Caloric restriction mimetic
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. A number of genes and pathways have also been shown to regulate the actions of CR in model organisms and these represent attractive targets for drug discovery and for developing CRM.
Candidate compounds include:
- Resveratrol is found in red wine and grapes. Many supplement companies market inexpensive concentrates. Resveratrol is a natural phenolic 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[by whom?] 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 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 (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
- Agents that modulate sirtuins (called STAC –sirtuin-activating compounds), for example, fisetin
- 4-Phenylbutyrate (PBA)
- 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
- Mannoheptulose (glycolytic inhibitor)
- de Magalhaes JP, Wuttke D, Wood SH, Plank M, Vora C (2012). "Genome-environment interactions that modulate aging: powerful targets for drug discovery". Pharmacol Rev 64 (1): 88–101. doi:10.1124/pr.110.004499. PMID 22090473.
- Arkad'eva, AV; Mamonov, AA, Popovich, IG, Anisimov, VN, Mikhel'son, VM, Spivak, IM (2011). "[Metformin slows down ageing processes at the cellular level in SHR mice].". Tsitologiia 53 (2): 166–74. PMID 21516824.
- Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M (2007). "Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress". Cell Metab. 6 (4): 280–93. doi:10.1016/j.cmet.2007.08.011. PMID 17908557.