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Ageing is a the accumulation of changes in an organism over time, where many functions of the body begin to become less productive. Calorie restriction is a theory where by reducing calorie intake increases longevity by slowing down many processes that cause organisms to age (7). In this review we will discuss the theory of Calorie restriction through the examination of four independent studies that explore different hypothesises of how calorie restriction leads to a longer life span, so that in the future it may help to increase longevity in humans and prevent the onset of age-related diseases. One of the studies major hypotheses in aging is that calorie restriction increases longevity by simply slowing metabolism and reducing oxygen radicals and accompanying cellular damage throughout the body. The second study found that calorie restriction increases the growth hormone which increases insulin sensitivity and therefore reduce the onset of age-related disease such as type 2 diabetes. The third study then further explains the effects of calorie restriction reducing insulin resistance increases the cognitive function which usually decreases with age. Finally, the fourth study examines the effects of gene mutations and how they mimic the effects of calorie restriction to increase longevity.
Calorie restriction (CR) is a dietary regimen that restricts calorie intake (7). CR is the only experimental manipulation that has shown that a reduction in calorie intake of 20-40% might slow aging, reduce age-related chronic diseases (for example amnesia, diabetes, cancer and cardiovascular disorders) and extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates, but it is not yet known if this fully extends to humans (1). The mechanisms through which this occurs have been unclear and have thought to be a number of possibilities. CR induces metabolic changes,lowers glucose levels, improves insulin sensitivity, alters neuroendocrine function in animals, immunological response and increases levels of protective hormones and reduces mitochondrial damage and oxidative stress. These all have various effects on the function and aging of components of the body and age-related disorders. Ihumans, it is clear that chronic high calorie intake
over time is a risk factor in cardiovascular disease, many types of cancers, type-2 diabetes and stroke.
focus of this review will be on four different hypothesises that have been investigated to try and understand the process of aging and how to slow it down. One of them investigated the effects of CR on mitochondria increasing the efficiency energy production so that less oxidative stress occurs via reactive oxygen species. It also investigated how CR causes proliferation of mitochondria so that energy production remains efficient without increasing respiration rate. The second study investigated how CR reduces insulin resistance and increases the production of Growth hormones and how this increases longevity. The third study investigated how CR can increase cognitive function by reducing insulin resistance and reducing low-grade inflammatory responses. Finally the fourth study investigated how gene mutations can mimic the effects of CR in increasing longevity and if CR can still increase longevity in these organisms.
Calorie restriction and metabolism
One of the major hypotheses in aging is that calorie restriction increases longevity by simply slowing metabolism, and reducing oxygen radicals and accompanying cellular damage throughout the body (8). Oxygen radicals are highly reactive chemical species that carry an unpaired electron, which can damage surrounding macromolecules, lipids, proteins and DNA(8). Energy metabolism in aerobic organisms is connected to reactive oxygen species (ROS). In eukaryotes, the major loci of this damage is the mitochondrion which generates ROS which generate toxic by-products during normal respiration (4). These factors which decrease lifespan, increases susceptibility to age-related functional decline and disease. Studies have demonstrated that CR decreases mitochondria electron flow and proton leaks to reduce damage caused by ROS resulting from oxidative stress.
The study concerning mitochondrial biogenesis and bioenergetic efficiency (4) proposed that CR can reduce oxidative stress within mitochondria through improving energy production through a balanced respiration maintaining lower oxygen consumption associated with low ROS production. This was done by using an in vitromodel of CR and using various assays to determine whether mitochondrial mass and function are increased in human and rat cells. study showed a clear decrease of ROS production compared to normally fed AL cells.The mitochondrial membrane potential is the central area of energy flow controlling the generation of ROS(4). Invivoand invitrodata has showed that CR decreased membrane potential in mitochondria which was shown to be caused by decreased mitochondrial respiration and also increased proton leakage. CR was shown to produce very efficient electron transport through the respiratory chain therefore lowering oxygen consumption and ROS production(4). This change in mitochondrial efficiency could reduce molecular and cellular damage resulting from oxidative stress and thus reduce the rate of aging at a cellular level (4). CR was able to lower respiration and increase proton leakage at the same time which produced a lower oxygen consumption and a decrease in membrane potential therefore reducing ROS.
The study also looked at the hypothesis that at the same time CR can stimulate proliferation of mitochondria through a peroxisome proliferation-activated receptor coactivator 1α signalling pathway to increase respiratory efficiency. (4). CR supports efficient respiration by increasing the number of low potential mitochondria per cell without any change in the respiration rate. Larger amounts of low-potential mitochondria would maintain respiratory chain activity and still be capable of handling reduced oxygen consumption while maintaining ATP synthesis but with a lower ROS production.
This study showed that CR does slow metabolism and ROS production and causes proliferation of mitochondria which will lead to less cell and DNA damage and therefore slow down aging.
Insulin and growth factors effects on aging
research indicates that changes in insulin and glucose metabolism are key indicators of ageing. somatrophic axis which consists of the pituitary-derived growth hormone (GH) and insulin-like growth factor-1 (IGF-1) undergoes progressive changes with age (3). Starting in young adulthood, GH and IGF-1 begin to decline exponentially, but, in many individuals circulating insulin levels might increase as they age. This occurs because the tissues that respond to insulin to lower the blood sugar levels become resistant to its action, leading to an increase in blood glucose and over stimulation of pancreatic beta cells, which produce more insulin in an attempt to maintain blood sugar at a normal level. Chronic stimulation of pancreatic beta-cells in these individuals will ultimately lead to these cells failing and, therefore, to diabetes. In nematodes, an insulin-like signalling pathway is believed to be involved in lifespan regulation, and down regulating this pathway leads to a great increases in longevity. Declining GH concentrations also correlate with weight-gain, dyslipidemia and sarcopenia at a later age (3). Studies have shown that reduced IGF-1 is mostly due to decreased GH secretion and that the age related decline of GH secretion correlates with increased abdominal visceral fat.
The study concerning the effect of caloric restriction interventions on growth hormone in non-obese men and women (3) hypothesised that like in rodents, CR can increase GH and therefore decrease abdominal visceral fat and increase Insulin leading to a decrease in age related diseases. The aim of the study was to evaluate for the first time changes in GH secretory dynamics after 6 months of CR in non-obese humans.
The study found that GH was increased over the six months with people undertaking the CR diet compared to people not on the CR diet. This increase in GH correlated with an increase in insulin sensitivity.
In a similar study investigated using rodents, increased concentrations of IGF-1 through CR has been associated with anti-carcinogenic benefits. Furthermore, genetic mutants of GH and GH-resistance display a delayed aging phenotype and an extended lifespan compared to normal mice. These genetically modified mice that suffer defects in the production of GH or IGF-1 express significantly lower levels of circulating IGF-1 and have decreased onset of age-related cancers. is known to alter the expression numerous hormones, stimulate the sympathetic nervous , and promote vasoconstriction, all of which could potentially longevity (3). In the study it was also found that the amount of visceral fat had an effect on longevity. People that undertook the CR diet and lost weight was found to have an increase in insulin. Physiologic mechanisms for improvement may include decreases in circulating fatty concentrations, intramyocellular triacylglycerol and secreted cytokines from adipocytes (3). molecular mechanisms involved in the relation between and insulin sensitivity, may include he ectopic fat hypothesis, which shows that subjects without fat severe insulin resistance(3).
This study quite convincingly showed that CR increases GH and therefore insulin sensitivity which was proven to be very effective in decreasing age-related disease and increasing longevity.
Calorie restriction and cognitive function
Studies have shown that CR is beneficial to cognitive function as we age (5). In animal models of aging and neurogenerative disease, CR protected hippocampal, striatal, and cortical neurons, and decreased functional decline. Metabolic factors like insulin-resistance and low-grade inflammation is believed to contribute to age-related cognitive impairments. Although improved insulin signalling in the brain has been suggested to have neuroprotective effects, increased peripheral circulating insulin may promote the development of cognitive impairments which CR helps reduce.
This study was done to see if CR improves memory in elderly humans (5) and rodents in which they assessed peripheral blood levels for insulin, glucose, markers of inflammation and neurotrophic levels in peripheral blood all of which are believed to increase cognitive function and which CR is hypothesised to have an effect on. CR has been shown to increase memory performance in rats and as a first was studied in humans to see if CR improves memory in the elderly. of insulin, insulin receptors, and insulin-regulated pathways in the brain are involved in glutamate and GABA-mediated synaptic plasticity and in gene expressions which are required for long-term memory recolection (5). In the hippocampus, insulin has been shown to induce NMDA receptor phosphorylation, and to increase channel activities of NMDA receptors, which play an important role in learning and memory formation (5). Thus, it has been shown that insulin signalling promotes neuroprotective and neuromodulatory effects in the brain. Neuronal function may also be enhanced via neurotrophic factors, which was shown to be activated by CR via adaptive cellular stress response pathways. Neurotrophic factors, such as IGF-1 and BDNF, are widely known to be involved in neuronal growth and neurogenesis and might also protect mature neurons from degeneration (5). IGF-1 is also a ligand for insulin receptors, thus activating insulin pathways in the brain. Both IGF-1 and BDNF-levels have been suggested to be enhanced after CR in rodents. CR has been shown to exert anti-inflammatory effects, including down-regulation of hs-CRP levels in rodents and TNF in humans(5).
This study shows that CR does improve memory in the elderly through decreasing insulin resistance which protects many neurons and induce receptors involved in memory. The study also showed that CR increased anti-inflammatory effects which reduced low-grade inflammation which increases memory loss.
Gene mutation mimics Calorie restriction effects on ageing
In many organisms it is found that certain gene mutations increase longevity. These gene mutations have been found to mimic the effects of CR in yeast and insects. Although some of these genes seem to increase in activity due to CR. In the study, Long-lived Indy and calorie restriction interact to extend lifespan (2) investigated to see whether the Drosophila gene Indy (for I'm not dead yet) can be further activated to increase longevity by CR. They found thatthat Indy induce an altered state of CR-like phenotypes, including changes in starvation , lipid storage, physical activity, and life span. We that decreasing Indy a calorie restriction-like that confers life span extension. This study did find that the drosophila that had the mutant Indy gene did not increase in activity when undergoing a CR diet, but increased when undergoing a normal or high calorie diet. However in previous studies has found that the SIRT1 gene only found in mammals which mimics the effects of CR was activated by CR through increasing insulin sensitivity. Another study, targeted disruption if growth hormone receptor interferes with the beneficial actions of calorie restriction (1), investigated whether growth hormone receptor knockout (GHRKO) mice which are mutant mice had a longer life expectancy then normal mice. GHRKO mice do not express the GH receptor, when compared to the normal mice on the CR diet they showedextremely low levels of IGF-I in peripheral circulation, reduced postnatal growth, delayed puberty, diminished body size, reduced plasma insulin and glucose, and enhanced sensitivity to injected insulin (2). CR was also tested on the GHRKO mice and found to have no effect at increasing longevity. The failure of CR to increase average life span of GHRKO mice or maximal life span of GHRKO males was associated with its failure to further increase insulin sensitivity in these animals. Previous studies that some of the mutations that extend life act through mechanisms similar and perhaps identical to those that are responsible for the effects of CR.
These studies showed that there are many gene mutations that act to mimic the CR-phenotype by activating the same pathways that CR does.
The review has discussed how calorie restriction can increase longevity through interacting with several pathways that have proven to slow down aging. The first study showed that calorie restriction slowed down metabolism and reduced oxygen radicals and the cellular damage throughout the body. The second study found that calorie restriction increases the growth hormone which increases insulin sensitivity and therefore reduce the onset of age-related disease such as type 2 diabetes. The third study then further explains the effects of calorie restriction reducing insulin resistance increases the cognitive function which usually decreases with age. Finally, the fourth study showed that there are gene mutations that act to mimic the CR-phenotype by activating the same pathways that CR does proving that CR does have an obvious effect on aging.
From these studies we are able to understand more of the effects that CR has on the body and on aging. Although we do not yet fully understand the pathways through which CR is able to reduce these effects on aging we are coming closer to the answer. These studies are very significant in furthering the fundamental basis of aging. Through fully understanding the process and relationship between calorie restriction and longevity we may one day be able to increase longevity to its full extent in not only yeasts and insects but also humans and even possibly lead to a pharmaceutical tablet that mimics the CR-phenotype in increasing longevity.