Caloric restriction mimetic
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.
- 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:
- Exanadin (exenatide), a glucagon-like peptide-1 (GLP-1)modulator
- Olbetam (Acipimox)
- Peroxisome proliferator-activated receptor gamma inhibitors, such as Rosiglitazone and Gugulipids
- Agents that modulate sirtuins (called STAC –sirtuin-activating compounds), for example, fisetin
- 4-Phenylbutyrate (PBA)
- Gymnemoside (modulates glucose absorption)
- Adiponectin (together with leptin, it regulates adipose tissue metabolism. It is activated by PPAR inhibitors such as rosiglitazone)
- Dipeptidyl peptidase 4 (DPP-4) inhibitors
- Modulators of neuropeptide Y (NPY)
- Mannoheptulose (glycolytic inhibitor)
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