Theories Of Longevity And Calorific Restriction Biology Essay

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There are lots of theories gathered / collected / accumulated that have tried to explain the ageing of humans. Specific research is being especially carried out into the percentage of elderly population that has increased over the years, the amount of national expenditure / GDP used / spent on the elderly population, and together with the fact the average human lifespan is increasing / lengthening and these areas have caused interest for further research to be undertaken in the field in order to find out more about ageing and any break-throughs that can help improve the medical technology (Weinert et al., 2003). The physiologist Max Ruber developed the theory about 'the rate of living theory' in 1908 where he said the relationship of metabolic rate; body size and overall longevity are all interlinked (Brys, K. et al., 2007). But / yet / however / on the other hand the actual biological and cellular mechanisms are not known as to how they regulate ageing. The early theories of ageing were thought to be linked to a single gene or because of a defect / deficiency in the bodily functions that s how ageing may have arised / arisen but is now thought that ageing has occurred due to complex multi factorial processes that can be affected by both genetics and environmental factors (Weinert et al., 2003).

Theories of longevity (? what is longevity?)

Calorific Restriction

A study by Clive McCay et al., had featured in 1935 edition in journal of nutrition where they stated / found that a Calorific Restriction / Restricted diet / intake / lifestyle on rodents had increased their lifespan (Koubova, 2003) considerably by up to 50%. It can be said that CR can extend lifespan / ageing of rodents but the levels / amounts of rich vitamins and minerals must be maintained / kept constant in order for them to obtain / have high energy levels for a healthy lifespan (Sohal, R. S. et al., 1996). Furthermore / also / additionally it was noticed the CR diet delayed severe chronic diseases in the rodents and they were functioning well in memory related exercises. This research was also discovered to have increased the lifespan of yeasts, rotifers, worms, fish and spiders in 1996.

In the McCay study, he had hypothesised that the initial process behind the effects of longevity in the rodents was due to the fact the reduced availability of enriched calorific food postponed / stop the mating and food reproduction till better conditions were presented to the rodents. Therefore, the study showed that the rodent's body used the energy into physical maintenance and this resulted in a longer lifespan. This study / research was also supported by another study's results that showed that those rodents who were given a high enriched calorific diet reproduced at an earlier rate and had a reduced lifespan in comparison to the calorie restricted rodents. Although it was thought that the initial part of the hypothesis was correct with regards to the delayed / postponed maturation of the reproduction and sexual encounters and was thought that this may have been the mechanism by which the calorific restriction diet increased longevity. However this theory was later disproved as it was found that calorie restriction diet that was started in older animals had increased their lifespan but to the same extent / amount / level / degree. In a research study by Fontana et al., in 2007, he stated that rodents who initially reduced their calorie intake by 30% to 60% below the usual ad libitum intake early in life (shortly after the weaning to 6 months stage) caused a 30% to 60% proportionate increase in their maximum life span but there was also seen a 44% reduced calorie intake started in adulthood (about 12 months) extended / increased their lifespan by only 10% to 20%. It was also noted in these experiments that the rodents had been subjected to calorific restriction diets maintained / sustained / retained their immune function and their youthful appearance for a long phase / period of time and also performed well in memory related exercises. Also it was found from the experiments that the rodents who were on the calorie restriction diet were also more resistant to carcinogens and had less / reduced oxidative damage occurring as fewer free radicals were present.

Generally through researches it is seen that CR effects lifespan and longevity and improves the health of the animals; however / but the mechanism by which the CR improves lifespan and longevity is not yet known and is unclear and numerous scientific communities have speculated many theories about the mechanism.

Where some studies involved human test subjects with CR diets / intakes showed that the subjects had / were able to maintain good health. There have been some cases that have shown that CR has been able to lower some ageing biomarkers such as cholesterol, blood pressure (diastolic and systolic) and fasting glucose levels in obese subjects. {- sentence confusing??? -. If these are biomarkers may be they are linked with the reduction of diseases related to ageing such as type 2 diabetes. - Sentence confusing??? -}. This theory / thought / idea is thought to be a factual / truthful / accurate / realistic conclusion, and ethical issues stop further testing to be carried out on non-obese subjects and therefore the theory's claim is still un-validated / proved. The reason / one of the reasons why this has not happened is due to the fact CR diet has negative side effects e.g. / for example when a person undertaking CR diet may become severely underweight and malnourished e.g. 1. If correct vitamins and nutrients are not given / maintained (fat soluble vitamins will be required in order to maintain the body mass - healthy body mass), e.g. 2. And need to be given correct vitamins and minerals in order to support the dietary requirements.

Other negative side effects linked to CR diet are that possible muscle degeneration (atrophy can occur due to the usage of valuable (beneficial) accumulation (mass) and hypoglycaemia (shortage of glucose in the blood) in turn leads to neuroglycopenia (shortage of glucose in the brain)). Cellular observations and symptoms linked to eating disorders can be leucopoenia (reduction of number of white blood cells in the blood), lymphocytopenia (decrease in the number of lymphocytes in the blood), impaired cell-mediate immunity, hypotension, amenorrhea (the absence or stopping of the menstrual periods) and infertility (Fontana et al., 2007). Anorexia Nervosa is a medical condition that occurs due to severe calorie restriction diet being carried out in people with psychological problems that makes them detest food and gives them the illusion that their weight is obese in comparison to their actual weight / health. CR diet can also affect sexual desire, by reducing it, which was also found in the animal models. These attributes commonly put off individuals taking the CR diet.

Studies on rodents and other animals have showed that CR diet effects longevity by reducing the total number of calorie intake (total number of calories derived from carbohydrates, fats or proteins to a level that is 25-65% under the ad libitum). Control animals without disrupting / controversially affecting the host to suffer from malnutrient (Fontana et al., 2007). Another observation seen from these rodent studies were a reduce in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease and it is thought that may be in the future with further research in the field a perfected calorie restricted diet regime can be used in humans in order to reduce the chances of these neurodegenerative diseases commencing / starting / initiating / appearing. Another observation found in the calorific restriction studies is that the rodent's brain's plasticity and ability for self-repair had improved giving greater potential for learning and memory competence / capability and again this could be particularly useful for humans (Koubova et al., 2003).

The small Japanese Islands of Okinawa are a good example of naturally controlled CR diet studies in human subjects that still maintain weights. Their typical diet consists of soy, seaweed and fish which are food full of rich nutrients that are also contain low calories in comparison to meat and poultry but can still be consumed with combination foods in minute amounts. And this is all representable / represented / found in CR diet. This CR diet has 20% reduced calories in comparison to the average mainland Japanese person's typical diet and there are significantly more calories in the western countries like UK and America. It is also known that the Okinawa Islands grow 3 times more green and yellow vegetables in comparison to their Japanese mainland counterparts. It was also found that the Okinawa Islands have higher percentages of healthier people living over one hundred years of age than anywhere else on the planet. These observations are also similar to the ones found / seen in rodent models. It was also noted that the number of heart attacks in the Okinawa populations is also minor, about 80% less than the number of cases found in America.

In the United Kingdom it has the highest death related incidents due to heart failure / disease and this observation questions the life style of people living in Britain in comparison to those living in other countries around the world. Other major diseases that cause high mortality rates in numerous countries are breast and prostate cancer but in Okinawa Islands there are less cases due to breast and prostate cancer and the levels of incidence of obesity is also very low and rare / uncommon / unusual / atypical. Some other studies have shown that the Okinawas have little weight gain with age due to their reduced calorific diet intake and thus causes lower mortality rates from age related pathologies.

From the studies it was also found / noted that the people of Okinawa islands had the highest levels of Dehydroepiandrosterone (DHEA) which is a steroid that can produce a wide range of biological effects in mammas. In humans DHEAS secretion reduces with age but in the older Okinawas population it was found that they had large amounts of DHEAS. It is thought a reason for this can be that diet can increase the amounts of sulphate ester which is a steroid precursor of dehydroepiandrosterone and it is thought that this can produce memory enhancement / improvement and anti-ageing (lots of theories if this is the case then can be extremely useful (Enomoto et al., 2008)). These findings can explain to some extent why Okinawa people have prolonged average and maximum life span. Another study showed that when Okinawa people have a foreign country's like lifestyle they had decreased longevity in comparison to those Okinawa people who still have a CR lifestyle and this demonstrates that Okinawa Island lifestyle is beneficial for an increase longevity and good health. A research carried out on CR dieted monkeys showed they had DHEA present and other observations found were, decreased body temperature and reduced insulin concentration and these observations were thought to have improved their longevity / lifespan. The Okinawa population have naturally been adapted to their CR diet and therefore they have been able to maintain rich intakes of vitamins and minerals. In 1988 Broomley stated that 'experimental studies about longevity on animals and survey of treatment effects in humans show that environmental factors such as nutritional, drugs, radiation and toxic substances, temperature and stresses can effect longevity and functional capacity'. And the observations made from Okinawa population have shown that lifestyle plays an important part in increasing life longevity / lifespan.

Other observations that were found in CR animal models are high levels / amounts of protein synthetic rates, elevated / increased sensitivity to hormone stimulates in particular / especially insulin and improved maintenance of mitochondrial energy production. Mitochondrial energy production is vital as stated by souhami et al., 2002 'defective mitochondria are central to the process of ageing' (Souhami et al., 2002).

The Theories behind Calorific Restriction

The rate of living theory is thought due to / to be linked to ageing that has been caused by the cumulative / accumulation / build up of oxidative damage that has arisen / occurred from reactive oxygen species (ROS) which have been formed / produced / created / synthesised during the respiration process (as a result of respiration) (Harman, 1988). During normal respiration process free radicals are produced and these precipitate / cause / encourage / induce / trigger off oxidative damage of / to DNA, RNA, proteins and lipids. Souhani, 2002 states that mitochondria are the main intracellular source of free radicals (as respiration process occurs in the mitochondria) and with increasing age the more free radicals are produced / generated while at the same time anti-oxidant production declines. This suggests that defective mitochondria are central to the process of ageing'' (Souhani, 2002). Other studies have linked these mitochondrial findings to be the interconnection between ageing and oxidative damage (Stadtman, 1992 and Harman, 1988). The rate of living theory can evaluate (measure) the reliability (integrity) of the molecular processes and may be able to explain how calorific restriction intake / diet can reduce the rate of metabolism and therefore the ROS species, which eventually promotes / increases / encourages longevity. Research studies involving / including / incorporating fruit fly animal models that are able to produce an enzyme superoxide dismutase which can break down free radicals and therefore increase / lengthen the overall lifespan by as much as a third (Parkes et al., 1998). It is thought that the ageing process occurs due to the oxidative damage of protein and DNA and joined / together / tied with inadequate / insufficient DNA repair as well as / in addition to / also genetic instability of mitochondrial and nuclear genomes. The calorific restriction diet aims to / intends to / tries to reduce these 3 cellular processes that cause ageing. Also other cellular / bodily / systemic processes associated with ageing is chronic inflammation where / which causes increased production of adipokine and cytokine with relation to alteration in fatty acid metabolism and excessive release of free fatty acids into the plasma and which in turn genetics tissue insulin resistance and this is thought to be linked to ageing process. Other cellular processes that are also thought to have an effect on ageing is the build up / accumulation of advance glycation end product (AGE) which when accumulated / built-up with other proteins causes problems for / interferes with the normal cellular functions and sympathetic nervous system and angiotensin system activation and this is why it is thought that it plays a part in cellular ageing and it is seen that calorific restriction diet can improve these problems (Fontana, L. et al., 2007).

There are several factors that affect life span such as incidence of disease and disability, absence of pathology and persistence of function and due to many research studies, it has been shown that experimentally it is possible to prolong / lengthen / extend functional plasticity and life span.

In this mini review several theories have been briefly identified / discussed and of which some have been talked about / discussed in detail at molecular, cellular and systemic levels / stages. The theories discussed in detail were evolutionary, gene regulation, cellular senescence, free radical and neuro-endocrineimmuno theories.

Another effect concerning the theories:

Calorific restricted / restriction diet is also beneficial in lowering visceral fat from the body which is directly linked to insulin sensitivity. Through research it is found when surgically removing visceral adipose tissues the peripheral and hepatic insulin sensitivity is restored to an adequate / a sufficient / a satisfactory degree. The benefits / advantages of this are that concentrations of insulin and insulin related substances are lowered / reduced from the body for example / e.g. 'insulin-like growth factor 1' (IGF-1) has up-regulated / or able to generate the self-repair mechanisms of cells (Koubova et al., 2003) stated by Koubova research but this connection has not yet been established and it does not go against / contradict / counteract other factors.

Reduced Metabolic Rate: -

Another hypothesis that is linked to longevity is the overall reduction in / of the metabolic rate which in turn reduces the production of free radical (s) species. This theory supports the fact that calorie restricted / restriction diet (can) lowers / (lower) / reduces / (reduce) intracellular oxidative damage of cells and tissues and therefore prolongs / increases / lengthens the overall lifespan. The principal importance of oxidation process and metabolism rate is that they play an important role in cellular ageing as free radicals cause increased damage to mitochondrial and nuclear DNA, enzymes and structural proteins in the body.

It is known that mitochondria are the main source of producing intracellular free radicals as a result of the respiration process therefore it can be said that with increasing age the amount of free radical produced also increases as they are proportionally linked / associated / connected. Therefore the elevated concentrations of free radicals in the body further damage the mitochondria and decrease the amount of antioxidant production / synthesis. Hence the calorific restriction diet decreases / lowers the free radical species in the body and this in turn allows the mitochondria to function / work properly / successfully / efficiently / effectively for longer periods of time and thus / in so doing / by this means / in this manner increases the lifespan of the target organism (Souhami et al., 2002).

On the other hand / but due to the nature / characteristic / temperament of the calorific restricted diet the target organism can experience weight loss and tissue mass loss and this therefore reduces the metabolic rate. However there are draw backs to the CR diet as seen / known / talked before that loss of weight and tissue mass reduction can occur and in turn resulting in lowering of metabolic rate. On the whole / in general / generally / largely overall it still can be said that 'decreased production of reactive oxygen species (ROS) and modulation of the endogenous antioxidant systems, which decrease the oxidative stress and free radical - induced tissue damage' (Fontana et al., 2007) still supports that this increases the longevity of an organism consequently / as a result /thus the effects of the calorific restriction diet on a physical and intracellular levels / level help / helps the body and thus results in increasing the longevity of the target organism.

Lack of protein turnover: -

Another possible cause of ageing is the lack of protein turnover as the oxidatively damaged proteins accumulate and the protein turnover reduces resulting in ageing. The calorific restriction diet / intake can help prevent / stop ageing from protein turnover as the host body runs out of fat to break down for energy, protein degradation is triggered / activated / prompted / switched on and therefore resulting in increased protein turnover rate. Nevertheless / however these studies show / indicate / point out that the protein turnover does increase with calorific restriction in take / diet but not all damaged proteins were broken down / degraded and still continued to accumulated / build-up. In general / overall the research studies do show / indicate that protein turnover does increase with a calorific restricted diet but the actual effect / alteration on the rate of ageing has not yet been convincingly / finally determined (Koubova et al., 2003).

Particular gene which has been discovered that has been linked to longevity

There has been a particular gene which is / has been discovered to be (the) (link) / linked / connected / (connection) to longevity and it is called / it is known as the Silent Information Regulator 2 (SIR2) gene as its function / purpose is to suppress / inhibit / restrain / control DNA instability and therefore it is known as the longevity gene. The SIR2 gene suppresses / controls instable DNA by silencing / stopping chromatin by using the histone deacetylation process which is found / situated on the targeted region's (including DNA) of the yeast's genome. The silenced chromatin can not be structurally accessed / available / reachable / reached by the RNA polymerases and recombinant enzyme which results in reducing / lowering the gene expression and in turn stabilising the repeated DNA (Koubova et al., 2003).

There have been mutations found in the SIR2 gene which has resulted in the shortening of the yeast overall lifespan where as / although / at the same time over - expression of the SIR2 gene results in extending the yeast's lifespan (Koubova et al., 2003). The SIR2 gene was first determined / found / discovered in yeast cells and the mammal version of this gene was later found / discovered / established and is known as the SIRT1 gene and it is this particular gene that is thought to help / assist / support increase longevity in accordance / concurrence with the calorific restriction diet / method / in take.

Picard in his study in 2004 stated that 'in yeast, the SIR2 gene mediates the life-extending effects of calorie restriction. Here we show that the mammalian SIR2 orthologue, SIRT1 (Sirtuin 1), activates a critical component of calorie restriction in mammals; that is, fat mobilization in white adipocytes. Upon food withdrawal SIRT1 protein binds to represses genes controlled by the fat regulator PPAR-gamma (Peroxisome Proliferator-Activated Receptor-Gamma), including genes mediating fat storage' (Picard et al., 2004). Picard stated in his study in 2004 that the gene that can lengthen lifespan in yeast due to being in a calorific restricted environment / undertaking a calorific restriction diet is the SIR2 gene and in mammals the alternative gene is called the mammalian SIR2 orthologue SIRT1 (Sirtuin 1) and when this gene is activated / triggered / stimulated / initiated / set on by the effects of having a calorie restricted intake diet then fat mobilization occurs in white adipocytes. The cellular mechanism is that food intake is restricted and the SIRT1 protein binds to and suppresses / inhibits / represses the genes controlled by the fat regulator PPAR - gamma and the genes that mediate (bring about) fat storage. Evidence through studies has shown that SIR2 enzyme in the yeast cells increase the life span by 30% due to being stimulated by the effects of calorie restriction. In mammals the SIRT1 gene that is equivalent to the gene in yeast is shown to be activated due to calorific restriction and this helps to protect the cells in the body from decay (and stress) due to stress.

One of the factors that shows that with a calorific restriction diet cells of the body are protected as reduced / decreased signals by Insulin and IGF-1 which result in activation of forkhead transcription factors and this causes the cells to be resistant to stress more. The increase in stress is found in all organisms and species that have undertaken a calorific restriction diet (Koubova et al., 2003) - ??? Relates to previous text.

On the whole, from the various research studies carried out, it has been found that under taking a calorific restriction diet the target organism's various bodily processes is effected and thus affects the ageing process of the specific organism. It was also found that a mammal's life span can be increased if a calorie restricted diet was followed and this is a multifactorial event which has many consequences on the cell biology of the endocrine system and metabolism (Koubova et al., 2003).

It was also found that calorie restriction diet intake helps the body to improve its ability to repair DNA and remove damaged proteins and lipids within the cells. Calorie restriction also helps reduce the quantities of glycated proteins and formation of advanced glycation end (AGE) products and collagen cross-linking. Calorific restriction helps / promotes / its advantage is that it can: lower body weight and adiposity (fat cells), lowering of core body temperature and resting energy expenditure, reduction in T3 concentration, delaying immune senescence and improving risk factors for cardio-metabolic diseases (Fontana et al., 2007).


In conclusion, it can be stated that how calorific restriction helps increase longevity in humans is still yet not fully known or understood. Further research studies still need to be carried out in the subject area in order to understand the prospects / hope of longevity, nevertheless the current tests and observations found since McCay's original research findings have encouraged a promising scientific prospective future.