{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T04:52:45Z","timestamp":1776401565518,"version":"3.51.2"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014862","name":"YangZhou Municipal Science and Technology Bureau","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014862","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Biological aging varies significantly between individuals, yet how its longitudinal dynamics influence urolithiasis risk remains poorly understood. This investigation sought to delineate distinct biological aging trajectories and quantify the mediating role of metabolic dysfunction in incident stone formation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed longitudinal physiological data from 27, 948 participants who underwent routine health screenings at the Affiliated Hospital of Yangzhou University (HMC-AHYU) between 2022 and 2024. The kml3d unsupervised machine learning algorithm was employed to identify latent trajectories of biological aging based on the Klemera-Doubal method (KDM) and Homeostatic Dysregulation (HD). We used Cox proportional hazards models and causal mediation analyses to evaluate the association between aging patterns and incident urolithiasis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Trajectory modeling delineated four distinct patterns of biological aging: Stable Low-Risk (Class A), Stable Moderate-Risk (Class B), Remissive High-Risk (Class C), and Progressive High-Risk (Class D). Compared to the Stable Low-Risk group, the Progressive High-Risk group was associated with an increased risk of lithogenesis in the unadjusted model (HR\u00a0=\u00a01.21, 95% CI: 1.00\u20131.45, P\u00a0=\u00a00.047), which was fully attenuated after adjusting for metabolic factors (HR\u00a0=\u00a01.14, 95% CI: 0.95\u20131.37, P\u00a0=\u00a00.170). Causal mediation analysis confirmed that this association was predominantly driven by BMI (22.9%, P&amp;lt;0.001) and hypertension (10.4%, P\u00a0=\u00a00.032). Conversely, the Remissive High-Risk group maintained a significantly lower risk across all models (HR\u00a0=\u00a00.87, 95% CI: 0.76\u20130.99, P\u00a0=\u00a00.041).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Longitudinal biological aging trajectories are robust early predictors of urolithiasis. While progressive aging increases risk via metabolic factors (obesity and hypertension), the remissive trajectory suggests that physiological recovery is possible. Targeting these metabolic mediators may offer an effective strategy for stone prevention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1824716","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T04:12:51Z","timestamp":1776399171000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Longitudinal biological aging trajectories and incident urolithiasis: a causal mediation analysis role of metabolic dysfunction in a large Chinese cohort"],"prefix":"10.3389","volume":"17","author":[{"given":"Jialong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Urology, Affiliated Hospital of Yangzhou University","place":["Yangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingzhou","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Urology, Affiliated Hospital of Yangzhou University","place":["Yangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingyin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, Affiliated Hospital of Yangzhou University","place":["Yangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeyuan","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Urology, Affiliated Hospital of Yangzhou University","place":["Yangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sishuai","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Urology, Affiliated Hospital of Yangzhou University","place":["Yangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, Affiliated Hospital of Yangzhou University","place":["Yangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/bju.13828","article-title":"Prevalence of kidney stones in China: an ultrasonography based cross-sectional study","volume":"120","author":"Zeng","year":"2017","journal-title":"BJU Int"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s00345-017-2008-6","article-title":"Epidemiology of stone disease across the world","volume":"35","author":"Sorokin","year":"2017","journal-title":"World J Urol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1111\/bju.16179","article-title":"Prevalence of urolithiasis in China: a systematic review and meta-analysis","volume":"133","author":"Tan","year":"2024","journal-title":"BJU Int"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/srep41630","article-title":"Prevalence of kidney stones in mainland China: a systematic review","volume":"7","author":"Wang","year":"2017","journal-title":"Sci Rep"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-020-0320-7","article-title":"Determining the true burden of kidney stone disease","volume":"16","author":"Thongprayoon","year":"2020","journal-title":"Nat Rev Nephrol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2012.03.052","article-title":"Prevalence of kidney stones in the United States","volume":"62","author":"Scales","year":"2012","journal-title":"Eur Urol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1001\/jama.293.4.455","article-title":"Obesity, weight gain, and the risk of kidney stones","volume":"293","author":"Taylor","year":"2005","journal-title":"JAMA"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1097\/mnh.0b013e3282f8b34d","article-title":"Nephrolithiasis as a systemic disorder","volume":"17","author":"Sakhaee","year":"2008","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"B9","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1053\/j.ajkd.2006.09.002","article-title":"Diabetes mellitus and the risk of urinary tract stones: a population-based case-control study","volume":"48","author":"Lieske","year":"2006","journal-title":"Am J Kidney Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.10.039","article-title":"Geroscience: linking aging to chronic disease","volume":"159","author":"Kennedy","year":"2014","journal-title":"Cell"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2005.10.004","article-title":"A new approach to the concept and computation of biological age","volume":"127","author":"Klemera","year":"2006","journal-title":"Mech Ageing Dev"},{"key":"B12","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1371\/journal.pone.0122541","article-title":"Detection of homeostatic dysregulation trends using differential biomarkers","volume":"14","author":"Liu","year":"2015","journal-title":"Aging Cell"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/gls233","article-title":"Modeling the rate of senescence: can estimated biological age predict mortality more accurately than chronological age","volume":"68","author":"Levine","year":"2013","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1506264112","article-title":"Quantification of biological aging in young adults","volume":"112","author":"Belsky","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.clinpsy.121208.131413","article-title":"Group-based trajectory modeling in clinical research","volume":"6","author":"Nagin","year":"2010","journal-title":"Annu Rev Clin Psychol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/eurjpc\/zwad254","article-title":"Biological age and its rate of increase are associated with cardiac structure and function: a longitudinal cohort study","volume":"14","author":"Ganau","year":"2022","journal-title":"Aging (Albany NY)"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cmpb.2011.05.008","article-title":"kml and kml3d: R packages to cluster longitudinal data","volume":"65","author":"Genolini","year":"2015","journal-title":"J Stat Softw"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3758\/brm.40.3.879","article-title":"Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models","volume":"40","author":"Preacher","year":"2008","journal-title":"Behav Res Methods"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2020.101136","article-title":"Social hallmarks of aging: Suggestions for geroscience research","volume":"63","author":"Crimmins","year":"2020","journal-title":"Ageing Res Rev"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-018-0042-y","article-title":"A framework for selection of blood-based biomarkers for geroscience-guided clinical trials","volume":"40","author":"Justice","year":"2018","journal-title":"Geroscience"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3390\/nu16020214","article-title":"Analysis of Dietary Patterns Associated with Kidney Stone Disease Based on Data-Driven Approaches: A Case-Control Study in Shanghai","volume":"16","author":"Wang","year":"2024","journal-title":"Nutrients"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00386.x","article-title":"The metabolic syndrome and uric acid nephrolithiasis: novel links of obesity and uric acid stones","volume":"65","author":"Abate","year":"2004","journal-title":"Kidney Int"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2009.10.004","article-title":"Kidney Early Evaluation Program (KEEP): update on findings from 2000 to 2006","volume":"50","author":"Vassalotti","year":"2007","journal-title":"Am J Kidney Dis"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1097\/MOU.0000000000001379","article-title":"Lithotripsy in percutaneous surgery: is there a paradigm shift","volume":"36","author":"Schinin\u00e0","year":"2026","journal-title":"Curr Opin Urol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"16008","DOI":"10.1007\/978-1-4471-4387-1_74","article-title":"Kidney stones","volume":"2","author":"Khan","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2015.07.040","article-title":"EAU guidelines on diagnosis and conservative management of urolithiasis","volume":"67","author":"T\u00fcrk","year":"2015","journal-title":"Eur Urol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.18632\/aging.202913","article-title":"Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial","volume":"13","author":"Fitzgerald","year":"2021","journal-title":"Aging (Albany NY)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/nrm.2017.89","article-title":"Biochemical and cellular properties of insulin receptor signalling","volume":"19","author":"Haeusler","year":"2018","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2018.04.080","article-title":"Menopause and risk of kidney stones","volume":"200","author":"Prochaska","year":"2018","journal-title":"J Urol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/ajh.2007.62","article-title":"The association of nephrolithiasis with hypertension and obesity: a review","volume":"21","author":"Obligado","year":"2008","journal-title":"Am J Hypertens"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.2147\/CLEP.S370591","article-title":"Global, Regional, and National Burden of Urolithiasis from 1990 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019","volume":"14","author":"Zhang","year":"2022","journal-title":"Clin Epidemiol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgae295","article-title":"Metabolic Syndrome and the Risk of Kidney Stones: Evidence from 487 860 UK Biobank Participants","volume":"110","author":"Liu","year":"2025","journal-title":"J Clin Endocrinol Metab"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2016.12.021","article-title":"The hallmarks of aging","volume":"153","author":"L\u00f3pez-Ot\u00edn","year":"2013","journal-title":"Cell"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-publhealth-060220-042648","article-title":"Social Epidemiology: Past, Present, and Future","volume":"43","author":"Diez Roux","year":"2022","journal-title":"Annu Rev Public Health"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1161354","DOI":"10.3389\/fnut.2025.1538289","article-title":"Association between biological aging and kidney stones: Evidence from NHANES 2007-2018","volume":"14","author":"Wei","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1365-2","article-title":"From discoveries in ageing research to therapeutics for healthy ageing","volume":"571","author":"Campisi","year":"2019","journal-title":"Nature"},{"key":"B37","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1038\/s43587-021-00044-4","article-title":"Disparities in the pace of biological aging among midlife adults of the same chronological age have implications for future frailty and genetics","volume":"1","author":"Elliott","year":"2021","journal-title":"Nat Aging"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002718","article-title":"A new aging measure captures morbidity and mortality risk across diverse subpopulations from NHANES IV: A cohort study","volume":"15","author":"Liu","year":"2018","journal-title":"PloS Med"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/jgs.17011","article-title":"Heterogeneity of aging: individual response to stressors","volume":"69","author":"Ferrucci","year":"2021","journal-title":"J Am Geriatr Soc"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1824716\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T04:12:54Z","timestamp":1776399174000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1824716\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,17]]},"references-count":39,"alternative-id":["10.3389\/fendo.2026.1824716"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1824716","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,17]]},"article-number":"1824716"}}