Calorie restriction mimetics (CRM), also known as energy restriction mimetics, are a hypothetical class of dietary supplements or drug candidates that would, in principle, mimic the substantial anti-aging effects that calorie restriction (CR) has on many laboratory animals and humans. CR is defined as a reduction in calorie intake of 20% (mild CR) to 50% (severe CR) without incurring malnutrition or a reduction in essential nutrients. [1] 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 . [2] A number of genes and pathways have been shown to be involved with 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. [1] [3] [4]
Candidate compounds include:
Other candidate CRM are:
Life extension is the concept of extending the human lifespan, either modestly through improvements in medicine or dramatically by increasing the maximum lifespan beyond its generally-settled biological limit of around 125 years. Several researchers in the area, along with "life extensionists", "immortalists", or "longevists", postulate that future breakthroughs in tissue rejuvenation, stem cells, regenerative medicine, molecular repair, gene therapy, pharmaceuticals, and organ replacement will eventually enable humans to have indefinite lifespans through complete rejuvenation to a healthy youthful condition (agerasia). The ethical ramifications, if life extension becomes a possibility, are debated by bioethicists.
Maximum life span is a measure of the maximum amount of time one or more members of a population have been observed to survive between birth and death. The term can also denote an estimate of the maximum amount of time that a member of a given species could survive between birth and death, provided circumstances that are optimal to that member's longevity.
Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.
Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of Type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome, and is sometimes used as an off-label adjunct to lessen the risk of metabolic syndrome in people who take antipsychotic medication. It has been shown to inhibit inflammation, and is not associated with weight gain. Metformin is taken by mouth.
A low-protein diet is a diet in which people decrease their intake of protein. A low-protein diet is used as a therapy for inherited metabolic disorders, such as phenylketonuria and homocystinuria, and can also be used to treat kidney or liver disease. Low protein consumption appears to reduce the risk of bone breakage, presumably through changes in calcium homeostasis. Consequently, there is no uniform definition of what constitutes low-protein, because the amount and composition of protein for an individual with phenylketonuria would differ substantially from one with homocystinuria or tyrosinemia.
The DAF-2 gene encodes for the insulin-like growth factor 1 (IGF-1) receptor in the worm Caenorhabditis elegans. DAF-2 is part of the first metabolic pathway discovered to regulate the rate of aging. DAF-2 is also known to regulate reproductive development, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and resistance to bacterial pathogens. Mutations in DAF-2 and also Age-1 have been shown by Cynthia Kenyon to double the lifespan of the worms. In a 2007 episode of WNYC’s Radiolab, Kenyon called DAF-2 "the grim reaper gene.”
Acarbose (INN) is an anti-diabetic drug used to treat diabetes mellitus type 2 and, in some countries, prediabetes. It is a generic sold in Europe and China as Glucobay, in North America as Precose, and in Canada as Prandase.
Calorie restriction is a dietary regimen that reduces the energy intake from foods and beverages without incurring malnutrition. The possible effect of calorie restriction on body weight management, longevity, and aging-associated diseases has been an active area of research.
The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.
A branched-chain amino acid (BCAA) is an amino acid having an aliphatic side-chain with a branch. Among the proteinogenic amino acids, there are three BCAAs: leucine, isoleucine, and valine. Non-proteinogenic BCAAs include 2-aminoisobutyric acid and alloisoleucine.
The CRON-diet is a nutrient-rich, reduced calorie diet developed by Roy Walford, Lisa Walford, and Brian M. Delaney. The CRON-diet involves calorie restriction in the hope that the practice will improve health and retard aging, while still attempting to provide the recommended daily amounts of various nutrients. Other names include CR-diet, Longevity diet, and Anti-Aging Plan. The Walfords and Delaney, among others, founded the CR Society International to promote the CRON-diet.
Leonard Pershing Guarente is an American biologist best known for his research on life span extension in the budding yeast Saccharomyces cerevisiae, roundworms, and mice. He is a Novartis Professor of Biology at the Massachusetts Institute of Technology.
Michael Ristow is a German medical researcher who has published influential articles on biochemical aspects of mitochondrial metabolism and particularly the possibly health-promoting role of reactive oxygen species in diseases like type 2 diabetes, obesity and cancer, as well as general aging due to a process called mitohormesis.
Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.
SRT-1720 is an experimental drug that was studied by Sirtris Pharmaceuticals intended as a small-molecule activator of the sirtuin subtype SIRT1. The compound has been studied in animals, but safety and efficacy in humans have not been established.
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
mTOR Complex 2 (mTORC2) is an acutely rapamycin-insensitive protein complex formed by serine/threonine kinase mTOR that regulates cell proliferation and survival, cell migration and cytoskeletal remodeling. The complex itself is rather large, consisting of seven protein subunits. The catalytic mTOR subunit, DEP domain containing mTOR-interacting protein (DEPTOR), mammalian lethal with sec-13 protein 8, and TTI1/TEL2 complex are shared by both mTORC2 and mTORC1. Rapamycin-insensitive companion of mTOR (RICTOR), mammalian stress-activated protein kinase interacting protein 1 (mSIN1), and protein observed with rictor 1 and 2 (Protor1/2) can only be found in mTORC2. Rictor has been shown to be the scaffold protein for substrate binding to mTORC2.
Genetics of aging is generally concerned with life extension associated with genetic alterations, rather than with accelerated aging diseases leading to reduction in lifespan.
Superoxide dismutase (SOD) mimetics are synthetic compounds that mimic the native superoxide dismutase enzyme. SOD mimetics effectively convert the superoxide anion, a reactive oxygen species, into hydrogen peroxide, which is further converted into water by catalase. Reactive oxygen species are natural byproducts of cellular respiration and cause oxidative stress and cell damage, which has been linked to causing cancers, neurodegeneration, age-related declines in health, and inflammatory diseases. SOD mimetics are a prime interest in therapeutic treatment of oxidative stress because of their smaller size, longer half-life, and similarity in function to the native enzyme.
Rafael de Cabo is a Spanish scientist and Branch Chief of the Translational Gerontology Branch at the National Institute on Aging, a division of the U.S. National Institutes of Health. His research on calorie restriction in rhesus macaques suggested that calorie restriction in monkeys have no significant effects on their lifespan. In 2011, his research on obese mice suggested that resveratrol mimetic helps extend longevity and his research on male mice suggested that metformin have a longevity effect.
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