Glycine

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Glycine (Aminoacetic acid, Aminoethanoic acid, Glycocoll)
Molecular Weight: 75.07
Chemical formula: C2H5NO2
Linear Formula: NH2CH2COOH
CASNo = 56-40-6, CASNo = (HCl): 6000-43-7
ATC code B05CX03

Glycine (aminoacetic acid) is most important and simple, nonessential amino acid in humans, animals, and many mammals.[1] Glycine is a precursor for several important compounds such as creatine, purines and glucose, and is involved in a wide range of metabolic pathways.[2] Besides participating in synthesizing structural biomolecules, glycine serves as one of the predecessors of glutathione, one of the most important antioxidants in the human body,[3][4][5] and also supplementation that is important in avoiding the development of chronic inflammation.[6]

Glycine supplementation has been shown to extend lifespan in various animal models.[7] [8][9][10][11]

GlyNAC (combination of glycine and N-acetylcysteine)

Cellular increases in oxidative stress and decline in mitochondrial function are identified as key defects in aging. Defects linked to oxidative stress and impaired mitochondrial fuel oxidation, such as inflammation, insulin resistance, endothelial dysfunction, and aging hallmarks, are present in older humans and are associated with declining strength and cognition, as well as the development of sarcopenic obesity. Investigations on the origins of elevated oxidative stress and mitochondrial dysfunction in older humans led to the discovery that deficiencies of the antioxidant tripeptide glutathione (γ-Glutamylcysteinylglycine) and its precursor amino acids glycine and cysteine may be contributory. Supplementation with GlyNAC (combination of glycine and N-acetylcysteine as a cysteine precursor) was found to improve/correct cellular glycine, cysteine, and glutathione deficiencies; lower oxidative stress; and improve mitochondrial function, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, and multiple aging hallmarks; and improve muscle strength, exercise capacity, cognition, and body composition.[8][12][13][14] The mice that received GlyNAC lived 24% longer than those that did not receive GlyNAC.[8][15]

Glycine is genetically associated with lower coronary heart disease risk and lower incidence of type 2 diabetes.[16] Glycine improved the endothelium function in aged rats possibly by enhancing eNOS expression and reducing the role of superoxide anion and contractile prostanoids that increase the nitric oxide bioavailability.[17][18]

Glycine serves as the acceptor for a methylation reaction catalyzed by glycine N-methyltransferase, which takes a methyl group from S-adenosyl-L-methionine and transfers it to glycine to form sarcosine (methylglycine) and S-adenosyl-L-homocysteine. Glycine N-methyltransferase prolongs life in flies when overexpressed.[19]

Glycinamide (2-aminoacetamide) hydrochloride

Because glycine residues occupy 1/3 of amino acid residues in collagen protein,[20] the supply of glycine may be a limiting factor for collagen synthesis and must be present in the diet in large amounts to satisfy the demands for collagen synthesis for prevention of osteoarthritis.[21] An optimized form of glycine precursor glycinamide (2-aminoacetamide) increased collagen production much more effectively than glycine, especially synergistically in combination with ascorbic acid.[22] Moreover, some 2-aminoacetamide derivatives have good anti-inflammatory activity. Among them, compound f15 showed the most prominent performance and blocked the excitation of nuclear factor κB (NF-кB) signaling pathway in a concentration-dependent manner. Furthermore, in-vivo experiment showed that f15 reduced arthritic index in adjuvant-induced arthritis rats and inhibited the production of TNF-α and IL-1β in serum.[23]

Glycine improves sleep quality

Glycine at a dose of 3 g/day before bedtime subjectively improves sleep quality and reduces sleepiness and fatigue during the day in individuals with insomniac tendencies or restricted sleep time. Glycine administration before bedtime also decreases core body temperature in human subjects.[24]

The glycine cleavage system

Glycine takes part in one-carbon metabolism as a methyl group provider through the glycine cleavage system.[25] The glycine cleavage system is a multienzyme complex consisting of four individual components: glycine decarboxylase, amino methyltransferase, glycine cleavage system protein H, and dihydrolipoamide dehydrogenase.[26] It has been revealed that glycine influenced stem cell pluripotency by controlling the synthesis of SAM (S-adenosylmethionine - a methyl donor in histone as well as DNA methylation[27]), thus promoting H3K4me3 modification, and open euchromatin.[25][28] This process is present in human and mouse pluripotent stem cells.[25][29]

References

  1. ↑ Razak, M. A., Begum, P. S., Viswanath, B., & Rajagopal, S. (2017). Multifarious beneficial effect of nonessential amino acid, glycine: a review. Oxidative medicine and cellular longevity, 2017:1716701. PMID: 28337245 PMCID: PMC5350494 DOI: 10.1155/2017/1716701
  2. ↑ Wang, W., Wu, Z., Dai, Z., Yang, Y., Wang, J., & Wu, G. (2013). Glycine metabolism in animals and humans: implications for nutrition and health. Amino acids, 45, 463-477. PMID: 23615880 DOI: 10.1007/s00726-013-1493-1
  3. ↑ Sekhar, R. V., Patel, S. G., Guthikonda, A. P., Reid, M., Balasubramanyam, A., Taffet, G. E., & Jahoor, F. (2011). Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation–. The American journal of clinical nutrition, 94(3), 847-853. PMID: 21795440 PMCID: PMC3155927 DOI: 10.3945/ajcn.110.003483
  4. ↑ Sekhar, R. V., McKay, S. V., Patel, S. G., Guthikonda, A. P., Reddy, V. T., Balasubramanyam, A., & Jahoor, F. (2011). Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine. Diabetes care, 34(1), 162-167. PMID: 20929994 PMCID: PMC3005481 DOI: 10.2337/dc10-1006
  5. ↑ Ruiz-Ramírez, A., Ortiz-Balderas, E., Cardozo-Saldaña, G., Diaz-Diaz, E., & El-Hafidi, M. (2014). Glycine restores glutathione and protects against oxidative stress in vascular tissue from sucrose-fed rats. Clinical Science, 126(1), 19-29. PMID: 23742196 DOI: 10.1042/CS20130164
  6. ↑ Aguayo-Cerón, K. A., Sánchez-Muñoz, F., Gutierrez-Rojas, R. A., Acevedo-Villavicencio, L. N., Flores-Zarate, A. V., Huang, F., ... & Romero-Nava, R. (2023). Glycine: The Smallest Anti-Inflammatory Micronutrient. International Journal of Molecular Sciences, 24(14), 11236. https://doi.org/10.3390/ijms241411236
  7. ↑ Miller, R. A., Harrison, D. E., Astle, C. M., Bogue, M. A., Brind, J., Fernandez, E., ... & Strong, R. (2019). Glycine supplementation extends lifespan of male and female mice. Aging cell, 18(3), e12953. PMID: 30916479 PMCID: PMC6516426 DOI: 10.1111/acel.12953
  8. ↑ 8.0 8.1 8.2 Kumar, P., Osahon, O. W., & Sekhar, R. V. (2022). GlyNAC (glycine and N-acetylcysteine) supplementation in mice increases length of life by correcting glutathione deficiency, oxidative stress, mitochondrial dysfunction, abnormalities in mitophagy and nutrient sensing, and genomic damage. Nutrients, 14(5), 1114. PMID: 35268089 PMCID: PMC8912885 DOI: 10.3390/nu14051114
  9. ↑ Brind, J., Malloy, V., Augie, I., Caliendo, N., Vogelman, J. H., Zimmerman, J. A., & Orentreich, N. (2011). Dietary glycine supplementation mimics lifespan extension by dietary methionine restriction in Fisher 344 rats. https://doi.org/10.1096/fasebj.25.1_supplement.528.2
  10. ↑ Liu, Y. J., Janssens, G. E., McIntyre, R. L., Molenaars, M., Kamble, R., Gao, A. W., ... & Houtkooper, R. H. (2019). Glycine promotes longevity in Caenorhabditis elegans in a methionine cycle-dependent fashion. PLoS genetics, 15(3), e1007633. PMID: 30845140 PMCID: PMC6424468 DOI: 10.1371/journal.pgen.1007633
  11. ↑ Johnson, A. A., & Cuellar, T. L. (2023). Glycine and aging: Evidence and mechanisms. Ageing Research Reviews, 101922. PMID: 37004845 DOI: 10.1016/j.arr.2023.101922
  12. ↑ Sekhar, R. V. (2021). GlyNAC supplementation improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, aging hallmarks, metabolic defects, muscle strength, cognitive decline, and body composition: Implications for healthy aging. The Journal of Nutrition, 151(12), 3606-3616. PMID: 34587244 DOI: 10.1093/jn/nxab309
  13. ↑ Kumar, P., Liu, C., Suliburk, J., Hsu, J. W., Muthupillai, R., Jahoor, F., ... & Sekhar, R. V. (2023). Supplementing glycine and N-acetylcysteine (GlyNAC) in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, physical function, and aging hallmarks: a randomized clinical trial. The Journals of Gerontology: Series A, 78(1), 75-89. PMID: 35975308 PMCID: PMC9879756 (available on 2023-08-17) DOI: 10.1093/gerona/glac135
  14. ↑ Kumar, P., Liu, C., Hsu, J. W., Chacko, S., Minard, C., Jahoor, F., & Sekhar, R. V. (2021). Glycine and N‐acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial. Clinical and Translational Medicine, 11(3), e372. PMID: 33783984 PMCID: PMC8002905 DOI: 10.1002/ctm2.372
  15. ↑ GlyNac More Anti-Aging Proof!
  16. ↑ Wittemans, L. B., Lotta, L. A., Oliver-Williams, C., Stewart, I. D., Surendran, P., Karthikeyan, S., ... & Langenberg, C. (2019). Assessing the causal association of glycine with risk of cardio-metabolic diseases. Nature communications, 10(1), 1060. PMID: 30837465 PMCID: PMC6400990 DOI: 10.1038/s41467-019-08936-1
  17. ↑ Gómez-Zamudio, J. H., García-Macedo, R., Lázaro-Suárez, M., Ibarra-Barajas, M., Kumate, J., & Cruz, M. (2015). Vascular endothelial function is improved by oral glycine treatment in aged rats. Canadian Journal of Physiology and Pharmacology, 93(6), 465-473. PMID: 25988540 DOI: 10.1139/cjpp-2014-0393
  18. ↑ Zakaria, E. R., Joseph, B., Hamidi, M., Zeeshan, M., Algamal, A., Sartaj, F., ... & Madan, D. (2019). Glycine improves peritoneal vasoreactivity to dialysis solutions in the elderly. Qatar Medical Journal, 2019(3), 19. PMID: 31903325 PMCID: PMC6929513 DOI: 10.5339/qmj.2019.19
  19. ↑ Tain, L. S., Jain, C., Nespital, T., Froehlich, J., Hinze, Y., Grönke, S., & Partridge, L. (2020). Longevity in response to lowered insulin signaling requires glycine N‐methyltransferase‐dependent spermidine production. Aging Cell, 19(1), e13043. PMID: 31721422 PMCID: PMC6974722 DOI: 10.1111/acel.13043
  20. ↑ Nassa, M., Anand, P., Jain, A., Chhabra, A., Jaiswal, A., Malhotra, U., & Rani, V. (2012). Analysis of human collagen sequences. Bioinformation, 8(1), 26. PMID: 22359431 PMCID: PMC3282272 DOI: 10.6026/97320630008026
  21. ↑ de Paz-Lugo, P., Lupiáñez, J. A., & Meléndez-Hevia, E. (2018). High glycine concentration increases collagen synthesis by articular chondrocytes in vitro: acute glycine deficiency could be an important cause of osteoarthritis. Amino Acids, 50(10), 1357-1365. PMID: 30006659 PMCID: PMC6153947 DOI: 10.1007/s00726-018-2611-x
  22. ↑ Lee, J. E., & Boo, Y. C. (2022). Combination of Glycinamide and Ascorbic Acid Synergistically Promotes Collagen Production and Wound Healing in Human Dermal Fibroblasts. Biomedicines, 10(5), 1029. PMID: 35625765 PMCID: PMC9138459 DOI: 10.3390/biomedicines10051029
  23. ↑ Liu, T., Zhu, Y., Chen, S., Du, J., Xing, S., Dong, S., ... & Li, Z. (2022). Protective effects of (4-(1, 2, 4-oxadiazol-5-yl) phenyl)-2-aminoacetamide derivatives to adjuvant-induced arthritis rats by regulating the NF-κB signaling pathway. Inflammopharmacology, 30(6), 2417-2426. PMID: 36203113 DOI: 10.1007/s10787-022-01081-0
  24. ↑ Kawai, N., Sakai, N., Okuro, M., Karakawa, S., Tsuneyoshi, Y., Kawasaki, N., ... & Nishino, S. (2015). The sleep-promoting and hypothermic effects of glycine are mediated by NMDA receptors in the suprachiasmatic nucleus. Neuropsychopharmacology, 40(6), 1405-1416. PMID: 25533534 PMCID: PMC4397399 DOI: 10.1038/npp.2014.326
  25. ↑ 25.0 25.1 25.2 Tian, S., Feng, J., Cao, Y., Shen, S., Cai, Y., Yang, D., ... & Gao, P. (2019). Glycine cleavage system determines the fate of pluripotent stem cells via the regulation of senescence and epigenetic modifications. Life Science Alliance, 2(5). PMID: 31562192 PMCID: PMC6765226 DOI: 10.26508/lsa.201900413
  26. ↑ Narisawa, A., Komatsuzaki, S., Kikuchi, A., Niihori, T., Aoki, Y., Fujiwara, K., ... & Kure, S. (2012). Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans. Human molecular genetics, 21(7), 1496-1503. PMID: 22171071 PMCID: PMC3298276 DOI: 10.1093/hmg/ddr585
  27. ↑ Liu, Y., Cui, D. X., Pan, Y., Yu, S. H., Zheng, L. W., & Wan, M. (2022). Metabolic-epigenetic nexus in regulation of stem cell fate. World Journal of Stem Cells, 14(7), 490. PMID: 36157525 PMCID: PMC9350619 DOI: 10.4252/wjsc.v14.i7.490
  28. ↑ Kang, P. J., Zheng, J., Lee, G., Son, D., Kim, I. Y., Song, G., ... & You, S. (2019). Glycine decarboxylase regulates the maintenance and induction of pluripotency via metabolic control. Metabolic engineering, 53, 35-47. PMID: 30779965 DOI: 10.1016/j.ymben.2019.02.003
  29. ↑ Zhang, J., Ratanasirintrawoot, S., Chandrasekaran, S., Wu, Z., Ficarro, S. B., Yu, C., ... & Daley, G. Q. (2016). LIN28 regulates stem cell metabolism and conversion to primed pluripotency. Cell stem cell, 19(1), 66-80. PMID: 27320042 DOI: 10.1016/j.stem.2016.05.009
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