Immune aging biomarkers for clinical trials

Abstract Aging profoundly remodels the immune system, impairing defense, repair and homeostatic function across tissues. Because the immune system operates in every organ, its deterioration has been proposed to drive or exacerbate systemic dysfunction and accelerate overall biological aging, making it an attractive biomarker and target for geroscience-guided trials. Despite this central role, there is no consensus on how to quantify immune aging, especially in clinical trials. Here, we establish a translational framework to identify immune aging biomarkers for this purpose. We define five evaluation criteria for immune aging biomarkers and apply these to candidate biomarkers, discussing their utility in the context of a major international healthspan competition, XPRIZE Healthspan. Metrics encapsulating multidimensional aspects of immune function, inflammaging scores and functional assays performed best against our selection criteria. Finally, we identify promising emerging measures, together with critical gaps that must be addressed to develop reliable, predictive biomarkers of human immune competence. Our framework provides a coherent path toward actionable and clinically meaningful immune aging biomarkers capable of quantifying immune fitness and resilience, and accelerating the clinical translation of geroscience-guided interventions. This is a preview of subscription content, access via your institution Access options Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription $32.99 / 30 days cancel any time Subscribe to this journal Receive 12 print issues and online access $259.00 per year only $21.58 per issue Buy this article - Purchase on SpringerLink - Instant access to the full article PDF. USD 39.95 Prices may be subject to local taxes which are calculated during checkout Similar content being viewed by others References Kuo, P. -L. et al. Longitudinal phenotypic aging metrics in the Baltimore longitudinal study of aging. Nat. Aging 2, 635–643 (2022). Kennedy, B. K. et al. Geroscience: linking aging to chronic disease. Cell 159, 709–713 (2014). Justice, J. N. XPRIZE healthspan is a global competition to restore function. Nat. Aging 4, 165–166 (2024). López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: an expanding universe. Cell 186, 243–278 (2023). Yousefzadeh, M. J. et al. An aged immune system drives senescence and ageing of solid organs. Nature 594, 100–105 (2021). Bartleson, J. M. et al. SARS-CoV-2, COVID-19 and the aging immune system. Nat. Aging 1, 769–782 (2021). Lord, J. M. et al. Accelerated immune ageing is associated with COVID-19 disease severity. Immun. Ageing 21, 6 (2024). Wu, F. et al. Immunological biomarkers of aging. J. Immunol. 214, 889–902 (2025). Sender, R. et al. The total mass, number, and distribution of immune cells in the human body. Proc. Natl Acad. Sci. USA 120, e2308511120 (2023). Terekhova, M., Bohacova, P. & Artyomov, M. N. Human immune aging. Immunity 58, 2646–2669 (2025). Doherty, T. M., Weinberger, B., Didierlaurent, A. & Lambert, P. -H. Age-related changes in the immune system and challenges for the development of age-specific vaccines. Ann. Med. 57, 2477300 (2025). Kulkarni, U. et al. Excessive neutrophil levels in the lung underlie the age-associated increase in influenza mortality. Mucosal Immunol. 12, 545–554 (2019). Chen, J., Kelley, W. J. & Goldstein, D. R. Role of aging and the immune response to respiratory viral infections: potential implications for COVID-19. J. Immunol. 205, ji2000380 (2020). Smith, C. A., Kulkarni, U., Chen, J. & Goldstein, D. R. Influenza virus inoculum volume is critical to elucidate age-dependent mortality in mice. Aging Cell 18, e12893 (2019). Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 14, 576–590 (2018). Fulop, T. et al. Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes?. Front. Immunol. 8, 1960 (2018). Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018). Mogilenko, D. A., Shchukina, I. & Artyomov, M. N. Immune ageing at single-cell resolution. Nat. Rev. Immunol. 22, 484–498 (2022). Weyand, C. M. & Goronzy, J. J. Aging of the immune system. mechanisms and therapeutic targets. Ann. Am. Thorac. Soc. 13, S422–S428 (2016). Lynch, H. E. et al. Thymic involution and immune reconstitution. Trends Immunol. 30, 366–373 (2009). Elyahu, Y. & Monsonego, A. Thymus involution sets the clock of the aging T-cell landscape: Implications for declined immunity and tissue repair. Ageing Res. Rev. 65, 101231 (2021). Spadaro, O. et al. Caloric restriction in humans reveals immunometabolic regulators of health span. Science 375, 671–677 (2022). Yang, H., Youm, Y. -H. & Dixit, V. D. Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution. J. Immunol. 183, 3040–3052 (2009). Su, T. -Y. et al. Aging is associated with functional and molecular changes in distinct hematopoietic stem cell subsets. Nat. Commun. 15, 7966 (2024). Beerman, I. et al. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc. Natl Acad. Sci. USA 107, 5465–5470 (2010). Jaiswal, S. & Ebert, B. L. Clonal hematopoiesis in human aging and disease. Science 366, eaan4673 (2019). Bouzid, H. et al. Clonal hematopoiesis is associated with protection from Alzheimer’s disease. Nat. Med. 29, 1662–1670 (2023). Masters, A. R. et al. Assessment of lymph node stromal cells as an underlying factor in age-related immune impairment. J. Gerontol. A Biol. Sci. Med. Sci. 74, 1734–1743 (2019). Gao, X., Zhang, J. & Tamplin, O. J. The aging hematopoietic stem cell niche: a mini review. Front. Hematol. 4, 1525132 (2025). Ross, J. B. et al. Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Nature 628, 162–170 (2024). Mogilenko, D. A. et al. Comprehensive profiling of an aging immune system reveals clonal GZMK+ CD8+ T cells as conserved hallmark of inflammaging. Immunity 54, 99–115 (2021). Mol, J. de, Kuiper, J., Tsiantoulas, D. & Foks, A. C. The dynamics of B cell aging in health and disease. Front. Immunol. 12, 733566 (2021). Mittelbrunn, M. & Kroemer, G. Hallmarks of T cell aging. Nat. Immunol. 22, 687–698 (2021). Sun, X. et al. Longitudinal analysis reveals age-related changes in the T cell receptor repertoire of human T cell subsets. J. Clin. Invest. 132, e158122 (2022). Park, M. D. et al. Restoring resident tissue macrophages to combat aging and cancer. Nat Aging 5, 1383–1392 (2025). Adé, K. et al. Inflammation drives age-induced loss of tissue resident macrophages. Preprint at bioRxiv https://doi.org/10.1101/2022.10.02.510513 (2022). Krishnarajah, S. et al. Single-cell profiling of immune system alterations in lymphoid, barrier and solid tissues in aged mice. Nat. Aging 2, 74–89 (2022). Mesa, K. R. et al. Niche-specific dermal macrophage loss promotes skin capillary ageing. Nature 648, 173–181 (2025). Keenan, C. R. & Allan, R. S. Epigenomic drivers of immune dysfunction in aging. Aging Cell 18, e12878 (2019). Wang, K. et al. Epigenetic regulation of aging: implications for interventions of aging and diseases. Signal Transduct. Target. Ther. 7, 374 (2022). Beerman, I. et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell 12, 413–425 (2013). Yanai, H. et al. DNA methylation drives hematopoietic stem cell aging phenotypes after proliferative stress. GeroScience https://doi.org/10.1007/s11357-024-01360-4 (2024). Bruhn-Olszewska, B. et al. The effects of loss of Y chromosome on male health. Nat. Rev. Genet. 26, 320–335 (2025). Roberts, A. L. et al. Age acquired skewed X chromosome inactivation is associated with adverse health outcomes in humans. eLife 11, e78263 (2022). Fali, T. et al. New insights into lymphocyte differentiation and aging from telomere length and telomerase activity measurements. J. Immunol. 202, 1962–1969 (2019). Karimian, K. et al. Human telomere length is chromosome end–specific and conserved across individuals. Science 384, 533–539 (2024). Smoom, R., Lichtental, D., Kaestner, K. H. & Tzfati, Y. The house mouse maintains constant telomere length throughout life. Nucleic Acids Res. 53, gkaf830 (2025). McGuire, P. J. Mitochondrial dysfunction and the aging immune system. Biology 8, 26 (2019). Bektas, A. et al. Age-associated changes in human CD4+ T cells point to mitochondrial dysfunction consequent to impaired autophagy. Aging 11, 9234–9263 (2019). Thomas, R., Wang, W. & Su, D. -M. Contributions of age-related thymic involution to immunosenescence and inflammaging. Immun. Ageing 17, 2 (2020). Verbrugge, L. M. & Jette, A. M. The disablement process. Soc. Sci. Med. 38, 1–14 (1994). Reid, K. F. & Fielding, R. A. Skeletal muscle power. Exerc. Sport Sci. Rev. 40, 4–12 (2012). Kritchevsky, S. B. & Justice, J. N. Testing the geroscience hypothesis: early days. J. Gerontol. A Biol. Sci. Med. Sci. 75, 99–101 (2020). Moqri, M. et al. Biomarkers of aging for the identification and evaluation of longevity interventions. Cell 186, 3758–3775 (2023). Moqri, M. et al. Validation of biomarkers of aging. Nat. Med. 30, 360–372 (2024). Herzog, C. M. S. et al. Challenges and recommendations for the translation of biomarkers of aging. Nat. Aging 4, 1372–1383 (2024). Ahuja, S. K. et al. Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection. Nat. Commun. 14, 3286 (2023). Manoharan, M. S. et al. The 15-year survival advantage: immune resilience as a salutogenic force in healthy aging. Aging Cell 24, e70063 (2025). Franck, M. et al. Nonuniversality of inflammaging across human populations. Nat. Aging 5, 1471–1480 (2025). Gong, Q. et al. Multi-omic profiling reveals age-related immune dynamics in healthy adults. Nature 648, 696–706 (2025). Weng, N., Akbar, A. N. & Goronzy, J. CD28− T cells: their role in the age-associated decline of immune function. Trends Immunol. 30, 306–312 (2009). Liu, Y. et al. Expression of p16INK4a in peripheral blood T-cells is a biomarker of human aging. Aging Cell 8, 439–448 (2009). Hillary, R. F. et al. Blood-based epigenome-wide analyses of chronic low-grade inflammation across diverse population cohorts. Cell Genom. 4, 100544 (2024). Dawoud, A., Green, L. & Rackham, O. Loss of chromosome Y shapes the immune cell fate with aging in men. Aging Cell 25, e70528 (2026). Alpert, A. et al. A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring. Nat. Med. 25, 487–495 (2019). Sayed, N. et al. An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging. Nat. Aging 1, 598–615 (2021). Goyani, P., Christodoulou, R. & Vassiliou, E. Immunosenescence: aging and immune system decline. Vaccines 12, 1314 (2024). Rodrigues, L. P. et al. Hallmarks of aging and immunosenescence: connecting the dots. Cytokine Growth Factor Rev. 59, 9–21 (2021). Raza, K. et al. Specific features of immune ageing are detected in the earliest stages in rheumatoid arthritis development. eBioMedicine 119, 105900 (2025). Foster, M. A. et al. Investigating the potential of a prematurely aged immune phenotype in severely injured patients as predictor of risk of sepsis. Immun. Ageing 19, 60 (2022). Bröde, P. et al. Calibrating a comprehensive immune age metric to analyze the cross sectional age-related decline in cardiorespiratory fitness. Biology 11, 1576 (2022). Gajewski, P. D. et al. A systematic analysis of biological, sociodemographic, psychosocial, and lifestyle factors contributing to work ability across the working life span: cross-sectional study. JMIR Form. Res. 7, e40818 (2023). Sánchez-Sánchez, J. L. et al. Biological ageing acceleration and functional capacities across the lifespan in the INSPIRE-T cohort. J. Cachexia Sarcopenia Muscle 16, e70046 (2025). Wang, R. Z. et al. Inflammatory age and its impact on age-related health in older Chinese adults. Arch. Gerontol. Geriatr. 125, 105476 (2024). Schmunk, L. J. et al. A novel framework to build saliva-based DNA methylation biomarkers: quantifying systemic chronic inflammation as a case study. Aging Cell 24, e14444 (2025). Schafer, M. J. et al. The senescence-associated secretome as an indicator of age and medical risk. JCI Insight 5, e133668 (2020). Cummings, S. R. et al. Biomarkers of cellular senescence and major health outcomes in older adults. GeroScience 47, 3407–3415 (2025). St Sauver, J. L. et al. Biomarkers of cellular senescence and risk of death in humans. Aging Cell https://doi.org/10.1111/acel.14006 (2023). Fielding, R. A. et al. Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study. GeroScience https://doi.org/10.1007/s11357-022-00685-2 (2022). Mielke, M. M. et al. Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study. J. Nutr. Health Aging 29, 100529 (2025). Centers for Disease Control. QuickStats: death rates from influenza and pneumonia among persons aged ≥65 years, by sex and age group — National Vital Statistics System, United States, 2018. MMWR Morb. Mortal. Wkly Rep. 69, 1470 (2020). Montgomery, R. R. Age-related alterations in immune responses to West Nile virus infection. Clin. Exp. Immunol. 187, 26–34 (2016). Abel, L. & Casanova, J. -L. Human determinants of age-dependent patterns of death from infection. Immunity 57, 1457–1465 (2024). Mannick, J. B. et al. Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. Lancet Healthy Longev. 2, e250–e262 (2021). Mannick, J. B. et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 10, eaaq1564 (2018). Morrisette-Thomas, V. et al. Inflamm-aging does not simply reflect increases in pro-inflammatory markers. Mech. Ageing Dev. 139, 49–57 (2014). Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019). FRANCESCHI, C. et al. Inflamm-aging: an evolutionary perspective on immunosenescence. Ann. N.Y. Acad. Sci. 908, 244–254 (2000). Diniz, B. S. et al. Association of molecular senescence markers in late-life depression with clinical characteristics and treatment outcome. JAMA Netw. Open 5, e2219678 (2022). Dioum, E. H. M. et al. Oats lower age-related systemic chronic inflammation (iAge) in adults at risk for cardiovascular disease. Nutrients 14, 4471 (2022). Fuentealba, M. et al. Multi-omics analysis reveals biomarkers that contribute to biological age rejuvenation in response to single-blinded randomized placebo-controlled therapeutic plasma exchange. Aging Cell 24, e70103 (2025). Nimmerjahn, F., Vidarsson, G. & Cragg, M. S. Effect of posttranslational modifications and subclass on IgG activity: from immunity to immunotherapy. Nat. Immunol. 24, 1244–1255 (2023). Vinicki, M. et al. Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome. GeroScience 47, 1777–1788 (2025). Rapčan, B. et al. Glycan clock of ageing—analytical precision and time-dependent inter- and i-individual variability. GeroScience 46, 5781–5796 (2024). Sun, S. et al. Immunoglobulin G N-glycosylation predicts long-term risk of ischemic stroke: a nested case-control study. J. Transl. Med. 23, 1175 (2025). Wang, H. et al. Immunoglobulin G N-glycome as a biomarker of mortality risk in Escherichia coli induced sepsis. Front. Immunol. 16, 1532145 (2025). Hoshi, R. A. et al. N-Glycosylation profiles of immunoglobulin G and future cardiovascular events. Circ. Res. 134, e3–e14 (2024). Burel, J. G. et al. IgG glycosylation associates with risk of progression from latent to active tuberculosis. J. Infect. 88, 106115 (2024). Song, M., Graubard, B. I., Rabkin, C. S. & Engels, E. A. Neutrophil-to-lymphocyte ratio and mortality in the United States general population. Sci. Rep. 11, 464 (2021). Dillon, K., Goodman, Z. T., Kaur, S. S., Levin, B. & McIntosh, R. Neutrophil-to-Lymphocyte ratio amplifies the effects of aging on decrements in grip strength and its functional neural underpinnings. J. Gerontol. A Biol. Sci. Med. Sci. 78, 882–889 (2023). Yoshida, Y., Iwasa, H., Kim, H. & Suzuki, T. Association between neutrophil-to-lymphocyte ratio and physical function in older adults: a community-based cross-sectional study in Japan. Int. J. Environ. Res. Public Health 19, 8996 (2022). Willik et al. Balance between innate versus adaptive immune system and the risk of dementia: a population-based cohort study. J. Neuroinflammation 16, 68 (2019). Bhat, T. et al. Neutrophil to lymphocyte ratio and cardiovascular diseases: a review. Expert Rev. Cardiovasc. Ther. 11, 55–59 (2013). Ethier, J. -L., Desautels, D., Templeton, A., Shah, P. S. & Amir, E. Prognostic role of neutrophil-to-lymphocyte ratio in breast cancer: a systematic review and meta-analysis. Breast Cancer Res. 19, 2 (2017). Jacobs, T. et al. The neutrophil to lymphocyte ratio associates with markers of Alzheimer’s disease pathology in cognitively unimpaired elderly people. Immun. Ageing 21, 32 (2024). Neupane, R. et al. Immune disorder in atherosclerotic cardiovascular disease―clinical implications of using circulating T-cell subsets as biomarkers. Circ. J. 83, 1431–1438 (2019). Yang, Q. -K. et al. CONUT score or/and peripheral blood CD4+/CD8+ ratio-based web dynamic nomograms to predict the individualized survival of patients with advanced osteosarcoma. Cancer Manag. Res. 12, 4193–4208 (2020). Adriaensen, W. et al. CD4:8 ratio >5 is associated with a dominant naive T-cell phenotype and impaired physical functioning in CMV-seropositive very elderly people: results from the BELFRAIL study. J. Gerontol. A Biol. Sci. Med. Sci. 70, 143–154 (2015). Formiga, F., Ferrer, A., Padros, G., Contra, A. & Pujol, R. Inverted CD4:CD8 ratio is not associated with three-year mortality in a sample of community-dwelling oldest old: The Octabaix immune study. J. Nutr. Health Aging 18, 425–428 (2014). Ragab, A. A. Y. et al. Immune cell phenotypes and mortality in the framingham heart study. Immun. Ageing 21, 37 (2024). Fang, Y. et al. Circulating immune cell phenotypes are associated with age, sex, CMV, and smoking status in the framingham heart study offspring participants. Aging 15, 3939–3966 (2023). Ramasubramanian, R. et al. Evaluation of T-cell aging-related immune phenotypes in the context of biological aging and multimorbidity in the Health and Retirement Study. Immun. Ageing 19, 33 (2022). Wielscher, M. et al. DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases. Nat. Commun. 13, 2408 (2022). McGee, K. C. et al. A combination nutritional supplement reduces DNA methylation age only in older adults with a raised epigenetic age. GeroScience 46, 4333–4347 (2024). Reading, C. L. et al. An exploratory analysis of bezisterim treatment associated with decreased biological age acceleration, and improved clinical measure and biomarker changes in mild-to-moderate probable Alzheimer’s disease. Front. Neurosci. 19, 1516746 (2025). Middelkamp, V. & Kekäläinen, E. Measuring thymic output across the human lifespan: a critical challenge in laboratory medicine. GeroScience 47, 6797–6806 (2025). Lakhonina, N. et al. T cell receptor rearrangement excision circles (TREC) study as an approach to ‘in vivo’ thymus gland function investigation. Arthritis Res. Ther. 14, P37 (2012). Mikhael, N. L. & Elsorady, M. Clinical significance of T cell receptor excision circle (TREC) quantitation after allogenic HSCT. Blood Res. 54, 274–281 (2019). Sandhar, B. et al. Heterogeneity of thymic output in the elderly and its association with sex and smoking. JCI Insight 10, e189008 (2025). Sparks, R. et al. A unified metric of human immune health. Nat. Med. 30, 2461–2472 (2024). Chen, X. et al. Impact of infection on healthcare costs and clinical outcomes in elderly hospitalized patients with multimorbidity. Heliyon 10, e31560 (2024). Lord, J. M. The effect of aging of the immune system on vaccination responses. Hum. Vacc. Immunother. 9, 1364–1367 (2013). Collier, D. A. et al. Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2. Nature 596, 417–422 (2021). Goodwin, K., Viboud, C. & Simonsen, L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 24, 1159–1169 (2006). Semelka, C. T. et al. Frailty and COVID-19 mRNA vaccine antibody response in the COVID-19 community research partnership. J. Gerontol. A Biol. Sci. Med. Sci. 77, 1366–1370 (2022). Macdonald, C. et al. Association between antibody responses post-vaccination and severe COVID-19 outcomes in Scotland. NPJ Vaccines 9, 107 (2024). Martin, D. E. et al. The effect of metformin on influenza vaccine responses in nondiabetic older adults: a pilot trial. Immun. Ageing 20, 18 (2023). Agrawal, A. et al. Altered innate immune functioning of dendritic cells in elderly humans: a role of phosphoinositide 3-kinase-signaling pathway. J. Immunol. 178, 6912–6922 (2007). Merani, S., Kuchel, G. A., Kleppinger, A. & McElhaney, J. E. Influenza vaccine-mediated protection in older adults: impact of influenza infection, cytomegalovirus serostatus and vaccine dosage. Exp. Gerontol. 107, 116–125 (2018). McElhaney, J. E. et al. T cell responses are better correlates of vaccine protection in the elderly. J. Immunol. 176, 6333–6339 (2006). Wells, S. B. et al. Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age. Nat. Immunol. 26, 1612–1625 (2025). Lam, N. et al. Asynchronous aging and turnover of human circulating and tissue-resident memory T cells across sites. Immunity 58, 2271–2288 (2025). Pawelec, G. Age and immunity: what is “immunosenescence”? Exp. Gerontol. 105, 4–9 (2018). Lee, K. -A., Flores, R. R., Jang, I. H., Saathoff, A. & Robbins, P. D. Immune senescence, immunosenescence and aging. Front. Aging 3, 900028 (2022). Wrona, M. V., Ghosh, R., Coll, K., Chun, C. & Yousefzadeh, M. J. The 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience. Front. Aging 5, 1490302 (2024). Goronzy, J. J. & Weyand, C. M. Understanding immunosenescence to improve responses to vaccines. Nat. Immunol. 14, 428–436 (2013). Moskalev, A., Stambler, I. & Caruso, C. Innate and adaptive immunity in aging and longevity: the foundation of resilience. Aging Dis. 11, 1363–1373 (2020). Verster, J. C., Kraneveld, A. D. & Garssen, J. The assessment of immune fitness. J. Clin. Med. 12, 22 (2022). Dolan, M., Libby, K. A., Ringel, A. E., Galen, P. van & McAllister, S. S. Ageing, immune fitness and cancer. Nat. Rev. Cancer 25, 848–872 (2025). Dantzer, R., Cohen, S., Russo, S. J. & Dinan, T. G. Resilience and immunity. Brain Behav. Immun. 74, 28–42 (2018). Montano, M. Immune resilience: rewriting the rules of healthy aging. Aging Cell 24, e70089 (2025). Baessler, A. & Vignali, D. A. A. T cell exhaustion. Ann. Rev. Immunol. 42, 179–206 (2024). Slaets, H., Veeningen, N., Keizer, P. L. J. de, Hellings, N. & Hendrix, S. Are immunosenescent T cells really senescent? Aging Cell 23, e14300 (2024). Suryadevara, V. et al. SenNet recommendations for detecting senescent cells in different tissues. Nat. Rev. Mol. Cell Biol. 25, 1001–1023 (2024). Beltra, J. -C. et al. Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity 52, 825–841 (2020). Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015). Márquez, E. J. et al. Sexual-dimorphism in human immune system aging. Nat. Commun. 11, 751 (2020). Franceschi, C. & Campisi, J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci. 69, S4–S9 (2014). Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. New Engl. J. Med. 377, 1119–1131 (2017). Acknowledgements The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Author information Authors and Affiliations Contributions A.C., J.J. and C.H. conceived the manuscript and wrote the first draft. All authors contributed to the critical evaluation, furtherdevelopment of concepts and ideas, review and editing of the manuscript. Corresponding authors Ethics declarations Competing interests XPRIZE Healthspan is offered with support from co-title sponsors Hevolution Foundation and C. Wilson, founder and chairman of SOLVE FSHD, and Pharmaceutical Sponsor GSK. O.O.A. is a cofounder of Terrain Bio, Transit Therapeutics and Monet Therapeutics, and has filed intellectual property related to CRISPR-based genome editing and aging/rejuvenation. D.E.M.-H. is a cofounder and shareholder at Chronomics, a company focused on multi-omics and epigenetic biomarker development and diagnostic infrastructure. A.N.A. is a judge of the XPrize Healthspan scheme, chair of the scientific advisory board of the Walgreens Boots Alliance and University of Manchester collaborative skin initiative, and chair of the advisory board for the Singapore Ethnic Ageing grant at Singapore A*STAR Skin Research Labs. S.S.S.-O. holds equity and consults for CytoReason. W.W. is a cofounder of the company Cygenia, which provides services for epigenetic clocks to other scientists. D.F. is a founder of Edifice Health, a company that commercializes the iAge test. The other authors declare no competing interests. Peer review Peer review information Nature Medicine thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Karen O’Leary, in collaboration with the Nature Medicine team. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary information Supplementary Information (download PDF ) Supplementary Table 1 Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Cipriano, A., Justice, J., Poganik, J.R. et al. Immune aging biomarkers for clinical trials. Nat Med (2026). https://doi.org/10.1038/s41591-026-04493-5 Received: Accepted: Published: Version of record: DOI: https://doi.org/10.1038/s41591-026-04493-5