Caloric restriction mimetic

Calorie restriction mimetics (CRM), also known as Energy restriction mimetics, designate a hypothetical class of dietary supplement or drug candidate that would in principle mimic the substantial anti-aging effects that calorie restriction (CR) has on many laboratory animals. 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.^[1] 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.^[2] A number of genes and pathways have been shown to be involved 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.^[1][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, wines, 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 oxoacetate increases the ratio of oxidized to reduced 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 carbohydrate metabolism-controlled cellular senescence mechanism.^[18]

Because of its parallel effects on these pathways, oxaloacetate was proposed as a CR mimetic.^[16] 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.^[16][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.^[10][20]

• 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) has failed to extend lifespan in normal mice or rats in numerous studies, either alone^[21][22] or as part of combination therapy.^[23][24]
• 2-deoxy-D-glucose, or 2DG. 2-Deoxyglucose was the first agent pursued as a possible CRM.^[2][4][25] 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.^[2][25] It was reported to extend the lives of C. elegans worms;^[26] however, studies in different strains of rats found that 2DG did not extend lifespan at several tested doses, and exhibited toxic effects^[25] "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."^[25]
• It has been suggested that rapamycin, a drug that inhibits the mechanistic Target Of Rapamycin (mTOR) pathway, might be a CR mimetic.^[4][27] 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.^[9][27][28] While knocking out elements of the mTOR cascade seems to block the lifespan effects of rapamycin in invertebrate animals,^[27] surprisingly the effects of CR and rapamycin on metabolism and gene expression exhibit substantial differences in mice,^[29][30][31] with evidence suggesting that the mechanisms of the two anti-aging therapies may be in large part distinct and possibly additive.^[30][31]

Other candidate CRM are:

• Peroxisome proliferator-activated receptor gamma inhibitors, such as Rosiglitazone and Gugulipids, working as insulin sensitizers, making fat cells more repsonsive 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, extracted from the salvia 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^[4]
• Mannoheptulose (glycolytic inhibitor)^[4]
• Modulators of neuropeptide Y (NPY)
• 4-Phenylbutyrate (PBA)
• Gymnemoside (modulates glucose absorption)
• Spermidine^[32]

References

1. Nikolai, Sibylle; Pallauf, Kathrin; Huebbe, Patricia; Rimbach, Gerald (22 September 2015). "Energy restriction and potential energy restriction mimetics" (PDF). Nutrition Research Reviews. 28: 1–21. doi:10.1017/S0954422415000062. PMID 26391585. Retrieved 8 November 2015.
2. Lane MA; Ingram DK; Roth GS (Winter 1998). "2-Deoxy-D-glucose feeding in rats mimics physiologic effects of calorie restriction". J Anti-Aging Med. 1 (4): 327–37. doi:10.1089/rej.1.1998.1.327. Retrieved 1 October 2013.
3. 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. PMC 3250080. PMID 22090473.
4. Ingram, DK; Roth, GS (Feb–Mar 2011). "Glycolytic inhibition as a strategy for developing calorie restriction mimetics". Experimental Gerontology. 46 (2-3): 148–54. doi:10.1016/j.exger.2010.12.001. PMID 21167272.
5. Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L (October 2007). "Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans". Mech. Ageing Dev. 128 (10): 546–52. doi:10.1016/j.mad.2007.07.007. PMID 17875315.
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 (April 29, 2005). "Substrate specific activation of sirtuins by resveratrol". Journal of Biological Chemistry. 280 (17): 17038–17045. doi:10.1074/jbc.M500655200. PMID 15684413. Retrieved 7 September 2013.
7. Zou, S; Carey JR; Liedo P; Ingram DK; Müller HG; Wang JL; Yao F; Yu B; Zhou A (Jun–Jul 2009). "The prolongevity effect of resveratrol depends on dietary composition and calorie intake in a tephritid fruit fly". Experimental Gerontology. 44 (6-7): 472–6. doi:10.1016/j.exger.2009.02.011. PMC 3044489. PMID 19264118.
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 (August 2008). "Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span". Cell Metab. 8 (2): 157–68. doi:10.1016/j.cmet.2008.06.011. PMC 2538685. PMID 18599363.
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 (February 2011). "Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice". J. Gerontol. A Biol. Sci. Med. Sci. 66 (2): 191–201. doi:10.1093/gerona/glq178. PMC 3021372. PMID 20974732.
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 (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. 68 (1): 6–16. doi:10.1093/gerona/gls070. PMC 3598361. PMID 22451473.
11. da Luz, PL; Tanaka L; Brum PC; Dourado PM; Favarato D; Krieger JE; Laurindo FR (September 2012). "Red wine and equivalent oral pharmacological doses of Resveratrol delay vascular aging but do not extend life span in rats". Atherosclerosis. 224 (1): 136–42. doi:10.1016/j.atherosclerosis.2012.06.007. PMID 22818625.
12. Dhahbi, JM; Mote PL; Fahy GM; Spindler SR (Nov 17, 2005). "Identification of potential caloric restriction mimetics by microarray profiling". Physiol Genomics. 23 (3): 343–50. doi:10.1152/physiolgenomics.00069.2005. PMID 16189280.
13. Arkad'eva, A.V.; Mamonov, A.A.; Popovich, I.G.; Anisimov, V.N.; Mikhel'son, V.M.; Spivak, I.M. (2011). "Metformin slows down ageing processes at the cellular level in SHR mice". Tsitologiia. 53 (2): 166–74. PMID 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 (Jul 31, 2013). "Metformin improves healthspan and lifespan in mice". Nature Communications. 4: 2192. Bibcode:2013NatCo...4E2192M. doi:10.1038/ncomms3192. PMID 23900241.
15. Smith, DL Jr; Elam CF Jr; Mattison JA; Lane MA; Roth GS; Ingram DK; Allison DB (May 2010). "Metformin supplementation and life span in Fischer-344 rats". J Gerontol A Biol Sci Med Sci. 65 (5): 468–74. doi:10.1093/gerona/glq033. PMID 20304770.
16. Williams, D.S.; Cash, A.; Hamadani, L.; Diemer, T. (2009). "Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway". Aging Cell. 8 (6): 765–8. doi:10.1111/j.1474-9726.2009.00527.x. PMID 19793063.
17. Haslam, J.M.; Krebs, H.A. (1968). "The permeabiliity of mitochondria to oxaloacetate and malate". Biochem J. 107 (5): 659–67. doi:10.1042/bj1070659. PMID 16742587.
18. Lee, S.m.; Dho, S.H.; Maeng, J.S.; Kim, J.Y.; Kwon, K.S. (2012). "Cytosolic malate dehydrogenase regulates senescence in human fibroblasts". Biogerontology. 13 (5): 525–36. doi:10.1007/s10522-012-9397-0. PMID 22971926.
19. Edwards, Clair B.; Copes, Neil; Brito, Andres G.; Canfield, John; Bradshaw, Patrick C. (2013). "Malate and Fumarate Extend Lifespan in Caenorhabditis elegans". PLOS ONE. 8 (3): e58345. Bibcode:2013PLoSO...858345E. doi:10.1371/journal.pone.0058345. PMC 3589421. PMID 23472183.
20. Spindler, S. "Diet, Drugs, Supplements and Lifespan". 2012 Health Conference Series. HealthActivator. Retrieved 9 April 2015.
21. Lee CK, Pugh TD, Klopp RG, Edwards J, Allison DB, Weindruch R, Prolla TA (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. 36 (8): 1043–57. doi:10.1016/j.freeradbiomed.2004.01.015. PMID 15059645.
22. Merry BJ, Kirk AJ, Goyns MH (June 2008). "Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span". Mech Ageing Dev. 129 (6): 341–8. doi:10.1016/j.mad.2008.04.004. PMID 18486188.
23. Spindler SR; Mote PL (2007). "Screening candidate longevity therapeutics using gene-expression arrays". Gerontology. 53 (5): 306–21. doi:10.1159/000103924. PMID 17570924.
24. Spindler SR; Mote PL; Flegal JM (Dec 2013). "Lifespan effects of simple and complex nutraceutical combinations fed isocalorically to mice". Age (Dordr). Online First (2): 705–718. doi:10.1007/s11357-013-9609-9. PMID 24370781.
25. 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 (Mar 15, 2010). "Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats". Toxicol Appl Pharmacol. 243 (3): 332–9. doi:10.1016/j.taap.2009.11.025. PMC 2830378. PMID 20026095.
26. 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.
27. Stanfel MN; Shamieh LS; Kaeberlein M; Kennedy BK (Oct 2009). "The TOR pathway comes of age". Biochim Biophys Acta. 1790 (10): 1067–74. doi:10.1016/j.bbagen.2009.06.007. PMC 3981532. PMID 19539012. Retrieved 8 July 2014.
28. Harrison DE, Strong R, Sharp ZD, et al. (8 July 2009). "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice". Nature. 460 (7253): 392–5. Bibcode:2009Natur.460..392H. doi:10.1038/nature08221. PMC 2786175. PMID 19587680. Lay summary – The Times (2009-07-08).
29. 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 (Jun 2014). "Rapamycin-Mediated Lifespan Increase in Mice is Dose and Sex-Dependent and Appears Metabolically Distinct from Dietary Restriction". Aging Cell. 13 (3): 468–77. doi:10.1111/acel.12194. PMC 4032600. PMID 24341993. Retrieved 8 July 2014.
30. Yu Z; Wang R; Fok WC; Coles A; Salmon AB; Pérez VI (April 2014). "Rapamycin and Dietary Restriction Induce Metabolically Distinctive Changes in Mouse Liver". J Gerontol A Biol Sci Med Sci. 70 (4): 410–20. doi:10.1093/gerona/glu053. PMID 24755936.
31. 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 (Apr 2014). "Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver". Aging Cell. 13 (2): 311–9. doi:10.1111/acel.12175. PMID 24304444.
32. 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. doi:10.1038/nm.4222.

External links

• A List of Potential CR Mimetics
• An article with full details, written by Dr Marios Kyriazis