CR mimetics


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Emuladores de la restricción calórica.

Los emuladores de la restricción calórica (CRM- por sus siglas en inglés) tratan de emular los efectos principales que la restricción calórica tiene en animales de laboratorio. En otras palabras, la administración de un CRM resulta en los mismos cambios fisiológicos que produce una restricción calórica. Un modo en el que los CRM trabajan es influenciando genes específicos que afectan la muerte y reparación de las células.

Candidate compounds include:

  • Resveratrol is found in red wine and grapes. Many supplement companies market inexpensive concentrates. Resveratrol is a polyphenol plant chemical with proven beneficial cardiovascular effects. What is more, resveratrol is a potent CRM. In yeast, it stimulates Sir2, increasing DNA stability and extending life-span by 70%. It is believed that it works the same way in humans, i.e. by activating the human homologue SIRT1, which results in reduced apoptosis in the liver, blood and skin, and reduced risk of age-related chronic disease. Research shows that resveratrol possesses an anticancer activity that is mediated through p53 modulation. A derivative of resveratrol can also block cells from dividing, without involving p53, thus safeguarding against unauthorised cell replication that may result in cancer.
  • Metformin mimics the gene expression of CR mice and has extended mice's maximum life spans. It is already clinically approved to treat diabetes, and has been used for this indication for the past 40 years. It is considered to be a receptor sensitizer, because it enhances the sensitivity of insulin receptors on the surface of muscle and fat cells. Metformin is able to activate genes that reduce the production of glucose by the liver, thus reducing the risk of glycosylation and other age-related damage. In addition, metformin can reduce the gene expression for enzymes that increase oxidation of fatty acids. In experiments, genes encoding for glucokinase and liver-type pyruvate kinase, (two enzymes that are involved in glycolysis) was increased by 250% following treatment with metformin. It is worth remembering that CR also results in modulation of genes that affect glucose formation in the liver, influence glycolysis, and affects containment of the by-products of glycolysis, which may contribute to glycosylation, and reduction of tissue levels of AGEs (Advanced Glycation Endproducts), as well as a reduction in fatty acid oxidation, all of which correspond to the same actions of metformin genetic effects. Therefore, the case for metformin's being a CRM is strengthened further.
  • Rimonabant (Acomplia), 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)
  • 2-deoxy-D-glucose, or 2-DG. 2-DG interferes in glycolysis,
  • starving a cell of fuel. Deoxyglucose is the first CRM described. This compound inhibits glycolysis and can mimic some of the effects of CR, in particular increased insulin sensitivity, reduced glucose levels, and other biochemical changes. Research is still underway to identify more about its possible benefits on humans. What is known about 2-deoxyglucose is that it can be toxic in high dosage.

Other candidate CRM are:

  • Anti-glycators such as aminoguanidine and carnosine
  • Exanadin (exanatide), a GLP (Glucagon-Like Peptide) modulator
  • Olbetam (Acipimox)
  • PPAR Gamma modulators, such as Rosiglitazone and Gugulipids
  • Leptin
  • Agents that modulate sirtuins (called STAC –sirtuin activating compounds), for example fisetin
  • 4-phenylbutyrate (PBA)
  • Hydroxycitrate
  • Gymnemoside (modulates glucose metabolism)
  • Adiponectin, (together with leptin, it takes part in fat metabolism. It is activated by PPAR blockers such as rosiglitazone)
  • DPP-4 inhibitors (diapeptidyl peptidase 4)
  • Modulators of NPY, the neuropeptide
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