Calorie restriction mimetic

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A calorie restriction mimic (CRM) describes a partially hypothetical class of food supplements that are supposed to imitate the life-prolonging effects of calorie restriction determined in animal experiments (in English calorie restriction , abbreviated CR, and sometimes also referred to as energy restriction ).

properties

Calorie restriction is defined as a reduction in calorie intake of 20% (mild CR) to 50% (severe CR) without the risk of malnutrition or an undersupply of essential nutrient components.

A calorie restriction mimic should intervene in the metabolic pathways relevant for calorie restriction and, like a CR itself, thereby slow down the aging process, maintain health and enable a longer lifespan. The mimetics are intended to achieve the effects of calorie restriction without having to reduce food intake. It has been shown in various model organisms that a number of genes and metabolic pathways are influenced by CR. These represent potential targets for drug research and for the development of CRM. So far, the existence of effective CRM has not been proven.

history

The term was coined by Lane, Ingram and Roth of the National Institute on Aging in a 1998 publication in the Journal of Anti-Aging Medicine.

Discussed potential candidates

  • Spermidine , a biogenic polyamine , has a reinforcing effect on autophagy , a cellular process that is crucial for the general cellular activity of proteins as well as the function of mitochondria and cardiomyocytes (heart muscle cells) . The biochemical and microbiological mechanisms of spermidine are being investigated in the Frank Madeo, Aging and Cell Death laboratory at the Karl-Franzens University in Graz . There, the color mouse model organism showed heart, tumor and neuroprotective, dementia prophylactic effects and an improvement in kidney function. Frank Madeo's research team examines the possible uses for humans. In August 2018, Austrian, French and English clinicians and researchers published the results of a twenty-year clinical observation period (1995-2015), during which the intake of spermidine in the eating habits of a group of people was regularly recorded. 829 people between 45 and 84 years old (49 percent male) took part in the study. During this period, 341 of the people died, 40.5 percent of them in the lower third of the spermidine intake, 24 percent in the middle and 15 percent in the upper third. The different mortality risk of people in the upper third compared to that of the lower third corresponded to an age 5 to 7 years lower. A long-term treatment with spermidine is safe and well tolerated in older cognitively impaired people according to a joint study by the Berlin Charité with French and Austrian working groups .
  • Resveratrol (3,5,4'-trihydroxy- trans- stilbene) is a stilbenoid naturally produced by several plants , a type of natural phenol and phytoalexin . It comes u. a. in grapes. Resveratrol increases the lifespan of model organisms such as B. yeasts , worms ( Caenorhabditis elegans ), and fruit flies . Scientists involved in these studies founded Sirtris Pharmaceuticals , a company working on the development of resveratrol analogs as proprietary drugs. Resveratrol is also marketed as a dietary supplement. However, studies by independent scientists failed to replicate many results. Resveratrol in various doses did not extend the lifespan of non-overweight, genetically unmodified mice. The same is true for rats.
  • The antidiabetic drug metformin was suggested 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 for the treatment of diabetes and has been used for this indication for over 40 years. It increases 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, reducing the risk of glycation (non-enzymatic glycation) and other age-related damage; these effects can also be seen in CR. Metformin has also been reported to extend the lifespan of short-lived or genetically cancerous strains of mice. However, two studies in rats and mice with normal genetics and longevity showed no effect of metformin on maximal lifespan and only a very small effect on mean lifespan.
  • Oxaloacetate is a metabolic intermediate in the citric acid cycle . In the model organism Caenorhabditis elegans , a roundworm, supplementation with oxaloacetate increases the ratio of reduced to oxidized nicotinamide adenine dinucleotide (NAD + / NADH) and activates the AMPK and FOXO signaling pathways, similar to a CR. 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 isolated from cells and tested in media enriched with oxaloacetate, this increase can be dramatic. In tests by two independent groups of scientists in four university laboratories, however, supplementation with oxaloacetate had no effect on the lifespan of healthy laboratory mice.
  • 2-deoxy- D- glucose , or 2DG. 2-deoxyglucose pioneered calorie restriction mimetics. The substance inhibits glycolysis and can simulate some of the physiological effects of CR, in particular increased insulin sensitivity, decreased glucose levels, and decreased body temperature. The life span of the roundworm C. elegans was extended; however, studies in different strains of rats have not given positive results, instead problems with toxicity.
  • Rapamycin , a drug that inhibits the mechanistic target of rapamycin (mTOR) signaling pathway , is another candidate for a CR mimetic. This assumption is based on the reaction of mTORC1 activity to nutrient availability, the inhibition of mTOR activity by CR, the extension of the maximum lifespan by (1) genetically inhibited mTOR signaling in invertebrates and (2) the pharmacological inhibition of mTOR Rapamycin, in both invertebrates and mice. Nevertheless, the effects of CR and rapamycin on metabolism and gene expression also show substantial differences in mice, suggesting that the mechanisms of CR and rapamycin can also be different and possibly additive.

Individual evidence

  1. ↑ a b Sibylle Nikolai, Kathrin Pallauf, Patricia Huebbe, Gerald Rimbach: Energy restriction and potential energy restriction mimetics . In: Nutrition Research Reviews . 28, September 22, 2015, pp. 1–21. doi : 10.1017 / S0954422415000062 . PMID 26391585 . Retrieved November 8, 2015.
  2. ↑ JP de Magalhaes, D Wuttke, SH Wood, M Plank, C Vora: Genome-environment interactions that modulate aging: powerful targets for drug discovery . In: Pharmacol Rev . 64, No. 1, 2012, pp. 88-101. doi : 10.1124 / pr.110.004499 . PMID 22090473 . PMC 3250080 (free full text).
  3. ↑ a b c DK Ingram, GS Roth: Glycolytic inhibition as a strategy for developing calorie restriction mimetics . In: Experimental Gerontology . 46, No. 2-3, Feb-Mar 2011, pp. 148-54. doi : 10.1016 / j.exger.2010.12.001 . PMID 21167272 .
  4. ↑ a b c Lane MA, Ingram DK, Roth GS: 2-Deoxy-D-glucose feeding in rats mimics physiologic effects of calorie restriction . In: J Anti-Aging Med . 1, No. 4, Winter 1998, pp. 327-37. doi : 10.1089 / rej.1.1998.1.327 .
  5. ↑ Frank Madeo et al .: Induction of autophagy by spermidine promotes longevity . In: US National Library of Medicine National Institutes of Health (Ed.): Nat Cell Biol . November 11, 2009, p. 1305-1314 , doi : 10.1038 / ncb1975 , PMID 19801973 .
  6. ^ Frank Madeo, Tobias Eisenberg, Federico Pietrocola, Guido Kroemer: Spermidines in health and disease . In: American Association for the Advancement of Science (Ed.): Science . tape 359/6374 , January 26, 2018, doi : 10.1126 / science.aan2788 , PMID 29371440 .
  7. ↑ Kiechl S, Pechlaner R, Willeit P, Notdurfter M, Paulweber B, Willeit K, Werner P, Ruckenstuhl C, Iglseder B, Weger S, Mairhofer B, Gartner M, Kedenko L, Chmelikova M, Stekovic S, Stuppner H, Oberhollenzer F, Kroemer G, Mayr M, Eisenberg T, Tilg H, Madeo F, Willeit J .: Higher spermidine intake is linked to lower mortality: a prospective population-based study . In: The American Journal of Clinical Nutrition . tape 108 (2) , August 1, 2018, p. 371-380 , doi : 10.1093 / ajcn / nqy102 , PMID 29955838 .
  8. ↑ Claudia Schwarz et al .: Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline . In: US National Library of Medecine. National Institutes of Health (Ed.): Aging (Albany NY) . tape 10/1 , January 10, 2018, p. 19-33 , doi : 10.18632 / aging.101354 , PMID 29315079 .
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  13. ↑ a b 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 . In: J. Gerontol. A Biol. Sci. Med. Sci. . 66, No. 2, February 2011, pp. 191-201. doi : 10.1093 / gerona / glq178 . PMID 20974732 . PMC 3021372 (free full text).
  14. ↑ a b Randy Strong, 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 . In: J Gerontol A Biol Sci Med Sci . 68, No. 1, January 2013, pp. 6-16. doi : 10.1093 / gerona / gls070 . PMID 22451473 . PMC 3598361 (free full text).
  15. ↑ PL da Luz, 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 . In: Atherosclerosis . 224, No. 1, September 2012, pp. 136-42. doi : 10.1016 / j.atherosclerosis.2012.06.007 . PMID 22818625 .
  16. ↑ JM Dhahbi, Mote PL, Fahy GM, Spindler SR: Identification of potential caloric restriction mimetics by microarray profiling . In: Physiol Genomics . 23, No. 3, November 17, 2005, pp. 343-50. doi : 10.1152 / physiolgenomics.00069.2005 . PMID 16189280 .
  17. ↑ Arkad'eva, AV, Mamonov, AA, Popovich, IG, Anisimov, VN, Mikhel'son, VM, Spivak, IM: Metformin slows down aging processes at the cellular level in SHR mice . In: Tsitologiia . 53, No. 2, 2011, pp. 166-74. PMID 21516824 .
  18. ↑ 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 . In: Nature Communications . 4, July 31, 2013, p. 2192. doi : 10.1038 / ncomms3192 . PMID 23900241 . PMC 3736576 (free full text).
  19. ^ DL Jr Smith, Elam CF Jr, Mattison JA, Lane MA, Roth GS, Ingram DK, Allison DB: Metformin supplementation and life span in Fischer-344 rats . In: J Gerontol A Biol Sci Med Sci . 65, No. 5, May 2010, pp. 468-74. doi : 10.1093 / gerona / glq033 . PMID 20304770 .
  20. ↑ Williams, DS, Cash, A., Hamadani, L., Diemer, T .: Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK / FOXO-dependent pathway . In: Aging Cell . 8, No. 6, 2009, pp. 765-8. doi : 10.1111 / j.1474-9726.2009.00527.x . PMID 19793063 .
  21. ↑ Haslam, JM, Krebs, HA: The permeabiliity of mitochondria to oxaloacetate and malate . In: Biochem J . 107, No. 5, 1968, pp. 659-67. doi : 10.1042 / bj1070659 . PMID 16742587 .
  22. ↑ a b c 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 . In: Toxicol Appl Pharmacol . 243, No. 3, March 15, 2010, pp. 332-9. doi : 10.1016 / j.taap.2009.11.025 . PMID 20026095 . PMC 2830378 (free full text).
  23. ↑ 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 . In: Cell Metab. . 6, No. 4, 2007, pp. 280-93. doi : 10.1016 / j.cmet.2007.08.011 . PMID 17908557 .
  24. ↑ a b Stanfel MN, Shamieh LS, Kaeberlein M, Kennedy BK: The TOR pathway comes of age . In: Biochim Biophys Acta . 1790, No. 10, October 2009, pp. 1067-74. doi : 10.1016 / j.bbagen.2009.06.007 . PMID 19539012 . PMC 3981532 (free full text).
  25. ^ Harrison DE, Strong R, Sharp ZD: Rapamycin fed late in life extends lifespan in genetically heterogeneous mice . In: Nature . 460, No. 7253, July 8, 2009, pp. 392-5. bibcode : 2009Natur.460..392H . doi : 10.1038 / nature08221 . PMID 19587680 . PMC 2786175 (free full text).
  26. ↑ 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 . In: Aging Cell . 13, No. 3, June 2014, pp. 468-77. doi : 10.1111 / acel.12194 . PMID 24341993 . PMC 4032600 (free full text).
  27. ↑ a b Yu Z, Wang R, Fok WC, Coles A, Salmon AB, Pérez VI: Rapamycin and Dietary Restriction Induce Metabolically Distinctive Changes in Mouse Liver . In: J Gerontol A Biol Sci Med Sci . 70, No. 4, April 2014, pp. 410-20. doi : 10.1093 / gerona / glu053 . PMID 24755936 .
  28. ↑ a b 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 . In: Aging Cell . 13, No. 2, April 2014, pp. 311-9. doi : 10.1111 / acel.12175 . PMID 24304444 .