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- Caloric_restriction_mimetic abstract "Calorie restriction mimetics (CRM) are a hypothetical class of drugs that would in principle mimic the substantial anti-aging effects that calorie restriction (CR) has on many laboratory animals. In other words, an effective CRM would alter the key metabolic pathways involved in the effects of CR itself, leading to preserved youthful health and longer lifespan without the need to reduce food intake. The term was coined by Lane, Ingram, Roth of the National Institute on Aging in a seminal 1998 paper in the Journal of Anti-Aging Medicine, the forerunner of Rejuvenation Research. A number of genes and pathways have been shown to be involved the actions of CR in model organisms and these represent attractive targets for drug discovery and for developing CRM. However, no effective CRM have been identified to date.Candidate compounds include:Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants, including grapes, wines, and especially the roots of the Japanese Knotweed, from which it is extracted commercially. Resveratrol was proposed to be a CRM based on a series of early reports which found that it increased the lifespan of yeasts, the worm Caenorhabditis elegans, and fruit flies. Scientists involved in these studies went on to found Sirtris Pharmaceuticals, a company working to develop resveratrol analogs as proprietary drugs. This led many companies to produce and market resveratrol dietary supplements. However, studies by independent scientists have failed to replicate these results Moreover, in every experiment to date, resveratrol at several doses has failed to extend the lifespan of lean, genetically normal mice or rats.The antidiabetic drug metformin was proposed as a possible CRM after it was found that mice administered the drug exhibit similar gene expression changes as CR mice. It is already clinically approved to treat diabetes, and has been used for this indication for the past 40 years. It enhances the sensitivity of insulin receptors on the surface of muscle and fat cells and activates genes that reduce the production of glucose by the liver, thus reducing the risk of non-enzymatic glycation and other age-related damage; these effects are also seen in CR. Subsequently, metformin was reported to extend the lifespan of short-lived or genetically cancer-prone mouse strains. However, two studies in rats and mice with normal genetics and longevity have found no effect of metformin on maximum lifespan, and only a very small effect on median lifespan.Oxaloacetate is a metabolic intermediate of the citric acid cycle. In the short-lived roundworm Caenorhabditis elegans, supplementation with oxoacetate increases the ratio of oxidized to reduced nicotinamide adenine dinucleotide (NAD+:NADH) to activate AMPK and FOXO signaling pathways similar to what occurs in calorie restriction. The increase in the NAD+/NADH ratio is due to the reaction of oxaloacetate to malate in the cytoplasm via the enzyme malate dehydrogenase. In mitochondria that have been isolated out of cells and tested in oxaloacetate-enriched medium, this increase can be quite dramatic. Decreases in the NAD+/NADH ratio has been proposed carbohydrate metabolism-controlled cellular senescence mechanism.Because of its parallel effects on these pathways, oxaloacetate was proposed as a CR mimetic. In the short-lived roundworm Caenorhabditis elegans, supplementing the medium with oxaloacetate does increase average life expectancy; it was unclear whether it had an effect on maximum lifespan. However, when tested by two independent groups of scientists across four university laboratories, oxaloacetate supplements had no effect on lifespan in healthy laboratory mice. Rimonabant (Acomplia) is an anti-obesity drug approved for use in the European Union but rejected approval by the FDA. This is an endocannabinoid-1 receptor blocker. Endocannabinoids are cannabis-like chemicals that stimulate appetite and also regulate energy balance. Overstimulation of the endoannabinoid receptor in the hypothalamus promotes appetite and stimulates lipogenesis. It also blocks the beneficial actions of adiponectin. Rimonabant inhibits these and so it reduces appetite, balances energy, and increases adiponectin, which reduces intra-abdominal fat. It improves lipid profile, glucose tolerance, and waist measurement. Therefore, it has similar effects as CR.Lipoic Acid (α-Lipoic Acid, Alpha Lipoic Acid, or ALA) has failed to extend lifespan in normal mice or rats in numerous studies, either alone or as part of combination therapy.2-deoxy-D-glucose, or 2DG. 2-Deoxyglucose was the first agent pursued as a possible CRM. This compound inhibits glycolysis, and can mimic some of the physiological effects of CR, in particular increased insulin sensitivity, reduced glucose levels, reduced body temperature, and other biochemical changes. It was reported to extend the lives of C. elegans worms; however, studies in different strains of rats found that 2DG did not extend lifespan at several tested doses, and exhibited toxic effects "Histopathological analysis of the hearts revealed increasing vacuolarization of cardiac myocytes with dose, and tissue staining revealed the vacuoles were free of both glycogen and lipid."It has been suggested that rapamycin, a drug that inhibits the mechanistic Target Of Rapamycin (mTOR) pathway, might be a CR mimetic. based on the responsiveness of mTORC1 activity to nutrient availability; the fact that mTOR activity is inhibited by CR; the fact that genetically inhibiting mTOR signaling extends maximum lifespan in invertebrate animals, and pharmacologically inhibiting mTOR with rapamycin extends maximum lifespan in both invertebrates and mice. While knocking out elements of the mTOR cascade seems to block the lifespan effects of rapamycin in invertebrate animals, surprisingly the effects of CR and rapamycin on metabolism and gene expression exhibit substantial differences in mice, with evidence suggesting that the mechanisms of the two anti-aging therapies may be in large part distinct and possibly additive.Other candidate CRM are: Peroxisome proliferator-activated receptor gamma inhibitors, such as Rosiglitazone and Gugulipids, working as insulin sensitizers, making fat cells more repsonsive to insuline by binding to the their PPAR receptors Agents that modulate sirtuins (called STAC –sirtuin-activating compounds), for example, fisetin Exanadin (exenatide), a glucagon-like peptide-1 (GLP-1)modulator, extracted from the salvia of the Gila monster belongs to the group of incretin mimetics, facilitating glucose control. Adiponectin (together with leptin, it regulates adipose tissue metabolism. It is activated by PPAR inhibitors such as rosiglitazone) Acipimox Hydroxycitrate Dipeptidyl peptidase 4 (DPP-4) inhibitors Iodoacetate Mannoheptulose (glycolytic inhibitor) Modulators of neuropeptide Y (NPY) 4-Phenylbutyrate (PBA) Gymnemoside (modulates glucose absorption)↑ 1.0 1.1 1.2 ↑ ↑ 3.0 3.1 3.2 3.3 3.4 ↑ ↑ ↑ ↑ ↑ 8.0 8.1 ↑ 9.0 9.1 ↑ ↑ ↑ ↑ ↑ ↑ 15.0 15.1 15.2 ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ 24.0 24.1 24.2 24.3 ↑ ↑ 26.0 26.1 26.2 ↑ ↑ ↑ 29.0 29.1 ↑ 30.0 30.1".
- Caloric_restriction_mimetic wikiPageExternalLink 114-calorie-restriction-mimetics.
- Caloric_restriction_mimetic wikiPageExternalLink cr-mimetics.html.
- Caloric_restriction_mimetic wikiPageID "680590".
- Caloric_restriction_mimetic wikiPageLength "21263".
- Caloric_restriction_mimetic wikiPageOutDegree "52".
- Caloric_restriction_mimetic wikiPageRevisionID "682889284".
- Caloric_restriction_mimetic wikiPageWikiLink 2-Deoxy-D-glucose.
- Caloric_restriction_mimetic wikiPageWikiLink 2-deoxy-D-glucose.
- Caloric_restriction_mimetic wikiPageWikiLink AMPK.
- Caloric_restriction_mimetic wikiPageWikiLink Acipimox.
- Caloric_restriction_mimetic wikiPageWikiLink Adiponectin.
- Caloric_restriction_mimetic wikiPageWikiLink Caenorhabditis_elegans.
- Caloric_restriction_mimetic wikiPageWikiLink Calorie_restriction.
- Caloric_restriction_mimetic wikiPageWikiLink Category:Biogerontology.
- Caloric_restriction_mimetic wikiPageWikiLink Citric_acid_cycle.
- Caloric_restriction_mimetic wikiPageWikiLink Diabetes.
- Caloric_restriction_mimetic wikiPageWikiLink Diabetes_mellitus.
- Caloric_restriction_mimetic wikiPageWikiLink Dipeptidyl_peptidase-4.
- Caloric_restriction_mimetic wikiPageWikiLink Dipeptidyl_peptidase_4.
- Caloric_restriction_mimetic wikiPageWikiLink Drosophila.
- Caloric_restriction_mimetic wikiPageWikiLink Exenatide.
- Caloric_restriction_mimetic wikiPageWikiLink FOXO.
- Caloric_restriction_mimetic wikiPageWikiLink FOX_proteins.
- Caloric_restriction_mimetic wikiPageWikiLink Fallopia_japonica.
- Caloric_restriction_mimetic wikiPageWikiLink Fisetin.
- Caloric_restriction_mimetic wikiPageWikiLink Gila_monster.
- Caloric_restriction_mimetic wikiPageWikiLink Glucagon-like_peptide-1.
- Caloric_restriction_mimetic wikiPageWikiLink Glycation.
- Caloric_restriction_mimetic wikiPageWikiLink Glycolysis.
- Caloric_restriction_mimetic wikiPageWikiLink Hydroxycitrate.
- Caloric_restriction_mimetic wikiPageWikiLink Hydroxycitric_acid.
- Caloric_restriction_mimetic wikiPageWikiLink Iodoacetate.
- Caloric_restriction_mimetic wikiPageWikiLink Iodoacetic_acid.
- Caloric_restriction_mimetic wikiPageWikiLink Japanese_knotweed.
- Caloric_restriction_mimetic wikiPageWikiLink Leptin.
- Caloric_restriction_mimetic wikiPageWikiLink Life_expectancy.
- Caloric_restriction_mimetic wikiPageWikiLink Lipoic_Acid.
- Caloric_restriction_mimetic wikiPageWikiLink Lipoic_acid.
- Caloric_restriction_mimetic wikiPageWikiLink MTORC1.
- Caloric_restriction_mimetic wikiPageWikiLink Malate_dehydrogenase.
- Caloric_restriction_mimetic wikiPageWikiLink Mammalian_target_of_rapamycin.
- Caloric_restriction_mimetic wikiPageWikiLink Mannoheptulose.
- Caloric_restriction_mimetic wikiPageWikiLink Marios_Kyriazis.
- Caloric_restriction_mimetic wikiPageWikiLink Maximum_life_span.
- Caloric_restriction_mimetic wikiPageWikiLink Maximum_lifespan.
- Caloric_restriction_mimetic wikiPageWikiLink Mechanistic_target_of_rapamycin.
- Caloric_restriction_mimetic wikiPageWikiLink Metformin.
- Caloric_restriction_mimetic wikiPageWikiLink Mitochondria.
- Caloric_restriction_mimetic wikiPageWikiLink Mitochondrion.
- Caloric_restriction_mimetic wikiPageWikiLink National_Institute_on_Aging.
- Caloric_restriction_mimetic wikiPageWikiLink Natural_phenol.
- Caloric_restriction_mimetic wikiPageWikiLink Neuropeptide_Y.
- Caloric_restriction_mimetic wikiPageWikiLink Nicotinamide_adenine_dinucleotide.
- Caloric_restriction_mimetic wikiPageWikiLink Oxaloacetate.
- Caloric_restriction_mimetic wikiPageWikiLink Oxaloacetic_acid.
- Caloric_restriction_mimetic wikiPageWikiLink Peroxisome_proliferator-activated_receptor_gamma.
- Caloric_restriction_mimetic wikiPageWikiLink Phenols.
- Caloric_restriction_mimetic wikiPageWikiLink Phytoalexin.
- Caloric_restriction_mimetic wikiPageWikiLink Rapamycin.
- Caloric_restriction_mimetic wikiPageWikiLink Rejuvenation_Research.
- Caloric_restriction_mimetic wikiPageWikiLink Resveratrol.
- Caloric_restriction_mimetic wikiPageWikiLink Rimonabant.
- Caloric_restriction_mimetic wikiPageWikiLink Rosiglitazone.
- Caloric_restriction_mimetic wikiPageWikiLink Sirolimus.
- Caloric_restriction_mimetic wikiPageWikiLink Sirtris_Pharmaceuticals.
- Caloric_restriction_mimetic wikiPageWikiLink Sirtuin.
- Caloric_restriction_mimetic wikiPageWikiLink Sirtuin-activating_compound.
- Caloric_restriction_mimetic wikiPageWikiLink Stilbenoid.
- Caloric_restriction_mimetic wikiPageWikiLink Yeast.
- Caloric_restriction_mimetic wikiPageWikiLinkText "Caloric restriction mimetic".
- Caloric_restriction_mimetic wikiPageWikiLinkText "caloric restriction mimetic".
- Caloric_restriction_mimetic wikiPageWikiLinkText "calorie restriction mimetic".
- Caloric_restriction_mimetic hasPhotoCollection Caloric_restriction_mimetic.
- Caloric_restriction_mimetic wikiPageUsesTemplate Template:Citation_needed.
- Caloric_restriction_mimetic subject Category:Biogerontology.
- Caloric_restriction_mimetic hypernym Class.
- Caloric_restriction_mimetic type Article.
- Caloric_restriction_mimetic type Article.
- Caloric_restriction_mimetic type Specialty.
- Caloric_restriction_mimetic comment "Calorie restriction mimetics (CRM) are a hypothetical class of drugs that would in principle mimic the substantial anti-aging effects that calorie restriction (CR) has on many laboratory animals. In other words, an effective CRM would alter the key metabolic pathways involved in the effects of CR itself, leading to preserved youthful health and longer lifespan without the need to reduce food intake.".
- Caloric_restriction_mimetic label "Caloric restriction mimetic".
- Caloric_restriction_mimetic sameAs m.032dcg.
- Caloric_restriction_mimetic sameAs Q5023660.
- Caloric_restriction_mimetic sameAs Q5023660.
- Caloric_restriction_mimetic wasDerivedFrom Caloric_restriction_mimetic?oldid=682889284.
- Caloric_restriction_mimetic isPrimaryTopicOf Caloric_restriction_mimetic.