Caloric restriction mimetic explained

Calorie restriction mimetics (CRM), also known as energy restriction mimetics, are a hypothetical class of dietary supplements or drug candidates that would, in principle, mimic the substantial anti-aging effects that calorie restriction (CR) has on many laboratory animals and humans. CR is defined as a reduction in calorie intake of 20% (mild CR) to 50% (severe CR) without incurring malnutrition or a reduction in essential nutrients. An effective CRM would alter the key metabolic pathways involved in the effects of CR itself, leading to preserved youthful health and longer lifespan without the need to reduce food intake. The term was coined by Lane, Ingram, Roth of the National Institute on Aging in a seminal 1998 paper in the Journal of Anti-Aging Medicine, the forerunner of Rejuvenation Research.^[1] A number of genes and pathways have been shown to be involved with the actions of CR in model organisms and these represent attractive targets for drug discovery and for developing CRM. However, no effective CRM have been identified to date.^{[2] [3] [4]}

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^{[5] [6] [7]} Moreover, in every experiment to date, resveratrol at several doses has failed to extend the lifespan of lean, genetically normal mice^{[8] [9] [10]} or rats.^[11]
• 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.^[12] 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.^[13] 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.^{[14] [15]}
• 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.^[16] 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.^[17] Decreases in the NAD+/NADH ratio has been proposed as a carbohydrate metabolism-controlled cellular senescence mechanism.^[18]

Because of its parallel effects on these pathways, oxaloacetate was proposed as a CR mimetic. In the short-lived roundworm Caenorhabditis elegans, supplementing the medium with oxaloacetate does increase average life expectancy; it was unclear whether it had an effect on maximum lifespan.^[19] However, when tested by two independent groups of scientists across four university laboratories, oxaloacetate supplements had no effect on lifespan in healthy laboratory mice.^[20]

• 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.^[21] Rimonabant was never approved by the FDA for use in the United States.^[22] 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^{[23] [24]} or as part of combination therapy.^{[25] [26]}
• 2-deoxy-D-glucose, or 2DG. 2-Deoxyglucose was the first agent pursued as a possible CRM.^[27] 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. It was reported to extend the lives of C. elegans worms;^[28] 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.^[29] 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.^[30] While knocking out elements of the mTOR cascade seems to block the lifespan effects of rapamycin in invertebrate animals, surprisingly the effects of CR and rapamycin on metabolism and gene expression exhibit substantial differences in mice,^{[31] [32] [33]} 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.^{[34] [35]}
• 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^[36]

External links

• A List of Potential CR Mimetics

Notes and References

1. Lane MA . Ingram DK . Roth GS. 2-Deoxy-D-glucose feeding in rats mimics physiologic effects of calorie restriction. J Anti-Aging Med. Winter 1998. 1. 4. 327–37. 10.1089/rej.1.1998.1.327.
2. Energy restriction and potential energy restriction mimetics . Sibylle . Nikolai . Kathrin . Pallauf . Patricia . Huebbe . Rimbach . Gerald . Nutrition Research Reviews . 22 September 2015 . 28. 2. 100–120 . 10.1017/S0954422415000062 . 26391585 . 8 November 2015. free .
3. de Magalhaes . JP . Wuttke . D . Wood . SH . Plank . M . Vora . C . Genome-environment interactions that modulate aging: powerful targets for drug discovery . Pharmacol Rev . 64 . 1 . 88–101 . 2012 . 22090473 . 10.1124/pr.110.004499 . 3250080.
4. Ingram . DK . Roth . GS . Glycolytic inhibition as a strategy for developing calorie restriction mimetics. Experimental Gerontology. Feb–Mar 2011. 46. 2–3. 148–54 . 10.1016/j.exger.2010.12.001 . 21167272 . 5634847 .
5. Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L . Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans . Mech. Ageing Dev. . 128 . 10 . 546–52 . October 2007 . 17875315 . 10.1016/j.mad.2007.07.007 . 1780784 .
6. Kaeberlein. Matt . Thomas McDonagh . Birgit Heltweg . Jeffrey Hixon . Eric A. Westman . Seth D. Caldwell . Andrew Napper . Rory Curtis . Peter S. DiStefano . Stanley Fields . Antonio Bedalov . Brian K. Kennedy . Substrate specific activation of sirtuins by resveratrol. Journal of Biological Chemistry. April 29, 2005. 280. 17. 17038–17045. 10.1074/jbc.M500655200. 15684413. free .
7. Zou. S. Carey JR . Liedo P . Ingram DK . Müller HG . Wang JL . Yao F . Yu B . Zhou A . The prolongevity effect of resveratrol depends on dietary composition and calorie intake in a tephritid fruit fly. Experimental Gerontology. Jun–Jul 2009. 44. 6–7. 472–6. 10.1016/j.exger.2009.02.011. 19264118. 3044489.
8. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R . Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span . Cell Metab. . 8 . 2 . 157–68 . August 2008 . 18599363 . 2538685 . 10.1016/j.cmet.2008.06.011 .
9. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R . Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice . J. Gerontol. A Biol. Sci. Med. Sci. . 66 . 2 . 191–201 . February 2011 . 20974732 . 3021372 . 10.1093/gerona/glq178 .
10. Strong. Randy . Richard A. Miller . Clinton M. Astle . Joseph A. Baur . Rafael de Cabo . Elizabeth Fernandez . Wen Guo . Martin Javors . James L. Kirkland . James F. Nelson . David A. Sinclair . Bruce Teter . David Williams . Nurulain Zaveri . Nancy L. Nadon . David E. Harrison . 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. January 2013. 68. 1. 6–16. 10.1093/gerona/gls070. 22451473. 3598361.
11. da Luz. PL. Tanaka L . Brum PC . Dourado PM . Favarato D . Krieger JE . Laurindo FR . Red wine and equivalent oral pharmacological doses of Resveratrol delay vascular aging but do not extend life span in rats. Atherosclerosis. September 2012. 224. 1. 136–42. 10.1016/j.atherosclerosis.2012.06.007. 22818625.
12. Dhahbi. JM. Mote PL . Fahy GM . Spindler SR . Identification of potential caloric restriction mimetics by microarray profiling. Physiol Genomics. Nov 17, 2005. 23. 3. 343–50. 16189280. 10.1152/physiolgenomics.00069.2005. 10.1.1.327.4892.
13. Arkad'eva, A.V. . Mamonov, A.A. . Popovich, I.G. . Anisimov, V.N. . Mikhel'son, V.M. . Spivak, I.M. . Metformin slows down ageing processes at the cellular level in SHR mice . Tsitologiia . 2011 . 53 . 2 . 166–74 . 21516824 .
14. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R . Metformin improves healthspan and lifespan in mice. Nature Communications. Jul 31, 2013. 4. 2192. 10.1038/ncomms3192. 23900241. 2013NatCo...4.2192M. 3736576.
15. Smith. DL Jr . Elam CF Jr . Mattison JA . Lane MA . Roth GS . Ingram DK . Allison DB. Metformin supplementation and life span in Fischer-344 rats. J Gerontol A Biol Sci Med Sci. May 2010. 65. 5. 468–74. 10.1093/gerona/glq033. 20304770 . 2854888.
16. Williams, D.S. . Cash, A. . Hamadani, L. . Diemer, T. . Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway . Aging Cell . 2009 . 8 . 6 . 765–8 . 19793063 . 10.1111/j.1474-9726.2009.00527.x . 2988682.
17. Haslam, J.M. . Krebs, H.A. . The permeabiliity of mitochondria to oxaloacetate and malate . Biochem J . 1968 . 107 . 5 . 659–67 . 16742587 . 10.1042/bj1070659 . 1198718.
18. Lee, S.m. . Dho, S.H. . Maeng, J.S. . Kim, J.Y. . Kwon, K.S. . Cytosolic malate dehydrogenase regulates senescence in human fibroblasts . Biogerontology . 2012 . 13 . 5 . 525–36 . 22971926 . 10.1007/s10522-012-9397-0. 14068141 .
19. Edwards, Clair B. . Copes, Neil . Brito, Andres G. . Canfield, John . Bradshaw, Patrick C. . Malate and Fumarate Extend Lifespan in Caenorhabditis elegans . PLOS ONE . 2013 . 8 . 3 . e58345 . 10.1371/journal.pone.0058345 . 3589421 . 2013PLoSO...858345E . 23472183. free .
20. Web site: Spindler. S. Diet, Drugs, Supplements and Lifespan. https://archive.today/20150409222322/http://healthactivator.com/member-home/members-module-1-2-2/stephen-spindler/. dead. 9 April 2015. 2012 Health Conference Series. HealthActivator. 9 April 2015.
21. Sam . Amir H. . Salem . Victoria . Ghatei . Mohammad A. . 2011 . Rimonabant: From RIO to Ban . Journal of Obesity . 2011 . 432607 . 10.1155/2011/432607 . 2090-0708 . 3136184 . 21773005. free .
22. Moreira . Fabrício A. . Crippa . José Alexandre S. . June 2009 . The psychiatric side-effects of rimonabant . Brazilian Journal of Psychiatry . en . 31 . 2 . 145–153 . 10.1590/S1516-44462009000200012 . 19578688 . 1516-4446. free .
23. Lee CK, Pugh TD, Klopp RG, Edwards J, Allison DB, Weindruch R, Prolla TA . The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice. Free Radic Biol Med. Apr 15, 2004. 36. 8. 1043–57. 15059645. 10.1016/j.freeradbiomed.2004.01.015.
24. Merry BJ, Kirk AJ, Goyns MH . Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span. Mech Ageing Dev. June 2008. 129. 6. 341–8. 18486188. 10.1016/j.mad.2008.04.004. 29497185.
25. Spindler SR. Mote PL. Screening candidate longevity therapeutics using gene-expression arrays. Gerontology. 2007. 53. 5. 306–21. 17570924. 10.1159/000103924. 42831700.
26. Spindler SR. Mote PL. Flegal JM. Lifespan effects of simple and complex nutraceutical combinations fed isocalorically to mice. Age (Dordr). Dec 2013. 36. 10.1007/s11357-013-9609-9. 24370781. 2. 705–718. 4039264.
27. Minor RK, Smith DL, Sossong AM, Kaushik S, Poosala S, Spangler EL, Roth GS, Lane M, Allison DB, de Cabo R, Ingram DK, Mattison JA . Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats. Toxicol Appl Pharmacol. Mar 15, 2010. 243. 3. 332–9. 10.1016/j.taap.2009.11.025. 20026095. 2830378.
28. Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M . Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress . Cell Metab. . 6 . 4 . 280–93 . 2007 . 17908557 . 10.1016/j.cmet.2007.08.011. free .
29. Stanfel MN. Shamieh LS. Kaeberlein M. Kennedy BK. The TOR pathway comes of age. Biochim Biophys Acta. Oct 2009. 1790. 10. 1067–74. 10.1016/j.bbagen.2009.06.007. 19539012. 3981532.
30. Harrison DE, Strong R, Sharp ZD. 8 July 2009. 392–5. 7253. 460 . Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. 19587680. Nature. 2786175. 10.1038/nature08221. 2009Natur.460..392H. etal.
31. Miller RA. Harrison DE. Astle CM. Fernandez E. Flurkey K. Han M. Javors MA. Li X. Nadon NL. Nelson JF. Pletcher S. Salmon AB. Sharp ZD. Van Roekel S. Winkleman L. Strong R. Rapamycin-Mediated Lifespan Increase in Mice is Dose and Sex-Dependent and Appears Metabolically Distinct from Dietary Restriction. Aging Cell. Jun 2014. 13. 3. 468–77. 10.1111/acel.12194. 24341993. 4032600.
32. Yu Z. Wang R. Fok WC. Coles A. Salmon AB. Pérez VI. Rapamycin and Dietary Restriction Induce Metabolically Distinctive Changes in Mouse Liver. J Gerontol A Biol Sci Med Sci. April 2014. 70. 4. 410–20. 10.1093/gerona/glu053. 24755936. 4447794.
33. Fok WC. Bokov A. Gelfond J. Yu Z. Zhang Y. Doderer M. Chen Y. Javors M. Wood WH 3rd. Zhang Y. Becker KG. Richardson A. Pérez VI. Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver. Aging Cell. Apr 2014. 13. 2. 311–9. 10.1111/acel.12175. 24304444. 3989927.
34. Cell . 2014 . 156 . 6 . 1167–1178 . 10.1016/j.cell.2014.01.061 . 24630720 . Denzel MS, Storm NJ, Gutschmidt A, Baddi A, Hinze Y, Jarosch E, Sommer T, Hoppe T, Antebi A . Hexosamine pathway metabolites enhance protein quality control and prolong life. free .
35. Nature Communications . 2014 . 5 . 3563 . 10.1038/ncomms4563 . 24714520 . Weimer S, Priebs J, Kuhlow D, Groth M, Priebe S, Mansfeld J, Merry TL, Dubuis S, Laube B, Pfeiffer AF, Schulz TJ, Guthke R, Platzer M, Zamboni N, Zarse K, Ristow M . D-Glucosamine supplementation extends life span of nematodes and of ageing mice . 3988823. 2014NatCo...5.3563W .
36. Eisenberg. Tobias. Abdellatif. Mahmoud. Schroeder. Sabrina. Primessnig. Uwe. Stekovic. Slaven. Pendl. Tobias. Harger. Alexandra. Schipke. Julia. Zimmermann. Andreas. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nature Medicine. 10.1038/nm.4222. 22. 12. 1428–1438. 27841876. 5806691. 2016.