{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:42:22Z","timestamp":1792172542901,"version":"4.4.0"},"reference-count":47,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Environmental Health Sciences","award":["Z01-ES102245"],"award-info":[{"award-number":["Z01-ES102245"]}]},{"name":"National Institute of Environmental Health Sciences","award":["Z01-ES044005"],"award-info":[{"award-number":["Z01-ES044005"]}]},{"name":"National Institute of Environmental Health Sciences","award":["Z01-ES049033"],"award-info":[{"award-number":["Z01-ES049033"]}]},{"name":"National Institute of Environmental Health Sciences","award":["Z01-ES049032"],"award-info":[{"award-number":["Z01-ES049032"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Iron is necessary for bodily function, but abnormal levels can increase the risk of chronic diseases. Studies of leukocyte telomere length suggest blood iron levels are positively associated with cellular senescence and accelerated aging. However, associations between blood iron and more robust metrics of biological aging, specifically those based on DNA methylation, have not been examined. Methods: In a random sample of women from the Sister Study (n = 1260) with measured serum iron (ferritin, iron, transferrin saturation), we used linear regression models to assess cross-sectional associations between standardized serum iron and three methylation-based biological aging metrics (GrimAgeAccel, PhenoAgeAccel, and DunedinPACE), with and without adjustment for smoking, alcohol, menopause status, education, time since menopause, exercise, and diet. Results: In adjusted models, a one standard deviation increase in serum ferritin was positively associated with higher standardized levels of DunedinPACE, GrimAgeAccel, and PhenoAgeAccel (DunedinPACE: 0.05, (0.00, 0.10); PhenoAgeAccel: 0.06 (0.00, 0.11); GrimAgeAccel: 0.06 (0.01, 0.11)). In contrast, higher serum iron and transferrin saturation were inversely associated with the biological aging metrics (serum iron, DunedinPACE: \u22120.02, (\u22120.07, 0.03); PhenoAgeAccel: \u22120.04 (\u22120.10, 0.01); GrimAgeAccel: \u22120.05 (\u22120.10, \u22120.01); transferrin saturation (DunedinPACE: \u22120.01, (\u22120.06, 0.05); PhenoAgeAccel: \u22120.01 (\u22120.06, 0.05); GrimAgeAccel: \u22120.05 (\u22120.10, \u22120.01))). Conclusions: The positive association with ferritin is consistent with the proposed role of oxidative stress in accelerated aging associated with high iron exposure. However, the observed inverse associations with serum iron and transferrin saturation are not consistent with this common explanation, and future studies are needed to examine potential explanations.<\/jats:p>","DOI":"10.3390\/nu17091409","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T03:43:37Z","timestamp":1745379817000},"page":"1409","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Association Between Body Iron Status and Biological Aging"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0299-1114","authenticated-orcid":false,"given":"Ann","family":"Von Holle","sequence":"first","affiliation":[{"name":"Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5479-8685","authenticated-orcid":false,"given":"Sahana","family":"Ramamurthy","sequence":"additional","affiliation":[{"name":"North Carolina State University, Raleigh, NC 27606, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3580-6405","authenticated-orcid":false,"given":"Mary V.","family":"D\u00edaz Santana","sequence":"additional","affiliation":[{"name":"Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob K.","family":"Kresovich","sequence":"additional","affiliation":[{"name":"Department of Cancer Epidemiology, Moffit Cancer Center, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack A.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9034-8902","authenticated-orcid":false,"given":"Zongli","family":"Xu","sequence":"additional","affiliation":[{"name":"Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie M.","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale P.","family":"Sandler","sequence":"additional","affiliation":[{"name":"Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7713-8556","authenticated-orcid":false,"given":"Clarice R.","family":"Weinberg","sequence":"additional","affiliation":[{"name":"Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.cell.2016.12.034","article-title":"A Red Carpet for Iron Metabolism","volume":"168","author":"Muckenthaler","year":"2017","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1001S","DOI":"10.1093\/jn\/nxx036","article-title":"Biomarkers of Nutrition for Development (BOND)\u2014Iron Review","volume":"148","author":"Lynch","year":"2018","journal-title":"J. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Galaris, D., Barbouti, A., and Pantopoulos, K. (2019). Iron homeostasis and oxidative stress: An intimate relationship. Biochim. Biophys. Acta BBA\u2014Mol. Cell Res., 1866.","DOI":"10.1016\/j.bbamcr.2019.118535"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nchembio.1416","article-title":"The role of iron and reactive oxygen species in cell death","volume":"10","author":"Dixon","year":"2014","journal-title":"Nat. Chem. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4262","DOI":"10.1007\/s12011-022-03523-w","article-title":"Ferroptosis as a Mechanism for Health Effects of Essential Trace Elements and Potentially Toxic Trace Elements","volume":"201","author":"Xu","year":"2022","journal-title":"Biol. Trace Element Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100896","DOI":"10.1016\/j.mam.2020.100896","article-title":"Genetic iron overload disorders","volume":"75","author":"Corradini","year":"2020","journal-title":"Mol. Asp. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1606S","DOI":"10.3945\/ajcn.117.155887","article-title":"Laboratory methodologies for indicators of iron status: Strengths, limitations, and analytical challenges","volume":"106","author":"Pfeiffer","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_8","first-page":"51","article-title":"The Regulation of Iron Absorption and Homeostasis","volume":"37","author":"Wallace","year":"2016","journal-title":"Clin. Biochem. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.jand.2018.09.007","article-title":"Association between Body Iron Status and Leukocyte Telomere Length, a Biomarker of Biological Aging, in a Nationally Representative Sample of U.S. Adults","volume":"119","author":"Liu","year":"2019","journal-title":"J. Acad. Nutr. Diet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1002\/ajh.23438","article-title":"Telomere length and elevated iron: The influence of phenotype and HFE genotype","volume":"88","author":"Mainous","year":"2013","journal-title":"Am. J. Hematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1017\/S0007114517001696","article-title":"Transferrin saturation concentrations associated with telomeric ageing: A population-based study","volume":"117","author":"Shin","year":"2017","journal-title":"Br. J. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1370\/afm.25","article-title":"Elevated Serum Transferrin Saturation and Mortality","volume":"2","author":"Mainous","year":"2004","journal-title":"Ann. Fam. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eaaz6876","DOI":"10.1126\/science.aaz6876","article-title":"Determinants of telomere length across human tissues","volume":"369","author":"Demanelis","year":"2020","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1093\/epirev\/mxs008","article-title":"Telomere Length in Epidemiology: A Biomarker of Aging, Age-Related Disease, Both, or Neither?","volume":"35","author":"Sanders","year":"2013","journal-title":"Epidemiol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Turner, K.J., Vasu, V., and Griffin, D.K. (2019). Telomere Biology and Human Phenotype. Cells, 8.","DOI":"10.3390\/cells8010073"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Vaiserman, A., and Krasnienkov, D. (2021). Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives. Front. Genet., 11.","DOI":"10.3389\/fgene.2020.630186"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e51507","DOI":"10.7554\/eLife.51507","article-title":"Longitudinal trajectories, correlations and mortality associations of nine biological ages across 20-years follow-up","volume":"9","author":"Li","year":"2020","journal-title":"eLife"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"573","DOI":"10.18632\/aging.101414","article-title":"An epigenetic biomarker of aging for lifespan and healthspan","volume":"10","author":"Levine","year":"2018","journal-title":"Aging"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"303","DOI":"10.18632\/aging.101684","article-title":"DNA methylation GrimAge strongly predicts lifespan and healthspan","volume":"11","author":"Lu","year":"2019","journal-title":"Aging"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e73420","DOI":"10.7554\/eLife.73420","article-title":"DunedinPACE, a DNA methylation biomarker of the pace of aging","volume":"11","author":"Belsky","year":"2022","journal-title":"eLife"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"127003-1","DOI":"10.1289\/EHP1923","article-title":"The Sister Study Cohort: Baseline Methods and Participant Characteristics","volume":"125","author":"Sandler","year":"2017","journal-title":"Environ. Health Perspect."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1093\/jnci\/djz065","article-title":"Blood DNA Methylation and Breast Cancer: A Prospective Case-Cohort Analysis in the Sister Study","volume":"112","author":"Xu","year":"2020","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e1919536","DOI":"10.1001\/jamanetworkopen.2019.19536","article-title":"Prediagnostic Immune Cell Profiles and Breast Cancer","volume":"3","author":"Kresovich","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s13058-018-0994-y","article-title":"Vitamin D, DNA methylation, and breast cancer","volume":"20","author":"Sandler","year":"2018","journal-title":"Breast Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1093\/jnci\/djz020","article-title":"Methylation-Based Biological Age and Breast Cancer Risk","volume":"111","author":"Kresovich","year":"2019","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.1093\/nar\/gkv907","article-title":"ENmix: A novel background correction method for Illumina HumanMethylation450 BeadChip","volume":"44","author":"Xu","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1158\/1055-9965.EPI-20-0715","article-title":"Association Between Serum Iron Biomarkers and Breast Cancer","volume":"30","author":"Sandler","year":"2021","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1016\/j.jand.2018.05.021","article-title":"Update of the Healthy Eating Index: HEI-2015","volume":"118","author":"Pannucci","year":"2018","journal-title":"J. Acad. Nutr. Diet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"439","DOI":"10.6339\/JDS.201407_12(3).0004","article-title":"On the implication of structural zeros as independent variables in regression analysis: Applications to alcohol research","volume":"12","author":"He","year":"2014","journal-title":"J. Data Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1182\/blood-2004-05-1812","article-title":"Prevalence of anemia in persons 65 years and older in the United States: Evidence for a high rate of unexplained anemia","volume":"104","author":"Guralnik","year":"2004","journal-title":"Blood"},{"key":"ref_31","unstructured":"R Core Team (2023, March 15). R: A Language and Environment for Statistical Computing. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.bbagen.2011.07.014","article-title":"Non-transferrin bound iron: A key role in iron overload and iron toxicity","volume":"1820","author":"Brissot","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"19095","DOI":"10.1074\/jbc.272.31.19095","article-title":"Formation, Prevention, and Repair of DNA Damage by Iron\/Hydrogen Peroxide*","volume":"272","author":"Henle","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.etap.2015.10.002","article-title":"The influence of oxidative stress induced by iron on telomere length","volume":"40","author":"Kepinska","year":"2015","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s13148-023-01575-w","article-title":"Effects of iron homeostasis on epigenetic age acceleration: A two-sample Mendelian randomization study","volume":"15","author":"Wang","year":"2023","journal-title":"Clin. Epigenetics."},{"key":"ref_36","unstructured":"Dumitrescu, R.G., and Verma, M. (2018). DNA Methylation as a Biomarker of Aging in Epidemiologic Studies. Cancer Epigenetics for Precision Medicine: Methods and Protocols. Methods in Molecular Biology, Springer Science + Business Media."},{"key":"ref_37","first-page":"1220","article-title":"Eleven Telomere, Epigenetic Clock, and Biomarker-Composite Quantifications of Biological Aging: Do They Measure the Same Thing?","volume":"187","author":"Belsky","year":"2018","journal-title":"Am. J. Epidemiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1097\/00062752-200503000-00001","article-title":"Anemia of inflammation: The hepcidin link","volume":"12","author":"Roy","year":"2005","journal-title":"Curr. Opin. Hematol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Pagani, A., Nai, A., Silvestri, L., and Camaschella, C. (2019). Hepcidin and Anemia: A Tight Relationship. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01294"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1182\/blood.2021013472","article-title":"The role of iron in chronic inflammatory diseases: From mechanisms to treatment options in anemia of inflammation","volume":"140","author":"Marques","year":"2022","journal-title":"Blood"},{"key":"ref_41","first-page":"16430","article-title":"Iron status in chronic inflammatory disease: Therapeutic implications","volume":"133","author":"Cappellini","year":"2023","journal-title":"Pol. Arch. Intern. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1053\/j.seminhematol.2015.07.004","article-title":"Anemia of Chronic Disorders: New Diagnostic Tools and New Treatment Strategies","volume":"52","author":"Weiss","year":"2015","journal-title":"Semin. Hematol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.mcna.2016.09.005","article-title":"Anemia of Inflammation","volume":"101","author":"Fraenkel","year":"2017","journal-title":"Med. Clin. N. Am."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejim.2018.04.013","article-title":"Iron deficiency in chronic and acute heart failure: A contemporary review on intertwined conditions","volume":"52","author":"Cunha","year":"2018","journal-title":"Eur. J. Intern. Med."},{"key":"ref_45","first-page":"16","article-title":"Age as a Modifiable Risk Factor for Chronic Disease","volume":"17","author":"Bland","year":"2018","journal-title":"Integr. Med."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., Monti, D., Capri, M., and Salvioli, S. (2018). The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates. Front. Med., 5.","DOI":"10.3389\/fmed.2018.00061"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1183\/09031936.00134014","article-title":"Ageing and the border between health and disease","volume":"44","author":"MacNee","year":"2014","journal-title":"Eur. Respir. J."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/9\/1409\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:19:47Z","timestamp":1760030387000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/9\/1409"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,23]]},"references-count":47,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["nu17091409"],"URL":"https:\/\/doi.org\/10.3390\/nu17091409","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,23]]}}}