Biology:Immunosenescence

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Immunosenescence is the gradual deterioration of the immune system, brought on by natural age advancement. It affects both innate and adaptive immunity, including changes in lymphocyte production, immune cell function, and inflammatory regulation.[1] Immunosenescence involves both the host's capacity to respond to infections and the development of long-term immune memory. Age-associated immune deficiency is found in both long- and short-lived species as a function of their age relative to life expectancy rather than elapsed time.[2]

Immunosenescence has been studied in animal models, including mice, marsupials, and monkeys.[3][4][5] In humans, it is associated with increased rates of morbidity and mortality in older adults. Along with anergy and T-cell exhaustion, immunosenescence is among the major dysfunctional states of the immune system. Strategies to reverse immunosenescence and the mechanisms underlying immune system aging remain active areas of research.[6]

Immunosenescence is not a random, deteriorative phenomenon. It instead appears to reflect an evolutionary pattern in reverse where there is a gradual loss of features that had been optimized for effective immunity earlier in life. Many of the parameters affected by immunosenescence are thought to be under genetic control.[7]

Age-associated decline in immune function

The mechanisms and functional consequences of aging in the immune system remain an active area of research. Senescence refers to replicative senescence from cell biology, which describes the condition when the upper limit of cell divisions (Hayflick limit) has been exceeded, and such cells commit apoptosis or lose their functional properties. In the immune system, there has been evidence that immune cells such as T lymphocytes display markers of senescence. However, immunosenescence refers more broadly to age-related changes in both adaptive and innate immune function and structure.[8]

Adaptive immunity changes

Adaptive immunity is responsible for tailored, long-term immune response. Age-related changes in adaptive immunity affect both T and B lymphocytes.[1]

T-cell changes

Thymic involution is the gradual shrinkage of the thymus gland with age and is considered to be a major contributor to adaptive immune aging.[9] In humans, beginning early in life and accelerating during puberty, functional thymic tissue is progressively replaced with adipose (fat) tissue. This reduces the production of naive T cells and subsequently decreases T-cell receptor (TCR) diversity.[1][10] As TCR diversity decrease, the range of antigens that the immune system's can recognize on antigen-presenting cells (APCs) is also limited. And as thymic output is reduced, overall T-cell numbers are instead maintained partly through peripheral homeostatic proliferation. This is a process in which existing T cells divide outside of the thymus to preserve cell numbers. While this compensatory mechanism helps maintain T-cell quantity, it does not generate new receptors. At the same time, antigen-experienced memory and highly differentiated T cells accumulate with age, partly due to repeated antigenic stimulation. Over time, the combination of thymic involution and the expansion of existing clones reduces TCR diversity in both naïve and memory T-cell populations.[10]

Persistent viral infections can also shape how T-cell populations change with age. One virus that has been studied extensively in this context is cytomegalovirus (CMV). CMV is a member of the herpesvirus family and, once acquired, remains in the body for life in a latent state. In most healthy adults it causes few or no symptoms, but the immune system must continually monitor and control the infection. Over time, this ongoing immune surveillance promotes the expansion of CMV-specific memory T cells. In older individuals, these cells can occupy a large fraction of the total T-cell pool. As these CMV-specific clones expand, they reduce the relative diversity of the overall T-cell repertoire.[11]

Taken together, these age-related alterations in T-cell production, diversity, and clonal expansion contribute to broader changes in immune function. As a result, older adults may become more vulnerable to infections that the immune system has not previously encountered. Aging of the immune system has also been associated with a greater risk of cancer, autoimmune disorders, and several other chronic health conditions.[11]

B-cell changes

B lymphocytes normally respond to antigen exposure by proliferating and differentiating into antibody-secreting plasma cells. However, several aspects of B-cell biology change during aging. One major change is a reduction in the overall production of new B cells. This decline is linked to impaired development within the bone marrow, including a decrease in precursor populations such as pre-B cells. Because of this developmental slowdown, the number of naïve B cells entering the circulation gradually decreases.[12]

Aging also affects how B cells function after activation. Studies have shown that antibodies produced by older B cells often have lower affinity for their target antigens. In addition, the efficiency of class-switch recombination tends to decline with age. Class-switch recombination is the mechanism that allows B cells to change the class of antibody they produce—for example switching from IgM to IgG or IgA—which is important for building strong and long-lasting immune protection.[12]

When this process becomes less efficient, immune responses to new pathogens are weaker. This contributes to reduced protection against unfamiliar infections and can also lower the effectiveness of vaccines in older populations. Some subsets of memory B cells may also produce higher levels of inflammatory signaling molecules, suggesting they could contribute to the chronic low-grade inflammation frequently observed in aging individuals.[12]

Innate immunity changes

The effects of immunosenescence are not limited to the adaptive immune system. Components of the innate immune system—our body's first line of defense against pathogens—also undergo age-related changes. One important factor involves hematopoietic stem cells (HSCs), which give rise to all blood and immune cells. As these stem cells age, their capacity for self-renewal declines and their differentiation patterns shift. In particular, aging HSCs tend to produce more cells of the myeloid lineage than lymphoid cells. This imbalance alters the overall composition of immune cells and may contribute to reduced immune responsiveness in older individuals.[13]

Other cells:

  • HSCs provide the regulated lifelong supply of leukocyte progenitors that eventually differentiate into specialized immune cells. With age, these cells gradually lose their self-renewal capacity. This is due to the accumulation of oxidative damage to DNA by aging and cellular metabolic activity[14] and telomeric shortening.
  • Decreased phagocytic capability in neutrophils, macrophages, and dendritic cells (DCs) [15]
  • Natural killer (NK) cells exhibit phenotypic changes that may lead to decline in cytotoxic ability.[12] A shift within NK cell subpopulations may also be what leads to reduced proliferation and pathogen clearance

T-cell biomarkers of age-dependent dysfunction

T cells' functional capacity is most influenced by aging effects. Age-related alterations are evident in all T-cell development stages, making them a significant factor in immunosenescence.[16] T-cell function decline begins with the progressive involution of the thymus, which is the organ essential for T-cell maturation. This decline in turn reduces IL-2 production[17][18] and reduction/exhaustion on the number of thymocytes (i.e. immature T cells), thus reducing peripheral naïve T cell output.[19][20] Once matured and circulating throughout the peripheral system, T cells undergo deleterious age-dependent changes. This leaves the body practically devoid of virgin T cells, which makes it more prone to a variety of diseases.[21]

  • shift in the CD4+/CD8+ ratio[22]
  • the accumulation and clonal expansion of memory and effector T cells[23][24]
  • impaired development of CD4+ T follicular helper cells (specialized in facilitating peripheral B cell maturation, and the generation of antibody-producing plasma cells and memory B cells)[25]
  • deregulation of intracellular signal transduction capabilities[26]
  • diminished capacity to produce effector lymphokines[27][24][28]
  • shrinkage of antigen-recognition repertoire of T-cell receptor (TcR) diversity[29][30]
  • down-regulation of CD28 costimulatory molecules[31]
  • cytotoxic activity of Natural Killer T cells (NKTs) decreases[32] due to reduction of the expression of cytotoxicity activating receptors (NKp30, NKp46, etc.) and (simultaneously) increase in the expression of the inhibitory (KIR, NKG2C, etc.) receptors of NK cells[33]
  • reduction of cytotoxic activity due to impaired expression of associated molecules such as IFN-γ, granzyme B or perforin[34][35]
  • impaired proliferation in response to antigenic stimulation[27][24][29][30]
  • accumulation and clonal expansion of memory and effector T cells[23][24]
  • hampered immune defences against viral pathogens, especially by cytotoxic CD8+ T cells[28]
  • Progressive accumulation of cytotoxic CD4⁺ T cells expressing EOMES, which may represent an adaptive mechanism that preserves tissue integrity and restrains senescent cell accumulation[36][37]
  • changes in cytokine profile, e.g., increased pro-inflammatory cytokines milieu present in the elderly[38] (IL-6)[39]
  • increased PD-1 expression[40]
  • glycolysis as a preferential pathway of energetic metabolism - functionally impaired mitochondria produce ROS excessively[41]
  • presence of T cell-specific biomarkers of senescence (circular RNA100783, micro-RNAs MiR-181a)[42][43]

Challenges

Older adults frequently present with non-specific signs and symptoms, and clues of focal infection are often absent or obscured by chronic conditions.[2] This complicates diagnosis and treatment.

Vaccination in older adults

Reduced vaccine efficacy in older people stems from their limited ability—relative to younger adults—to respond to immunization with novel, non-persistent pathogens and correlates with alterations in CD4:CD8 ratios and impaired dendritic cell function.[44] Therefore, vaccination in earlier life stages seems more likely to be effective, although the duration of the effect varies by pathogen.[45][39]

Rescue of the advanced-age phenotype

Removal of senescent cells with senolytics has been proposed as a means to enhance immunity during aging.[46] Immune system aging in mice can be partially restrained by restoring thymus growth, which can be achieved by transplanting proliferative thymic epithelial cells from young mice.[47] Metformin has been proven to moderate aging in preclinical studies.[48] Its protective effect is probably caused primarily by impaired mitochondrial metabolism, particularly decreased reactive oxygen production,[49] increased AMP:ATP ratio,[50] and lower NAD/NADH ratio. Coenzyme NAD+ wanes in various tissues in an age-dependent manner; thus, redox potential associated changes seem to be critical in the aging process,[51] and NAD+ supplements may have protective effects.[52] Rapamycin, an antitumor and immunosuppressant, acts similarly.[53]

References

  1. ↑ 1.0 1.1 1.2 Goyani, Priyanka; Christodoulou, Rafail; Vassiliou, Evros (November 2023). "Immunosenescence: Aging and Immune System Decline" (in en). Vaccines 12 (12): 1314. doi:10.3390/vaccines12121314. ISSN 2076-393X. PMID 39771976. 
  2. ↑ 2.0 2.1 "Immunosenescence and infectious diseases". Microbes and Infection 3 (10): 851–857. August 2001. doi:10.1016/S1286-4579(01)01443-5. PMID 11580980. 
  3. ↑ "Immunosenescence in a captive semelparous marsupial, the red-tailed phascogale (Phascogale calura)". BMC Zoology 3. 2018. doi:10.1186/s40850-018-0036-3. 
  4. ↑ "Limitations in the isolation and stimulation of splenic mononuclear cells in a dasyurid marsupial, Phascogale calura". BMC Research Notes 11 (1). October 2018. doi:10.1186/s13104-018-3824-5. PMID 30305168. 
  5. ↑ "Immune memory and aging: an infinite or finite resource?". Current Opinion in Immunology 22 (4): 535–540. August 2010. doi:10.1016/j.coi.2010.06.011. PMID 20674320. 
  6. ↑ Li, Wendi; Xiao, Lin; Li, Haiyang; Cui, Wei (December 2025). "Global research trends of immunosenescence and immunotherapy: A bibliometric study" (in en). Human Vaccines & Immunotherapeutics 21 (1). doi:10.1080/21645515.2025.2469403. ISSN 2164-5515. PMID 39992200. PMC 11853558. https://www.tandfonline.com/doi/full/10.1080/21645515.2025.2469403. 
  7. ↑ Villar-Álvarez, Felipe; de la Rosa-Carrillo, David; Fariñas-Guerrero, Fernando; Jiménez-Ruiz, Carlos A. (July 2022). "Immunosenescence, Immune Fitness and Vaccination Schedule in the Adult Respiratory Patient" (in en). Open Respiratory Archives 4 (3). doi:10.1016/j.opresp.2022.100181. PMID 37496575. PMC 9109993. https://linkinghub.elsevier.com/retrieve/pii/S2659663622000273. 
  8. ↑ Lee, Kyoo-A; Flores, Rafael R.; Jang, In Hwa; Saathoff, Ashley; Robbins, Paul D. (May 2022). "Immune Senescence, Immunosenescence and Aging". Frontiers in Aging 3. doi:10.3389/fragi.2022.900028. ISSN 2673-6217. PMID 35821850. 
  9. ↑ Liang, Zhanfeng; Dong, Xue; Zhang, Zhaoqi; Zhang, Qian; Zhao, Yong (August 2022). "Age-related thymic involution: Mechanisms and functional impact" (in en). Aging Cell 21 (8). doi:10.1111/acel.13671. ISSN 1474-9718. PMID 35822239. 
  10. ↑ 10.0 10.1 Santamaria, Jérémy C.; Irla, Magali (February 2026). "Age-related thymic involution: Mechanistic insights and rejuvenating approaches to restore immune function" (in en). Science Advances 12 (7). doi:10.1126/sciadv.aeb2970. ISSN 2375-2548. PMID 41686895. 
  11. ↑ 11.0 11.1 Liu, Xiaodan; Liu, Chang; Zhang, Ting (October 2025). "The Immunoregulatory Mechanisms of Human Cytomegalovirus from Primary Infection to Reactivation" (in en). Pathogens 14 (10): 998. doi:10.3390/pathogens14100998. ISSN 2076-0817. PMID 41156609. 
  12. ↑ 12.0 12.1 12.2 12.3 Gao, Haoyu; Nepovimova, Eugenie; Adam, Vojtech; Heger, Zbynek; Valko, Marian; Wu, Qinghua; Kuca, Kamil (September 2024). "Age-associated changes in innate and adaptive immunity: role of the gut microbiota". Frontiers in Immunology 15. doi:10.3389/fimmu.2024.1421062. ISSN 1664-3224. PMID 39351234. PMC 11439693. https://www.frontiersin.org/articles/10.3389/fimmu.2024.1421062/full. 
  13. ↑ "Revisiting hematopoiesis: applications of the bulk and single-cell transcriptomics dissecting transcriptional heterogeneity in hematopoietic stem cells". Briefings in Functional Genomics 21 (3): 159–176. March 2022. doi:10.1093/bfgp/elac002. PMID 35265979. 
  14. ↑ Shevyrev, Daniil; Tereshchenko, Valeriy; Berezina, Tatiana N.; Rybtsov, Stanislav (March 2023). "Hematopoietic Stem Cells and the Immune System in Development and Aging" (in en). International Journal of Molecular Sciences 24 (6): 5862. doi:10.3390/ijms24065862. ISSN 1422-0067. https://www.mdpi.com/1422-0067/24/6/5862. 
  15. ↑ Yu, Weiru; Yu, Yifei; Sun, Siyuan; Lu, Chenxu; Zhai, Jianan; Lei, Yumei; Bai, Feirong; Wang, Ran et al. (November 2024). "Immune Alterations with Aging: Mechanisms and Intervention Strategies" (in en). Nutrients 16 (22): 3830. doi:10.3390/nu16223830. ISSN 2072-6643. PMID 39599617. PMC 11597283. https://www.mdpi.com/2072-6643/16/22/3830. 
  16. ↑ "T cell function in the aged: Lessons learned from animal models". Clinical and Applied Immunology Reviews 6 (2): 73–97. 2006. doi:10.1016/j.cair.2006.06.001. 
  17. ↑ "Replicative senescence of CD8 T cells: effect on human ageing". Experimental Gerontology 39 (4): 517–524. April 2004. doi:10.1016/j.exger.2003.09.024. PMID 15050285. 
  18. ↑ "Tolerance, not immunity, crucially depends on IL-2". Nature Reviews. Immunology 4 (9): 665–674. September 2004. doi:10.1038/nri1435. PMID 15343366. Bibcode: 2004NatRI...4..665M. 
  19. ↑ "Thymic involution in aging". Journal of Clinical Immunology 20 (4): 250–256. July 2000. doi:10.1023/A:1006611518223. PMID 10939712. 
  20. ↑ "Reduction in the developmental potential of intrathymic T cell progenitors with age". Journal of Immunology 173 (1): 245–250. July 2004. doi:10.4049/jimmunol.173.1.245. PMID 15210781. 
  21. ↑ "Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space". Vaccine 18 (16): 1717–1720. February 2000. doi:10.1016/S0264-410X(99)00513-7. PMID 10689155. 
  22. ↑ "Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly". Journal of Immunology 176 (4): 2645–2653. February 2006. doi:10.4049/jimmunol.176.4.2645. PMID 16456027. 
  23. ↑ 23.0 23.1 "Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load". Experimental Gerontology 34 (8): 911–921. December 1999. doi:10.1016/S0531-5565(99)00068-6. PMID 10673145. 
  24. ↑ 24.0 24.1 24.2 24.3 "Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1)". Blood 100 (10): 3698–3702. November 2002. doi:10.1182/blood-2002-02-0657. PMID 12393723. 
  25. ↑ "The aged microenvironment contributes to the age-related functional defects of CD4 T cells in mice". Aging Cell 11 (5): 732–740. October 2012. doi:10.1111/j.1474-9726.2012.00836.x. PMID 22607653. 
  26. ↑ "Age-related impairment of p56lck and ZAP-70 activities in human T lymphocytes activated through the TcR/CD3 complex". Experimental Gerontology 34 (2): 197–216. April 1999. doi:10.1016/S0531-5565(98)00061-8. PMID 10363787. 
  27. ↑ 27.0 27.1 "Impaired immune response to Candida albicans in aged mice". Journal of Medical Microbiology 55 (Pt 12): 1649–1656. December 2006. doi:10.1099/jmm.0.46740-0. PMID 17108267. 
  28. ↑ 28.0 28.1 "Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1)". Experimental Gerontology 38 (8): 911–920. August 2003. doi:10.1016/S0531-5565(03)00134-7. PMID 12915213. 
  29. ↑ 29.0 29.1 "The influence of age on T cell generation and TCR diversity". Journal of Immunology 174 (11): 7446–7452. June 2005. doi:10.4049/jimmunol.174.11.7446. PMID 15905594. 
  30. ↑ 30.0 30.1 "Aging of the immune system: how much can the adaptive immune system adapt?". Immunity 24 (5): 495–499. May 2006. doi:10.1016/j.immuni.2006.05.001. PMID 16713964. 
  31. ↑ "The Evolving Role of CD8+CD28− Immunosenescent T Cells in Cancer Immunology". International Journal of Molecular Sciences 20 (11): 2810. June 2019. doi:10.3390/ijms20112810. PMID 31181772. 
  32. ↑ "NK and NKT cell functions in immunosenescence". Aging Cell 3 (4): 177–184. August 2004. doi:10.1111/j.1474-9728.2004.00107.x. PMID 15268751. 
  33. ↑ "Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance". Cancer Immunology, Immunotherapy 65 (4): 417–426. April 2016. doi:10.1007/s00262-015-1750-0. PMID 26288343. 
  34. ↑ "Decreased perforin and granzyme B expression in senescent HIV-1-specific cytotoxic T lymphocytes". Virology 332 (1): 16–19. February 2005. doi:10.1016/j.virol.2004.11.028. PMID 15661136. 
  35. ↑ "T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment". Current Opinion in Immunology 25 (2): 214–221. April 2013. doi:10.1016/j.coi.2012.12.003. PMID 23298609. 
  36. ↑ Elyahu, Yehezqel; Feygin, Ilana; Eremenko, Ekaterina; Pinkas, Noa; Zemer, Alon; Shicht, Amit; Berner, Omer; Avigdory-Meiri, Roni et al. (October 2025). "CD4 T cells acquire Eomesodermin to modulate cellular senescence and aging" (in en). Nature Aging 5 (10): 1970–1982. doi:10.1038/s43587-025-00953-8. ISSN 2662-8465. https://www.nature.com/articles/s43587-025-00953-8. 
  37. ↑ Elyahu, Yehezqel; Hekselman, Idan; Eizenberg-Magar, Inbal; Berner, Omer; Strominger, Itai; Schiller, Maya; Mittal, Kritika; Nemirovsky, Anna et al. (2019-08-02). "Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes" (in en). Science Advances 5 (8). doi:10.1126/sciadv.aaw8330. ISSN 2375-2548. PMID 31457092. Bibcode: 2019SciA....5.8330E. 
  38. ↑ "Aging and the skin immune system". Archives of Dermatology 133 (10): 1256–1262. October 1997. doi:10.1001/archderm.133.10.1256. PMID 9382564. 
  39. ↑ 39.0 39.1 "Age and immunity: What is "immunosenescence"?". Experimental Gerontology 105: 4–9. May 2018. doi:10.1016/j.exger.2017.10.024. PMID 29111233. 
  40. ↑ "PD-1+ memory phenotype CD4+ T cells expressing C/EBPalpha underlie T cell immunodepression in senescence and leukemia". Proceedings of the National Academy of Sciences of the United States of America 106 (37): 15807–15812. September 2009. doi:10.1073/pnas.0908805106. PMID 19805226. Bibcode: 2009PNAS..10615807S. 
  41. ↑ "p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8⁺ T cells". The Journal of Clinical Investigation 124 (9): 4004–4016. September 2014. doi:10.1172/JCI75051. PMID 25083993. 
  42. ↑ "A CD153+CD4+ T follicular cell population with cell-senescence features plays a crucial role in lupus pathogenesis via osteopontin production". Journal of Immunology 194 (12): 5725–5735. June 2015. doi:10.4049/jimmunol.1500319. PMID 25972477. 
  43. ↑ "Comprehensive circular RNA profiling reveals that circular RNA100783 is involved in chronic CD28-associated CD8(+)T cell ageing". Immunity & Ageing 12 (1). 2015-10-08. doi:10.1186/s12979-015-0042-z. PMID 26451160. 
  44. ↑ "Low Thymic Activity and Dendritic Cell Numbers Are Associated with the Immune Response to Primary Viral Infection in Elderly Humans". Journal of Immunology 195 (10): 4699–4711. November 2015. doi:10.4049/jimmunol.1500598. PMID 26459351. 
  45. ↑ "Long-lasting stem cell-like memory CD8+ T cells with a naïve-like profile upon yellow fever vaccination". Science Translational Medicine 7 (282): 282ra48. April 2015. doi:10.1126/scitranslmed.aaa3700. PMID 25855494. https://serval.unil.ch/notice/serval:BIB_44DEAD18C07E. 
  46. ↑ "Can blocking inflammation enhance immunity during aging?". The Journal of Allergy and Clinical Immunology 145 (5): 1323–1331. 2020. doi:10.1016/j.jaci.2020.03.016. PMID 32386656. https://discovery.ucl.ac.uk/id/eprint/10108233/. 
  47. ↑ "Young, proliferative thymic epithelial cells engraft and function in aging thymuses". Journal of Immunology 194 (10): 4784–4795. May 2015. doi:10.4049/jimmunol.1403158. PMID 25870244. 
  48. ↑ "Metformin as a Tool to Target Aging". Cell Metabolism 23 (6): 1060–1065. June 2016. doi:10.1016/j.cmet.2016.05.011. PMID 27304507. 
  49. ↑ "Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats". Free Radical Biology & Medicine 49 (6): 1082–1087. September 2010. doi:10.1016/j.freeradbiomed.2010.06.022. PMID 20600832. 
  50. ↑ "Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I". The Journal of Biological Chemistry 275 (1): 223–228. January 2000. doi:10.1074/jbc.275.1.223. PMID 10617608. 
  51. ↑ "Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo". Nature Medicine 24 (9): 1384–1394. September 2018. doi:10.1038/s41591-018-0125-4. PMID 30038219. 
  52. ↑ "Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence". Cell Metabolism 27 (3): 529–547. March 2018. doi:10.1016/j.cmet.2018.02.011. PMID 29514064. 
  53. ↑ "Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin". Cancer Biology & Therapy 15 (5): 586–592. May 2014. doi:10.4161/cbt.28164. PMID 24556924. 



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