Goronzy, J. J. & Weyand, C. M. Mechanisms underlying T cell ageing. Nat. Rev. Immunol. 19, 573–583 (2019).
Google Scholar
Goronzy, J. J. & Weyand, C. M. Successful and maladaptive T cell aging. Immunity 46, 364–378 (2017).
Google Scholar
Soto-Heredero, G., Gomez de Las Heras, M. M., Escrig-Larena, J. I. & Mittelbrunn, M. Extremely differentiated T cell subsets contribute to tissue deterioration during aging. Annu. Rev. Immunol. 41, 181–205 (2023).
Google Scholar
Duggal, N. A., Niemiro, G., Harridge, S. D. R., Simpson, R. J. & Lord, J. M. Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity? Nat. Rev. Immunol. 19, 563–572 (2019).
Google Scholar
Moqri, M. et al. Validation of biomarkers of aging. Nat. Med. 30, 360–372 (2024).
Google Scholar
Ferrari, A. F. S. D. et al. Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet 403, 2133–2161 (2024).
Shen, X. et al. Nonlinear dynamics of multi-omics profiles during human aging. Nat. Aging 4, 1619–1634 (2024).
Google Scholar
Weyand, C. M. & Goronzy, J. J. Aging of the immune system. Mechanisms and therapeutic targets. Ann. Am. Thorac. Soc. 13 Suppl 5, S422–S428 (2016).
Google Scholar
Abel, L. & Casanova, J.-L. Human determinants of age-dependent patterns of death from infection. Immunity 57, 1457–1465 (2024).
Google Scholar
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).
Google Scholar
de Boer, R. J., Tesselaar, K. & Borghans, J. A. M. Better safe than sorry: naive T-cell dynamics in healthy ageing. Semin. Immunol. 70, 101839 (2023).
Google Scholar
Qi, Q., Zhang, D. W., Weyand, C. M. & Goronzy, J. J. Mechanisms shaping the naive T cell repertoire in the elderly — thymic involution or peripheral homeostatic proliferation? Exp. Gerontol. 54, 71–74 (2014).
Google Scholar
Summers, C. et al. Neutrophil kinetics in health and disease. Trends Immunol. 31, 318–324 (2010).
Google Scholar
Fujino, T., Asada, S., Goyama, S. & Kitamura, T. Mechanisms involved in hematopoietic stem cell aging. Cell. Mol. Life Sci. 79, 473 (2022).
Google Scholar
Kapadia, C. D. & Goodell, M. A. Tissue mosaicism following stem cell aging: blood as an exemplar. Nat. Aging 4, 295–308 (2024).
Google Scholar
Conrad, N. et al. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. Lancet 401, 1878–1890 (2023).
Google Scholar
Neuberger, M. S. Antigen receptor signaling gives lymphocytes a long life. Cell 90, 971–973 (1997).
Google Scholar
Martin, B., Becourt, C., Bienvenu, B. & Lucas, B. Self-recognition is crucial for maintaining the peripheral CD4+ T-cell pool in a nonlymphopenic environment. Blood 108, 270–277 (2006).
Google Scholar
Aiello, A. E., Chiu, Y. L. & Frasca, D. How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms? Geroscience 39, 261–271 (2017).
Google Scholar
Lanfermeijer, J. et al. Age and CMV-infection jointly affect the EBV-specific CD8+ T-cell repertoire. Front. Aging 2, 665637 (2021).
Google Scholar
Verdon, D. J. & Jenkins, M. R. Identification and targeting of mutant peptide neoantigens in cancer immunotherapy. Cancers 13, 4245 (2021).
Wang, S. J., Dougan, S. K. & Dougan, M. Immune mechanisms of toxicity from checkpoint inhibitors. Trends Cancer 9, 543–553 (2023).
Google Scholar
Ibis, B., Aliazis, K., Cao, C., Yenyuwadee, S. & Boussiotis, V. A. Immune-related adverse effects of checkpoint immunotherapy and implications for the treatment of patients with cancer and autoimmune diseases. Front. Immunol. 14, 1197364 (2023).
Google Scholar
Abad Lopez, A. P., Trilleras, J., Arana, V. A., Garcia-Alzate, L. S. & Grande-Tovar, C. D. Atmospheric microplastics: exposure, toxicity, and detrimental health effects. RSC Adv. 13, 7468–7489 (2023).
Google Scholar
Finch, C. E. & Thorwald, M. A. Inhaled pollutants of the gero-exposome and later-life health. J. Gerontol. A Biol. Sci. Med. Sci. 79, glae107 (2024).
Finch, C. E. Air pollution, dementia, and lifespan in the socio-economic gradient of aging: perspective on human aging for planning future experimental studies. Front. Aging 4, 1273303 (2023).
Google Scholar
Jin, J. et al. CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging. Nat. Aging 3, 600–616 (2023).
Google Scholar
Jin, J., Zhang, H., Weyand, C. M. & Goronzy, J. J. Lysosomes in T cell immunity and aging. Front. Aging 2, 809539 (2021).
Google Scholar
Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: an expanding universe. Cell 186, 243–278 (2023).
Google Scholar
Mittelbrunn, M. & Kroemer, G. Hallmarks of T cell aging. Nat. Immunol. 22, 687–698 (2021).
Google Scholar
Gressler, A. E., Leng, H., Zinecker, H. & Simon, A. K. Proteostasis in T cell aging. Semin. Immunol. 70, 101838 (2023).
Google Scholar
Adkar, S. S. & Leeper, N. J. Efferocytosis in atherosclerosis. Nat. Rev. Cardiol. 21, 762–779 (2024).
Google Scholar
Weyand, C. M. & Goronzy, J. J. The immunology of rheumatoid arthritis. Nat. Immunol. 22, 10–18 (2021).
Google Scholar
Gorisse, L. et al. Protein carbamylation is a hallmark of aging. Proc. Natl Acad. Sci. USA 113, 1191–1196 (2016).
Google Scholar
Nicolas, C. et al. Carbamylation and glycation compete for collagen molecular aging in vivo. Sci. Rep. 9, 18291 (2019).
Google Scholar
Schmelzer, C. E. H. & Duca, L. Elastic fibers: formation, function, and fate during aging and disease. FEBS J. 289, 3704–3730 (2022).
Google Scholar
Doue, M. et al. Carbamylation of elastic fibers is a molecular substratum of aortic stiffness. Sci. Rep. 11, 17827 (2021).
Google Scholar
Palatella, M., Guillaume, S. M., Linterman, M. A. & Huehn, J. The dark side of Tregs during aging. Front. Immunol. 13, 940705 (2022).
Google Scholar
Rocamora-Reverte, L., Melzer, F. L., Wurzner, R. & Weinberger, B. The complex role of regulatory T cells in immunity and aging. Front. Immunol. 11, 616949 (2020).
Google Scholar
Darrigues, J., van Meerwijk, J. P. M. & Romagnoli, P. Age-dependent changes in regulatory T lymphocyte development and function: a mini-review. Gerontology 64, 28–35 (2018).
Google Scholar
Jin, K. et al. NOTCH-induced rerouting of endosomal trafficking disables regulatory T cells in vasculitis. J. Clin. Invest. 131, e136042 (2021).
Donato, A. J., Machin, D. R. & Lesniewski, L. A. Mechanisms of dysfunction in the aging vasculature and role in age-related disease. Circ. Res. 123, 825–848 (2018).
Google Scholar
Vatner, S. F. et al. Vascular stiffness in aging and disease. Front. Physiol. 12, 762437 (2021).
Google Scholar
Fritze, O. et al. Age-related changes in the elastic tissue of the human aorta. J. Vasc. Res. 49, 77–86 (2012).
Google Scholar
Tembely, D. et al. The elastin receptor complex: an emerging therapeutic target against age-related vascular diseases. Front. Endocrinol. 13, 815356 (2022).
Weyand, C. M. & Goronzy, J. J. Immune mechanisms in medium and large-vessel vasculitis. Nat. Rev. Rheumatol. 9, 731–740 (2013).
Google Scholar
Weyand, C. M., Liao, Y. J. & Goronzy, J. J. The immunopathology of giant cell arteritis: diagnostic and therapeutic implications. J. Neuroophthalmol. 32, 259–265 (2012).
Google Scholar
Sato, Y., Tada, M., Goronzy, J. J. & Weyand, C. M. Immune checkpoints in autoimmune vasculitis. Best Pract. Res. Clin. Rheumatol. 38, 101943 (2024).
Google Scholar
Kaymakci, M. S. et al. Subclinical aortic inflammation in patients with polymyalgia rheumatica. Rheumatology 63, 3289–3296 (2024).
Google Scholar
Kaymakci, M. S. et al. Persistent aortic inflammation in patients with giant cell arteritis. Autoimmun. Rev. 22, 103411 (2023).
Google Scholar
Jin, K. et al. Regulatory T cells in autoimmune vasculitis. Front. Immunol. 13, 844300 (2022).
Google Scholar
Watanabe, R., Berry, G. J., Liang, D. H., Goronzy, J. J. & Weyand, C. M. Pathogenesis of giant cell arteritis and takayasu arteritis—similarities and differences. Curr. Rheumatol. Rep. 22, 68 (2020).
Google Scholar
Weyand, C. M. & Goronzy, J. J. Immunology of giant cell arteritis. Circ. Res. 132, 238–250 (2023).
Google Scholar
Jakobsson, K. et al. Body mass index and the risk of giant cell arteritis: results from a prospective study. Rheumatology 54, 433–440 (2015).
Google Scholar
Sato, Y. et al. Stem-like CD4+ T cells in perivascular tertiary lymphoid structures sustain autoimmune vasculitis. Sci. Transl. Med. 15, eadh0380 (2023).
Google Scholar
Watanabe, R. et al. MMP (matrix metalloprotease)-9-producing monocytes enable T cells to invade the vessel wall and cause vasculitis. Circ. Res. 123, 700–715 (2018).
Google Scholar
Gattinoni, L., Klebanoff, C. A. & Restifo, N. P. Paths to stemness: building the ultimate antitumour T cell. Nat. Rev. Cancer 12, 671–684 (2012).
Google Scholar
Vodnala, S. K. et al. T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science 363, eaau0135 (2019).
Im, S. J. et al. Characteristics and anatomic location of PD-1+TCF1+ stem-like CD8 T cells in chronic viral infection and cancer. Proc. Natl Acad. Sci. USA 120, e2221985120 (2023).
Google Scholar
Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211 (2019).
Google Scholar
Sturmlechner, I., Jain, A., Mu, Y., Weyand, C. M. & Goronzy, J. J. T cell fate decisions during memory cell generation with aging. Semin. Immunol. 69, 101800 (2023).
Google Scholar
Jain, A., Sturmlechner, I., Weyand, C. M. & Goronzy, J. J. Heterogeneity of memory T cells in aging. Front. Immunol. 14, 1250916 (2023).
Google Scholar
Zhang, H. et al. Aging-associated HELIOS deficiency in naive CD4+ T cells alters chromatin remodeling and promotes effector cell responses. Nat. Immunol. 24, 96–109 (2023).
Google Scholar
Durand, M. & Thomas, S. L. Incidence of infections in patients with giant cell arteritis: a cohort study. Arthritis Care Res. 64, 581–588 (2012).
Schmidt, J. et al. Incidence of severe infections and infection-related mortality during the course of giant cell arteritis: a multicenter, prospective, double-cohort study. Arthritis Rheumatol. 68, 1477–1482 (2016).
Google Scholar
Zhou, Z. et al. The five major autoimmune diseases increase the risk of cancer: epidemiological data from a large-scale cohort study in China. Cancer Commun. 42, 435–446 (2022).
Giat, E., Ehrenfeld, M. & Shoenfeld, Y. Cancer and autoimmune diseases. Autoimmun. Rev. 16, 1049–1057 (2017).
Google Scholar
Kermani, T. A. et al. Malignancy risk in patients with giant cell arteritis: a population-based cohort study. Arthritis Care Res. 62, 149–154 (2010).
Kendziora, R. W. et al. Age-related histopathological findings in temporal arteries. Histopathology 83, 782–790 (2023).
Google Scholar
Broomfield, B. J. & Groom, J. R. Defining the niche for stem-like CD8+ T cell formation and function. Curr. Opin. Immunol. 89, 102454 (2024).
Google Scholar
Duckworth, B. C., Qin, R. Z. & Groom, J. R. Spatial determinates of effector and memory CD8+ T cell fates. Immunol. Rev. 306, 76–92 (2022).
Google Scholar
Ge, Y. et al. The aging skin microenvironment dictates stem cell behavior. Proc. Natl Acad. Sci. USA 117, 5339–5350 (2020).
Google Scholar
Wen, Z. et al. The microvascular niche instructs T cells in large vessel vasculitis via the VEGF–Jagged1–Notch pathway. Sci. Transl. Med. 9, eaal3322 (2017).
Smets, P. et al. Vascular endothelial growth factor levels and rheumatic diseases of the elderly. Arthritis Res. Ther. 18, 283 (2016).
Google Scholar
Piggott, K. et al. Blocking the NOTCH pathway inhibits vascular inflammation in large-vessel vasculitis. Circulation 123, 309–318 (2011).
Google Scholar
Shin, B. & Rothenberg, E. V. Multi-modular structure of the gene regulatory network for specification and commitment of murine T cells. Front. Immunol. 14, 1108368 (2023).
Google Scholar
Shin, B., Chang, S. J., MacNabb, B. W. & Rothenberg, E. V. Transcriptional network dynamics in early T cell development. J. Exp. Med. 221, e20230893 (2024).
Wilkens, A. B. et al. NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness. Blood 140, 2261–2275 (2022).
Google Scholar
Shu, D. H. et al. Immunotherapy response induces divergent tertiary lymphoid structure morphologies in hepatocellular carcinoma. Nat. Immunol. 25, 2110–2123 (2024).
Google Scholar
Kim, C. M. et al. The efficacy of immune checkpoint inhibitors in elderly patients: a meta-analysis and meta-regression. ESMO Open 7, 100577 (2022).
Google Scholar
Yao, J. et al. Efficacy and safety of immune checkpoint inhibitors in elderly patients with advanced non-small cell lung cancer: a systematic review and meta-analysis. eClinicalMedicine 81, 103081 (2025).
Eochagain, C. M. et al. Management of immune checkpoint inhibitor-associated toxicities in older adults with cancer: recommendations from the International Society of Geriatric Oncology (SIOG). Lancet Oncol. 26, e90–e102 (2025).
Google Scholar
Hysa, E. et al. Polymyalgia rheumatica and giant cell arteritis induced by immune checkpoint inhibitors: a systematic literature review highlighting differences from the idiopathic forms. Autoimmun. Rev. 23, 103589 (2024).
Google Scholar
Rivellese, F., Pontarini, E. & Pitzalis, C. Tertiary lymphoid organs in rheumatoid arthritis. Curr. Top. Microbiol. Immunol. 426, 119–141 (2020).
Google Scholar
Li, Y. et al. The DNA repair nuclease MRE11A functions as a mitochondrial protector and prevents T cell pyroptosis and tissue inflammation. Cell Metab. 30, 477–492 (2019).
Google Scholar
Weyand, C. M. & Goronzy, J. J. Immune aging in rheumatoid arthritis. Arthritis Rheum. https://doi.org/10.1002/art.43105 (2025).
Weyand, C. M. & Goronzy, J. J. Metabolic checkpoints in rheumatoid arthritis. Semin. Arthritis Rheum. 70S, 152586 (2025).
Google Scholar
Zheng, Y., Liu, Q., Goronzy, J. J. & Weyand, C. M. Immune aging – a mechanism in autoimmune disease. Semin. Immunol. 69, 101814 (2023).
Google Scholar
Weyand, C. M. & Goronzy, J. J. Immunometabolism in the development of rheumatoid arthritis. Immunol. Rev. 294, 177–187 (2020).
Google Scholar
Blank, C. U. et al. Defining ‘T cell exhaustion’. Nat. Rev. Immunol. 19, 665–674 (2019).
Google Scholar
Zeng, Z., Wei, F. & Ren, X. Exhausted T cells and epigenetic status. Cancer Biol. Med. 17, 923–936 (2020).
Google Scholar
Zu, H. & Chen, X. Epigenetics behind CD8+ T cell activation and exhaustion. Genes Immun. 25, 525–540 (2024).
Google Scholar
Maggi, E. et al. T cell landscape in the microenvironment of human solid tumors. Immunol. Lett. 270, 106942 (2024).
Google Scholar
Khan, N., Vidyarthi, A., Amir, M., Mushtaq, K. & Agrewala, J. N. T-cell exhaustion in tuberculosis: pitfalls and prospects. Crit. Rev. Microbiol. 43, 133–141 (2017).
Google Scholar
Minato, N., Hattori, M. & Hamazaki, Y. Physiology and pathology of T-cell aging. Int. Immunol. 32, 223–231 (2020).
Google Scholar
Fukushima, Y., Ueno, R., Minato, N. & Hattori, M. Senescence-associated T cells in immunosenescence and diseases. Int. Immunol. 37, 143–152 (2025).
Google Scholar
Noll, J. H., Levine, B. L., June, C. H. & Fraietta, J. A. Beyond youth: understanding CAR T cell fitness in the context of immunological aging. Semin. Immunol. 70, 101840 (2023).
Google Scholar
Han, S., Georgiev, P., Ringel, A. E., Sharpe, A. H. & Haigis, M. C. Age-associated remodeling of T cell immunity and metabolism. Cell Metab. 35, 36–55 (2023).
Google Scholar
Havel, J. J., Chowell, D. & Chan, T. A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer 19, 133–150 (2019).
Google Scholar
Iwama, S., Kobayashi, T. & Arima, H. Management, biomarkers and prognosis in people developing endocrinopathies associated with immune checkpoint inhibitors. Nat. Rev. Endocrinol. 21, 289–300 (2025).
Munir, A. Z., Gutierrez, A., Qin, J., Lichtman, A. H. & Moslehi, J. J. Immune-checkpoint inhibitor-mediated myocarditis: CTLA4, PD1 and LAG3 in the heart. Nat. Rev. Cancer 24, 540–553 (2024).
Google Scholar
Ohtsuki, S. et al. Deficiency of the CD155–CD96 immune checkpoint controls IL-9 production in giant cell arteritis. Cell Rep. Med. 4, 101012 (2023).
Google Scholar
Zhang, H. et al. CD28 signaling controls metabolic fitness of pathogenic T cells in medium and large vessel vasculitis. J. Am. Coll. Cardiol. 73, 1811–1823 (2019).
Google Scholar
Zhang, H. et al. Inhibition of JAK–STAT signaling suppresses pathogenic immune responses in medium and large vessel vasculitis. Circulation 137, 1934–1948 (2018).
Google Scholar
Watanabe, R., Zhang, H., Berry, G., Goronzy, J. J. & Weyand, C. M. Immune checkpoint dysfunction in large and medium vessel vasculitis. Am. J. Physiol. Heart Circ. Physiol. 312, H1052–H1059 (2017).
Google Scholar
Zhang, H. et al. Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis. Proc. Natl Acad. Sci. USA 114, E970–E979 (2017).
Google Scholar
Deng, J., Younge, B. R., Olshen, R. A., Goronzy, J. J. & Weyand, C. M. TH17 and TH1 T-cell responses in giant cell arteritis. Circulation 121, 906–915 (2010).
Google Scholar
Ghosh, A. K. et al. Elevated endoplasmic reticulum stress response contributes to adipose tissue inflammation in aging. J. Gerontol. A Biol. Sci. Med. Sci. 70, 1320–1329 (2015).
Google Scholar
van Beek, A. A., Van den Bossche, J., Mastroberardino, P. G., de Winther, M. P. J. & Leenen, P. J. M. Metabolic alterations in aging macrophages: ingredients for inflammaging? Trends Immunol. 40, 113–127 (2019).
Google Scholar
Shaw, A. C., Goldstein, D. R. & Montgomery, R. R. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 13, 875–887 (2013).
Google Scholar
Zhao, T. V. et al. Hyperactivity of the CD155 immune checkpoint suppresses anti-viral immunity in patients with coronary artery disease. Nat. Cardiovasc. Res. 1, 634–648 (2022).
Google Scholar