{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T11:39:14Z","timestamp":1786534754875,"version":"build-2736575974"},"reference-count":32,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institute for Personalized Medicine of Georgia (PMI), Tbilisi, Georgia"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/objectives: Melatonin has circadian, antioxidant, mitochondrial, and immunomodulatory functions, but human data linking relative melatonergic status to coordinated systemic biomarker burden remain limited. We examined this association and tested its internal robustness to alternative score construction, outlier handling, and missing-data assumptions. Methods: We performed an adult-only cross-sectional secondary analysis of a deidentified biomarker dataset. Of 322 source records, six participants younger than 18 years and two records without age were excluded, yielding 314 adults. Plasma melatonin and 24 h urinary aMT6s were converted to within-cohort rank percentiles and averaged to form a relative melatonergic-axis score. Equal-weight z-score composites represented inflammation, oxidative damage, antioxidant deficit, and biological aging\/biological injury; their mean was the integrated systemic biomarker-burden score. Analyses included Kruskal\u2013Wallis tests; Spearman correlations with bootstrap confidence intervals; standardized regression adjusted for age, sex, and BMI; robust covariance estimates; principal component analysis (PCA), winsorization, leave-one-domain\/marker-out analyses, and missing-BMI sensitivity models. Results: The lower, intermediate, and higher relative melatonergic tertiles included 105, 104, and 105 adults, respectively. The melatonergic-axis score correlated inversely with integrated systemic burden (Spearman \u03c1 = \u22120.944; 5000-resample bootstrap 95% CI, \u22120.953 to \u22120.931; p &lt; 0.001). In age-, sex-, and BMI-adjusted complete-case models (N = 250), each 1 SD higher axis score was associated with a 0.95 SD lower integrated burden (\u03b2 = \u22120.949; HC3 95% CI, \u22120.983 to \u22120.915; p &lt; 0.001). Results were similar for separate plasma melatonin and aMT6s models, winsorized composites, a PCA-derived score (PC1 explained 75.5% of marker variance; \u03c1 = \u22120.947), leave-one-domain\/marker-out analyses, and missing-BMI sensitivity models. Conclusions: Lower relative melatonergic status was associated with a highly coordinated adverse systemic biomarker pattern. The exceptional magnitude of the association requires audit of primary assay provenance and independent external replication. Because cancer, microbiome, and liquid biopsy endpoints were not measured, oncology implications remain untested prospective hypotheses.<\/jats:p>","DOI":"10.3390\/cancers18162597","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T11:02:11Z","timestamp":1786532531000},"page":"2597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Relative Melatonergic Status and Systemic Inflammatory, Oxidative, and Biological Aging Burden in Adults: An Exploratory Cross-Sectional Biomarker Analysis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9589-7417","authenticated-orcid":false,"given":"Alexandre","family":"Tavartkiladze","sequence":"first","affiliation":[{"name":"Department of Medical Oncology and Cellular Therapy, Faculty of Medicine, Tbilisi State Medical University, Tbilisi 0186, Georgia"},{"name":"Institute for Personalized Medicine of Georgia (PMI), Tbilisi 0186, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levan","family":"Tavartkiladze","sequence":"additional","affiliation":[{"name":"Institute for Personalized Medicine of Georgia (PMI), Tbilisi 0186, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6763-4225","authenticated-orcid":false,"given":"Russel J.","family":"Reiter","sequence":"additional","affiliation":[{"name":"Department of Cellular & Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1283-8487","authenticated-orcid":false,"given":"Michel","family":"Burnier","sequence":"additional","affiliation":[{"name":"Service of Nephrology and Hypertension, Lausanne University Hospital (CHUV), University of Lausanne, 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Engin","family":"Ulukaya","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Istinye University, Istanbul 34396, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Revaz","family":"Turmanidze","sequence":"additional","affiliation":[{"name":"Institute for Personalized Medicine of Georgia (PMI), Tbilisi 0186, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pati","family":"Revazishvili","sequence":"additional","affiliation":[{"name":"Institute for Personalized Medicine of Georgia (PMI), Tbilisi 0186, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41580-020-0230-3","article-title":"Reactive oxygen species (ROS) as pleiotropic physiological signalling agents","volume":"21","author":"Sies","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1016\/j.freeradbiomed.2010.09.006","article-title":"Oxidative stress, inflammation, and cancer: How are they linked?","volume":"49","author":"Reuter","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_5","first-page":"120","article-title":"8-Hydroxy-2\u2032-deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis","volume":"27","author":"Valavanidis","year":"2009","journal-title":"J. Environ. Sci. Health C Environ. Carcinog. Ecotoxicol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"360438","DOI":"10.1155\/2014\/360438","article-title":"Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal","volume":"2014","author":"Ayala","year":"2014","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.redox.2016.12.035","article-title":"Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress","volume":"11","author":"Sies","year":"2017","journal-title":"Redox Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3289","DOI":"10.1016\/j.bbagen.2012.11.020","article-title":"Glutathione peroxidases","volume":"1830","author":"Maiorino","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/nprot.2009.197","article-title":"Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue","volume":"5","author":"Weydert","year":"2010","journal-title":"Nat. Protoc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41574-018-0059-4","article-title":"Inflammaging: A new immune-metabolic viewpoint for age-related diseases","volume":"14","author":"Franceschi","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_11","first-page":"84","article-title":"The role of immunosenescence in the development of age-related diseases","volume":"68","author":"Dupuis","year":"2016","journal-title":"Rev. Investig. Clin."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1152\/physiol.00011.2014","article-title":"Melatonin: Exceeding expectations","volume":"29","author":"Reiter","year":"2014","journal-title":"Physiology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.pneurobio.2010.12.004","article-title":"Melatonin\u2014A pleiotropic, orchestrating regulator molecule","volume":"93","author":"Hardeland","year":"2011","journal-title":"Prog. Neurobiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1677\/erc.0.0100153","article-title":"Melatonin and mammary cancer: A short review","volume":"10","author":"Cos","year":"2003","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1056\/NEJMra1600266","article-title":"The human intestinal microbiome in health and disease","volume":"375","author":"Lynch","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1126\/science.aaa4972","article-title":"Cancer and the microbiota","volume":"348","author":"Garrett","year":"2015","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1038\/nrc3610","article-title":"The microbiome and cancer","volume":"13","author":"Schwabe","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1146\/annurev-immunol-051116-052133","article-title":"Microbes and cancer","volume":"35","author":"Dzutsev","year":"2017","journal-title":"Annu. Rev. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1038\/s41568-023-00594-2","article-title":"Bacteria in cancer initiation, promotion and progression","volume":"23","author":"Garrett","year":"2023","journal-title":"Nat. Rev. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/s41579-023-00973-4","article-title":"The microbial landscape of colorectal cancer","volume":"22","author":"White","year":"2024","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1126\/science.1224820","article-title":"Intestinal inflammation targets cancer-inducing activity of the microbiota","volume":"338","author":"Arthur","year":"2012","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6897","DOI":"10.1158\/1078-0432.CCR-04-0378","article-title":"Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases","volume":"10","author":"Allard","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1056\/NEJMoa040766","article-title":"Circulating tumor cells, disease progression, and survival in metastatic breast cancer","volume":"351","author":"Cristofanilli","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.molmed.2010.07.001","article-title":"Circulating tumour cells in cancer patients: Challenges and perspectives","volume":"16","author":"Pantel","year":"2010","journal-title":"Trends Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nrc3820","article-title":"Challenges in circulating tumour cell research","volume":"14","author":"Pantel","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1200\/JCO.2012.45.2011","article-title":"Liquid biopsies: Genotyping circulating tumor DNA","volume":"32","author":"Diaz","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/nrc.2017.7","article-title":"Liquid biopsies come of age: Towards implementation of circulating tumour DNA","volume":"17","author":"Wan","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/nature22364","article-title":"Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution","volume":"545","author":"Abbosh","year":"2017","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"178","DOI":"10.20517\/evcna.2022.20","article-title":"Cell-free DNA as a biomarker in cancer","volume":"3","author":"Eibl","year":"2022","journal-title":"Extracell. Vesicles Circ. Nucleic Acids"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41571-024-00967-y","article-title":"Minimal residual disease as a target for liquid biopsy in patients with solid tumours","volume":"22","author":"Pantel","year":"2025","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1002\/cncr.35263","article-title":"Detection of circulating tumor DNA with ultradeep sequencing of plasma cell-free DNA for monitoring minimal residual disease and early detection of recurrence in early-stage lung cancer","volume":"130","author":"Tan","year":"2024","journal-title":"Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1056\/NEJMoa2200075","article-title":"Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer","volume":"386","author":"Tie","year":"2022","journal-title":"N. Engl. J. Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/16\/2597\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T11:12:29Z","timestamp":1786533149000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/16\/2597"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,12]]},"references-count":32,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cancers18162597"],"URL":"https:\/\/doi.org\/10.3390\/cancers18162597","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,12]]}}}