GEROPROTECTIVE POTENTIAL OF PLANT AND SYNTHETIC ANTIOXIDANTS

Aging is an inevitable stage of life, a natural process that we all experience and often strive to slow down. As life expectancy on Earth continues to rise, the quest for longevity and vitality becomes increasingly significant. However, alongside this increase in lifespan, we face the emergence of diseases associated with aging and genetic mutations that can lead to various health complications. This dual challenge has long been a concern for researchers and healthcare professionals.

To mitigate the negative impact of aging on health, it is crucial to explore ways to slow down this process. This article discusses several promising options that suggest their effectiveness against aging, potentially acting as geroprotectors. Among these, antioxidants are perhaps the most popular choice due to their ability to reduce oxidative stress caused by free radicals—unstable molecules that can damage cells and contribute to aging.

In addition to traditional antioxidants, synthetic antioxidants such as enzyme mimetics are becoming a focal point of therapeutic research. These compounds aim to replicate the action of natural enzymes that combat oxidative stress, offering a novel approach to age-related health issues. Furthermore, polyphenols, naturally occurring compounds found in various fruits, vegetables, and beverages like tea and red wine, have garnered attention for their potential health benefits.

Together, these compounds may contribute to new research opportunities aimed at combating age-related pathology and improving overall health outcomes. By understanding and harnessing the power of antioxidants, enzyme mimetics, and polyphenols, we may pave the way for innovative interventions that not only extend lifespan but also enhance the quality of life for individuals as they age. The pursuit of effective geroprotectors represents a vital frontier in promoting healthy aging and preventing age-related diseases.

1. Akhlaghi M., Ghobadi S., Mohammad Hosseini M., Gholami Z., Mohammadian F. Flavanols are potential anti-obesity agents, a systematic review and meta-analysis of controlled clinical trials. Nutr. Metab. Cardiovasc. Dis. 2018; 28 (7): 675-690.

2. Balducci L., Falandry C., Monfardini S. Senotherapy, cancer, and aging. J. Geriatr. Oncol. 2024; 15 (4): 101671.

3. Barreiro-Sisto U., Fernández-Fariña S., GonzálezNoya A.M., Pedrido R., Maneiro M. Enemies or Allies? Hormetic and Apparent Non-Dose-Dependent Effects of Natural Bioactive Antioxidants in the Treatment of Inflammation. Int. J. Mol. Sci. 2024; 25 (3): 1892.

4. Basu A., Betts N.M., Nguyen A., Newman E.D., Fu D., Lyons T.J. Freeze-Dried Strawberries Lower Serum Cholesterol and Lipid Peroxidation in Adults with Abdominal Adiposity and Elevated Serum Lipids. J. Nutr. 2014; 144: 830-837.

5. Batinic-Haberle I., Tome M.E. Thiol regulation by Mn porphyrins, commonly known as SOD mimics. Redox. Biol. 2019; 25: 101139.

6. Bensalem J., Dudonné S., Etchamendy N., Pellay H., Amadieu C., Gaudout D., Dubreuil S., Paradis M.E., Pomerleau S., Capuron L., Hudon C., Layé S., Desjardins Y., Pallet V. Polyphenols From Grape and Blueberry Improve Episodic Memory in Healthy Elderly with Lower Level of Memory Performance: A Bicentric Double-Blind, Randomized, Placebo-Controlled Clinical Study. J. Gerontol. A. Biol. Sci. Med. Sci. 2019; 18 (7): 996-1007.

7. Bjelakovic G., Nikolova D., Gluud L.L., Simonetti R.G., Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst. Rev. 2012; 3: CD007176.

8. Boccellino M. Health Effects of Natural Antioxidants. Int. J. Mol. Sci. 2023; 24 (13): 10792.

9. Bocsan I.C., Măgureanu D.C., Pop R.M., Levai A.M., Macovei Ș.O., Pătrașca I.M., Chedea V.S., Buzoianu A.D. Antioxidant and Anti-Inflammatory Actions of Polyphenols from Red and White Grape Pomace in Ischemic Heart Diseases. Biomedicines. 2022; 10: 2337.

10. Brown K., Theofanous D., Britton R.G., Aburido G., Pepper C., Sri Undru S., Howells L. Resveratrol for the Management of Human Health: How Far Have We Come? A Systematic Review of Resveratrol Clinical Trials to Highlight Gaps and Opportunities. Int. J. Mol. Sci. 2024; 25 (2): 747.

11. Chandrasekaran V., Hediyal T.A., Anand N., Kendaganna P.H., Gorantla V.R., Mahalakshmi A.M., Ghanekar R.K., Yang J., Sakharkar M.K., Chidambaram S.B. Polyphenols, Autophagy and Neurodegenerative Diseases: A Review. Biomolecules. 2023; 13 (8): 1196.

12. Clement M.V., Luo L. Organismal aging and oxidants beyond macromolecules damage. Proteomics. 2020; 20 (5): 1800400.

13. Do H.T., Li H., Chreifi G., Poulos T.L., Silverman R.B. Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold. J. Med. Chem. 2019; 62 (5): 2690-2707.

14. Dorheim M.-A., Tracey W.R., Pollock J.S., Grammas P. Nitric oxide synthase activity is elevated in brain microvessels in Alz-heimer's disease. Biochem. Biophys. Res. Commun. 1994; 205: 659-665.

15. Drechsel D.A., Estévez A.G., Barbeito L., Beckman J.S. Nitric oxide-mediated oxidative damage and the progressive demise of motor neurons in ALS. Neurotoxic. Res. 2012; 22: 251-264.

16. Du N., Yang R., Jiang S., Niu Z., Zhou W., Liu C., Gao L.; Sun Q. Anti-Aging Drugs and the Related Signal Pathways. Biomedicines. 2024; 12: 127.

17. Erlund I., Koli R., Alfthan G., Marniemi J., Puukka P., Mustonen P., Mattila P., Jula A. Favorable effects of berry consumption on platelet function, blood pressure, and HDL cholesterol. Am. J. Clin. Nutr. 2008; 87: 323-331.

18. Forman H.J., Zhang H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat. Rev. Drug. Discov. 2021; 20 (9): 689-709.

19. Fridlyanskaya I., Alekseenko L., Nikolsky N. Senescence as a General Cellular Response to Stress: A Mini-Review. Exp. Gerontol. 2015; 72: 124-128.

20. Fusco D., Colloca G., Lo Monaco M.R., Cesari M. Effects of antioxidant supplementation on the aging process. Clinical Interventions in Aging. 2007; 2: 377-387.

21. Gonzalez P.K., Zhuang J., Doctrow S.R., Malfroy B., Benson P.F., Menconi M.J., Fink M.P. EUK-8, a synthetic superoxide dismutase and catalase mimetic, ameliorates acute lung injury in endotoxemic swine. J. Pharmacol. Exp. Ther. 1995; 275 (2): 798-806.

22. Gorgoulis V., Adams P.D., Alimonti A., Bennett D.C., Bischof O., Bishop C., Campisi J., Collado M., Evangelou K., Ferbeyre G. Cellular Senescence: Defining a Path Forward. Cell. 2019; 179: 813-827.

23. Hair R, Sakaki JR, Chun OK. Anthocyanins, Microbiome and Health Benefits in Aging. Molecules. 2021; 26 (3): 537.

24. Hall C.N., Garthwaite J. What is the real physiological NO concentration in vivo? Nitric Oxide. 2009; 21: 92-103.

25. Halliwell B., Gutteridge J.M.C. Free radicals in biology and medicine. Oxford; 2015: 896.

26. Halliwell B., Zhao K., Whiteman M. The gastrointestinal tract: a major site of antioxidant action? Free Radic. Res. 2000; 33 (6): 819-830.

27. Halliwell B. Reactive oxygen species (ROS), oxygen radicals and antioxidants: where are we now,

28. where is the field going and where should we go? Biochem. Biophys. Res. Commun. 2022; 633: 17-19.

29. Halliwell B. Understanding mechanisms of antioxidant action in health and disease. Nat. Rev. Mol. Cell. Biol. 2024; 25 (1): 13-33.

30. Harman D. Aging: A theory based on free radical and radiation chemistry. J. Gerontol. 1956; 11: 298-300.

31. Harman D. Prolongation of life: Role of free radical reactions in aging J. Am. Geriatr. Soc. 1969; 17: 721-735.

32. Jayarathne S., Stull A.J., Park O.H., Kim J.H., Thompson L., Moustaid-Moussa N. Protective Effects of Anthocyanins in Obesity-Associated Inflammation and Changes in Gut Microbiome. Mol. Nutr. Food Res. 2019; 63 (20): 1900149.

33. Jenkins D.J.A., Spence J.D., Giovannucci E.L., Kim Y.I., Josse R.G., Vieth R., Sahye-Pudaruth S., Paquette M., Patel D., Blanco Mejia S., Viguiliouk E., Nishi S.K., Kavanagh M., Tsirakis T., Kendall C.W.C., Pichika S.C., Sievenpiper J.L. Supplemental Vitamins and Minerals for Cardiovascular Disease Prevention and Treatment: JACC Focus Seminar. J. Am. Coll. Cardiol. 2021; 77 (4): 423-436.

34. Jenner A.M., Rafter J., Halliwell B. Human fecal water content of phenolics: the extent of colonic exposure to aromatic compounds. Free Radic. Biol. Med. 2005; 38 (6): 763-772.

35. John Orie K., Ukachukwu Duru R., Ioro Ngochindo R. Syntheses, complexation and biological activity of Aminopyridines: A mini-review. American Journal of Heterocyclic Chemistry. 2021; 7 (2): 11-25.

36. Kaplan A., Zelicha H., Yaskolka Meir A. The effect of a high-polyphenol Mediterranean diet (Green-MED) combined with physical activity on age-related brain atrophy: the Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study (DIRECT PLUS). Am. J. Clin. Nutr. 2022; 115 (5): 1270-1281.

37. Kibou Z., Aissaoui N., Daoud I., Seijas J.A., Vázquez-Tato M.P., Klouche Khelil N., Choukcou-Braham N. Efficient synthesis of 2-aminopyridine derivatives: Antibacterial activity assessment and Molecular Docking Studies. Molecules. 2022; 27 (11): 3439.

38. Kučera J., Binó L., Štefková K., Jaroš J., Vašíček O., Večeřa J., Kubala L., Pacherník J. Apocynin and Diphenyleneiodonium Induce Oxidative Stress and Modulate PI3K/Akt and MAPK/Erk Activity in Mouse Embryonic Stem Cells. Oxid. Med. Cell Longev. 2016; 7409196.

39. Kulakov I.V., Matsukevich M.V., Shulgau Z.T., Sergazy S., Seilkhanov T.M., Puzari A., Fisyuk A.S. Synthesis and antiradical activity of 4-aryl(hetaryl)-substituted 3-aminopyridine-2 (1H)-ones. Chemistry of Heterocyclic Compounds. 2015; 51 (11-12): 991-996.

40. La Grotta R., Frigé C., Matacchione G., Olivieri F., de Candia P., Ceriello A., Prattichizzo F. Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms. Int. J. Mol. Sci. 2022; 23 (20): 12325.

41. Lagu S.B., Yejella R.P., Nissankararao S., Bhandare R.R., Golla V.S., Subrahmanya Lokesh B.V., Rahman M.M., Shaik A.B. Antitubercular activity assessment of fluorinated chalcones, 2-aminopyridine-3-carbonitrile and 2-amino-4h-pyran-3-carbonitrile derivatives: In vitro, molecular docking and in-silico drug likeliness studies. PLoS One. 2022; 17 (6): 0265068.

42. Li T.S., Marbán E. Physiological Levels of Reactive Oxygen Species Are Required to Maintain Genomic Stability in Stem Cells. Stem Cells. 2010; 28: 1178-1185.

43. Liguori I., Russo G., Curcio F., Bulli G., Aran L., Della-Morte D., Gargiulo G., Testa G., Cacciatore F., Bonaduce D., Abete P. Oxidative stress, aging, and diseases. Clin. Interv. Aging. 2018; 13: 757-772.

44. Liu F., Shan S., Li H., Shi J., Hao R., Yang R., Li Z. Millet shell polyphenols prevent atherosclerosis by protecting the gut barrier and remodeling the gut microbiota in ApoE−/− mice. Food Funct. 2021; 12: 7298-7309.

45. Long L.H., Hoi A., Halliwell B. Instability of, and generation of hydrogen peroxide by, phenolic compounds in cell culture media. Arch. Biochem. Biophys. 2010; 501 (1): 162-169.

46. Lu L.Y., Ou N., Lu Q.B. Antioxidant Induces DNA Damage, Cell Death and Mutagenicity in Human Lung and Skin Normal Cells. Sci. Rep. 2013; 3: 3169.

47. Lushchak O., Schosserer M., Grillari J. Senopathies-Diseases Associated with Cellular Senescence. Biomolecules. 2023;13 (6): 966.

48. Mannick J.B., Morris M., Hockey H.P., Roma G., Beibel M., Kulmatycki K., Watkins M., Shavlakadze T., Zhou W., Quinn D., Glass D.J., Klickstein L.B. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 2018; 10 (449): 1564.

49. Marín L., Miguélez E.M., Villar C.J., Lombó F. Bioavailability of dietary polyphenols and gut microbiota metabolism: Antimicrobial properties // Biomed. Res. Int. – 2015. – P. 905215.

50. Matziouridou C., Marungruang N., Nguyen T.D., Nyman M., Hållenius F.F. Lingonberries reduce atherosclerosis in Ap-oe-/-mice in association with altered gut microbiota composition and improved lipid profile. Mol. Nutr. Food Res. 2016; 60: 1150-1160.

51. Mena P., Bresciani L., Brindani N., Ludwig I.A., Pereira-Caro G. Phenyl-γ-valerolactones and phenylvaleric acids, the main colonic metabolites of flavan-3-ols: synthesis, analysis, bioavailability, and bioactivity. Nat. Prod. Rep. 2019; 36 (5): 714-752.

52. Munguía L., Ortiz M., González C., Portilla A., Meaney E., Villarreal F., Nájera N., Ceballos G. Beneficial Effects of Flavonoids on Skeletal Muscle Health: A Systematic Review and Meta-Analysis. J. Med. Food. 2022; 25 (5): 465-486.

53. Nederveen J.P., Mastrolonardo A.J., Xhuti D., Di Carlo A., Manta K., Fuda M.R., Tarnopolsky M.A. Novel Multi-Ingredient Supplement Facilitates Weight Loss and Improves Body Composition in Overweight and Obese Individuals: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Nutrients. 2023; 15 (17): 3693.

54. Norris P.J., Waldvogel H.J., Faull R.L.M., Love D.R., Emson P.C. Decreased neuronal nitric oxide synthase messenger RNA and somatostatin messenger RNA in the striatum of Huntington’s disease. Neuronsicence. 1996; 72: 1037-1047.

55. Orie K.J., Duru R.U., Ngochindo R.I. Synthesis and complexation of monotosylated 4-aminopyridine with nickel (II) and iron (II) ions. Makara Journal of Science. 2021; 23 (3): 172-179

56. Oteiza P.I., Fraga C.G., Galleano M. Linking biomarkers of oxidative stress and disease with flavonoid consumption: from experimental models to humans. Redox Biol. 2021; 42: 101914.

57. Pandey K.B., Rizvi S.I. Plant Polyphenols as Dietary Antioxidants in Human Health and Disease. Oxidative Med. Cell. Longev. 2009; 2: 270-278.

58. Panwar V., Singh A., Bhatt M., Tonk R.K., Azizov S., Raza A.S., Sengupta S., Kumar D., Garg M. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal. Transduct. Target. Ther. 2023; 8 (1): 375.

59. Popescu I., Deelen J., Illario M., Adams J. Challenges in anti-aging medicine-trends in biomarker discovery and therapeutic interventions for a healthy lifespan. J. Cell. Mol. Med. 2023; 27 (18): 2643-2650.

60. Ramaiah P, Baljon KJ, Hjazi A, Qasim MT, Salih Al-Ani OA, Imad S, Hussien BM, Alsalamy A, Garousi N. Dietary polyphenols and the risk of metabolic syndrome: a systematic review and meta-analysis. BMC Endocr Disord. 2024; 24 (1): 26.

61. Rao R.N., Chanda K. 2-aminopyridine – an unsung hero in drug discovery. Chemical Communications. 2022; 58 (3): 343-382.

62. Saadon K.E., Taha N.M., Mahmoud N.A., Elhagali G.A., Ragab A. Synthesis, characterization, and in vitro antibacterial activity of some new pyridinone and pyrazole derivatives with some in silico ADME and Molecular Modeling Study. Journal of the Iranian Chemical Society. 2022; 19 (9): 3899-3917.

63. Salhi F., Cheikh N., Villemin D., Bar N. Synthesis of 2-aminopyridine lactones and studies of their antioxidant, antibacterial and antifungal properties. ECSOC-25. 2022; 8 (1): 94.

64. Schaffer S., Halliwell B. Do polyphenols enter the brain and does it matter? Some theoretical and practical considerations. Genes Nutr. 2012; 7 (2): 99-109.

65. Schönberger E., Mihaljevi´c V., Steiner K., Šari´c S., Kurevija T., Majnari´c L.T., Bili´c Curˇci´c, I., ´Canecki-Varži´c S. Immunomodulatory Effects of SGLT2 Inhibitors – Targeting Inflammation and Oxidative Stress in Aging. Int. J. Environ. Res. Public Health. 2023; 20: 6671.

66. Scisciola L., Olivieri F., Ambrosino C., Barbieri M., Rizzo M.R., Paolisso G. On the wake of metformin: Do anti-diabetic SGLT2 inhibitors exert anti-aging effects? Ageing Res. Rev. 2023; 92: 102131.

67. Sergazy S., Shulgau Z., Zhulikeyeva A., Ramankulov Y., Palamarchuk I.V., Kulakov I.V. Cytoprotective activity of newly synthesized 3-(Arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones derivatives. Molecules. 2022; 27 (17): 5362.

68. Serino A., Salazar G. Protective Role of Polyphenols against Vascular Inflammation, Aging and Cardiovascular Disease. Nutrients. 2018; 11: 53.

69. Sies H. Oxidative stress: concept and some practical aspects. Antioxidants. 2020; 9: 852.

70. Silwal P., Nguyen-Thai A.M., Mohammad H.A., Wang Y., Robbins P.D., Lee J.Y., Vo N.V. Cellular Senescence in Intervertebral Disc Aging and Degeneration: Molecular Mechanisms and Potential Therapeutic Opportunities. Biomolecules. 2023; 13 (4): 686.

71. Sims N.R., Anderson M.F. Mitochondrial contributions to tissue damage in stroke. Neurochem. Int. 2002; 40: 511-526.

72. Smeriglio A., Barreca D., Bellocco E., Trombetta D. Proanthocyanidins and hydrolysable tannins: Occurrence, dietary intake and pharmacological effects. Br. J. Pharmacol. 2017; 174: 1244-1262.

73. Stoia M, Oancea S. Low-Molecular-Weight Synthetic Antioxidants: Classification, Pharmacological Profile, Effectiveness and Trends. Antioxidants (Basel). 2022; 11 (4): 638.

74. Torreilles F., Salman-Tabcheh S., Guérin M., Torreilles J. Neurodegenerative disorders: the role of peroxynitrite. Brain Res. Rev. 1999; 30: 153-163.

75. Tyuryaeva I., Lyublinskaya O. Expected and Unexpected Effects of Pharmacological Antioxidants. Int. J. Mol. Sci. 2023; 24 (11): 9303.

76. Vasu D., Do H.T., Li H., Hardy C.D., Awasthi A., Poulos T.L., Silverman R.B. Potent, Selective, and Membrane Permeable 2-Amino-4-Substituted Pyridine-Based Neuronal Nitric Oxide Synthase Inhibitors. J. Med. Chem. 2023; 66 (14): 9934-9953.

77. Vasu D., Li H., Hardy C.D., Poulos T.L., Silverman R.B. 2-Aminopyridines with a shortened amino sidechain as potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors. Bioorg. Med. Chem. 2022; 69: 116878.

78. Vincent A., Thauvin M., Quévrain E., Mathieu E., Layani S., Seksik P., Batinic-Haberle I., Vriz S., Policar C., Delsuc N. Evaluation of the compounds commonly known as superoxide dismutase and catalase mimics in cellular models. J. Inorg. Biochem. 2021; 219: 111431.

79. Vono R., Jover Garcia E., Spinetti G., Madeddu P. Oxidative Stress in Mesenchymal Stem Cell Senescence: Regulation by Coding and Noncoding RNAs. Antioxid. Redox. Signal. 2018; 29: 864-879.

80. Wang B., Tang X., Mao B., Zhang Q., Tian F., Zhao J., Cui S., Chen W. Anti-aging effects and mechanisms of anthocyanins and their intestinal microflora metabolites. Crit. Rev. Food. Sci. Nutr. 2024; 64 (8): 2358-2374.

81. Warraich U.-e-A., Hussain F., Kayani H.U. Aging oxidative stress, Antioxidants and computational modeling. Heliyon. 2020. Vol. 6, No. 5.

82. Weaver S.R., Rendeiro C., McGettrick H.M., Philp A., Lucas S.J.E. Fine wine or sour grapes? A systematic review and meta-analysis of the impact of red wine polyphenols on vascular health. Eur. J. Nutr. 2021; 60 (1): 1-28.

83. Williamson G., Kay C.D., Crozier A. The bioavailability, transport, and bioactivity of dietary flavonoids: a review from a historical perspective. Compr. Rev. Food Sci. Food Saf. 2018; 17 (5): 1054-112.

84. Wolrd Health Organization. Available online: https:// www.who.int/news-room/fact-sheets/detail/ageing-andhealth Wood E., Hein S., Mesnage R., Fernandes F., Abhayaratne N., Xu Y., Zhang Z., Bell L., Williams C., Rodriguez-Mateos A. Wild blueberry (poly)phenols can improve vascular function and cognitive performance in healthy older individuals: a double-blind randomized controlled trial. Am. J. Clin. Nutr. 2023; 117 (6): 1306-1319.

85. Wu M.H., Liu J.Y., Tsai F.L., Syu J.J., Yun C.S., Chen L.Y., Ye J.C. The adverse and beneficial effects of polyphenols in green and black teas in vitro and in vivo. Int. J. Med. Sci. 2023; 20 (10): 1247-1255.

86. Yan L., Guo M.S., Zhang Y., Yu L., Wu J.M., Tang Y., Ai W., Zhu F.D., Law B.Y., Chen Q., Yu C.L., Wong V.K., Li H., Li M., Zhou X.G., Qin D.L., Wu A.G. Dietary Plant Polyphenols as the Potential Drugs in Neurodegenerative Diseases: Current Evidence, Advances, and Opportunities. Oxid. Med. Cell Longev. 2022; 5288698: 40.

87. Yaskolka Meir A., Keller M., Hoffmann A. The effect of polyphenols on DNA methylation-assessed biological age attenuation: the DIRECT PLUS randomized controlled trial. BMC Med. 2023; 21 (1): 364.

88. Zeb A. Concept, mechanism, and applications of phenolic antioxidants in foods. J. Food. Biochem. 2020; 44 (9): 13394.

89. Zhang L., Dawson V.L., Dawson T.M. Role of nitric oxide in Parkinson’s disease. Pharmacol. Ther. 2006; 109: 33-41.

90. Zhang Y., Balasooriya H., Sirisena S., Ng K. The effectiveness of dietary polyphenols in obesity management: A systematic review and meta-analysis of human clinical trials. Food. Chem. 2023; 15 (404): 134668.

91. Zhong H., Xu J., Yang M., Hussain M., Liu X., Feng F., Guan R. Protective Effect of Anthocyanins against Neurodegenerative Diseases through the Microbial-Intestinal-Brain Axis: A Critical Review. Nutrients. 2023; 15 (3): 496.