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 which ultimately affect either cell repair or cell death.

Candidate compounds include:

Resveratrol is found in red wine and grapes^{[citation needed]}. 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 which is mediated through p53 modulation. A derivative of resveratrol can also block cells from dividing, without involving p53, thus safeguarding against unauthorised cell replication which may result in cancer.

metformin mimics the gene expression of CR mice^{[citation needed]}, and has extended mice's maximum life spans^{[citation needed]}. 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 which 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 which increase oxidation of fatty acids. In experiments, genes encoding for glucokinase and liver-type pyruvate kinase, (two enzymes which are involved in glycolysis) was increased by 250% following treatment with metformin. It is worth remembering that CR also results in modulation of genes, which affect glucose formation in the liver, influence glycolysis, 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 being a CRM is strengthened further.

Rimonabant (Acomplia), an anti-obesity drug. This is an endocannabinoid-1 receptor blocker. Endocannabinoids are cannabis-like chemicals which stimulate appetite and also regulate energy balance. Overstimulation of the endoannabinoid receptor in the hypothalamus promotes appetite and stimulate 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)^{[citation needed]}
2-deoxy-D-glucose, or 2-DG^[1]. 2-DG interferes in glycolysis, starving a cell of fuel. Deoxyglucose is the first CRM described. This compound inhibit glycolysis and can mimic some of the effects of CR, particularly increased insulin sensitivity, reduced glucose levels and other biochemical changes. Research is still under way 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 Y
Iodoacetate^{[citation needed]}

References

^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)

External links

[glucose_restriction-1] 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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