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We examined associations between DNA methylation\u2013based protein level estimates (EpiScores) and five fitness traits\u2014VO\n                    <jats:sub>2<\/jats:sub>\n                    max, GripStrength, JumpMax, body mass index (BMI), and cognition\u2014in a cohort of 290 mostly old individuals (mean age of 60\u2009\u00b1\u200911\u2009years). EpiScores for 109 plasma proteins were obtained using the MethylDetectR tool and tested for associations with fitness traits. We found 33 significant fitness predictor\u2013EpiScore associations independent from age and sex. Integration with available EpiScore\u2013disease associations revealed overlapping pathways linking fitness and chronic disease risk. We found 51 fitness predictor\u2013disease associations based on EpiScores. The BMI was positively associated with diabetes, stroke, ischemic heart disease, lung cancer, COPD, IBD, and depression, while showing a negative association with rheumatoid arthritis. Cognition was negatively associated with rheumatoid arthritis, depression, and COPD. GripStrength showed negative associations with diabetes and COPD. Finally, jump performance was negatively associated with diabetes, stroke, lung cancer, rheumatoid arthritis, and COPD. We also developed a workflow for evaluating patient\u2010level disease risk by using DNA methylation and fitness measurements. The patient\u2010level risk scores showed strong positive correlations with an independent external CVD EpiScore benchmark supporting validity. Our findings highlight the link between cognitive and physical fitness and protein EpiScores as interpretable molecular markers with potential value for early disease risk stratification and for personalized prevention of aging\u2010related diseases.\n                  <\/jats:p>","DOI":"10.1111\/acel.70467","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T03:19:55Z","timestamp":1775704795000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Physical Fitness Is Negatively Associated With\n                    <scp>DNA<\/scp>\n                    Methylation\u2010Based Risk of Aging\u2010Related Diseases"],"prefix":"10.1111","volume":"25","author":[{"given":"Samiha","family":"Nasser","sequence":"first","affiliation":[{"name":"HUN\u2010REN Institute for Computer Science and Control (SZTAKI)  Budapest Hungary"},{"name":"Faculty of Informatics E\u00f6tv\u00f6s Lor\u00e1nd University (ELTE)  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Keringer","sequence":"additional","affiliation":[{"name":"Doctoral School, and Research Center for Molecular Exercise Science Hungarian University of Sport Science  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaodong","family":"Gu","sequence":"additional","affiliation":[{"name":"Faculty of Sport Science Ningbo University  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istvan","family":"Boldogh","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Texas Medical Branch at Galveston  Galveston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqing","family":"Ba","sequence":"additional","affiliation":[{"name":"Division of Human Health, Key Laboratory of Molecular Epigenetics of Ministry of Education Northeast Normal University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuru","family":"Higuchi","sequence":"additional","affiliation":[{"name":"Faculty of Sport Sciences Waseda University  Tokorozawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9541-246X","authenticated-orcid":false,"given":"Csaba","family":"Kerepesi","sequence":"additional","affiliation":[{"name":"HUN\u2010REN Institute for Computer Science and Control (SZTAKI)  Budapest Hungary"},{"name":"HUN\u2010REN\u2010SZTAKI\u2010SU Rejuvenation Research Group HUN\u2010REN Office for Supported Research Groups (TKI)  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Radak","sequence":"additional","affiliation":[{"name":"Doctoral School, and Research Center for Molecular Exercise Science Hungarian University of Sport Science  Budapest Hungary"},{"name":"Faculty of Sport Science Ningbo University  Ningbo China"},{"name":"Faculty of Sport Sciences Waseda University  Tokorozawa Japan"},{"name":"Institute of Sport Sciences and Physical Education, Faculty of Sciences University of P\u00e9cs  P\u00e9cs Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaccao.2025.07.001"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22031185"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(15)00127-8"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-020-0353-1"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.123.004265"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.14-2878"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2015.80"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwy025"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/jncics\/pkaa109"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.71802"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms221910417"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.124.1.75"},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","unstructured":"Hillary R. 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