{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:09:21Z","timestamp":1790870961268,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Peking University Medical\u2013Qingyan Boshi Joint Laboratory","award":["L202206"],"award-info":[{"award-number":["L202206"]}]},{"name":"Peking University Medical\u2013Qingyan Boshi Joint Laboratory","award":["7232238"],"award-info":[{"award-number":["7232238"]}]},{"name":"Peking University Medical\u2013Qingyan Boshi Joint Laboratory","award":["2023YFC3604702"],"award-info":[{"award-number":["2023YFC3604702"]}]},{"name":"Natural Science Foundation of Beijing Municipality","award":["L202206"],"award-info":[{"award-number":["L202206"]}]},{"name":"Natural Science Foundation of Beijing Municipality","award":["7232238"],"award-info":[{"award-number":["7232238"]}]},{"name":"Natural Science Foundation of Beijing Municipality","award":["2023YFC3604702"],"award-info":[{"award-number":["2023YFC3604702"]}]},{"name":"National Key Technologies R&amp;D Program of China","award":["L202206"],"award-info":[{"award-number":["L202206"]}]},{"name":"National Key Technologies R&amp;D Program of China","award":["7232238"],"award-info":[{"award-number":["7232238"]}]},{"name":"National Key Technologies R&amp;D Program of China","award":["2023YFC3604702"],"award-info":[{"award-number":["2023YFC3604702"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Objectives: Skin aging, often accelerated by dietary advanced glycation end products (AGEs), poses both cosmetic and health challenges. This study explores the protective effects of hydroxytyrosol (HT), a potent antioxidant found in olives, against AGEs-induced skin aging in mice. Methods: A total of forty-eight 8-month-old specific pathogen-free (SPF) male C57BL\/6J mice were randomly assigned to one of four groups: control, model, low-dose hydroxytyrosol (HT25), and high-dose hydroxytyrosol (HT50). An additional group of six 6-week-old SPF male C57BL\/6J mice served as the youth group. The experimental period lasted 16 weeks. Following the intervention, skin, serum, and ileum samples were collected. Results: The results demonstrated that HT50 significantly increased skin moisture, epidermal thickness, and dermal thickness (p &lt; 0.05). HT50 also significantly elevated hydroxyproline levels as well as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the skin while reducing malondialdehyde (MDA) content (p &lt; 0.05). Furthermore, HT50 significantly reduced the levels of interleukin-6 (IL-6), interleukin-1\u03b2 (IL-1\u03b2), and tumor necrosis factor-\u03b1 (TNF-\u03b1) (p &lt; 0.05). Regarding intestinal integrity, hydroxytyrosol intervention (either HT25 or HT50) significantly increased the positive staining ratios of zonula occludens-1 (ZO-1) and occludin in the ileum (p &lt; 0.05). Conclusions: HT improves skin hydration, thickness, and collagen levels while reducing oxidative stress and inflammation. Notably, HT also enhances intestinal barrier function, suggesting a role for the gut\u2013skin axis. These findings highlight HT\u2019s potential as a natural intervention for skin aging.<\/jats:p>","DOI":"10.3390\/nu17172810","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T16:18:15Z","timestamp":1756484295000},"page":"2810","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Improvement Effect and Mechanism of Hydroxytyrosol on Skin Aging Induced Advanced Glycation End Products"],"prefix":"10.3390","volume":"17","author":[{"given":"Rui","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9010-3895","authenticated-orcid":false,"given":"Yuxin","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haohao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxin","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junbo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5028-6639","authenticated-orcid":false,"given":"Wenli","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9751-1549","authenticated-orcid":false,"given":"Zhaofeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1093\/geront\/gnw003","article-title":"Age-Associated Skin Conditions and Diseases: Current Perspectives and Future Options","volume":"56","author":"Kottner","year":"2016","journal-title":"Gerontologist"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.molmed.2021.12.003","article-title":"Skin senescence: Mechanisms and impact on whole-body aging","volume":"28","author":"Franco","year":"2022","journal-title":"Trends Mol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1093\/gerona\/gls154","article-title":"Facial appearance reflects human familial longevity and cardiovascular disease risk in healthy individuals","volume":"68","author":"Gunn","year":"2013","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"463","DOI":"10.3233\/JAD-181191","article-title":"Neurodegenerative Disease-Related Proteins within the Epidermal Layer of the Human Skin","volume":"69","author":"Akerman","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e00630-19","DOI":"10.1128\/msystems.00630-19","article-title":"Human Skin, Oral, and Gut Microbiomes Predict Chronological Age","volume":"5","author":"Huang","year":"2020","journal-title":"mSystems"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"12S","DOI":"10.1097\/PRS.0000000000009668","article-title":"Targeting Cellular Senescence with Senotherapeutics: Development of New Approaches for Skin Care","volume":"150","author":"Thompson","year":"2022","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1177\/0963689717725755","article-title":"Fighting against Skin Aging: The Way from Bench to Bedside","volume":"27","author":"Zhang","year":"2018","journal-title":"Cell Transpl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s001250051591","article-title":"Advanced glycation end-products: A review","volume":"44","author":"Singh","year":"2001","journal-title":"Diabetologia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1161\/01.RES.84.5.489","article-title":"Activation of receptor for advanced glycation end products: A mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis","volume":"84","author":"Schmidt","year":"1999","journal-title":"Circ. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.foodchem.2015.06.049","article-title":"Analysis of advanced glycation endproducts in selected food items by ultra-performance liquid chromatography tandem mass spectrometry: Presentation of a dietary AGE database","volume":"190","author":"Scheijen","year":"2016","journal-title":"Food Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"461","DOI":"10.3945\/an.115.008433","article-title":"Dietary advanced glycation end products and their role in health and disease","volume":"6","author":"Uribarri","year":"2015","journal-title":"Adv. Nutr."},{"key":"ref_12","first-page":"1","article-title":"Sugar Sag: Glycation and the Role of Diet in Aging Skin","volume":"20","author":"Nguyen","year":"2015","journal-title":"Ski. Ther. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Chen, C.Y., Zhang, J.Q., Li, L., Guo, M.-M., He, Y.-F., Dong, Y.-M., Meng, H., and Yi, F. (2022). Advanced Glycation End Products in the Skin: Molecular Mechanisms, Methods of Measurement, and Inhibitory Pathways. Front. Med., 9.","DOI":"10.3389\/fmed.2022.837222"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1080\/1547691X.2021.1959677","article-title":"Dietary advanced glycation end-products elicit toxicological effects by disrupting gut microbiome and immune homeostasis","volume":"18","author":"Chen","year":"2021","journal-title":"J. Immunotoxicol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Twarda-Clapa, A., Olczak, A., Bia\u0142kowska, A.M., and Kozio\u0142kiewicz, M. (2022). Advanced Glycation End-Products (AGEs): Formation, Chemistry, Classification, Receptors, and Diseases Related to AGEs. Cells, 11.","DOI":"10.3390\/cells11081312"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Gill, V., Kumar, V., Singh, K., Kumar, A., and Kim, J.J. (2019). Advanced Glycation End Products (AGEs) May Be a Striking Link Between Modern Diet and Health. Biomolecules, 9.","DOI":"10.3390\/biom9120888"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1055\/s-0037-1613678","article-title":"AGE-RAGE Stress, Stressors, and Antistressors in Health and Disease","volume":"27","author":"Prasad","year":"2018","journal-title":"Int. J. Angiol."},{"key":"ref_18","first-page":"247","article-title":"Botanicals in Dermatology","volume":"11","author":"Reuter","year":"2010","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.jbiotec.2019.12.016","article-title":"Hydroxytyrosol: A natural compound with promising pharmacological activities","volume":"309","author":"Bertelli","year":"2020","journal-title":"J. Biotechnol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7609","DOI":"10.1021\/jf0706934","article-title":"New Insights into Controversies on the Antioxidant Potential of the Olive Oil Antioxidant Hydroxytyrosol","volume":"55","author":"Rietjens","year":"2007","journal-title":"J. Agric. Food Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Laurindo, L.F., de Maio, M.C., Minniti, G., de G\u00f3es Corr\u00eaa, N., Barbalho, S.M., Quesada, K., Guiguer, E.L., Sloan, K.P., Detregiachi, C.R.P., and Ara\u00fajo, A.C. (2023). Effects of Medicinal Plants and Phytochemicals in Nrf2 Pathways during Inflammatory Bowel Diseases and Related Colorectal Cancer: A Comprehensive Review. Metabolites, 13.","DOI":"10.3390\/metabo13020243"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1248\/bpb.b18-00979","article-title":"Olive-Derived Hydroxytyrosol Shows Anti-inflammatory Effect without Gastric Damage in Rats","volume":"42","author":"Yonezawa","year":"2019","journal-title":"Biol. Pharm. Bull."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"102582","DOI":"10.1016\/j.psj.2023.102582","article-title":"Hydroxytyrosol mitigates Mycoplasma gallisepticum-induced pulmonary injury through downregulation of the NF-\u03baB\/NLRP3\/IL-1\u03b2 signaling pathway in chicken","volume":"102","author":"Shan","year":"2023","journal-title":"Poult. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1017\/S0007114515000884","article-title":"Hydroxytyrosol improves mitochondrial function and reduces oxidative stress in the brain of db\/db mice: Role of AMP-activated protein kinase activation","volume":"113","author":"Zheng","year":"2015","journal-title":"Br. J. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4445","DOI":"10.1039\/D1FO03241K","article-title":"Age-dependent effects of a high-fat diet combined with dietary advanced glycation end products on cognitive function and protection with voluntary exercise","volume":"13","author":"Luo","year":"2022","journal-title":"Food Funct."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3570","DOI":"10.26599\/FSHW.2023.9250039","article-title":"Diet with high content of advanced glycation end products induces oxidative stress damage and systemic inflammation in experimental mice: Protective effect of peanut skin procyanidins","volume":"13","author":"Zhao","year":"2024","journal-title":"Food Sci. Hum. Wellness"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.26599\/FSHW.2022.9250094","article-title":"Effects of Maillard reaction and its product AGEs on aging and age-related diseases","volume":"13","author":"Peng","year":"2024","journal-title":"Food Sci. Hum. Wellness"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kim, E., Hwang, K., Lee, J., Han, S.Y., Kim, E.M., Park, J., and Cho, J.Y. (2018). Skin Protective Effect of Epigallocatechin Gallate. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010173"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jdermsci.2023.08.006","article-title":"Molecular insights of human skin epidermal and dermal aging","volume":"112","author":"Quan","year":"2023","journal-title":"J. Dermatol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7075","DOI":"10.1039\/D2FO00425A","article-title":"Photoprotective effects of sweet potato leaf polyphenols and caffeic acid against UV-induced skin-damage in BALB\/C nude mice","volume":"13","author":"Hong","year":"2022","journal-title":"Food Funct."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12574","DOI":"10.3390\/cimb46110746","article-title":"The Role of Cacao Powder in Enhancing Skin Moisture and Reducing Wrinkles: A 12-Week Clinical Trial and In Vitro Study","volume":"46","author":"Lee","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/srt.12300","article-title":"Analyses of changes on skin by aging","volume":"23","author":"Kazanci","year":"2016","journal-title":"Skin Res. Technol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s10103-012-1069-4","article-title":"Optical features for chronological aging and photoaging skin by optical coherence tomography","volume":"28","author":"Wu","year":"2013","journal-title":"Lasers Med. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4085","DOI":"10.1111\/jcmm.13685","article-title":"Actin cytoskeleton assembly regulates collagen production via TGF-\u03b2 type II receptor in human skin fibroblasts","volume":"22","author":"Qin","year":"2018","journal-title":"J. Cell Mol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"134","DOI":"10.3746\/pnf.2023.28.2.134","article-title":"AGEs Blocker\u2122 (Goji Berry, Fig, and Korean Mint Mixed Extract) Inhibits Skin Aging Caused by Streptozotocin-Induced Glycation in Hairless Mice","volume":"28","author":"Yoo","year":"2023","journal-title":"Prev. Nutr. Food Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3436","DOI":"10.1111\/jocd.15835","article-title":"A study on the delayed effect of tilapia skin collagen on skin aging for mice and its possible mechanism","volume":"22","author":"Pu","year":"2023","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_37","first-page":"507351","article-title":"Effects of dimethylaminoethanol and compound amino acid on D-galactose induced skin aging model of rat","volume":"2014","author":"Liu","year":"2014","journal-title":"Sci. World J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1901019","DOI":"10.1002\/mnfr.201901019","article-title":"Dietary AdvancedGlycationEnd Products\u2013InducedCognitive Impairment in Aged ICR Mice: Protective Role of Quercetin","volume":"64","author":"Yang","year":"2020","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.matbio.2024.12.007","article-title":"AGEing of collagen: The effects of glycation on collagen\u2019s stability, mechanics and assembly","volume":"35","author":"Sloseris","year":"2025","journal-title":"Matrix Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/phpp.12623","article-title":"In vivo confocal Raman spectroscopic imaging of the human skin extracellular matrix degradation due to accumulated intrinsic and extrinsic aging","volume":"37","author":"Ali","year":"2021","journal-title":"Photodermatol. Photoimmunol. Photomed."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/j.1365-2230.2009.03361.x","article-title":"Effects of blood glucose fluctuation on skin biophysical properties, structure and antioxidant status in an animal model","volume":"35","author":"Ye","year":"2010","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0047-6374(99)00022-6","article-title":"Advanced glycation in D-galactose induced mouse aging model","volume":"108","author":"Song","year":"1999","journal-title":"Mech. Ageing Dev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.cofs.2021.03.011","article-title":"Recent Developments in In-Vitro Assessment of Advanced Glycation End Products","volume":"40","author":"Serin","year":"2021","journal-title":"Curr. Opin. Food Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1111\/exd.12899","article-title":"Epidermal expression of receptor for advanced glycation end products (RAGE) is related to inflammation and apoptosis in human skin","volume":"25","author":"Iwamura","year":"2016","journal-title":"Exp. Dermatol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Velotti, F., and Bernini, R. (2023). Hydroxytyrosol Interference with Inflammaging via Modulation of Inflammation and Autophagy. Nutrients, 15.","DOI":"10.3390\/nu15071774"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Batarfi, W.A., Yunus, M.H.M., Hamid, A.A., Lee, Y.T., and Maarof, M. (2024). Hydroxytyrosol: A Promising Therapeutic Agent for Mitigating Inflammation and Apoptosis. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16121504"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1016\/j.cellsig.2013.06.013","article-title":"Cellular signalling of the receptor for advanced glycation end products (RAGE)","volume":"25","author":"Xie","year":"2013","journal-title":"Cell. Signal."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"101516","DOI":"10.1016\/j.psj.2021.101516","article-title":"Immunomodulatory and antioxidant effects of hydroxytyrosol in cyclophosphamide-induced immunosuppressed broilers","volume":"101","author":"Shan","year":"2022","journal-title":"Poult. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Terracina, S., Petrella, C., Francati, S., Lucarelli, M., Barbato, C., Minni, A., Ralli, M., Greco, A., Tarani, L., and Fiore, M. (2022). Antioxidant Intervention to Improve Cognition in the Aging Brain: The Example of Hydroxytyrosol and Resveratrol. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415674"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1136\/gut.33.7.933","article-title":"Cytokine production in patients with inflammatory bowel disease","volume":"33","author":"Nakamura","year":"1992","journal-title":"Gut"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Vitale, S., Strisciuglio, C., and Pisapia, L. (2017). Cytokine production profile in intestinal mucosa of paediatric inflammatory bowel disease. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182313"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/17\/2810\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:35:33Z","timestamp":1760034933000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/17\/2810"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,29]]},"references-count":51,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["nu17172810"],"URL":"https:\/\/doi.org\/10.3390\/nu17172810","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,29]]}}}