Aging is a complex physiological process that can be accelerated by chemical (high blood glucose levels) or physical (solar exposure) factors. It is accompanied by the accumulation of altered molecules in the human body. The accumulation of oxidatively modified and glycated proteins is associated with inflammation and the progression of chronic diseases (aging). The use of antiglycating agents is one of the recent approaches in the preventive strategy of aging and natural compounds seem to be promising candidates. Our study focused on the anti-aging effect of the flavonoid hesperetin, its glycoside hesperidin and its carbohydrate moieties rutinose and rhamnose on young and physiologically aged normal human dermal fibroblasts (NHDFs). The anti-aging activity of the test compounds was evaluated by measuring matrix metalloproteinases (MMPs) and inflammatory interleukins by ELISA. The modulation of elastase, hyaluronidase, and collagenase activity by the tested substances was evaluated spectrophotometrically by tube tests. Rutinose and rhamnose inhibited the activity of pure elastase, hyaluronidase, and collagenase. Hesperidin and hesperetin inhibited elastase and hyaluronidase activity. In skin aging models, MMP-1 and MMP-2 levels were reduced after application of all tested substances. Collagen I production was increased after the application of rhamnose and rutinose.

Department of Biochemistry and Microbiology University of Chemistry and Technology Prague Technická 3 166 28 Prague 6 Czech Republic

Department of Medical Chemistry and Biochemistry Faculty of Medicine and Dentistry Palacký University Olomouc Hněvotínská 3 775 15 Olomouc Czech Republic

Laboratory of Biotransformation Institute of Microbiology Academy of Sciences of the Czech Republic Vídeňská 1083 142 00 Prague 4 Czech Republic

See more in PubMed

Vostálová J., Tinková E., Biedermann D., Kosina P., Ulrichová J., Rajnochová Svobodová A. Skin protective activity of silymarin and its flavonolignans. Molecules. 2019;24:1022. doi: 10.3390/molecules24061022. PubMed DOI PMC

Blume-Peytavi U., Kottner J., Sterry W., Hodin M., Griffiths T., Watson R., Hay R., Griffiths C. Age-associated skin conditions and diseases: Current perspectives and future options. Gerontologist. 2016;56:S230–S242. doi: 10.1093/geront/gnw003. PubMed DOI

Wang A., Dreesen O. Biomarkers of cellular senescence and skin aging. Front. Genet. 2018;9:247. doi: 10.3389/fgene.2018.00247. PubMed DOI PMC

Csekes E., Račková L. Skin aging, cellular senescence and natural polyphenols. Int. J. Mol. Sci. 2021;22:12641. doi: 10.3390/ijms222312641. PubMed DOI PMC

Shen C., Lu C., Wu C., Li K., Kuo Y., Hsieh S., Yu C. The development of Maillard reaction, and advanced glycation end product (AGE)-receptor for AGE (RAGE) signaling inhibitors as novel therapeutic strategies for patients with AGE-related diseases. Molecules. 2020;25:5591. doi: 10.3390/molecules25235591. PubMed DOI PMC

Velichkova S., Foubert K., Pieters L. Natural products as a source of inspiration for novel inhibitors of advanced glycation endproducts (AGEs) formation. Planta Med. 2021;87:780–801. doi: 10.1055/a-1527-7611. PubMed DOI

Gkogkolou P., Böhm M. Advanced glycation end products: Key players in skin aging? Derm.-Endocrinol. 2014;4:259–270. doi: 10.4161/derm.22028. PubMed DOI PMC

Stanisic D., Liu L., dos Santos R., Costa A., Durán N., Tasic L. New sustainable process for hesperidin isolation and anti-ageing effects of hesperidin nanocrystals. Molecules. 2020;25:4534. doi: 10.3390/molecules25194534. PubMed DOI PMC

Lee H., Im A., Kim S., Kang H., Lee J., Chae S. The flavonoid hesperidin exerts anti-photoaging effect by downregulating matrix metalloproteinase (MMP)-9 expression via mitogen activated protein kinase (MAPK)-dependent signaling pathways. BMC Complement. Altern. Med. 2018;18:39. doi: 10.1186/s12906-017-2058-8. PubMed DOI PMC

Sheen Y., Huang H., Liao Y. The efficacy and safety of an antiaging topical serum containing hesperetin and sodium cyclic lysophosphatidic acid: A single-center clinical trial. J. Cosmet. Dermatol. 2021;20:3960–3967. doi: 10.1111/jocd.14063. PubMed DOI

Hering A., Ochocka J.R., Baranska H., Cal K., Stefanowicz-Hajduk J. Mangiferin and hesperidin transdermal distribution and permeability through the skin from solutions and honeybush extracts (Cyclopia sp.)-A comparison ex vivo study. Molecules. 2021;26:6547. doi: 10.3390/molecules26216547. PubMed DOI PMC

Wdowiak K., Walkowiak J., Pietrzak R., Bazan-Woźniak A., Cielecka-Piontek J. Bioavailability of hesperidin and its aglycone hesperetin-compounds found in citrus fruits as a parameter conditioning the pro-health potential (neuroprotective and antidiabetic activity)-mini-review. Nutrients. 2022;14:2647. doi: 10.3390/nu14132647. PubMed DOI PMC

Pageon H., Azouaoui A., Zucchi H., Ricois S., Tran C., Asselineau D. Potentially beneficial effects of rhamnose on skin ageing: An in vitro and in vivo study. Int. J. Cosmet. Sci. 2019;41:213–220. doi: 10.1111/ics.12523. PubMed DOI

Ravelojaona V., Molinari J., Robert L. Protection by rhamnose-rich polysaccharides against the cytotoxicity of Maillard reaction products. Biomed. Pharmacother. 2006;60:359–362. doi: 10.1016/j.biopha.2006.06.019. PubMed DOI

Robert L., Molinari J., Ravelojaona V., Andrès E., Robert A. Age- and passage-dependent upregulation of fibroblast elastase-type endopeptidase activity. Role of advanced glycation endproducts, inhibition by fucose- and rhamnose-rich oligosaccharides. Arch. Gerontol. Geriatr. 2010;50:327–331. doi: 10.1016/j.archger.2009.05.006. PubMed DOI

Ho C., Dreesen O. Faces of cellular senescence in skin aging. Mech. Ageing Dev. 2021;198:111525. doi: 10.1016/j.mad.2021.111525. PubMed DOI

Gu Y., Han J., Jiang C., Zhang Y. Biomarkers, oxidative stress and autophagy in skin aging. Ageing Res. Rev. 2020;59:101036. doi: 10.1016/j.arr.2020.101036. PubMed DOI

Franco A., Aveleira C., Cavadas C. Skin senescence: Mechanisms and impact on whole-body aging. Trends Mol. Med. 2022;28:97–109. doi: 10.1016/j.molmed.2021.12.003. PubMed DOI

Nguyen H., Katta R. Sugar sag: Glycation and the role of diet in aging skin. Skin Therapy Lett. 2015;20:1–5. PubMed

Robert L., Labat-Robert J., Robert A. Physiology of skin aging. Pathol. Biol. 2009;57:336–341. doi: 10.1016/j.patbio.2008.09.007. PubMed DOI

Santhanam R., Fakurazi S., Ahmad S., Abas F., Ismail I., Rukayadi Y., Akhtar M., Shaari K. Inhibition of UVB-induced pro-inflammatory cytokines and MMP expression by Zanthoxylum rhetsa bark extract and its active constituent hesperidin. Phytother. Res. 2018;32:1608–1616. doi: 10.1002/ptr.6092. PubMed DOI

Lee D., Oh J., Chung J. Glycosaminoglycan and proteoglycan in skin aging. J. Dermatol. Sci. 2016;83:174–181. doi: 10.1016/j.jdermsci.2016.05.016. PubMed DOI

Andrès E., Molinari J., Péterszegi G., Mariko B., Ruszova E., Velebny V., Faury G., Robert L. Pharmacological properties of rhamnose-rich polysaccharides, potential interest in age-dependent alterations of connectives tissues. Pathol. Biol. 2006;54:420–425. doi: 10.1016/j.patbio.2006.07.004. PubMed DOI

Faury G., Ruszova E., Molinari J., Mariko B., Raveaud S., Velebny V., Robert L. The α-l-Rhamnose recognizing lectin site of human dermal fibroblasts functions as a signal transducer. Biochim. Biophys. Acta (BBA)—Gen. Subjects. 2008;1780:1388–1394. doi: 10.1016/j.bbagen.2008.07.008. PubMed DOI

Vidhya R., Anbumani V., Dinakara Rao A., Anuradha C. Identification of novel human neutrophil elastase inhibitors from dietary phytochemicals using in silico and in vitro studies. J. Biomol. Struct. Dyn. 2022;40:3451–3461. doi: 10.1080/07391102.2020.1847685. PubMed DOI

Li X., Xu R., Cheng Z., Song Z., Wang Z., Duan H., Wu X., Ni T. Comparative study on the interaction between flavonoids with different core structures and hyaluronidase. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2021;262:120079. doi: 10.1016/j.saa.2021.120079. PubMed DOI

Man G., Mauro T., Zhai Y., Kim P., Cheung C., Hupe M., Crumrine D., Elias P., Man M. Topical hesperidin enhances epidermal function in an aged murine model. J. Investig. Dermatol. 2015;135:1184–1187. doi: 10.1038/jid.2014.486. PubMed DOI PMC

Roohbakhsh A., Parhiz H., Soltani F., Rezaee R., Iranshahi M. Molecular mechanisms behind the biological effects of hesperidin and hesperetin for the prevention of cancer and cardiovascular diseases. Life Sci. 2015;124:64–74. doi: 10.1016/j.lfs.2014.12.030. PubMed DOI

Quan T., Qin Z., Xia W., Shao Y., Voorhees J., Fisher G. Matrix-degrading metalloproteinases in photoaging. J. Investig. Dermatol. Symp. Proc. 2009;14:20–24. doi: 10.1038/jidsymp.2009.8. PubMed DOI PMC

Lu Z., Xia Q., Cheng Y., Lu Q., Li Y., Zeng N., Luan X., Li Y., Fan L., Luo D. Hesperetin attenuates UVA-induced photodamage in human dermal fibroblast cells. J. Cosmet. Dermatol. 2022;21:6261–6269. doi: 10.1111/jocd.15230. PubMed DOI

Hiraishi N., Maruno T., Tochio N., Sono R., Otsuki M., Takatsuka T., Tagami J., Kobayashi Y. Hesperidin interaction to collagen detected by physico-chemical techniques. Dent. Mater. 2017;33:33–42. doi: 10.1016/j.dental.2016.09.035. PubMed DOI

Péterszegi G., Andrès E., Molinari J., Ravelojaona V., Robert L. Effect of cellular aging on collagen biosynthesis. Arch. Gerontol. Geriatr. 2008;47:356–367. doi: 10.1016/j.archger.2007.08.019. PubMed DOI

Li M., Lin X., Lu J., Zhou B., Luo D. Hesperidin ameliorates UV radiation-induced skin damage by abrogation of oxidative stress and inflammatory in HaCaT cells. J. Photochem. Photobiol. B Biol. 2016;165:240–245. doi: 10.1016/j.jphotobiol.2016.10.037. PubMed DOI

de Araújo Andrade T., Heimfarth L., dos Santos D., dos Santos M., de Albuquerque-Júnior R., dos Santos-Neto A., de Araujo G., Lira A., Matos S., Frank L., et al. Hesperetin-based hydrogels protect the skin against UV radiation-induced damage. AAPS PharmSciTech. 2022;23:170. doi: 10.1208/s12249-022-02323-8. PubMed DOI

Huang A., Zhang Y., Ding H., Li B., Huang C., Meng X., Li J. Design, synthesis and investigation of potential anti-inflammatory activity of O-alkyl and O-benzyl hesperetin derivatives. Int. Immunopharmacol. 2018;61:82–91. doi: 10.1016/j.intimp.2018.05.009. PubMed DOI

Li X., Xie X., Zhang L., Meng Y., Li N., Wang M., Zhai C., Liu Z., Di T., Zhang L., et al. Hesperidin inhibits keratinocyte proliferation and imiquimod-induced psoriasis-like dermatitis via the IRS-1/ERK1/2 pathway. Life Sci. 2019;219:311–321. doi: 10.1016/j.lfs.2019.01.019. PubMed DOI

Kapešová J., Petrásková L., Markošová K., Rebroš M., Kotik M., Bojarová P., Křen V. Bioproduction of quercetin and rutinose catalyzed by rutinosidase: Novel concept of “solid state biocatalysis”. Int. J. Mol. Sci. 2019;20:1112. doi: 10.3390/ijms20051112. PubMed DOI PMC

Ndlovu G., Fouche G., Tselanyane M., Cordier W., Steenkamp V. In vitro determination of the anti-aging potential of four southern African medicinal plants. BMC Complement. Altern. Med. 2013;13:304. doi: 10.1186/1472-6882-13-304. PubMed DOI PMC

Ryšavá A., Čížková K., Franková J., Roubalová L., Ulrichová J., Vostálová J., Vrba J., Zálešák B., Rajnochová Svobodová A. Effect of UVA radiation on the Nrf2 signalling pathway in human skin cells. J. Photochem. Photobiol. B Biol. 2020;209:111948. doi: 10.1016/j.jphotobiol.2020.111948. PubMed DOI

Kumar P., Nagarajan A., Uchil P. Analysis of Cell Viability by the MTT Assay. Cold Spring Harbor Protocols. 2018;2018:6. doi: 10.1101/pdb.prot095505. PubMed DOI

Flavonoids as Aglycones in Retaining Glycosidase-Catalyzed Reactions: Prospects for Green Chemistry