Caloric restriction mimetics (CRM) try to mimic the substantial anti-aging effects caloric restriction (CR) has on many laboratory animals. In other words, the administration of a CRM results in the same physiological changes seen in CR itself. One way CRM work is by influencing specific genes that ultimately affect either cell repair or cell death.

Candidate compounds include:

• Resveratrol
  Resveratrol
  Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
  
   is found in red wine and grape
  Grape
  A grape is a non-climacteric fruit, specifically a berry, that grows on the perennial and deciduous woody vines of the genus Vitis. Grapes can be eaten raw or they can be used for making jam, juice, jelly, vinegar, wine, grape seed extracts, raisins, molasses and grape seed oil. Grapes are also...
  
  s. Many supplement companies market inexpensive concentrates. Resveratrol is a natural phenol
  Natural phenol
  Natural phenols, bioavailable phenols, plant phenolics, low molecular weight phenols or phenoloids are a class of natural products. They are small molecules containing one or more phenolic group. These molecules are smaller in size than polyphenols, containing less than 12 phenolic groups...
  
  ic 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, as well as 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
  Metformin
  Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
  
   mimics the gene expression of CR mice, and has extended mice's maximum lifespans. 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) 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
  Lipoic acid
  Lipoic acid , also known as α-lipoic acid and Alpha Lipoic Acid is an organosulfur compound derived from octanoic acid. LA contains two vicinal sulfur atoms attached via a disulfide bond and is thus considered to be oxidized...
  
   (α-Lipoic Acid, Alpha Lipoic Acid, or ALA)
• 2-deoxy-D-glucose
  2-Deoxy-D-glucose
  2-Deoxy-D-glucose is a glucose molecule which has the 2-hydroxyl group replaced by hydrogen, so that it cannot undergo further glycolysis. Glucose hexokinase traps this substance in most cells so that it makes a good marker for tissue glucose use and hexokinase activity. Many cancers have elevated...
  
  , or 2-DG. 2-DG interferes in glycolysis
  Glycolysis
  Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
  
  , 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
  Carnosine
  Carnosine is a dipeptide of the amino acids beta-alanine and histidine. It is highly concentrated in muscle and brain tissues....
  
  
• Exanadin (exanatide), a GLP (Glucagon-Like Peptide) modulator
• Olbetam (Acipimox)
• PPAR Gamma modulators, such as Rosiglitazone and Gugulipids
• Leptin
• Agents that modulate sirtuin
  Sirtuin
  Sirtuin or Sir2 proteins are a class of proteins that possess either histone deacetylase or mono-ribosyltransferase activity. Sirtuins regulate important biological pathways in bacteria, archaea and eukaryotes...
  
  s (called STAC –sirtuin-activating compound
  Sirtuin-activating compound
  Sirtuin-activating compounds are chemical compounds having an effect on sirtuins, a group of enzymes that use NAD+ to remove acetyl groups from proteins. They are caloric restriction mimetic candidates, molecules able to prevent aging-related diseases like Alzheimer's , diabetes, and...
  
  s), for example, fisetin
  Fisetin
  Fisetin is a flavonol, a structurally distinct chemical substance that belongs to the flavonoid group of polyphenols. It can be found in many plants, where it serves as a colouring agent...
  
  
• 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 Y
• Iodoacetate
  Iodoacetate
  Iodoacetic acid is a derivative of acetic acid. It is a toxic compound, because, like many alkyl halides, it is an alkylating agent. It reacts with cysteine residues in proteins...
  
  
• Mannoheptulose
  Mannoheptulose
  Mannoheptulose is a hexokinase inhibitor. It is a heptose, a monosaccharide with seven carbon atoms. By blocking the enzyme hexokinase, it prevents glucose phosphorylation. As a result, the breakdown of glucose is inhibited. It is found as D-mannoheptulose in avocados....
  
   (glycolytic inhibitor)

External links

• A List of Potential CR Mimetics
• R-Lipoic Acid: A Possible Anti-Aging Intervention
• http://www.antiaging-systems.com/extract/calorierestriction.htmAn article with full details, written by Dr Marios Kyriazis
  Marios Kyriazis
  Marios Kyriazis is a medical doctor and gerontologist who helped launch and formalise the concept of ‘Anti-aging medicine’ worldwide...
  
  ]