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<http://www.wsj.com/articles/SB10000872396390444772804577619394017185860> a :News_Article ;
dc:title "Big Calorie Cuts Don't Equal Longer Life, Study Suggests" .
<https://source.wustl.edu/2012/06/calorierestricted-diet-keeps-heart-young/> a :News_Article ;
dc:title "Calorie-restricted diet keeps heart young" .
<https://medicalxpress.com/news/2017-01-calorie-restriction-monkeys-prosper.html?utm_source=nwletter&utm_medium=email&utm_campaign=daily-nwletter> a :News_Report ;
dc:title "Calorie restriction lets monkeys live long and prosper" .
The most powerful non-genetic intervention to retard the biological ageing process is commonly known as dietary restriction (DR) which includes calorie/caloric restriction (CR) and other form of restricted diets. A reduction in dietary intake without malnutrition robustly extends the lifespan of many species from yeast to rodents. It is the only regimen that extends the lifespan and healthspan in as wide a spectrum of organisms as yeast, nematodes, mice, rats, dogs, and possibly non-human primates [Colman+Al:2009] [Mattison+Al:2012] [Weindruch+Al:1986].
Dietary restriction (DR) can slow down ageing and extend youthful healthy lifespan in evolutionarily very distantly related species from unicellular lifeforms (yeast), to invertebrates (flies, spiders, rotifers, nematodes), rodents (mice, rats), dogs, and possibly rabbits and monkeys. Restriction of energy intake extends the lifespan of mice and rats relative to nonobese ad libitum controls up to and including a 50% reduction, which increases lifespan by approximately the same proportion. As a side effect, many age-related diseases (neurodegeneration, metabolic disease, cardiovascular disease and cancer) and other changes are effectively postponed, progression decelerated, or even prevented totally. Although DR does not stop the ageing process, it definitely delays and/or retards the ageing process in many experimental animals [de_Magalhaes+Al:2012].
There are several DR regimens for which some evidence of age-retarding effects exists.
Lifespan extending DR regimens can be quantitative (caloric intake), qualitative (particular nutrients) or temporal (fasting) in their very nature:
Dietary restriction (DR) is a non-genetic intervention that slows down ageing across taxa. DR has clear positive effects on nematodes, flies and inbred mouse strains as well as rats. However results in wild-caught mice, primates and human populations indicate that the genetic background, the age of onset of DR, and the composition of the diet affect the longevity-promoting effect in mammals [Swindell:2012].
DR of total food intake, calorie or caloric restriction (CR), robustly extends lifespan and hence implies that the energy intake is the crucial factor, but intriguingly restricting only particular nutrients, notably some specific amino acids, was also effective in slowing down ageing to an extent comparable to CR, without a reduction in total caloric intake [Grandison+Al:2009]_ [Wu+Al:2013] [Lee+Al:2014]_ [Min+Tatar:2006] [Emran+Al:2014] [Troen+Al:2007]_. This raises the possibility that CR extends lifespan actually by lowering the level of specific nutrients (e.g. amino acids). Alternatively it is also possible that energy intake is not the only way to slow ageing and extend lifespan by dietary modulation. It is therefore logical to assume that diverse DR regimens either control the same effectors modulating ageing or different regimens may modulate different ageing systems. Nevertheless, by comparing different DR regimens which are effective in retarding ageing it will be possible to dissect the common affected processes (drivers) from the less important ones (passengers).
A diet containing a third less calories than usual extends the lifetime of mice and other mammals by up to 40% and drops their body temperature by half a degree or more [Pearson:2006]. A calorie restricted diet lowers IGF1 levels, promotes apoptosis over cell proliferation and slows down tumour progression. Restoring normal ad libitum IGF1 levels in mice under DR abrogates the protective effect of DR in particularly on neoplastic progression [Dunn+Al:1997].
Neither a reduction in fat nor in mineral content altered survival of rats under constant energy intake [Iwasaki+Al:1988b] [Kubo+Al:1987] [Shimokawa+Al:1996]. But, by reducing the total amount or just the amount of a particular nutrient such as carbohydrate (in yeast, worm, fly and rats), proteins (in rats and mice) or amino acids (in yeast, fruit fly, mouse and rats) lifespan was extended [Place+Cruickshank:2010].
60% CR in mice increased lifespan by up to 65% [Weindruch+Al:1986]. CR increased lifespan in species as diverse as fruit flies [Min+Al:2007], guppies [Comfort:1963] and dogs [Lawler+Al:2008]. CR exerts beneficial effects including delayed immune senescence, retardation of cancer development, alteration in gene expression, improved antioxidant protection and enhanced DNA repair [Orentreich+Al:1993]. CR increases insulin sensitivity [Wang+Al:2009] and heart function, and decreases inflammation and muscle wasting of ageing. It also prevents age-related diseases such as cardiovascular diseases [Willcox+Willcox:2014] [Lopez-Lluch+Navas:2016], metabolic disease [Lopez-Lluch+Navas:2016], neurodegeneration [Willcox+Willcox:2014] and cancer [Weindruch:1992] [Willcox+Willcox:2014]. In essence, it is effective against many kind of diseases especially age-related diseases. It may be interesting to identify any age-related physiological change or disease that is not affected by DR. This might give insight into its mechanism of action since the obvious question would be, why are these changes/disease not affected by DR?
CR promotes genomic stability by increasing DNA repair capacity, specifically base excision repair (BER) and completely reverses age-related decline in BER capacity in many tissues (brain, liver, spleen and testes), which is accompanied by a reversal in age-related loss of β-pol protein, mRNA and activity levels. BER capacity, β-pol protein and mRNA were already upregulated in young (4-6 months) [Cabelof+Al:2003].
CR mice have a higher metabolic rate. Therefore, the anti-ageing action of CR is not due to a reduction in metabolic intensity or to a decreased intake of energy per unit of lean body mass, but rather involves a total organism response involving the nervous and/or endocrine system [Masoro+Al:1991]. CR initiated after the age of 6 months (almost completely matured) was as effective as at 6 weeks of age in extending lifespan in rats [Yu+Al:1985]_, indicating that CR slows the growth and development program in adulthood [Masoro+Al:1991].
CR alone is sufficient to extend lifespan. Parasitoid wasps have a simple diet consistent of carbohydrate only. Only dietary dilution showed an effect with highest longevity at 80% sucrose (w/v), while there was no effect on fecundity [Ellers+Al:2011].
Protein restriction extends lifespan in yeast and flies, but it was originally not clear that it does so in rodents aside from as a side effect of CR [Iwasaki+Al:1988a]. 40-85% protein restriction increases maximum lifespan by up to 20% in 16 out of 18 studies in rodents [Trepanowski+Al:2011]_ [Pamplona+Barja:2006] [Leto+Al:1976] [Goodrick:1978] [Stoltzner:1977] [Fernandes+Al:1976] [Barrows+Kokkonen:1975] [Yu+Al:1985]_ [Horakova+Al:1988] [Davis+Al:1983] [Ross+Bras:1975] [Miller+Payne:1968] [Ross:1961].
The type of protein fed to rats has an impact on lifespan. For instance substituting soy protein for casein protein in rat diet increases the mean, median and maximum lifespan while caloric intake was the same [Gilani+Al:2009].
Methionine restriction extends lifespan in flies, mice and rats and a couple of other species, but is not as widely-documented as CR.
Methionine restriction (MR) extended lifespan in flies [Grandison+Al:2009]_ [Troen+Al:2007]_ [Lee+Al:2014]_, mice [Miller+Al:2005] [Sun+Al:2009] and rats [Orentreich+Al:1993] [Richie+Al:1994] [Zimmerman+Al:2003].
Lifespan in Drosophila can be modified by varying the glucose and methionine concentration in a chemically defined diet [Troen+Al:2007]_.
80% MR (0.86 to 0.17%) restriction extended lifespan by 30% in rats. MR abolished growth, although food intake was actually greater on a body weight basis. Increasing the energy intake of MR rats failed to increase their rate of growth, whereas restricting control to food intake of MR rats did not materially reduce growth. Thus, food restriction (i.e. decreased calories) was not a factor in lifespan extension [Orentreich+Al:1993]. Methionine restriction resulted in 42% increase in mean and 44% increase in maximum lifespan in rats [Richie+Al:1994].
Methionine restriction lowered IGF1, thyroxin (T4), insulin (25%) and fasting glucose (50%) [Miller+Al:2005]. MIF (migration inhibition factor) mRNA are increased in young adult mice of long-lived Snell dwarf and Ghr KO mice as well as under CR [Miller+Al:2002]. Methionine restriction also increased mRNA and the protein concentration of MIF [Miller+Al:2005].
Food restriction limited to the first 20 days of life extended median and maximal lifespan. Methionine restriction initiated at 12 months in mice increases mean, median (7% increase), and maximum lifespan. CR mice had increase in phosphorylation of Erk, Jnk2, and p38, as well as a decrease in phosphorylation of Akt, mTOR, and 4Ebp1. Methionine restricted mice did not exhibit a decrease of phosphorylation at mTOR and 4Ebp1 [Sun+Al:2009].
MR downregulates IGF1 and upregulates IGFBP1 [Takenaka+Al:2000]. Methionine supports protein synthesis and has the capacity to maintain IGF production (shared by all essential amino acids), function as a methyl donor (via SAM) and as precursor for taurine, polyamines, glutathione and sulphate. MR protocols have not included cysteine or most other non-essential amino acids [McCarty+Al:2009].
Lowering the content of sulfhydryl-containing amino acids by removing cysteine and restricting the concentration of methionine extend all parameters of survival and maintain blood levels of GSH without a reduction of energy intake [Zimmerman+Al:2003].
Methionine restriction exerts its beneficial effect, e.g. increased adiponectin and triiodothyronine without energy restriction [Malloy+Al:2006]. Although MR may not be associated with energy restriction, if protein synthesis is affected by methionine restriction, the digestion, absorption and metabolic use of dietary energy may be affected. Cysteine supplementation can reverse positive effects mediated by methionine restriction [Elshorbagy+Al:2011].
80% MR in rodents (without CR), like DR, increases maximum longevity and strongly decreases mitochondrial ROS generation and oxidative stress as well as lowers the degree of membrane fatty acid unsaturation in rat liver. Similar 40% MR in rats decreases mitochondrial ROS production and percent free radical leak at complex I during forward (but not during reverse) electron flow in brain and kidney mitochondria. MR induces changes to mitochondria in rat brain and kidney similar to caloric and protein restriction [Caro+Al:2009].
30-40% tryptophan restriction starting from weaning can delay ageing in Long-Evans females rats. The mortality was greater in the juvenile period, but substantially less than normal if fed at late ages [Ooka+Al:1988]. Mice on a tryptophan restricted diet exhibit greater survival and reduced growth [De_Marte+Enesco:1986].
The effect of tryptophan restriction is somewhat unclear in rodents, as it causes very high early mortality, and is again not as widely-documented as CR. Tryptophan restriction is confounded by involuntary CR (as measured by reduced food intake and/or body weight) in all of the cases.
Water restriction implemented similar to the protocol for the original caloric restriction experiment [McCay:1933] extends lifespan of rats (Sprague Dawley Females from Taconic labs) even more than caloric restriction [Clifton:2010]. Usually it assumed that it is detrimental not to have ad libitum water and it would be very healthy to drink a lot of water.
From an evolutionary point of view it makes sense that drought (when water resources are limited) should delay reproduction and ageing.
The lifespan extending effect could be due to "voluntary" caloric restriction, as the lack of water could just be inducing them to eat less.
But caloric restriction might be causing animals also to drink less; CR studies normally do not control for water intake. Replication of lifespan experiments under water restriction is required.
Prolonged fasting started at middle-age extends longevity, lowers visceral fat, reduces cancer incidence and skin lesions, rejuvenates the immune system, and retards bone mineral density loss [Brandhorst+Al:2015]. In rodents intermittent fasting only works as a side-effect of CR (the degree of lifespan extension is exactly what one would expect from the degree of unintentional reduction in energy intake) [Anson+Al:2003].
In yeast caloric restriction is usually applied by reducing the sugar content from 2% (ad libitum) to 0.5% (moderate CR) or even to 0.05% (severe CR). Though there is also extreme CR which is basically starvation in water without any sugar added.
Genetic manipulations in nutrient-signalling pathways mimic the effects of dietary restriction. It seems that caloric restriction requires mitochondrial respiration to increase longevity (chronological ageing), but not always (for replicative ageing) [Kaeberlein+Al:2007] [Dilova+Al:2007] [Chen+Guarente:2007] [Piper:2006] [Longo:2009] [Longo+Al:2012].
In the nematode, dietary restriction can be accomplished via a variety of protocols like reducing bacteria on liquid or solid media in plates. In fact, multiple methods of DR are used in C. elegans, including mutation that reduce pharyngeal pumping (food-intake impaired eat-2), removal of the bacteria food source, dilution of live or dead bacteria, and axenic culture [Mair+Dillin:2008].
Several dietary restriction regimens can extend the lifespan of fruit flies. Different laboratories use different diets and techniques to implement DR. However DR seems to fail in species like medflies and houseflies [Szafranski+Mekhail:2014].
Reducing the food consumption 25-60% without malnutrition extends the lifespan of rodents up to 50% [Weindruch+Al:1986] and delays the onset of age-related maladies [Colman+Al:2009] [Koubova+Guarente:2003]. In mice and rats, DR can extend longevity by up to 50%, delay physiological ageing and postpone or diminish the morbidity of most age-related diseases [Masoro:2005]. DR elicits major metabolic reprogramming towards efficient fuel utilization and the reduction in oxidative damage to macromolecules [Anderson+Weindruch:2012] [Sohal+Weindruch:1996]. DR triggers global reprogramming of mitochondrial protein acetylome [Hebert+Al:2013]. DR has to be applied continuously to produce the effect on maximum lifespan. If rats are refed at least up to 12 months of age, all the effects of DR on extending survival is lost. Therefore DR is acting as some type of metabolic brake.
Mice placed under CR live longer and exhibit resistance to age-associated diseases [Omodei+Fontana:2011] [Trepanowski+Al:2011]_ [Fontana+Al:2010]. These mice also consume most of their food within a few hours, however their peripheral clocks are well synchronized with the suprachiasmatic nucleus (which determines time of day in mammals) [Froy+Miskin:2010]. The synchrony observed in mice under CR could be the source of lifespan extension [Froy+Miskin:2010]. Longevity-conferring diets cause major metabolic changes in normal mice, but not in mice whose growth hormone receptor was knocked out [Westbrook+Al:2014]. Some inbred mouse strains do not live longer on DR. This has been found to be the case for DBA/2 male mice [Hempenstall+Al:2010] and several strains among the ILSXISS recombinant inbred panel.
DR does shorten the lifespan in even more ILSXISS strains than it extends [Liao+Al:2010]. Dietary restriction does not appear to extend the lifespan of wild mice [Harper+Al:2006]. All rodent studies might be biased to the effects of laboratory breeding [Swindell:2012]. However the problem with these studies using the ILSXISS panel of mice is that too few animals (about 8-12) were used to determine lifetime survival in each group. About 50, preferably over a 100 are needed for robust survival statistics in lifespan studies.
Reducing the amount of calories fed to rats nearly increases their mean and maximum lifespan by up to 50%. In rats, DR increases median lifespan by 14-45% in half of all experiments [Swindell:2012]. Severe DR extends lifespan of rats by nearly 50% [Abalan+Al:2010].
Whether DR also prolongs lifespan in primates is questionable. Studies in monkeys and humans indicate health benefits associated with a restricted diet and maybe also an extension of the lifespan.
Initial studies in rhesus monkeys indicate a longer lifespan, due to an overall reduced mortality (Wisconsin study) [Colman+Al:2009]. However this was only true if censorship due to non-age-related diseases was applied to the survival data. Another study conducted by the 'National Institute of Aging' (NIA) did not reveal any average lifespan benefit from a 30% DR in rhesus monkeys. DR improves some test results, but only in monkeys put on the diet when they were old. Still an effect on maximum lifespan remains unknown [Kolata:2012] [Mattison+Al:2012].
The Wisconsin monkeys received a much higher sucrose content in their food than the NIA animals. Wisconsin control animals could eat as much as they like, while the NIA control were given a set amount of food.
When done correctly, DR appears to confer health benefits for humans, such as lowering the risk of heart disease. Moderate CR in humans ameliorates multiple metabolic and hormonal factors that are implicated in the pathogenesis of age-related disease such as type 2 diabetes, cardiovascular diseases, and cancer [Most+Al:2016]. People on DR have hearts that function more like those found in people two decades younger [Stein+Al:2012].
There are three types of evidence that DR works in humans:
First of all, inhabitants of Okinawa (a Japanese island) practice a DR-like lifestyle as part of their culture, and Okinawans enjoy simple lives [Morgan:2003]. Okinawans are the longest-lived [Willcox+Al:2007a] and most disease-free population [Bernstein+Al:2004] on the globe. Okinawa has a high centenarian prevalence [Willcox+Al:2008a]. In fact, Okinawa has the highest prevalence of exceptionally long-lived individuals in the world [Willcox+Al:2006a]. Okinawan centenarians exhibit a high functional status throughout their 90s [Willcox+Al:2007b].
Okinawa centenarians have low plasma lipid peroxide implying protection against oxidative stress. Vitamin E tocopherols is also lower in Okinawa centenarians, but intracellular Beta-tocopherol is higher. Tocopherol:cholesterol and tocopherol:lipid peroxide (LPO) ratios were not different between age groups, although there was a correlation between α-Tocopherol and LPO in septuagenarians but not in centenarians [Suzuki+Al:2010]. Epidemiological analysis on Okinawans found a low-caloric intake and negative energy balance at younger ages, little weight gain with age, life-long low body mass index (BMI), relatively high plasma dehydroepiandrosterone (DHEA) levels at older ages, low-risk for mortality from age-related diseases, and survival patterns consistent with extended mean and maximum lifespan [Willcox+Al:2007a].
Epidemiological evidence indicates that CR might have contributed to an extension of average and maximum lifespan and lowered risk for age-associated chronic diseases [Willcox+Al:2006b]. Okinawa supercentenarians display an exceptionally healthy phenotype where clinically apparent major chronic diseases and disabilities were markedly delayed, with little clinical history of cardiovascular disease and no history of cancer or diabetes [Willcox+Al:2008b].
Whether the remarkable longevity of Okinawans is mainly due to their diet or because of their genetics is still an open question. This could be resolved by studying any Okinawans who migrated to another country and adopted diet of the new country. Such studies have been used to show the effect of diet on morbidity rates in Japanese subjects who emigrated to the USA.
Secondly, the Biosphere 2 crew, who lived in isolation for two years, had a low-caloric diet and experienced many physiological, haematological, hormonal and biochemical (e.g. Insulin, T3 glucose and cholesterol decreased) changes, which resemble those of rodents and monkeys maintained on DR and remained in excellent health and high physical and mental activity. Additional variations in several substances, not hitherto studied in DR animals, like androstenedione, thyroid binding globulin, renin, and transferrin were also observed [Walford+Al:2002].
The problem with this study is that the subject numbers were so low and the experiment had to be terminated when they could not produce sufficient food to support survival.
Thirdly, on-going studies on dietary restricting human volunteers (e.g. Caloric Restriction Society) already showed that it exerts beneficial effects on health and that, in particular, moderate protein restriction evokes similar adaptive responses as in dietary restricted rodents and monkeys [Fontana+Al:2008].
The Comprehensive Assessment of the Long-term Effects of Reducing INtake of Energy (CALERIE) research program is a systematic investigation of dietary restriction in non-obese human individuals [Rochon+Al:2011]. It was found that the dietary restricted humans had lower insulin resistance, lower LDL cholesterol levels, lower body temperature and blood insulin levels as well as less oxidative damage to the DNA [Economist:2006].
CR decreases serum IGF1 (40%), protects against cancer and slows ageing in rodents. While severe CR without malnutrition did not change IGF1 and IGF:IGFBP3 ratio levels in humans, total and free IGF1 were lower in moderately protein-restriction (1.67 to 0.95g/kg body weight per day) [Fontana+Al:2008].
It is not yet know what the optimum of food intake is and which factors are most important to restrict and, as one can easily assume, these vary by species as well as strains and in humans by individuals. For humans, the usual recommended diet for adult males is about 2500 calories/day.
The caloric intake of Okinawans was 1785 kcal/day [Willcox+Al:2007a], which is 15% and 40% less than the average of mainland Japanese (2068 kcal/day) and US (2980 kcal/day), respectively. Biospherians consumed 30% less (from 2500 to 1784 kcal/day) for the first 6 months and then 2000 kcal/day for the remaining 12 months, which was combined with high level of physical activity of 70-80 hour work/week [Walford+Al:1992]. Caloric Restriction Society members eat about 1800 kcal/day, which is 30% less than a typical Western diet [Holloszy+Fontana:2007].
In humans a severely restricted diet can lead to low testosterone levels and problems with maintaining bone density in male individuals [Naik:2012]. A moderately restricted diet is assumed to not reduce the quality of life. Rodents under DR are usually more active on the physical and mental levels even into advanced ages. Volunteering people practising DR report that they experience much higher concentration levels.
It is actually exactly the opposite; eating too much reduces the quality of life, making individuals tired during the daytime period and causing problems sleeping well during the night time. However severe or extreme DR may result in serious deleterious effects.
Dietary restriction is associated with a variety of changes like metabolic, transcriptional and epigenetic reprogramming. Those changes can be used as surrogates for biomarkers of longevity. How dietary restriction interferes with ageing is still unknown but several potential mechanistic explanations exist.
Genome Stability. Mice under dietary restriction accumulate longer telomeres [Biocompare:2013]. Dietary restriction seems to attenuate telomere erosion [Vera+Al:2013].
Hormesis. DR extends median and maximal lifespan. It does it actually by slowing down ageing. Starvation is the most extreme form of malnutrition and when prolonged can seriously damage an organism. However, the DR response has some similarities to starvation and it was proposed that DR (i.e. low nutrient state) utilizes a low level of stress which enhances defences and repair systems. These beneficial effects of a low stress stimulus is conceptualised as “hormesis”.
Genetics. The longevity promoting effect of DR seems to be mediated by specific signalling pathways. Defined genes appear to be essential for the lifespan-extending effect. Genes that mediate the effect of DR on longevity are designated as DR-essential genes. Sequences of DR-essential genes do not vary across species, but rather they appear to be conserved. It is probable that DR-essential genes are likely to change their activity under DR (i.e. become up- or downregulated). Upon DR, Insulin/IGF1/GH axis and TOR signalling are downregulated, while AMPK, sirtuins and FOXOs become upregulated.
Epigenetics. Epigenetic mechanisms have been recognized as major contributors to nutrition-related longevity and control of ageing. Dietary restriction affects DNA methylation and histone modifications via activation of DNA-methyltransferases and histone remodelling which primarily includes histone acetylation and methylation. This in turn reverses certain ageing gene expression changes and ensures the maintenance of the chromatin stability, resulting in delay of ageing and age-related diseases [Li+Al:2011].
Evolution. The most accepted evolutionary explanation of dietary restriction is that in times of famine when nutrients are limited, organisms trigger a specific genetic program to slow down ageing and reproduction in order to survive. A restricted diet might also trigger the higher turnover of molecules, cells and tissues and therefore provoke a light form of rejuvenation.
A variety of dietary regimens have been shown to be effective in interfering with the ageing process in multitude of evolutionary distinct species. How DR interferes with ageing and which kind of regimens work well in human is not yet certain. As DR works in almost all species (but not all strains/individuals) tested so far, it would be really surprising if it did not work at all in humans. It is therefore hoped that research on DR will reveal which factors in the diet are crucial for a healthy lifestyle. By making policy-makers aware of it, they could identify and define healthier diets. Further, understanding the actual mechanism underlying DR’s anti-ageing effect could lead to the identification of supplements or even development of pharmacological products mimicking the effect of DR without severely restricting one’s diet (i.e. DR-mimetics).
Research on dietary restriction might enable the identification of genes and molecules that mimic the effect of dietary restriction without the necessity to restrict the diet. Dietary restriction mimetics are genetic interventions or components (i.e. pharmacological interventions) that mimic the biochemical or functional effects of dietary restriction [Madeo+Al:2014]. The aim of research on dietary restriction is not enabling of living longer, but being in a young and youthful state. Staying youthful and healthy longer is definitely not a wrong aim. Generally, a low-caloric, nutrient-dense, diversified diet low in fat and proteins (preferential mainly plant-derived) and without any extra added sugar is beneficial. However, for interfering with the ageing process with a greater extent powerful anti-ageing drugs are needed.
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