Further, the expression of adipokines from adipose tissue is regulated by nutrients, which is exaggerated with aging. The adipose tissue derived hormone, adiponectin is another metabolic regulator, and as opposed to other fat-derived cytokines that oppose insulin action, adiponectin is an insulin sensitizer with anti-inflammatory properties and a potent activator of AMP-activated protein kinase AMPK.
The studies have linked MetS and obesity to tendency for cognitive functional decline. These patients are more likely to have small infarcts and develop vascular dementia as occurs in hypertensive patients. The IR-associated hyperglycemia per se produces cognitive dysfunction and the cognitive decline improves when glucose is lowered.
Skeletal muscle loss or sarcopenia is a major contributor to the frailty syndrome of aging and leads to reduced mobility and increased disability. It represents an unfavorable phenotypic change associated with aging and linked to a reduction in energy expenditure and IR. The causes of sarcopenia are multifactorial, but the proinflammatory state associated with aging and obesity is a major contributor.
IR leads to the decline in muscle quantity and quality and is linked to reduced skeletal muscle strength, reduced protein synthesis rates, and accelerated skeletal muscle loss. Thus, IR is both a cause and consequence of sarcopenia, leading to a vicious cycle of skeletal muscle loss and metabolic dysfunction.
The energy needs of individuals are determined by their body composition, especially the fat free lean mass and level of physical activity. Therefore, older adults have lower requirements for energy which may contribute to a reduction in appetite.
This, though, varies between individuals reflecting differences in their body composition and levels of physical activity. Further, there is a change in nutritional needs during the middle age and later, when no actual growth is taking place, though there is an increased need of nutrients to take care of increased wear and tear with age, but overall calorie requirements are less because of a sedentary nature of activity of daily living ADL.
The diet-gene interaction is a major determinant of health and illness [8]. The amount and type of food ingestion and caloric intake influence the general health and life span [9]. The extra calorie intake due to availability of palatable food and increased consumption causes overnutrition and nutritional overload [10], giving rise to excess stores in adipose tissue reservoirs culminating as weight gain and obesity, which lead to insulin resistance IR , metabolic syndrome MetS , type 2 diabetes mellitus T2DM and other metabolic alterations.
The calorie restriction, or caloric restriction, or energy restriction, is a dietary intervention that should reduce calorie intake without incurring malnutrition or a reduction in essential nutrients [11]. An optimal food intake and calorie restriction with adequate nutrition CRAN promotes health, metabolic homeostasis, disease protection and long life, in general.
The focus of positive lifestyle changes is often on a healthy diet and adequate exercise to minimize the risk of diseases like diabetes, hypertension and cardiovascular disease especially during the middle age and older years. The modality, CR is like going a step further. Several metabolic and genetic pathways have been identified that govern food ingestion, metabolism, and life span [12]. Various studies in yeast, fruit fly, nematodes like C elegans, rodent models and primates including Homo sapiens endose that a diet adequately fulfilling nutritional needs, but low in calories may improve health and extend the life span [13].
Experimentally, the food restriction has been shown to achieve increased lifespan in a broad spectrum of life forms from yeast [14] to primates [15].
The early nutritional studies in rodents indicated that the number of calories in the diet was the key factor, thus the term calorie restriction [16]. At the physiological level, the effects of CR are very well characterized, beginning with an acute phase upon imposition of the diet followed by an adaptive period of several weeks to reach a stable, altered physiological state [17].
A lower body temperature, lower blood glucose and insulin levels, and reduced body fat and weight characterize this altered state. The CR animals also appear to be more resistant to external stressors, including heat and oxidative stress [18]. Evolutionarily, CR may represent adaptation to food scarcity. Any organism that could slow aging and reproduction in times of scarcity and remain able to reproduce when food reappeared would enjoy an advantage [19]. In lower organisms, this strategy may lead to building of specialized body forms for survival, for example spores in microbes and dauer larvae in C Elegans [20].
The animals have reduced energy stores, i. About the change in metabolic rate, the initial studies reported a reduction in metabolic rate in CR animals. This finding fits well with the theory that oxidative damage from reactive oxygen species ROS is reduced, and a reduction in metabolic rate would decrease ROS production during electron transport and respiration. However, other studies found that the metabolic rate, when normalized to the lean body mass of the animals, did not decrease during CR [21].
In the studies, the CR animals enjoyed a higher metabolic activity adjusted for body weight over their lifetimes than did the ad libitum controls [22]. In budding yeast, as well as the nematode C Elegans, CR has been shown to actually result in an increase in respiration [23,24]. One of the most striking features of CR is that it appears to forestall or prevent many late-onset disorders and diseases.
For example, CR extends life span in certain lab strains of mice which normally would die of cancer. CR also extends life span in Fischer rats, which normally die of kidney disease. Further, CR has been shown efficacious in mouse models of a variety of diseases [27,28].
It is important to understand that the benefits of CR are not a passive result of lower caloric intake but the consequence of an active regulatory intervention mimicking the food scarcity activating certain genetic and metabolic programs that result in beneficial vital effects. Various genetic and molecular studies in model organisms, in fact, suggest that CR is a regulated process, in which the SIRT Silent Information Regulator 2 gene plays an important role.
The SIR2 gene was first identified and so-named because it mediates gene silencing in yeast [29]. The findings suggest that the SIR2 ortholog, Sirt1 in mammals may mediate a broad array of physiological effects that occur in animals on a CR diet. The elevated activity of SIRT1 orthologs has been shown to extend life span in yeast Saccharomyces cerevisiae , nematodes Caenorhabditis elegans and fruit flies Drosophila melanogaster. The regulation of SIRT1 activity by CR is complex, being tissue-specific as well as region-specific in nonhomogeneous tissues, such as the brain [30].
The activity of the sirtuin in the liver is reduced by CR and correlates with the reduced fat synthesis and is activated by a high-caloric diet. The SIRT1, thus figures prominently in the redistribution of resources during CR from growth, metabolism and reproduction to maintenance and survival.
The related genes in S Cerevisiae, C Elegans and D Melanogaster called sirtuins, encode NAD-dependent deacetylases and appear to promote longevity in the organisms [31]. In the mammals there are at least seven sirtuins SIRT , each sirtuin influencing diverse aspects of the metabolism and characterized by differences in subcellular localization, substrate preference, and biological function. In the study models ranging from yeast to mice, sirtuins have also been associated with the salutary effects of CR.
The mammalian Sir2 ortholog SIRT1 targets numerous regulatory factors affecting stress effects to metabolism [32]. The levels of SIRT1 increase in rodent and human tissues in response to CR leading to favorable changes in metabolism and stress tolerance [33]. The SIRT1 promotes oxidation of fatty acids in liver and skeletal muscle, cholesterol metabolism in liver, and lipid mobilization in white adipose tissue [34]. Sirt1 may also regulate CR by sensing low calories and triggering physiological changes linked to health and longevity [35].
Further, the small-molecule activators of SIRT1 have been shown to protect mice from the negative effects of a high-fat diet. CR lowers the core body temperature: An adaptive response to reduce energy expenditure when nutrients availability is curtailed. Lowering the temperature may prolong the lifespan of cold-blooded animals. Mice, which are warm blooded, have been genetically modified to have a reduced core body temperature which increases the lifespan independently of calorie restriction.
Hormesis: The CR is a low-intensity biological stressor. The CR diet imposes a low-intensity biological stress on the organism to elicit a defensive response that help to protect from disorders of aging. The CR places the organism in a defensive state to survive in adverse life situations, resulting in improved health and longer life through activation of longevity genes. Elegans, the CR extends life span primarily by increasing oxidative stress to stimulate the organism into having an increased resistance to further oxidative stress.
Hormonal alterations: Prolonged severe CR lowers total serum and free testosterone while increasing sex hormone binding globulin concentrations in humans. Calorie restriction has been shown to increases DHEA in primates, but not in post-pubescent primates. These effects are independent of adiposity. Lowering of the concentration of insulin and insulin-like growth factor 1 and growth hormone, has been shown to up-regulate autophagy, the repair mechanism of the cell.
The CR works by decreasing insulin levels and up-regulating autophagy. The free radicals may induce an endogenous response culminating in effective adaptations to protect against exogenous radicals. The sublethal mitochondrial stress with ROS may initiate beneficial alterations in cellular physiology produced by CR.
The CR is related to chromatin function. Elegans, the gene PHA-4 is responsible for the increased life span. These results are linked to reduced oxidative DNA damage.
Sirtuins: Sir2 has been implicated in the aging of S. Sir2 homologs have been identified in a wide range of organisms from bacteria to humans. Although all three genes are required for the silencing of mating type loci and telomeres, only SIR2 has been implicated in the silencing of rDNA. In addition, SIR2 related genes also regulate formation of some specialized survival forms, such as spores in S.
A study done by Kaeberlein et al. CR in S cerevisiae and C elegans: The classic experiments, diluting the energy source in growth media, namely glucose, extended the replicative life span of yeast mother cells [39]. The major genetic determinant of replicative life span in yeast is SIR2 and its increased activity extended it [40].
The evolutionary studies highlight that S. The phylogenetically conserved enzymatic activity of the SIR2 and its homologs is determined by NAD-dependent protein deacetylases [41]. The studies show that the mammalian Sirt1 enzyme deacetylates many histone and nonhistone substrates, and NAD is cleaved to produce nicotinamide NA and acetyl- ADP-ribose each reaction cycle [42].
The studies suggest that Sir2 senses the metabolic state of cells and sets the life span accordingly [43]. Further, the SIR2-related genes regulate formation of the specialized survival forms in lower organisms, spores in yeast [44] and dauer larvae in C elegans [45].
Further, an activator of the Sir2 enzyme, resveratrol, has been shown to extends yeast replicative life span [48]. Resveratrol requires the SIR2 gene for this longevity effect. But resveratrol and CR did not synergize to further extend the life span, suggesting that CR and resveratrol act through the same pathway. Resveratrol is a plant-derived polyphenol that appears to activate SIRT1 apart from having antioxidant, anti-inflammatory, and antitumorigenic properties.
Through activation of SIRT1, resveratrol may function as a CR mimetic and resveratrol treatment has been shown to increase life span in several organisms, including, high-fat-fed mice, in which it improved insulin sensitivity, mitochondrial function, and survival.
More recently, treatment of obese mice with SRT, a synthetic activator of SIRT1, resulted in similar improvements in survival as were observed in resveratroltreated mice. The mechanism by which CR activates the Sir2 enzyme is not fully understood, though a molecular pathway could be traced from caloric intake.
The CR triggers a more efficient use of glucose via an increase in respiration, analogous to a known metabolic shift that occurs in mammals during CR, in whom there is a transition in muscle cells from using glucose towards the use of fatty acids.
This metabolic shift spares glucose for the brain and correlates with the characteristic enhancement of insulin sensitivity in muscle and liver. But, this model for activation of Sir2p by CR in yeast, however, is not established. Consistent with this model, deleting PNC1 reduced or eliminated the ability of CR to extend life span [49].
To validate this, NA levels are in fact altered in CR cells. In another study, it was reported that CR is independent of SIR2 in a different, unrelated strain of yeast [51]. This finding endorses that there are than one pathway that mediate CR in yeast.
These observations suggest the role of SIR2 as mediator of CR for life span, which has been conserved in metazoans. The SIR2 activator, resveratrol also extends the life span in Drosophila [53] but does not further extend the longer life span of CR flies, indicating that Sir2 works in the same pathway as CR [54].
The CR does not extend the life span of Sir2 mutant flies. But, the longlived dwarf mice, with missing the growth hormone-IGF-1 axis and other pituitary hormones due to mutation in the pit-1 gene, shows further extension in their life span on a low-calorie diet [56]. Thus, the effect of CR in mammals is more complex than C.
Elegans and Drosophila, involving various organs and physiological axes. Thus, the metabolic pathways do not stand alone, but are interconnected and merge at various levels.
In mammals, the CR appears to affect metabolism and studies suggest that it may be advantageous to increase metabolism during CR, at least in some tissues to promote a longer lifespan in mammals. Upregulation of mitochondrial uncoupling proteins: The mice are suitable models for mammalian studies concerning effect of CR and metabolic and genetic alterations on lifespan. These mice eat more than weight-matched wild-type mice yet have a lower body weight, indicating that they have a higher than normal metabolic rate.
Further, these mice live longer than controls [57]. These mice also live longer than controls [58]. Another study in mice showed a positive correlation between oxygen consumption, i. In this study, the variation in metabolism was due to differences in the degree to which electron transport was coupled to ATP synthesis in mitochondria. The longer-lived mice had mitochondria that were more uncoupled. Also, the CR mice have more uncoupled mitochondria than controls, perhaps due to upregulation of mitochondrial uncoupling proteins by CR.
CR reduces the size of animals, likely creating a higher surface area and potentially greater heat loss, and thus the lower body temperature. The CR mice may increase uncoupling proteins in metabolic tissues, muscle, liver, and brown adipose tissue. It appears that the extra electron transport dissipated by uncoupling may activate a regulatory pathway to extend life span.
Because of proton leakage down the gradient, uncoupled mice would avoid hyperpolarization of the mitochondrial membrane and partially uncoupled electron transport may generate a lower level of ROS. CR and stress resistance: CR is known to increase the resistance to oxidative stress [60], which leads to longer life span by a greater ability to detoxify ROS and repair oxidative damage, and slow down cellular decay [61]. The genetic regulators of mammalian life span can also increase resistance to stress.
Absence of the protein p66 shc causes an increase in stress resistance and the KO mice and cells from KO mice are more resistant to oxidative stress, and the p66 KO mice live longer than wild-type. Experimentally, in vitro, the CR serum triggers a higher level of the mammalian SIR2 ortholog, Sirt1, in the fibroblasts, which is partially reversed by adding IGF-1 and insulin to the serum. Further, the connection between Sirt1 and stress resistance appears to be extensive.
The Sirt1 is an NAD-dependent deacetylase and appears to target many proteins that are not histones and an important one, p53, which is shown to be deacetylated and downregulated by Sirt1 [62].
Thus, Sirt1 negatively regulates p dependent apoptosis in response to cellular damage [63]. Another family of regulators targeted by Sirt1 are Foxo or forkhead proteins, which, like p53, can respond to stress and trigger apoptosis. The Sirt1 was shown to deacetylate and downregulate Foxo1, 3, and 4 and thus repress Foxo-mediated apoptosis [64].
Sirt1 also deacetylates and downregulates the Foxo coactivator p In addition, Sirt1 deacetylates the DNA repair protein Ku70, allowing it to bind to and inactivate the proapoptotic factor Bax [65]. Thus, Sirt1 appears to target numerous cellular factors, thereby resulting in a higher threshold for apoptosis [66]. CR and fat regulation: There are increasing evidence that mammalian aging is regulated in part by adiposity [67].
The WAT stores fat as triglycerides when food is abundant. When food is scarce, as in CR animals, cells shed their fat from adipose tissue. The WAT can sense nutritional status and sends appropriate signals to coordinate aging in all organs, and in addition, WAT is an endocrine organ and secretes hormones such as leptin and adiponectin [68].
The WAT also mediates many age-associated metabolic disorders such as T2DM and dyslipidemia which can negatively affect the lifespan [69]. The Sirt1, thus, regulates WAT by repressing p It exerts effects on hormones, including growth factors, which override cell-autonomous effects on apoptosis.
Such changes may permit or even mandate raising the threshold for apoptosis in hormone-responsive cells. The combined effect of changes in hormones and a higher threshold for apoptosis in responsive cells is an advantage for the survival. Chronic high food intake triggers an increase in blood glucose.
Insulin signals WAT to store fat as triglycerides. The triglycerides store influences the levels of hormones produced by the WAT cells, primarily increase in leptin and a decrease in adiponectin [70]. These hormonal changes influence the insulin sensitivity of metabolic organs. Adiponectin increases sensitivity to insulin in metabolic organs and its decrease exacerbates insulin resistance and rise in blood glucose [71]. This vicious cycle initiated by adiposity and culminating as T2DM Figure 4 , is antagonized by CR by lowering blood glucose and insulin, reducing fat stores, increasing adiponectin and improving insulin sensitivity.
Visceral fat increases with age and its increase induces inflammation. Inflammation accelerates process of aging. The CR causes the lipolysis of triglycerides in WAT and the release of free fatty acids, which are taken up and oxidized by metabolic organs.
Does a cell ever reach a state of equilibrium? The chemical reactions of metabolism are reversible, and they, too, would reach equilibrium if they occurred in the isolation of a test tube. Because systems at equilibrium are at a minimum of G and can do no work, a cell that has reached metabolic equilibrium is dead. A cell in our body is not in equilibrium. Why do cells need equilibrium? The existence of an electrochemical equilibrium in a cell is very important.
This strictly controlled osmolarity allows the cell to absorb just enough water from its surroundings for ideal cellular function, but not a tad bit more.
Ions are also used to perform useful functions for the cell. What is the relationship between the concept of free energy and metabolism? Free energy and metabolism. The breaking down of food particles we consume and derive energy from is called metabolism. It covers various processes that use nutrients in food to release Gibbs free energy, which is stored during the formation of ATP from ADP.
What do you mean by enzymes? Enzyme: Proteins that speeds up the rate of a chemical reaction in a living organism. An enzyme acts as catalyst for specific chemical reactions, converting a specific set of reactants called substrates into specific products. Without enzymes, life as we know it would not exist. What is the most random form of energy? Whenever energy is converted from one form into another, some of it is given off as heat, which is the most random form of energy.
Indeed, the only energy conversion that is percent efficient is conversion to heat, or burning. What happens when cells reach equilibrium? When the concentration of the solute is the same throughout a system, the system has reached equilibrium. If the substance can cross the cell membrane, its particles will tend to move toward the area where it is less concentrated until equilibrium is reached.
What do you mean by free energy? In physics and physical chemistry, free energy refers to the amount of internal energy of a thermodynamic system that is available to perform work. Helmholtz free energy is energy that may be converted into work at constant temperature and volume. How do cells get energy? Cells need a source of energy, they get this energy by breaking down food molecules to release, the stored chemical energy.
This process is called 'cellular respiration'. The process is happens in all the cells in our body. Oxygen is used to oxidize food, main oxidized food is sugar glucose.
What is another word for metabolism? Synonyms: metabolic process, transfiguration, metabolism, metamorphosis. What are the 3 metabolic types?
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