{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T03:09:50Z","timestamp":1791083390015,"version":"4.1.0"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging"],"abstract":"<jats:p>\n                    The relationship between disease onset and chronological age varies between individuals, driving the need for a more accurate, universal biomarker of biological aging. Among the emerging alternatives, the immune system represents a universally shared, complex system that consistently shows aging-related decline across diverse individuals. Specifically, T-cell dynamics, capturing both thymic involution and lifelong antigenic exposure, provide insights into immune system aging. Although existing aging clocks, such as those based on DNA methylation (i.e., Horvath\u2019s and GrimAge), offer valuable predictions of biological age and disease risk, these methods are often limited in ability and cost to reflect real-time immune function. We also explore cutting-edge techniques to measure T-cell states, such as flow cytometry, single-cell omics, cytometry by time-of-flight (CyTOF), and the potential of non-invasive retinal imaging, but these techniques also face these limitations. To account for the challenges with the above-mentioned methods, we propose the naive-to-exhausted T-cell ratio as a promising, quantifiable metric of immune aging. The conceptual framework benchmarks the naive-to-exhausted T-cell ratio against established epigenetic clocks, generating an \u201cimmune age curve\u201d that offers clinicians and researchers a practical approach to integrate immune aging assessments into clinical and preventative care. To test our hypothesis, we conducted survival association analysis based on naive-to-exhausted T-cell levels across all major cancers (including adrenal carcinoma (HR = 0.19 (CI [0.082, 0.44]),\n                    <jats:italic>p<\/jats:italic>\n                    = 1.92e-5), low-grade glioma (HR = 0.47 (CI [0.33, 0.67]),\n                    <jats:italic>p<\/jats:italic>\n                    = 2.4e-5), and sarcoma (HR = 0.52 (CI [0.35, 0.77],\n                    <jats:italic>p<\/jats:italic>\n                    = 0.000984)). The survival analysis shows that a higher ratio of naive to exhausted T cells is associated with significantly better overall survival rates, with hazard ratios (HRs) ranging from 2.7e-9 to 0.7. These preliminary results support the predictive value of naive-to-exhausted T-cell levels for biological aging and disease progression prediction across multiple organ systems.\n                  <\/jats:p>","DOI":"10.3389\/fragi.2025.1684051","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T06:15:20Z","timestamp":1763619320000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Estimation of biological aging based on T-cell differentiation trajectories: emerging and future avenues"],"prefix":"10.3389","volume":"6","author":[{"given":"Aarav M.","family":"Bhasin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ishaan K.","family":"Marwaha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lahiri S.","family":"Nooka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/1302811","article-title":"Methods to analyze time-to-event data: the cox regression analysis","volume":"2021","author":"Abd ElHafeez","year":"2021","journal-title":"Oxid. Med. Cell. Longev"},{"key":"B2","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.imlet.2022.04.008","article-title":"Single cell multiomic approaches to disentangle T cell heterogeneity","volume":"246","author":"Abondio","year":"2022","journal-title":"Immunol. Lett."},{"key":"B3","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/nri2959","article-title":"Are senescence and exhaustion intertwined or unrelated processes that compromise immunity?","volume":"11","author":"Akbar","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"64","DOI":"10.3844\/ajbbsp.2016.64.71","article-title":"Telomere length measurement by quantitative real-time PCR: a molecular marker for human age prediction","volume":"12","author":"Alhusseini","year":"2016","journal-title":"Am. J. Biochem. Biotechnol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2450","DOI":"10.1038\/s41591-024-03164-7","article-title":"Proteomic aging clock predicts mortality and risk of common age-related diseases in diverse populations","volume":"30","author":"Argentieri","year":"2024","journal-title":"Nat. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1146\/annurev-immunol-090222-110914","article-title":"T cell exhaustion","volume":"42","author":"Baessler","year":"2024","journal-title":"Annu. Rev. Immunol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1186\/s13059-019-1824-y","article-title":"DNA methylation aging clocks: challenges and recommendations","volume":"20","author":"Bell","year":"2019","journal-title":"Genome Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.3390\/cancers13061400","article-title":"Cancer and aging: two tightly interconnected biological processes","volume":"13","author":"Berben","year":"2021","journal-title":"Cancers"},{"key":"B9","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s12877-015-0031-2","article-title":"Factors associated with lower gait speed among the elderly living in a developing country: a cross-sectional population-based study","volume":"15","author":"Busch","year":"2015","journal-title":"BMC Geriatr."},{"key":"B10","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1038\/s41571-022-00689-z","article-title":"Clinical implications of T cell exhaustion for cancer immunotherapy","volume":"19","author":"Chow","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1161\/circgen.119.002610","article-title":"Metabolic age based on the BBMRI-NL 1 H-NMR metabolomics repository as biomarker of age-related disease","volume":"13","author":"Van Den Akker","year":"2020","journal-title":"Circ. Genomic Precis. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2424","DOI":"10.1182\/bloodadvances.2023011242","article-title":"Immune status and selection of patients for immunotherapy in myeloma: a proposal","volume":"8","author":"Dhodapkar","year":"2024","journal-title":"Blood Adv."},{"key":"B13","doi-asserted-by":"publisher","first-page":"3069","DOI":"10.1038\/s41598-022-06841-0","article-title":"Survival Genie, a web platform for survival analysis across pediatric and adult cancers","volume":"12","author":"Dwivedi","year":"2022","journal-title":"Sci. Rep."},{"key":"B14","article-title":"Activities of daily living","volume-title":"StatPearls","author":"Edemekong","year":"2025"},{"key":"B15","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/B978-0-12-384730-0.00127-0","article-title":"Flow cytometry","volume-title":"Encyclopedia of food microbiology","year":"2014"},{"key":"B16","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1038\/s41392-025-02371-z","article-title":"Immunosenescence: signaling pathways, diseases and therapeutic targets","volume":"10","author":"Fu","year":"2025","journal-title":"Signal Transduct. Target Ther."},{"key":"B17","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1038\/s41577-019-0180-1","article-title":"Mechanisms underlying T cell ageing","volume":"19","author":"Goronzy","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e001794","DOI":"10.1136\/bmjophth-2024-001794","article-title":"Estimating biological age from retinal imaging: a scoping review","volume":"9","author":"Grimbly","year":"2024","journal-title":"BMJ Open Ophthalmol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1016\/j.molcel.2012.10.016","article-title":"Genome-wide methylation profiles reveal quantitative views of human aging rates","volume":"49","author":"Hannum","year":"2013","journal-title":"Mol. Cell."},{"key":"B20","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-Seq data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinforma."},{"key":"B21","volume-title":"Dictionary of gerontology","author":"Harris","year":"1988"},{"key":"B22","doi-asserted-by":"publisher","first-page":"102446","DOI":"10.1016\/j.sbi.2022.102446","article-title":"Telomerase structural biology comes of age","volume":"76","author":"He","year":"2022","journal-title":"Curr. Opin. Struct. Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1186\/s13148-020-00905-6","article-title":"Epigenetic measures of ageing predict the prevalence and incidence of leading causes of death and disease burden","volume":"12","author":"Hillary","year":"2020","journal-title":"Clin. Epigenetics"},{"key":"B24","doi-asserted-by":"publisher","first-page":"R115","DOI":"10.1186\/gb-2013-14-10-r115","article-title":"DNA methylation age of human tissues and cell types","volume":"14","author":"Horvath","year":"2013","journal-title":"Genome Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1007\/s004390050711","article-title":"Telomeric length and telomerase activity vary with age in peripheral blood cells obtained from normal individuals","volume":"102","author":"Iwama","year":"1998","journal-title":"Hum. Genet."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e13664","DOI":"10.1111\/acel.13664","article-title":"Human age reversal: fact or fiction?","volume":"21","author":"Johnson","year":"2022","journal-title":"Aging Cell."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2805","DOI":"10.1007\/s11357-023-00826-1","article-title":"DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation","volume":"45","author":"Jokai","year":"2023","journal-title":"GeroScience"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e60547","DOI":"10.7554\/eLife.60547","article-title":"Label-free imaging of immune cell dynamics in the living retina using adaptive optics","volume":"9","author":"Joseph","year":"2020","journal-title":"eLife"},{"key":"B29","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1016\/j.fsigss.2007.10.153","article-title":"Estimating human age in forensic samples by analysis of telomere repeats","volume":"1","author":"Karlsson","year":"2008","journal-title":"Forensic Sci. Int. Genet. Suppl. Ser."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1491584","DOI":"10.3389\/fmed.2025.1491584","article-title":"Handgrip strength as a potential indicator of aging: insights from its association with aging-related laboratory parameters","volume":"12","author":"Kemala","year":"2025","journal-title":"Front. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"5825","DOI":"10.3390\/app15115825","article-title":"Walking-Age estimator based on gait parameters using kernel regression","volume":"15","author":"Kuroda","year":"2025","journal-title":"Appl. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/s41551-023-01144-9","article-title":"High-dimensional multi-pass flow cytometry via spectrally encoded cellular barcoding","volume":"8","author":"Kwok","year":"2023","journal-title":"Nat. Biomed. Eng."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1038\/s12276-020-0420-2","article-title":"Single-cell multiomics: technologies and data analysis methods","volume":"52","author":"Lee","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"B34","doi-asserted-by":"publisher","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":"B35","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s12979-019-0165-8","article-title":"Age related human T cell subset evolution and senescence","volume":"16","author":"Li","year":"2019","journal-title":"Immun. Ageing A"},{"key":"B36","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1038\/s41392-023-01502-8","article-title":"Inflammation and aging: signaling pathways and intervention therapies","volume":"8","author":"Li","year":"2023","journal-title":"Signal Transduct. Target Ther."},{"key":"B37","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.jim.2009.09.012","article-title":"Analyses and comparisons of telomerase activity and telomere length in human T and B cells: insights for epidemiology of telomere maintenance","volume":"352","author":"Lin","year":"2010","journal-title":"J. Immunol. Methods"},{"key":"B38","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/978-1-4939-7346-0_3","article-title":"Mass cytometry assays for antigen-specific T cells using CyTOF","volume-title":"Flow cytometry protocols","author":"Lin","year":"2018"},{"key":"B39","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41392-023-01451-2","article-title":"Immunosenescence: molecular mechanisms and diseases","volume":"8","author":"Liu","year":"2023","journal-title":"Signal Transduct. Target Ther."},{"key":"B40","doi-asserted-by":"publisher","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":"B41","doi-asserted-by":"publisher","first-page":"9484","DOI":"10.18632\/aging.204434","article-title":"DNA methylation GrimAge version 2","volume":"14","author":"Lu","year":"2022","journal-title":"Aging"},{"key":"B42","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/978-1-4939-6548-9_3","article-title":"FACS analysis of memory T lymphocytes","volume":"1514","author":"Lugli","year":"2017","journal-title":"Methods Mol. Biol. Clifton N. J."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1101\/gad.195339.112","article-title":"Telomere end processing: unexpected complexity at the end game","volume":"26","author":"Lundblad","year":"2012","journal-title":"Genes. Dev."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.imlet.2020.12.003","article-title":"The impact of ageing on monocytes and macrophages","volume":"230","author":"De Maeyer","year":"2021","journal-title":"Immunol. Lett."},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0117598","article-title":"Age and grip strength predict hand dexterity in adults","volume":"10","author":"Martin","year":"2015","journal-title":"PLOS ONE"},{"key":"B46","unstructured":"Fact sheet: aging in the United States\n          \n          \n            \n              Mather\n              M.\n            \n            \n              Paola\n              S.\n            \n          \n          \n          2024"},{"key":"B47","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1083\/jcb.201708092","article-title":"Senescence and aging: causes, consequences, and therapeutic avenues","volume":"217","author":"McHugh","year":"2018","journal-title":"J. Cell. Biol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"733566","DOI":"10.3389\/fimmu.2021.733566","article-title":"The dynamics of B cell aging in health and disease","volume":"12","author":"de Mol","year":"2021","journal-title":"Front. Immunol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/npp.2012.112","article-title":"DNA methylation and its basic function","volume":"38","author":"Moore","year":"2013","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"3758","DOI":"10.1016\/j.cell.2023.08.003","article-title":"Biomarkers of aging for the identification and evaluation of longevity interventions","volume":"186","author":"Moqri","year":"2023","journal-title":"Cell."},{"key":"B51","doi-asserted-by":"publisher","first-page":"e2300187","DOI":"10.1002\/bies.202300187","article-title":"Telomere length is not a useful tool for chronological age estimation in animals","volume":"46","author":"Pepke","year":"2024","journal-title":"BioEssays News Rev. Mol. Cell. Dev. Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1002\/jcsm.13110","article-title":"Grip strength is inversely associated with DNA methylation age acceleration","volume":"14","author":"Peterson","year":"2023","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"B53","doi-asserted-by":"publisher","first-page":"e14471","DOI":"10.1111\/acel.14471","article-title":"DeepQA: a unified transcriptome\u2010based aging clock using deep neural networks","volume":"24","author":"Qi","year":"2025","journal-title":"Aging Cell."},{"key":"B54","doi-asserted-by":"publisher","first-page":"e1913123","DOI":"10.1001\/jamanetworkopen.2019.13123","article-title":"Association of neurocognitive and physical function with gait speed in midlife","volume":"2","author":"Rasmussen","year":"2019","journal-title":"JAMA Netw. Open"},{"key":"B55","first-page":"595","article-title":"T cell ageing: effects of age on development, survival & function","volume":"138","author":"Salam","year":"2013","journal-title":"Indian J. Med. Res."},{"key":"B56","doi-asserted-by":"publisher","first-page":"171","DOI":"10.3389\/fgene.2020.00171","article-title":"DNA methylation biomarkers in aging and age-related diseases","volume":"11","author":"Salameh","year":"2020","journal-title":"Front. Genet."},{"key":"B57","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1038\/s41586-020-2499-y","article-title":"Ageing hallmarks exhibit organ-specific temporal signatures","volume":"583","author":"Schaum","year":"2020","journal-title":"Nature"},{"key":"B58","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/B978-0-12-823818-9.00013-4","article-title":"Anomaly detection","volume-title":"Anomaly detection and complex event processing over IoT data streams","author":"Schneider","year":"2022"},{"key":"B59","doi-asserted-by":"publisher","first-page":"4173","DOI":"10.1242\/jcs.106831","article-title":"Telomeres at a glance","volume":"125","author":"Sfeir","year":"2012","journal-title":"J. Cell. Sci."},{"key":"B60","doi-asserted-by":"publisher","first-page":"149","DOI":"10.4324\/9781032720869-8","article-title":"Ageing and health","author":"Steverson","year":"2024"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1840","DOI":"10.4081\/jphr.2020.1840","article-title":"Effect of age and weight on physical activity","volume":"9","author":"Suryadinata","year":"2020","journal-title":"J. Public Health Res."},{"key":"B62","doi-asserted-by":"publisher","first-page":"945964","DOI":"10.3389\/fnagi.2022.945964","article-title":"Retinal microvasculature and imaging markers of brain frailty in normal aging adults","volume":"14","author":"Tao","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"B63","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1126\/science.aad0501","article-title":"Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq","volume":"352","author":"Tirosh","year":"2016","journal-title":"Science"},{"key":"B64","doi-asserted-by":"publisher","first-page":"e84916","DOI":"10.7554\/eLife.84916","article-title":"Quantitative analyses of T cell motion in tissue reveals factors driving T cell search in tissues","volume":"12","author":"Torres","year":"2023","journal-title":"eLife"},{"key":"B65","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1002\/stem.5530130305","article-title":"Life span of naive and memory t cells","volume":"13","author":"Tough","year":"1995","journal-title":"STEM CELLS"},{"key":"B66","doi-asserted-by":"publisher","first-page":"3762651","DOI":"10.1155\/2017\/3762651","article-title":"Defining an optimal cut-point value in ROC analysis: an alternative approach","volume":"2017","author":"Unal","year":"2017","journal-title":"Comput. Math. Methods Med."},{"key":"B67","doi-asserted-by":"publisher","first-page":"1490302","DOI":"10.3389\/fragi.2024.1490302","article-title":"The 3 i\u2019s of immunity and aging: immunosenescence, inflammaging, and immune resilience","volume":"5","author":"Wrona","year":"2024","journal-title":"Front. Aging"},{"key":"B68","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s12979-024-00433-4","article-title":"The effect of T cell aging on the change of human tissue structure","volume":"21","author":"Xu","year":"2024","journal-title":"Immun. Ageing"},{"key":"B69","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1038\/s41746-025-01751-7","article-title":"A cross population study of retinal aging biomarkers with longitudinal pre-training and label distribution learning","volume":"8","author":"Yu","year":"2025","journal-title":"NPJ Digit. Med."},{"key":"B70","doi-asserted-by":"publisher","first-page":"e13739","DOI":"10.1002\/jcsm.13739","article-title":"Gait speed and all-cause mortality in whole-spectrum chronic kidney disease: a systematic review and meta-analysis included 6217 participants","volume":"16","author":"Zhang","year":"2025","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"B71","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1136\/bjophthalmol-2021-319807","article-title":"Retinal age gap as a predictive biomarker for mortality risk","volume":"107","author":"Zhu","year":"2023","journal-title":"Br. J. Ophthalmol."}],"container-title":["Frontiers in Aging"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fragi.2025.1684051\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T06:15:26Z","timestamp":1763619326000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fragi.2025.1684051\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,20]]},"references-count":71,"alternative-id":["10.3389\/fragi.2025.1684051"],"URL":"https:\/\/doi.org\/10.3389\/fragi.2025.1684051","relation":{},"ISSN":["2673-6217"],"issn-type":[{"value":"2673-6217","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,20]]},"article-number":"1684051"}}