Biology:Immunosenescence

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Short description: Immune system deterioration brought on by aging

Immunosenescence is the gradual deterioration of the immune system, brought on by natural age advancement. A 2020 review concluded that the adaptive immune system is affected more than the innate immune system.[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]

It has been studied in animal models including mice, marsupials and monkeys.[3][4][5] Immunosenescence is a contributory factor to the increased frequency of morbidity and mortality among the elderly. Along with anergy and T-cell exhaustion, immunosenescence belongs among the major immune system dysfunctional states. However, while T-cell anergy is a reversible condition, as of 2020 no techniques for immunosenescence reversal had been developed.[6][7]

Immunosenescence is not a random deteriorative phenomenon, rather it appears to inversely recapitulate an evolutionary pattern. Most of the parameters affected by immunosenescence appear to be under genetic control.[8] Immunosenescence can be envisaged as the result of the continuous challenge of the unavoidable exposure to a variety of antigens such as viruses and bacteria.[9]

Age-associated decline in immune function

Aging of the immune system is a controversial phenomenon. 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. Immunosenescence generally means a robust shift in both structural and functional parameters that has a clinically relevant outcome.[10] Thymus involution is probably the most relevant factor responsible for immunosenescence. Thymic involution is common in most mammals; in humans it begins after puberty, as the immunological defense against most novel antigens is necessary mainly during infancy and childhood.[11]

The major characteristic of the immunosenescent phenotype is a shift in T-cell subpopulation distribution. As the thymus involutes, the number of naive T cells (especially CD8+) decreases, thus naive T cells homeostatically proliferate into memory T cells as a compensation.[5] It is believed that the conversion to memory phenotype can be accelerated by restimulation of the immune system by persistent pathogens such as CMV and HSV. By age 40, an estimated 50% to 85% of adults have contracted human cytomegalovirus (HCMV).[1] Consistent, repeated stimulation by such pathogens leads to preferential differentiation of the T-cell memory phenotype, and a 2020 review reported that CD8+ T-cell precursors, specific for the most rare and less frequently present antigens shed the most.[5] However, such a distribution shift leads to increased susceptibility to non-persistent infection, cancer, autoimmune diseases, cardiovascular health conditions and many others.[12][13]

T cells are not the only immune cells affected by aging:

  • Hematopoietic stem cells (HSC), which provide the regulated lifelong supply of leukocyte progenitors that differentiate into specialised immune cells diminish in their self-renewal capacity.[14] This is due to the accumulation of oxidative damage to DNA by aging and cellular metabolic activity[15] and telomeric shortening.
  • The number of phagocytes declines in aged hosts, coupled with an intrinsic reduction of bactericidal activity.[16][17]
  • Natural killer (NK) cell cytotoxicity and the antigen-presenting function of dendritic cells diminishes with age.[18][19][20][21] The age-associated impairment of dendritic antigen-presenting cells (APCs) translates into a deficiency in cell-mediated immunity and thus, the inability for effector T-lymphocytes to modulate an adaptive immune response.
  • Humoral immunity declines, caused by a reduction in the population of antibody producing B-cells along with a smaller immunoglobulin diversity and affinity.[22][23]

In addition to changes in immune responses, the beneficial effects of inflammation devoted to the neutralisation of dangerous and harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.[24] Changes in the lymphoid compartment are not solely responsible for the malfunctioning of the immune system. Although myeloid cell production does not seem to decline with age, macrophages become dysregulated as a consequence of environmental changes.[25]

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.[26] 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[27][28] and reduction/exhaustion on the number of thymocytes (i.e. immature T cells), thus reducing peripheral naïve T cell output.[29][30] 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.[9]

  • shift in the CD4+/CD8+ ratio[31]
  • the accumulation and clonal expansion of memory and effector T cells[8][32]
  • 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)[33]
  • deregulation of intracellular signal transduction capabilities[34]
  • diminished capacity to produce effector lymphokines[35][32][36]
  • shrinkage of antigen-recognition repertoire of T-cell receptor (TcR) diversity[37][38]
  • down-regulation of CD28 costimulatory molecules[39]
  • cytotoxic activity of Natural Killer T cells (NKTs) decreases[19] 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[40]
  • reduction of cytotoxic activity due to impaired expression of associated molecules such as IFN-γ, granzyme B or perforin[41][6]
  • impaired proliferation in response to antigenic stimulation[35][32][37][38]
  • accumulation and clonal expansion of memory and effector T cells[8][32]
  • hampered immune defences against viral pathogens, especially by cytotoxic CD8+ T cells[36]
  • changes in cytokine profile, e.g., increased pro-inflammatory cytokines milieu present in the elderly[42] (IL-6)[10]
  • increased PD-1 expression[43]
  • glycolysis as a preferential pathway of energetic metabolism - functionally impaired mitochondria produce ROS excessively[44]
  • presence of T cell-specific biomarkers of senescence (circular RNA100783, micro-RNAs MiR-181a)[45][46]

Challenges

The elderly 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 the elderly

The reduced efficacy of vaccination in the elderly stems from their restricted ability to respond to immunization with novel non-persistent pathogens, and correlates with both CD4:CD8 alterations and impaired dendritic cell function.[47] Therefore, vaccination in earlier life stages seems more likely to be effective, although the duration of the effect varies by pathogen.[48][10]

Rescue of the advanced-age phenotype

Immune system aging in mice can be partly restricted by restoring thymus growth, which can be achieved by transplantation of proliferative thymic epithelial cells from young mice.[49] Metformin has been proven to moderate aging in preclinical studies.[50] Its protective effect is probably caused primarily by impaired mitochondria metabolism, particularly decreased reactive oxygen production[51] or increased AMP:ATP ratio[52] and lower NAD/NADH ratio. Coenzyme NAD+ is reduced in various tissues in an age-dependent manner, and thus redox potential associated changes seem to be critical in the aging process,[53] and NAD+ supplements may have protective effects.[54] Rapamycin, an antitumor and immunosuppresant, acts similarly.[55]

References

  1. ↑ 1.0 1.1 "T cells, aging and senescence". Experimental Gerontology 134: 110887. February 2020. doi:10.1016/j.exger.2020.110887. PMID 32092501. 
  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: 10. 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): 712. October 2018. doi:10.1186/s13104-018-3824-5. PMID 30305168. 
  5. ↑ 5.0 5.1 5.2 "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. ↑ 6.0 6.1 "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. 
  7. ↑ "T Cell Dysfunction and Exhaustion in Cancer" (in English). Frontiers in Cell and Developmental Biology 8: 17. 2020. doi:10.3389/fcell.2020.00017. PMID 32117960. 
  8. ↑ 8.0 8.1 8.2 "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. 
  9. ↑ 9.0 9.1 "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. 
  10. ↑ 10.0 10.1 10.2 "Age and immunity: What is "immunosenescence"?". Experimental Gerontology 105: 4–9. May 2018. doi:10.1016/j.exger.2017.10.024. PMID 29111233. 
  11. ↑ "An evolutionary perspective on the mechanisms of immunosenescence". Trends in Immunology 30 (7): 374–381. July 2009. doi:10.1016/j.it.2009.05.001. PMID 19541538. http://researchonline.rvc.ac.uk/id/eprint/3517/. 
  12. ↑ "Immunosenescence: deficits in adaptive immunity in the elderly". Tissue Antigens 70 (3): 179–189. September 2007. doi:10.1111/j.1399-0039.2007.00891.x. PMID 17661905. 
  13. ↑ "Immunosenescence: Influenza vaccination and the elderly". Current Opinion in Immunology 29: 38–42. August 2014. doi:10.1016/j.coi.2014.03.008. PMID 24769424. 
  14. ↑ "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. 
  15. ↑ High frequency electromagnetic waves such as gamma and xrays can penetrate and damage DNA. "Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells". Nature 431 (7011): 997–1002. October 2004. doi:10.1038/nature02989. PMID 15496926. Bibcode: 2004Natur.431..997I. 
  16. ↑ "Neutrophil ageing and immunesenescence". Mechanisms of Ageing and Development 122 (14): 1521–1535. September 2001. doi:10.1016/S0047-6374(01)00285-8. PMID 11511394. 
  17. ↑ "Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes". Immunological Reviews 205: 60–71. June 2005. doi:10.1111/j.0105-2896.2005.00260.x. PMID 15882345. 
  18. ↑ "Decreased natural killer cell activity is associated with atherosclerosis in elderly humans". Experimental Gerontology 37 (1): 127–136. December 2001. doi:10.1016/S0531-5565(01)00162-0. PMID 11738153. 
  19. ↑ 19.0 19.1 "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. 
  20. ↑ "The frail elderly: role of dendritic cells in the susceptibility of infection". Mechanisms of Ageing and Development 123 (8): 955–962. April 2002. doi:10.1016/S0047-6374(02)00033-7. PMID 12044944. 
  21. ↑ "Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies?". Cancer Immunology, Immunotherapy 65 (4): 453–463. April 2016. doi:10.1007/s00262-015-1720-6. PMID 26059279. 
  22. ↑ "B-cell diversity decreases in old age and is correlated with poor health status". Aging Cell 8 (1): 18–25. February 2009. doi:10.1111/j.1474-9726.2008.00443.x. PMID 18986373. 
  23. ↑ "Enhanced differentiation of splenic plasma cells but diminished long-lived high-affinity bone marrow plasma cells in aged mice". Journal of Immunology 170 (3): 1267–1273. February 2003. doi:10.4049/jimmunol.170.3.1267. PMID 12538685. 
  24. ↑ "Inflamm-aging. An evolutionary perspective on immunosenescence". Annals of the New York Academy of Sciences 908 (1): 244–254. June 2000. doi:10.1111/j.1749-6632.2000.tb06651.x. PMID 10911963. Bibcode: 2000NYASA.908..244F. 
  25. ↑ "Immunosenescence: a problem of lymphopoiesis, homeostasis, microenvironment, and signaling". Immunological Reviews 205: 5–6. June 2005. doi:10.1111/j.0105-2896.2005.00276.x. PMID 15882340. 
  26. ↑ "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. 
  27. ↑ "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. 
  28. ↑ "Tolerance, not immunity, crucially depends on IL-2". Nature Reviews. Immunology 4 (9): 665–674. September 2004. doi:10.1038/nri1435. PMID 15343366. 
  29. ↑ "Thymic involution in aging". Journal of Clinical Immunology 20 (4): 250–256. July 2000. doi:10.1023/A:1006611518223. PMID 10939712. 
  30. ↑ "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. 
  31. ↑ "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. 
  32. ↑ 32.0 32.1 32.2 32.3 "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. 
  33. ↑ "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. 
  34. ↑ "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. 
  35. ↑ 35.0 35.1 "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. 
  36. ↑ 36.0 36.1 "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. 
  37. ↑ 37.0 37.1 "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. 
  38. ↑ 38.0 38.1 "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. 
  39. ↑ "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. 
  40. ↑ "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. 
  41. ↑ "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. 
  42. ↑ "Aging and the skin immune system". Archives of Dermatology 133 (10): 1256–1262. October 1997. doi:10.1001/archderm.133.10.1256. PMID 9382564. 
  43. ↑ "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. 
  44. ↑ "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. 
  45. ↑ "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. 
  46. ↑ "Comprehensive circular RNA profiling reveals that circular RNA100783 is involved in chronic CD28-associated CD8(+)T cell ageing". Immunity & Ageing 12 (1): 17. 2015-10-08. doi:10.1186/s12979-015-0042-z. PMID 26451160. 
  47. ↑ "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. 
  48. ↑ "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. 
  49. ↑ "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. 
  50. ↑ "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. 
  51. ↑ "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. 
  52. ↑ "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. 
  53. ↑ "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. 
  54. ↑ "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. 
  55. ↑ "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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