Caloric restriction mimetic

Candidates

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, 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.
• Oxaloacetate is a metabolic intermediate of the citric acid cycle. In the short-lived roundworm Caenorhabditis elegans, supplementation with oxaloacetate increases the ratio of reduced to oxidized nicotinamide adenine dinucleotide (NAD+:NADH) to activate AMPK and FOXO signaling pathways similar to what occurs in calorie restriction. The increase in the NAD+/NADH ratio is due to the reaction of oxaloacetate to malate in the cytoplasm via the enzyme malate dehydrogenase. In mitochondria that have been isolated out of cells and tested in oxaloacetate-enriched medium, this increase can be quite dramatic. Decreases in the NAD+/NADH ratio has been proposed as a carbohydrate metabolism-controlled cellular senescence mechanism.

:Because of its parallel effects on these pathways, oxaloacetate was proposed as a CR mimetic. However, when tested by two independent groups of scientists across four university laboratories, oxaloacetate supplements had no effect on lifespan in healthy laboratory mice.

• Rimonabant (Acomplia) is an anti-obesity drug initially approved for use in the European Union but later withdrawn due to psychiatric side effects including anxiety and depression. Rimonabant was never approved by the FDA for use in the United States. This is an endocannabinoid-1 receptor blocker. Endocannabinoids are cannabis-like chemicals that stimulate appetite and also regulate energy balance. Overstimulation of the endocannabinoid 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, and is therefore comparable in effect to calorie restriction (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. 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.{{cite journal |display-authors=etal}} While knocking out elements of the mTOR cascade seems to block the lifespan effects of rapamycin in invertebrate animals, 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:

• Glucosamine or its derivative n-acetylglucosamine have extended the life of both nematodes and mice.
• Peroxisome proliferator-activated receptor gamma inhibitors, such as Rosiglitazone and Gugulipids, working as insulin sensitizers, making fat cells more responsive to insulin by binding to their PPAR receptors
• Agents that modulate sirtuins (called STAC –sirtuin-activating compounds), for example, fisetin
• Exanadin (exenatide), a glucagon-like peptide-1 (GLP-1)modulator (originally discovered in the venom of the Gila monster) belongs to the group of incretin mimetics, facilitating glucose control.
• Adiponectin (together with leptin, it regulates adipose tissue metabolism. It is activated by PPAR inhibitors such as rosiglitazone)
• Acipimox
• Hydroxycitrate
• Dipeptidyl peptidase 4 (DPP-4) inhibitors
• Iodoacetate
• Mannoheptulose (glycolytic inhibitor)
• Modulators of neuropeptide Y (NPY)
• 4-Phenylbutyrate (PBA)
• Gymnemoside (modulates glucose absorption)
• Spermidine

References

References

1. (Winter 1998). "2-Deoxy-D-glucose feeding in rats mimics physiologic effects of calorie restriction". J Anti-Aging Med.
2. (22 September 2015). "Energy restriction and potential energy restriction mimetics". Nutrition Research Reviews.
3. (2012). "Genome-environment interactions that modulate aging: powerful targets for drug discovery". Pharmacol Rev.
4. (Feb–Mar 2011). "Glycolytic inhibition as a strategy for developing calorie restriction mimetics". Experimental Gerontology.
5. (October 2007). "Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans". Mech. Ageing Dev..
6. Kaeberlein, Matt. (April 29, 2005). "Substrate specific activation of sirtuins by resveratrol". Journal of Biological Chemistry.
7. Zou, S. (Jun–Jul 2009). "The prolongevity effect of resveratrol depends on dietary composition and calorie intake in a tephritid fruit fly". Experimental Gerontology.
8. (August 2008). "Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span". Cell Metab..
9. (February 2011). "Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice". J. Gerontol. A Biol. Sci. Med. Sci..
10. Strong, Randy. (January 2013). "Evaluation of Resveratrol, Green Tea Extract, Curcumin, Oxaloacetic Acid, and Medium-Chain Triglyceride Oil on Life Span of Genetically Heterogeneous Mice". J Gerontol A Biol Sci Med Sci.
11. da Luz, PL. (September 2012). "Red wine and equivalent oral pharmacological doses of Resveratrol delay vascular aging but do not extend life span in rats". Atherosclerosis.
12. Dhahbi, JM. (Nov 17, 2005). "Identification of potential caloric restriction mimetics by microarray profiling". Physiol Genomics.
13. (2011). "Metformin slows down ageing processes at the cellular level in SHR mice". Tsitologiia.
14. (Jul 31, 2013). "Metformin improves healthspan and lifespan in mice". Nature Communications.
15. Smith, DL Jr. (May 2010). "Metformin supplementation and life span in Fischer-344 rats". J Gerontol A Biol Sci Med Sci.
16. (2009). "Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway". Aging Cell.
17. (1968). "The permeabiliity of mitochondria to oxaloacetate and malate". Biochem J.
18. (2012). "Cytosolic malate dehydrogenase regulates senescence in human fibroblasts". Biogerontology.
19. (2013). "Malate and Fumarate Extend Lifespan in Caenorhabditis elegans". PLOS ONE.
20. "Diet, Drugs, Supplements and Lifespan". HealthActivator.
21. (2011). "Rimonabant: From RIO to Ban". Journal of Obesity.
22. (June 2009). "The psychiatric side-effects of rimonabant". Brazilian Journal of Psychiatry.
23. (Apr 15, 2004). "The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice". Free Radic Biol Med.
24. (June 2008). "Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span". Mech Ageing Dev.
25. (2007). "Screening candidate longevity therapeutics using gene-expression arrays". Gerontology.
26. (Dec 2013). "Lifespan effects of simple and complex nutraceutical combinations fed isocalorically to mice". Age (Dordr).
27. (Mar 15, 2010). "Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats". Toxicol Appl Pharmacol.
28. (Oct 2009). "The TOR pathway comes of age". Biochim Biophys Acta.
29. (Jun 2014). "Rapamycin-Mediated Lifespan Increase in Mice is Dose and Sex-Dependent and Appears Metabolically Distinct from Dietary Restriction". Aging Cell.
30. (April 2014). "Rapamycin and Dietary Restriction Induce Metabolically Distinctive Changes in Mouse Liver". J Gerontol A Biol Sci Med Sci.
31. (Apr 2014). "Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver". Aging Cell.
32. (2014). "Hexosamine pathway metabolites enhance protein quality control and prolong life". Cell.
33. (2014). "D-Glucosamine supplementation extends life span of nematodes and of ageing mice". Nature Communications.
34. (2016). "Cardioprotection and lifespan extension by the natural polyamine spermidine". Nature Medicine.