to learn how to refeed the people starved Who HAD During World War II, entre 1944 and 1945, 36 healthy conscientious objectors participated in the Minnesota Starvation Experiment , published in 1950 as The Biology of Human Starvation by lead investigator Ancel Keys and colleagues. ^[81] [7] Because this was a case of calorie restriction per se . ^{[nb 1]}

EA Vallejo published in 1957, testing CR without malnutrition in nonobese elderly persons. ^[83] [84] About 30% CR for six months was achieved accidentally in the Biosphere 2 experiment during the 1990s. ^[83]

In the 2000s, the US National Institute on Aging and the National Institute of Diabetes and Digestive and Kidney Diseases mounted the CALERIE clinical trials with goals of 20%, 25% and 30% CR at three locations for six months to a year in Phase 1 and for two years in Phase 2. ^[85]

Animal testing

Animal testing of calorie restriction was first noticed when in 1935, Clive McCay of Cornell University used 40% calorie restriction without malnutrition to prove that it prolonged the life of rats. ^[86] Unlike the 100-year lifespan of humans, rat longevity can be tested in 5 years because they tend to live only 3 years. ^[86]

The findings have since been accepted and generalized to a range of other animals. ^{[ dubious – discuss ]} Researchers are investigating the possibility of parallel physiological links in non-human primates and humans. In response to these results, a small number of people have independently adopted the practice of calorie restriction in some forms as a potential anti-aging intervention. ^[87]

Research

Humans

Studies have been conducted to examine the effects of calorie restriction with adequate intake of nutrients in humans; however, long-term effects are unknown. ^[4] One objection to calorie restriction in humans is a claim that the physiological mechanisms of longevity are complex, and that the effect would be small to negligible. ^[88] Effects of calorie restriction in humans over multiple years or decades May be small in comparison to conventional medical and public health interventions, goal-have not yet beens Clearly Determined. ^[4] [89]

Biomarkers for cardiovascular risk

A review of the effects of calorie restriction on the aging heart and vasculature concluded that more data is needed, ie, calorie restriction with Adequate nutrition (CRAN) may have additional modulatory effects on cardiovascular aging (eg, cardiac and arterial stiffness and heart rate variability). ” ^[90] Studies of long-term practitioners of rigorous calorie restriction show that their risk factors for atherosclerosis are substantially improved in atherosclerosis and nonhuman primates.c-reactive protein ; serum triglycerides , low-density lipoprotein , high-density lipoprotein ; blood pressure ; and fasting blood sugar, are much more likely than normal dietary supplements and comparable or better than long-term endurance exercisers. ^[90] Similar effects were also seen during a “natural experiment” in Biosphere 2 , ^[90] and in the subject ” Minnesota Starvation Experiment ” during World War II. ^{[6] [ not in quote given ]}Cardiac “calorie restriction” for caloric restriction in subjects with caloric restriction and weight-loss. which would be consistent with less myocardial fibrosis. ^[90] “These effects, in combination with other benefits of calorie restriction, such as protection against obesity, diabetes, hypertension, and cancer, suggest that CR may have a major beneficial effect on health span. , life span, and quality of life in humans. ” ^[90]

Biomarkers for cancer risk

Long-term calorie restriction in humans results in a reduction of several metabolic and hormonal factors that have been associated with the most common types of cancer. which calorie restriction affords substantial protection against cancer morbidity and mortality. ^[1] [91] These include lower levels of total and abdominal fat, circulating insulin, testosterone, estradiol, and inflammatory cytokines linked to cancer. ^[1] Long-term calorie restriction can also reduce levels of serum Insulin-like growth factor 1 in humans, and increase levels of IGFBP-3; However, this effect is not reduced to the Dietary Reference Intake . ^[1]

Primates

In a 2017 collaborative report on rhesus monkeys by scientists of the US National Institute on Aging and the University of Wisconsin, caloric restriction in the presence of adequate nutrition was effective in delaying the effects of aging. ^[5] [92] Older age of onset, female sex, low body weight and fat mass, reduced food intake, diet quality, and lower fasting blood glucose levels were associated with decreased survival rates. ^[5] [92] Specifically, reduced food intake in older adults and older primates, but not in younger monkeys. ^[5]The study indicated that because of the nature of the condition and the presence of monkeys, it is important to note that these conditions are not ^[5]

Rodents

It has been known to reduce the number of calories fed to the laboratory. The life extension varies for each species, but on average there was a 30-40% increase in life span in both mice and rats. ^[38] In late adulthood, acute CR partially or completely reverses age-related alterations of liver, brain and heart proteins, and mice placed on CR at 19 months of age show an increase in life span. ^[93]

Yeast

Fungi models are very easy to manipulate, and many crucial steps towards the understanding of aging have been made with them. Many studies have been undertaken on the yeast and fission yeast to analyze the cellular mechanisms behind increased longevity due to calorie restriction. First, calorie restriction is often called dietary restriction because of the same effects on life span can be achieved by only changing the calories. Data from Guarente and others showed that genetic manipulation in nutrient-signaling pathways could mimic the effects of dietary restriction. In some cases, dietary restriction requires mitochondrial respiration to increase longevity (chronological aging), and in some other cases not (replicative aging). Nutrient sensing in yeast controls stress defense, mitochondrial functions, Sir2, and others. These functions are all known to regulate aging. Genes involved in these mechanisms are TOR, PKA, SCH9, MSN2 / 4, RIM15, and SIR2.^{[94] [95] [96] [97] [98]} Importantly, yeast responses to CR can be modulated by genetic background. Therefore, while some strains respond to calorie restriction with increased lifespan, in others calorie restriction shortens it ^[99]

Activity levels[edit]

Calorie restriction preserves muscle tissue in nonhuman primates ^[100] [101] and rodents. ^[102] [103] Mechanisms include reduced muscle cell apoptosis and inflammation; ^[102] protection against ^[103] or adaptation to ^[100] age-related mitochondrial abnormalities; and preserved muscle stem cell function. ^[104]Muscle tissue grows when stimulated, so it has been suggested that the calorie-restricted test animals exercise more than their companions on higher calories, perhaps because of a calorie restriction. However, studies show that overall activity levels are higher than calorie restriction than ad libitum . ^[105] Laboratory techniques of calorie restriction and feeding time. Monkeys undergoing calorie restriction also appear more immediately before and after meals. ^[106]

Behavior

Observations in some accounts of animals undergoing calorie restriction have increased in stereotyped behaviors . ^[106] For example, monkeys on calorie restriction have been shown to increase in licking, sucking, and rocking behavior. ^[107] A calorie restriction may also lead to increased aggressive behavior in animals. ^[106]

Obese controls

It has sometimes been suggested that the lives of calorie-restricted animals are only artificially shortened by weight-gain from unnatural ad libitum feeding in the laboratory. ^[108] However, studies designed to test this hypothesis suggest that reduced fat mass is not a major contributor to the longevity effects of calorie restriction. ^[4]