Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Immunosenescence in Human Disease: Mechanistic Insights and Therapeutic Opportunities

  • Young-In Kim (Department of Pharmacy, and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University) ;
  • Seo-Hee Oh (Department of Pharmacy, and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University) ;
  • Tae Kyoung Lim (Department of Pharmacy, and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University) ;
  • Heewon Lee (Department of Pharmacy, and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University) ;
  • Sebin Lee (Department of Pharmacy, and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University) ;
  • Sun-Young Chang (Department of Pharmacy, and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University)
  • Received : 2025.10.31
  • Accepted : 2026.01.29
  • Published : 2026.03.01
Download PDF
⟨ Previous Next ⟩

Abstract

Immunosenescence, an age-associated decline in immune function, is increasingly recognized as a central determinant of health and disease in older adults. Characterized by thymic involution, loss of naïve T cells, contraction of T cell receptor diversity, accumulation of senescent and exhausted lymphocytes, and a chronic inflammatory state known as inflammaging, immunosenescence compromises both innate and adaptive immune responses. Immunosenescence contributes to the pathogenesis of diverse age-related diseases. In autoimmune and metabolic diseases, premature accumulation of senescent T cells and impaired regulatory T cell function drive chronic inflammation and tissue damage, while in neurodegenerative diseases, microglial aging and sustained neuroinflammation exacerbate neuronal loss. These findings highlight immunosenescence as a unifying mechanism linking aging to systemic and organ-specific pathologies. Advances in biomarker discovery, including phenotypic markers, telomere attrition, and epigenetic signatures, have enabled the quantitative assessment of immune aging, while emerging therapeutic strategies, such as cytokine modulation, mTOR inhibition, senolytics, and epigenetic reprogramming, show promise in restoring immune competence. Here, we summarize recent research on immunosenescence in various diseases, particularly chronic inflammatory, metabolic, and neurodegenerative diseases, and suggest novel strategies for the development of senolytic drugs.

Keywords

Acknowledgement

This work was supported by the GRRC program of Gyeonggi province (GRRCAjou2023-B02). Graphics were created with BioRender.com.

References

  1. Albrecht, K., Troll, W., Callhoff, J., Strangfeld, A., Ohrndorf, S. and Mucke, J. (2025) Sex- and gender-related differences in systemic lupus erythematosus: a scoping review. Rheumatol. Int. 45, 160. https://doi.org/10.1007/s00296-025-05910-7
  2. Bang, M., Kim, D. G., Gonzales, E. L., Kwon, K. J. and Shin, C. Y. (2019) Etoposide induces mitochondrial dysfunction and cellular senescence in primary cultured rat astrocytes. Biomol. Ther. (Seoul) 27, 530-539. https://doi.org/10.4062/biomolther.2019.151
  3. Braiteh, F., Soriano, A. O., Garcia-Manero, G., Hong, D., Johnson, M. M., Silva Lde, P., Yang, H., Alexander, S., Wolff, J. and Kurzrock, R. (2008) Phase I study of epigenetic modulation with 5-azacytidine and valproic acid in patients with advanced cancers. Clin. Cancer Res. 14, 6296-6301. https://doi.org/10.1158/1078-0432.CCR-08-1247
  4. Broadley, I., Pera, A., Morrow, G., Davies, K. A. and Kern, F. (2017) Expansions of cytotoxic CD4(+)CD28(-) T cells drive excess cardiovascular mortality in rheumatoid arthritis and other chronic inflammatory conditions and are triggered by CMV infection. Front. Immunol. 8, 195. https://doi.org/10.3389/fimmu.2017.00195
  5. Brochard, V., Combadière, B., Prigent, A., Laouar, Y., Perrin, A., Beray-Berthat, V., Bonduelle, O., Alvarez-Fischer, D., Callebert, J., Launay, J. M., Duyckaerts, C., Flavell, R. A., Hirsch, E. C. and Hunot, S. (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J. Clin. Invest. 119, 182-192.
  6. Brode, P., Claus, M., Gajewski, P. D., Getzmann, S., Wascher, E. and Watzl, C. (2023) From immunosenescence to aging types-establishing reference intervals for immune age biomarkers by centile estimation. Int. J. Mol. Sci. 24, 13186.
  7. Callender, L. A., Carroll, E. C., Garrod-Ketchley, C., Schroth, J., Bystrom, J., Berryman, V., Pattrick, M., Campbell-Richards, D., Hood, G. A., Hitman, G. A., Finer, S. and Henson, S. M. (2021) Altered nutrient uptake causes mitochondrial dysfunction in senescent CD8(+) EMRA T cells during type 2 diabetes. Front. Aging 2, 681428.
  8. Cani, P. D., Amar, J., Iglesias, M. A., Poggi, M., Knauf, C., Bastelica, D., Neyrinck, A. M., Fava, F., Tuohy, K. M., Chabo, C., Waget, A., Delmee, E., Cousin, B., Sulpice, T., Chamontin, B., Ferrieres, J., Tanti, J. F., Gibson, G. R., Casteilla, L., Delzenne, N. M., Alessi, M. C. and Burcelin, R. (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761-1772. https://doi.org/10.2337/db06-1491
  9. Chen, W. and Frangogiannis, N. G. (2010) The role of inflammatory and fibrogenic pathways in heart failure associated with aging. Heart Fail. Rev. 15, 415-422. https://doi.org/10.1007/s10741-010-9161-y
  10. Choi, W., Woo, G. H., Kwon, T. H. and Jeon, J. H. (2025) Obesity-driven metabolic disorders: the interplay of inflammation and mitochondrial dysfunction. Int. J. Mol. Sci. 26, 9715.
  11. Codolo, G., Plotegher, N., Pozzobon, T., Brucale, M., Tessari, I., Bubacco, L. and de Bernard, M. (2013) Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PLoS One 8, e55375. https://doi.org/10.1371/journal.pone.0055375
  12. Crooke, S. N., Ovsyannikova, I. G., Poland, G. A. and Kennedy, R. B. (2019) Immunosenescence: a systems-level overview of immune cell biology and strategies for improving vaccine responses. Exp. Gerontol. 124, 110632. https://doi.org/10.1016/j.exger.2019.110632
  13. Diaz-Torne, C., Ortiz, M. D. A., Moya, P., Hernandez, M. V., Reina, D., Castellvi, I., De Agustin, J. J., Fuente, D., Corominas, H., Sanmarti, R., Zamora, C., Cantó, E. and Vidal, S. (2018) The combination of IL-6 and its soluble receptor is associated with the response of rheumatoid arthritis patients to tocilizumab. Semin. Arthritis Rheum. 47, 757-764. https://doi.org/10.1016/j.semarthrit.2017.10.022
  14. Dixon, D., Sattar, H., Moros, N., Kesireddy, S. R., Ahsan, H., Lakkimsetti, M., Fatima, M., Doshi, D., Sadhu, K. and Junaid Hassan, M. (2024) Unveiling the influence of AI predictive analytics on patient outcomes: a comprehensive narrative review. Cureus 16, e59954. https://doi.org/10.7759/cureus.59954
  15. Du, Y., He, C., An, Y., Huang, Y., Zhang, H., Fu, W., Wang, M., Shan, Z., Xie, J., Yang, Y. and Zhao, B. (2024) The role of short chain fatty acids in inflammation and body health. Int. J. Mol. Sci. 25, 7379.
  16. Fasth, A. E., Snir, O., Johansson, A. A., Nordmark, B., Rahbar, A., Af Klint, E., Björkström, N. K., Ulfgren, A. K., van Vollenhoven, R. F., Malmström, V. and Trollmo, C. (2007) Skewed distribution of proinflammatory CD4+CD28null T cells in rheumatoid arthritis. Arthritis Res. Ther. 9, R87.
  17. Faust, H. J., Zhang, H., Han, J., Wolf, M. T., Jeon, O. H., Sadtler, K., Peña, A. N., Chung, L., Maestas, D. R., Jr., Tam, A. J., Pardoll, D. M., Campisi, J., Housseau, F., Zhou, D., Bingham, C. O., 3rd and Elisseeff, J. H. (2020) IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis. J. Clin. Invest. 130, 5493-5507. https://doi.org/10.1172/JCI134091
  18. Ferrucci, L. and Fabbri, E. (2018) Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505-522. https://doi.org/10.1038/s41569-018-0064-2
  19. Fessler, J., Raicht, A., Husic, R., Ficjan, A., Schwarz, C., Duftner, C., Schwinger, W., Graninger, W. B., Stradner, M. H. and Dejaco, C. (2017) Novel senescent regulatory T-cell subset with impaired suppressive function in rheumatoid arthritis. Front. Immunol. 8, 300.
  20. Fetler, L. and Amigorena, S. (2005) Neuroscience. Brain under surveillance: the microglia patrol. Science 309, 392-393. https://doi.org/10.1126/science.1114852
  21. Fink, A. L. and Klein, S. L. (2018) The evolution of greater humoral immunity in females than males: implications for vaccine efficacy. Curr. Opin. Physiol. 6, 16-20. https://doi.org/10.1016/j.cophys.2018.03.010
  22. Fry, T. J. and Mackall, C. L. (2002) Interleukin-7: from bench to clinic. Blood 99, 3892-3904. https://doi.org/10.1182/blood.V99.11.3892
  23. Fulop, T., Larbi, A., Pawelec, G., Khalil, A., Cohen, A. A., Hirokawa, K., Witkowski, J. M. and Franceschi, C. (2023) Immunology of aging: the birth of inflammaging. Clin. Rev. Allergy Immunol. 64, 109-122.
  24. Gheitasi, R., Baumgart, S., Roell, D., Rose, N., Watzl, C., Dudziak, D., Andreas, N., Makarewicz, O., Drube, S., Schnizer, C., Kamradt, T., Weis, S. and Pletz, M. W.; CoNAN study group (2025) Age- and sex-associated differences in immune cell populations. iScience 28, 113092. https://doi.org/10.1016/j.isci.2025.113092
  25. González-Osuna, L., Sierra-Cristancho, A., Cafferata, E. A., Melgar-Rodríguez, S., Rojas, C., Carvajal, P., Cortez, C. and Vernal, R. (2022) Senescent CD4(+)CD28(-) T lymphocytes as a potential driver of Th17/Treg imbalance and alveolar bone resorption during periodontitis. Int. J. Mol. Sci. 23, 2543.
  26. Goronzy, J. J. and Weyand, C. M. (2013) Understanding immunosenescence to improve responses to vaccines. Nat. Immunol. 14, 428-436. https://doi.org/10.1038/ni.2588
  27. Goyani, P., Christodoulou, R. and Vassiliou, E. (2024) Immunosenescence: aging and immune system decline. Vaccines (Basel) 12, 1314. https://doi.org/10.3390/vaccines12121314
  28. Guégan, M., Bichon, M., Chaput, N., Houot, R. and Lemoine, J. (2025) Cancer immunotherapy in elderly patients: the concept of immune senescence challenged by clinical experience. Eur. J. Cancer 214, 115145.
  29. Gustafson, C. E., Kim, C., Weyand, C. M. and Goronzy, J. J. (2020) Influence of immune aging on vaccine responses. J. Allergy Clin. Immunol. 145, 1309-1321. https://doi.org/10.1016/j.jaci.2020.03.017
  30. Halle, A., Hornung, V., Petzold, G. C., Stewart, C. R., Monks, B. G., Reinheckel, T., Fitzgerald, K. A., Latz, E., Moore, K. J. and Golenbock, D. T. (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol. 9, 857-865. https://doi.org/10.1038/ni.1636
  31. Harding, A. T. and Heaton, N. S. (2022) The impact of estrogens and their receptors on immunity and inflammation during infection. Cancers (Basel) 14, 909. https://doi.org/10.3390/cancers14040909
  32. Henry, C. J., Huang, Y., Wynne, A. M. and Godbout, J. P. (2009) Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain Behav. Immun. 23, 309-317. https://doi.org/10.1016/j.bbi.2008.09.002
  33. Horvath, S. (2013) DNA methylation age of human tissues and cell types. Genome Biol. 14, R115. https://doi.org/10.1186/gb-2013-14-10-r115
  34. Horvath, S., Oshima, J., Martin, G. M., Lu, A. T., Quach, A., Cohen, H., Felton, S., Matsuyama, M., Lowe, D., Kabacik, S., Wilson, J. G., Reiner, A. P., Maierhofer, A., Flunkert, J., Aviv, A., Hou, L., Baccarelli, A. A., Li, Y., Stewart, J. D., Whitsel, E. A., Ferrucci, L., Matsuyama, S. and Raj, K. (2018) Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies. Aging (Albany N.Y.) 10, 1758-1775.
  35. Hou, Y., Chen, M., Bian, Y., Hu, Y., Chuan, J., Zhong, L., Zhu, Y. and Tong, R. (2024) Insights into vaccines for elderly individuals: from the impacts of immunosenescence to delivery strategies. NPJ Vaccines 9, 77. https://doi.org/10.1038/s41541-024-00874-4
  36. Jana, M., Palencia, C. A. and Pahan, K. (2008) Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer's disease. J. Immunol. 181, 7254-7262. https://doi.org/10.4049/jimmunol.181.10.7254
  37. Justice, J. N. and Kritchevsky, S. B. (2020) Putting epigenetic biomarkers to the test for clinical trials. Elife 9, e58592. https://doi.org/10.7554/eLife.58592
  38. Kim, Y. R., Jung, Y., Kang, I. and Yeo, E. J. (2025) Understanding sex differences in autoimmune diseases: immunologic mechanisms. Int. J. Mol. Sci. 26, 7101.
  39. Kirkland, J. L. and Tchkonia, T. (2020) Senolytic drugs: from discovery to translation. J. Intern. Med. 288, 518-536. https://doi.org/10.1111/joim.v288.5
  40. Klein, S. L. and Flanagan, K. L. (2016) Sex differences in immune responses. Nat. Rev. Immunol. 16, 626-638. https://doi.org/10.1038/nri.2016.90
  41. Kulkarni, A. S., Brutsaert, E. F., Anghel, V., Zhang, K., Bloomgarden, N., Pollak, M., Mar, J. C., Hawkins, M., Crandall, J. P. and Barzilai, N. (2018) Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. Aging Cell 17, e12723. https://doi.org/10.1111/acel.2018.17.issue-2
  42. Kumari, R. and Jat, P. (2021) Mechanisms of cellular senescence: cell cycle arrest and senescence associated secretory phenotype. Front. Cell Dev. Biol. 9, 645593.
  43. Kushner, J. A., Pandey, M. and Kohli, S. S. S. (2025) Biomarker integration and biosensor technologies enabling AI-driven insights into biological aging. Front. Aging 6, 1703698.
  44. Lee, E., Carreras-Gallo, N., Lopez, L., Turner, L., Lin, A., Mendez, T. L., Went, H., Tomusiak, A., Verdin, E., Corley, M., Ndhlovu, L., Smith, R. and Dwaraka, V. B. (2024) Exploring the effects of Dasatinib, Quercetin, and Fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions. Aging (Albany N.Y.) 16, 3088-3106. https://doi.org/10.18632/aging.v16i4
  45. Lee, E., Hwang, I., Park, S., Hong, S., Hwang, B., Cho, Y., Son, J. and Yu, J. W. (2019) MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration. Cell Death Differ. 26, 213-228. https://doi.org/10.1038/s41418-018-0124-5
  46. Lee, G. H. and Lee, W. W. (2016) Unusual CD4(+)CD28(-) T cells and their pathogenic role in chronic inflammatory disorders. Immune Netw. 16, 322-329. https://doi.org/10.4110/in.2016.16.6.322
  47. Levine, M. E., Lu, A. T., Quach, A., Chen, B. H., Assimes, T. L., Bandinelli, S., Hou, L., Baccarelli, A. A., Stewart, J. D., Li, Y., Whitsel, E. A., Wilson, J. G., Reiner, A. P., Aviv, A., Lohman, K., Liu, Y., Ferrucci, L. and Horvath, S. (2018) An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany N.Y.) 10, 573-591.
  48. Li, S., Wang, K., Wu, J. and Zhu, Y. (2025) The immunosenescence clock: a new method for evaluating biological age and predicting mortality risk. Ageing Res. Rev. 104, 102653. https://doi.org/10.1016/j.arr.2024.102653
  49. Li, X., Li, Y., Jin, Y., Zhang, Y., Wu, J., Xu, Z., Huang, Y., Cai, L., Gao, S., Liu, T., Zeng, F., Wang, Y., Wang, W., Yuan, T. F., Tian, H., Shu, Y., Guo, F., Lu, W., Mao, Y., Mei, X., Rao, Y. and Peng, B. (2023) Transcriptional and epigenetic decoding of the microglial aging process. Nat. Aging 3, 1288-1311. https://doi.org/10.1038/s43587-023-00479-x
  50. Li, Z., Zhang, J., Zhou, M., Li, J. L., Qiu, Q. C., Fu, J. H., Xue, S. L. and Qiu, H. Y. (2022) Epigenetic therapy with chidamide alone or combined with 5-azacitidine exerts antitumour effects on acute myeloid leukaemia cells in vitro. Oncol. Rep. 47, 66. https://doi.org/10.3892/or
  51. Liu, X., Li, F., Czosnyka, M., Czosnyka, Z., Yu, H., Tong, X., Xing, Y., Li, H., Pu, K., Feng, K., Zhang, K., Pang, M. and Ming, D. (2025) Multiomics and high-spatial-resolution omics: deciphering complexity in neurological disorders. Gigascience 14, giaf137.
  52. Liu, Z., Liang, Q., Ren, Y., Guo, C., Ge, X., Wang, L., Cheng, Q., Luo, P., Zhang, Y. and Han, X. (2023) Immunosenescence: molecular mechanisms and diseases. Signal Transduct. Target. Ther. 8, 200.
  53. Liuzzo, G., Biasucci, L. M., Trotta, G., Brugaletta, S., Pinnelli, M., Digianuario, G., Rizzello, V., Rebuzzi, A. G., Rumi, C., Maseri, A. and Crea, F. (2007) Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events. J. Am. Coll. Cardiol. 50, 1450-1458. https://doi.org/10.1016/j.jacc.2007.06.040
  54. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. and Kroemer, G. (2023) Hallmarks of aging: an expanding universe. Cell 186, 243-278. https://doi.org/10.1016/j.cell.2022.11.001
  55. Lun, H., Li, P., Li, J. and Liu, F. (2024) The effect of intestinal flora metabolites on macrophage polarization. Heliyon 10, e35755. https://doi.org/10.1016/j.heliyon.2024.e35755
  56. Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., Lonetto, M. A., Maecker, H. T., Kovarik, J., Carson, S., Glass, D. J. and Klickstein, L. B. (2014) mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268ra179. https://doi.org/10.1126/scitranslmed.3009892
  57. Mannick, J. B., Teo, G., Bernardo, P., Quinn, D., Russell, K., Klickstein, L., Marshall, W. and Shergill, S. (2021) 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. https://doi.org/10.1016/S2666-7568(21)00062-3
  58. Marquez, E. J., Chung, C. H., Marches, R., Rossi, R. J., Nehar-Belaid, D., Eroglu, A., Mellert, D. J., Kuchel, G. A., Banchereau, J. and Ucar, D. (2020) Sexual-dimorphism in human immune system aging. Nat. Commun. 11, 751.
  59. Martin, D. E., Cadar, A. N. and Bartley, J. M. (2023) Old drug, new tricks: the utility of metformin in infection and vaccination responses to influenza and SARS-CoV-2 in older adults. Front. Aging 4, 1272336.
  60. Martins, P. N., Tullius, S. G. and Markmann, J. F. (2014) Immunosenescence and immune response in organ transplantation. Int. Rev. Immunol. 33, 162-173. https://doi.org/10.3109/08830185.2013.829469
  61. Montagne, A., Barnes, S. R., Sweeney, M. D., Halliday, M. R., Sagare, A. P., Zhao, Z., Toga, A. W., Jacobs, R. E., Liu, C. Y., Amezcua, L., Harrington, M. G., Chui, H. C., Law, M. and Zlokovic, B. V. (2015) Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85, 296-302. https://doi.org/10.1016/j.neuron.2014.12.032
  62. Nanishi, E., Angelidou, A., Rotman, C., Dowling, D. J., Levy, O. and Ozonoff, A. (2022) Precision vaccine adjuvants for older adults: a scoping review. Clin. Infect. Dis. 75, S72-S80. https://doi.org/10.1093/cid/ciac302
  63. Naylor, K., Li, G., Vallejo, A. N., Lee, W. W., Koetz, K., Bryl, E., Witkowski, J., Fulbright, J., Weyand, C. M. and Goronzy, J. J. (2005) The influence of age on T cell generation and TCR diversity. J. Immunol. 174, 7446-7452. https://doi.org/10.4049/jimmunol.174.11.7446
  64. Ney, L. M., Wipplinger, M., Grossmann, M., Engert, N., Wegner, V. D. and Mosig, A. S. (2023) Short chain fatty acids: key regulators of the local and systemic immune response in inflammatory diseases and infections. Open Biol. 13, 230014. https://doi.org/10.1098/rsob.230014
  65. Nga, H. T., Nguyen, T. L. and Yi, H. S. (2024) T-cell senescence in human metabolic diseases. Diabetes Metab. J. 48, 864-881. https://doi.org/10.4093/dmj.2024.0140
  66. Nguyen, T. Q. T. and Cho, K. A. (2025) Targeting immunosenescence and inflammaging: advancing longevity research. Exp. Mol. Med. 57, 1881-1892. https://doi.org/10.1038/s12276-025-01527-9
  67. Noll, J. H., Levine, B. L., June, C. H. and Fraietta, J. A. (2023) Beyond youth: understanding CAR T cell fitness in the context of immunological aging. Semin. Immunol. 70, 101840. https://doi.org/10.1016/j.smim.2023.101840
  68. Olivieri, F., Marchegiani, F., Matacchione, G., Giuliani, A., Ramini, D., Fazioli, F., Sabbatinelli, J. and Bonafe, M. (2023) Sex/gender-related differences in inflammaging. Mech. Ageing Dev. 211, 111792. https://doi.org/10.1016/j.mad.2023.111792
  69. Park, J. and Shin, D. W. (2022) Senotherapeutics and their molecular mechanism for improving aging. Biomol. Ther. (Seoul) 30, 490-500. https://doi.org/10.4062/biomolther.2022.114
  70. Park, J. H., Lee, S. W., Choi, D., Lee, C. and Sung, Y. C. (2024) Harnessing the power of IL-7 to boost T cell immunity in experimental and clinical immunotherapies. Immune Netw. 24, e9. https://doi.org/10.4110/in.2024.24.e9
  71. Pasciuto, E., Burton, O. T., Roca, C. P., Lagou, V., Rajan, W. D., Theys, T., Mancuso, R., Tito, R. Y., Kouser, L., Callaerts-Vegh, Z., de la Fuente, A. G., Prezzemolo, T., Mascali, L. G., Brajic, A., Whyte, C. E., Yshii, L., Martinez-Muriana, A., Naughton, M., Young, A., Moudra, A., Lemaitre, P., Poovathingal, S., Raes, J., De Strooper, B., Fitzgerald, D. C., Dooley, J. and Liston, A. (2020) Microglia require CD4 T cells to complete the fetal-to-adult transition. Cell 182, 625-640.e24. https://doi.org/10.1016/j.cell.2020.06.026
  72. Pawelec, G., Derhovanessian, E. and Larbi, A. (2010) Immunosenescence and cancer. Crit. Rev. Oncol. Hematol. 75, 165-172. https://doi.org/10.1016/j.critrevonc.2010.06.012
  73. Pawlik, A., Ostanek, L., Brzosko, I., Brzosko, M., Masiuk, M., Machalinski, B. and Gawronska-Szklarz, B. (2003) The expansion of CD4+CD28- T cells in patients with rheumatoid arthritis. Arthritis Res. Ther. 5, R210-R213. https://doi.org/10.1186/ar766
  74. Pido-Lopez, J., Imami, N. and Aspinall, R. (2001) Both age and gender affect thymic output: more recent thymic migrants in females than males as they age. Clin. Exp. Immunol. 125, 409-413. https://doi.org/10.1046/j.1365-2249.2001.01640.x
  75. Puzianowska-Kuznicka, M., Owczarz, M., Wieczorowska-Tobis, K., Nadrowski, P., Chudek, J., Slusarczyk, P., Skalska, A., Jonas, M., Franek, E. and Mossakowska, M. (2016) Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study. Immun. Ageing 13, 21. https://doi.org/10.1186/s12979-016-0076-x
  76. Rehman, T. (2012) Role of the gut microbiota in age-related chronic inflammation. Endocr. Metab. Immune Disord. Drug Targets 12, 361-367. https://doi.org/10.2174/187153012803832620
  77. Rio, P., Caldarelli, M., Miccoli, E., Guazzarotti, G., Gasbarrini, A., Gambassi, G. and Cianci, R. (2025) Sex differences in immune responses to infectious diseases: the role of genetics, hormones, and aging. Diseases 13, 179. https://doi.org/10.3390/diseases13060179
  78. Ritzel, R. M., Doran, S. J., Glaser, E. P., Meadows, V. E., Faden, A. I., Stoica, B. A. and Loane, D. J. (2019) Old age increases microglial senescence, exacerbates secondary neuroinflammation, and worsens neurological outcomes after acute traumatic brain injury in mice. Neurobiol. Aging 77, 194-206. https://doi.org/10.1016/j.neurobiolaging.2019.02.010
  79. Rodrigues, L. P., Teixeira, V. R., Alencar-Silva, T., Simonassi-Paiva, B., Pereira, R. W., Pogue, R. and Carvalho, J. L. (2021) Hallmarks of aging and immunosenescence: connecting the dots. Cytokine Growth Factor Rev. 59, 9-21. https://doi.org/10.1016/j.cytogfr.2021.01.006
  80. Rodriguez, I. J., Lalinde Ruiz, N., Llano León, M., Martínez Enríquez, L., Montilla Velásquez, M. D. P., Ortiz Aguirre, J. P., Rodríguez Bohórquez, O. M., Velandia Vargas, E. A., Hernández, E. D. and Parra López, C. A. (2020) Immunosenescence study of T cells: a systematic review. Front. Immunol. 11, 604591.
  81. Rohm, T. V., Meier, D. T., Olefsky, J. M. and Donath, M. Y. (2022) Inflammation in obesity, diabetes, and related disorders. Immunity 55, 31-55. https://doi.org/10.1016/j.immuni.2021.12.013
  82. Salvioli, S., Basile, M. S., Bencivenga, L., Carrino, S., Conte, M., Damanti, S., De Lorenzo, R., Fiorenzato, E., Gialluisi, A., Ingannato, A., Antonini, A., Baldini, N., Capri, M., Cenci, S., Iacoviello, L., Nacmias, B., Olivieri, F., Rengo, G., Querini, P. R. and Lattanzio, F. (2023) Biomarkers of aging in frailty and age-associated disorders: State of the art and future perspective. Ageing Res. Rev. 91, 102044. https://doi.org/10.1016/j.arr.2023.102044
  83. Sciarra, F., Campolo, F., Franceschini, E., Carlomagno, F. and Venneri, M. A. (2023) Gender-specific impact of sex hormones on the immune system. Int. J. Mol. Sci. 24, 6302.
  84. Shimi, G., Sohouli, M. H., Ghorbani, A., Shakery, A. and Zand, H. (2024) The interplay between obesity, immunosenescence, and insulin resistance. Immun. Ageing 21, 13.
  85. Shirakawa, K. and Sano, M. (2021) T cell immunosenescence in aging, obesity, and cardiovascular disease. Cells 10, 2435. https://doi.org/10.3390/cells10092435
  86. Somasundaram, I., Jain, S. M., Blot-Chabaud, M., Pathak, S., Banerjee, A., Rawat, S., Sharma, N. R. and Duttaroy, A. K. (2024) Mitochondrial dysfunction and its association with age-related disorders. Front. Physiol. 15, 1384966.
  87. Song, P., An, J. and Zou, M. H. (2020) Immune clearance of senescent cells to combat ageing and chronic diseases. Cells 9, 671. https://doi.org/10.3390/cells9030671
  88. Suleimenova, M., Abzaliyev, K., Mansurova, M., Abzaliyeva, S., Kurmanova, A., Tokhtakulinova, G., Bugibayeva, A., Sundetova, D., Abdykassymova, M., Sagalbayeva, U., Bitemirova, R. and Yerkin, Z. (2025) A predictive model of cardiovascular aging by clinical and immunological markers using machine learning. Diagnostics (Basel) 15, 850. https://doi.org/10.3390/diagnostics15070850
  89. Thevaranjan, N., Puchta, A., Schulz, C., Naidoo, A., Szamosi, J. C., Verschoor, C. P., Loukov, D., Schenck, L. P., Jury, J., Foley, K. P., Schertzer, J. D., Larche, M. J., Davidson, D. J., Verdu, E. F., Surette, M. G. and Bowdish, D. M. E. (2017) Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe 21, 455-466.e4. https://doi.org/10.1016/j.chom.2017.03.002
  90. Trigunaite, A., Dimo, J. and Jorgensen, T. N. (2015) Suppressive effects of androgens on the immune system. Cell. Immunol. 294, 87-94. https://doi.org/10.1016/j.cellimm.2015.02.004
  91. Warrington, K. J., Takemura, S., Goronzy, J. J. and Weyand, C. M. (2001) CD4+,CD28- T cells in rheumatoid arthritis patients combine features of the innate and adaptive immune systems. Arthritis Rheum. 44, 13-20. https://doi.org/10.1002/(ISSN)1529-0131
  92. Wrona, M. V., Ghosh, R., Coll, K., Chun, C. and Yousefzadeh, M. J. (2024) The 3 I's of immunity and aging: immunosenescence, inflammaging, and immune resilience. Front. Aging 5, 1490302.
  93. Wu, F., Mu, W. C., Markov, N. T., Fuentealba, M., Halaweh, H., Senchyna, F., Manwaring-Mueller, M. N., Winer, D. A. and Furman, D. (2025) Immunological biomarkers of aging. J. Immunol. 214, 889-902. https://doi.org/10.1093/jimmun/vkae036
  94. Wu, L., Xie, X., Liang, T., Ma, J., Yang, L., Yang, J., Li, L., Xi, Y., Li, H., Zhang, J., Chen, X., Ding, Y. and Wu, Q. (2021) Integrated multiomics for novel aging biomarkers and antiaging targets. Biomolecules 12, 39. https://doi.org/10.3390/biom12010039
  95. Wu, X., Yang, X., Dai, Y., Zhao, Z., Zhu, J., Guo, H. and Yang, R. (2024) Single-cell sequencing to multi-omics: technologies and applications. Biomark Res. 12, 110. https://doi.org/10.1186/s40364-024-00643-4
  96. Xu, M., Tchkonia, T., Ding, H., Ogrodnik, M., Lubbers, E. R., Pirtskhalava, T., White, T. A., Johnson, K. O., Stout, M. B., Mezera, V., Giorgadze, N., Jensen, M. D., LeBrasseur, N. K. and Kirkland, J. L. (2015) JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl. Acad. Sci. U. S. A. 112, E6301-E6310. https://doi.org/10.1073/pnas.1515386112
  97. Yi, H. S., Kim, S. Y., Kim, J. T., Lee, Y. S., Moon, J. S., Kim, M., Kang, Y. E., Joung, K. H., Lee, J. H., Kim, H. J., Chun, K., Shong, M. and Ku, B. J. (2019) T-cell senescence contributes to abnormal glucose homeostasis in humans and mice. Cell Death Dis. 10, 249. https://doi.org/10.1038/s41419-019-1494-4