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Immunosenescence

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

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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] Recurring infections by latent herpes viruses can exhaust the immune system of elderly persons.[12] 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] Such a distribution shift leads to increased susceptibility to non-persistent infection, cancer, autoimmune diseases, cardiovascular health conditions and many others.[13][14]

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

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.[25] 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.[26]

T-cell biomarkers of age-dependent dysfunction

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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.[27] 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[28][29] and reduction/exhaustion on the number of thymocytes (i.e. immature T cells), thus reducing peripheral naïve T cell output.[30][31] 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]

Challenges

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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

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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.[48] Therefore, vaccination in earlier life stages seems more likely to be effective, although the duration of the effect varies by pathogen.[49][10]

Rescue of the advanced-age phenotype

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Removal of senescent cells with senolytic compounds has been proposed as a method of enhancing immunity during aging.[50]

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.[51] Metformin has been proven to moderate aging in preclinical studies.[52] Its protective effect is probably caused primarily by impaired mitochondria metabolism, particularly decreased reactive oxygen production[53] or increased AMP:ATP ratio[54] 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,[55] and NAD+ supplements may have protective effects.[56] Rapamycin, an antitumor and immunosuppresant, acts similarly.[57]

References

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  1. ^ a b Pangrazzi L, Weinberger B (February 2020). "T cells, aging and senescence". Experimental Gerontology. 134: 110887. doi:10.1016/j.exger.2020.110887. PMID 32092501. S2CID 211237913.
  2. ^ a b Ginaldi L, Loreto MF, Corsi MP, Modesti M, De Martinis M (August 2001). "Immunosenescence and infectious diseases". Microbes and Infection. 3 (10): 851–857. doi:10.1016/S1286-4579(01)01443-5. PMID 11580980.
  3. ^ Letendre C, Sawyer E, Young LJ, Old JM (2018). "Immunosenescence in a captive semelparous marsupial, the red-tailed phascogale (Phascogale calura)". BMC Zoology. 3: 10. doi:10.1186/s40850-018-0036-3. S2CID 53496572.
  4. ^ Letendre C, Young LJ, Old JM (October 2018). "Limitations in the isolation and stimulation of splenic mononuclear cells in a dasyurid marsupial, Phascogale calura". BMC Research Notes. 11 (1): 712. doi:10.1186/s13104-018-3824-5. PMC 6180634. PMID 30305168.
  5. ^ a b c Nikolich-Zugich J, Rudd BD (August 2010). "Immune memory and aging: an infinite or finite resource?". Current Opinion in Immunology. 22 (4): 535–540. doi:10.1016/j.coi.2010.06.011. PMC 2925022. PMID 20674320.
  6. ^ a b Crespo J, Sun H, Welling TH, Tian Z, Zou W (April 2013). "T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment". Current Opinion in Immunology. 25 (2): 214–221. doi:10.1016/j.coi.2012.12.003. PMC 3636159. PMID 23298609.
  7. ^ Zhang Z, Liu S, Zhang B, Qiao L, Zhang Y, Zhang Y (2020). "T Cell Dysfunction and Exhaustion in Cancer". Frontiers in Cell and Developmental Biology. 8: 17. doi:10.3389/fcell.2020.00017. PMC 7027373. PMID 32117960.
  8. ^ a b c Franceschi C, Valensin S, Fagnoni F, Barbi C, Bonafè M (December 1999). "Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load". Experimental Gerontology. 34 (8): 911–921. doi:10.1016/S0531-5565(99)00068-6. PMID 10673145. S2CID 32614875.
  9. ^ a b Franceschi C, Bonafè M, Valensin S (February 2000). "Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space". Vaccine. 18 (16): 1717–1720. doi:10.1016/S0264-410X(99)00513-7. PMID 10689155.
  10. ^ a b c Pawelec G (May 2018). "Age and immunity: What is "immunosenescence"?". Experimental Gerontology. 105: 4–9. doi:10.1016/j.exger.2017.10.024. PMID 29111233. S2CID 46819839.
  11. ^ Shanley DP, Aw D, Manley NR, Palmer DB (July 2009). "An evolutionary perspective on the mechanisms of immunosenescence". Trends in Immunology. 30 (7): 374–381. doi:10.1016/j.it.2009.05.001. PMID 19541538.
  12. ^ Nikolich-Zugich J (2008). "Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections". Nature Reviews Immunology. 8 (7): 512–522. doi:10.1038/nri2318. PMC 5573867. PMID 18469829.
  13. ^ Hakim FT, Gress RE (September 2007). "Immunosenescence: deficits in adaptive immunity in the elderly". Tissue Antigens. 70 (3): 179–189. doi:10.1111/j.1399-0039.2007.00891.x. PMID 17661905.
  14. ^ Haq K, McElhaney JE (August 2014). "Immunosenescence: Influenza vaccination and the elderly". Current Opinion in Immunology. 29: 38–42. doi:10.1016/j.coi.2014.03.008. PMID 24769424.
  15. ^ Monga I, Kaur K, Dhanda S (March 2022). "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. doi:10.1093/bfgp/elac002. PMID 35265979.
  16. ^ High frequency electromagnetic waves such as gamma and xrays can penetrate and damage DNA. Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, et al. (October 2004). "Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells". Nature. 431 (7011): 997–1002. Bibcode:2004Natur.431..997I. doi:10.1038/nature02989. PMID 15496926. S2CID 4370804.
  17. ^ Lord JM, Butcher S, Killampali V, Lascelles D, Salmon M (September 2001). "Neutrophil ageing and immunesenescence". Mechanisms of Ageing and Development. 122 (14): 1521–1535. doi:10.1016/S0047-6374(01)00285-8. PMID 11511394. S2CID 1898942.
  18. ^ Stout RD, Suttles J (June 2005). "Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes". Immunological Reviews. 205: 60–71. doi:10.1111/j.0105-2896.2005.00260.x. PMC 1201508. PMID 15882345.
  19. ^ Bruunsgaard H, Pedersen AN, Schroll M, Skinhøj P, Pedersen BK (December 2001). "Decreased natural killer cell activity is associated with atherosclerosis in elderly humans". Experimental Gerontology. 37 (1): 127–136. doi:10.1016/S0531-5565(01)00162-0. PMID 11738153. S2CID 32717204.
  20. ^ a b Mocchegiani E, Malavolta M (August 2004). "NK and NKT cell functions in immunosenescence". Aging Cell. 3 (4): 177–184. doi:10.1111/j.1474-9728.2004.00107.x. PMID 15268751. S2CID 19710282.
  21. ^ Uyemura K, Castle SC, Makinodan T (April 2002). "The frail elderly: role of dendritic cells in the susceptibility of infection". Mechanisms of Ageing and Development. 123 (8): 955–962. doi:10.1016/S0047-6374(02)00033-7. PMID 12044944. S2CID 11558962.
  22. ^ Sanchez-Correa B, Campos C, Pera A, Bergua JM, Arcos MJ, Bañas H, et al. (April 2016). "Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies?". Cancer Immunology, Immunotherapy. 65 (4): 453–463. doi:10.1007/s00262-015-1720-6. PMC 11029066. PMID 26059279. S2CID 20498123.
  23. ^ Gibson KL, Wu YC, Barnett Y, Duggan O, Vaughan R, Kondeatis E, et al. (February 2009). "B-cell diversity decreases in old age and is correlated with poor health status". Aging Cell. 8 (1): 18–25. doi:10.1111/j.1474-9726.2008.00443.x. PMC 2667647. PMID 18986373.
  24. ^ Han S, Yang K, Ozen Z, Peng W, Marinova E, Kelsoe G, Zheng B (February 2003). "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. doi:10.4049/jimmunol.170.3.1267. PMID 12538685.
  25. ^ Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (June 2000). "Inflamm-aging. An evolutionary perspective on immunosenescence". Annals of the New York Academy of Sciences. 908 (1): 244–254. Bibcode:2000NYASA.908..244F. doi:10.1111/j.1749-6632.2000.tb06651.x. PMID 10911963. S2CID 1843716.
  26. ^ Cambier J (June 2005). "Immunosenescence: a problem of lymphopoiesis, homeostasis, microenvironment, and signaling". Immunological Reviews. 205: 5–6. doi:10.1111/j.0105-2896.2005.00276.x. PMID 15882340. S2CID 39130596.
  27. ^ Linton PJ, Lustgarten J, Thoman M (2006). "T cell function in the aged: Lessons learned from animal models". Clinical and Applied Immunology Reviews. 6 (2): 73–97. doi:10.1016/j.cair.2006.06.001.
  28. ^ Effros RB (April 2004). "Replicative senescence of CD8 T cells: effect on human ageing". Experimental Gerontology. 39 (4): 517–524. doi:10.1016/j.exger.2003.09.024. PMID 15050285. S2CID 2954461.
  29. ^ Malek TR, Bayer AL (September 2004). "Tolerance, not immunity, crucially depends on IL-2". Nature Reviews. Immunology. 4 (9): 665–674. doi:10.1038/nri1435. PMID 15343366. S2CID 8449323.
  30. ^ Aspinall R, Andrew D (July 2000). "Thymic involution in aging". Journal of Clinical Immunology. 20 (4): 250–256. doi:10.1023/A:1006611518223. PMID 10939712. S2CID 25042349.
  31. ^ Min H, Montecino-Rodriguez E, Dorshkind K (July 2004). "Reduction in the developmental potential of intrathymic T cell progenitors with age". Journal of Immunology. 173 (1): 245–250. doi:10.4049/jimmunol.173.1.245. PMID 15210781.
  32. ^ Hadrup SR, Strindhall J, Køllgaard T, Seremet T, Johansson B, Pawelec G, et al. (February 2006). "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. doi:10.4049/jimmunol.176.4.2645. PMID 16456027.
  33. ^ a b c d Voehringer D, Koschella M, Pircher H (November 2002). "Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1)". Blood. 100 (10): 3698–3702. doi:10.1182/blood-2002-02-0657. PMID 12393723.
  34. ^ Lefebvre JS, Maue AC, Eaton SM, Lanthier PA, Tighe M, Haynes L (October 2012). "The aged microenvironment contributes to the age-related functional defects of CD4 T cells in mice". Aging Cell. 11 (5): 732–740. doi:10.1111/j.1474-9726.2012.00836.x. PMC 3444657. PMID 22607653.
  35. ^ Fülöp T, Gagné D, Goulet AC, Desgeorges S, Lacombe G, Arcand M, Dupuis G (April 1999). "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. doi:10.1016/S0531-5565(98)00061-8. PMID 10363787. S2CID 42659829.
  36. ^ a b Murciano C, Villamón E, Yáñez A, O'Connor JE, Gozalbo D, Gil ML (December 2006). "Impaired immune response to Candida albicans in aged mice". Journal of Medical Microbiology. 55 (Pt 12): 1649–1656. doi:10.1099/jmm.0.46740-0. PMID 17108267.
  37. ^ a b Ouyang Q, Wagner WM, Voehringer D, Wikby A, Klatt T, Walter S, et al. (August 2003). "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. doi:10.1016/S0531-5565(03)00134-7. PMID 12915213. S2CID 44591282.
  38. ^ a b Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, et al. (June 2005). "The influence of age on T cell generation and TCR diversity". Journal of Immunology. 174 (11): 7446–7452. doi:10.4049/jimmunol.174.11.7446. PMID 15905594.
  39. ^ a b Weng NP (May 2006). "Aging of the immune system: how much can the adaptive immune system adapt?". Immunity. 24 (5): 495–499. doi:10.1016/j.immuni.2006.05.001. PMC 2266981. PMID 16713964.
  40. ^ Huff WX, Kwon JH, Henriquez M, Fetcko K, Dey M (June 2019). "The Evolving Role of CD8+CD28− Immunosenescent T Cells in Cancer Immunology". International Journal of Molecular Sciences. 20 (11): 2810. doi:10.3390/ijms20112810. PMC 6600236. PMID 31181772.
  41. ^ Manser AR, Uhrberg M (April 2016). "Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance". Cancer Immunology, Immunotherapy. 65 (4): 417–426. doi:10.1007/s00262-015-1750-0. PMC 11028690. PMID 26288343. S2CID 32642259.
  42. ^ Yang OO, Lin H, Dagarag M, Ng HL, Effros RB, Uittenbogaart CH (February 2005). "Decreased perforin and granzyme B expression in senescent HIV-1-specific cytotoxic T lymphocytes". Virology. 332 (1): 16–19. doi:10.1016/j.virol.2004.11.028. PMID 15661136.
  43. ^ Sunderkötter C, Kalden H, Luger TA (October 1997). "Aging and the skin immune system". Archives of Dermatology. 133 (10): 1256–1262. doi:10.1001/archderm.133.10.1256. PMID 9382564.
  44. ^ Shimatani K, Nakashima Y, Hattori M, Hamazaki Y, Minato N (September 2009). "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. Bibcode:2009PNAS..10615807S. doi:10.1073/pnas.0908805106. PMC 2739871. PMID 19805226.
  45. ^ Henson SM, Lanna A, Riddell NE, Franzese O, Macaulay R, Griffiths SJ, et al. (September 2014). "p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8⁺ T cells". The Journal of Clinical Investigation. 124 (9): 4004–4016. doi:10.1172/JCI75051. PMC 4151208. PMID 25083993.
  46. ^ Tahir S, Fukushima Y, Sakamoto K, Sato K, Fujita H, Inoue J, et al. (June 2015). "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. doi:10.4049/jimmunol.1500319. hdl:2433/202671. PMID 25972477. S2CID 12736294.
  47. ^ Wang YH, Yu XH, Luo SS, Han H (2015-10-08). "Comprehensive circular RNA profiling reveals that circular RNA100783 is involved in chronic CD28-associated CD8(+)T cell ageing". Immunity & Ageing. 12 (1): 17. doi:10.1186/s12979-015-0042-z. PMC 4597608. PMID 26451160.
  48. ^ Schulz AR, Mälzer JN, Domingo C, Jürchott K, Grützkau A, Babel N, et al. (November 2015). "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. doi:10.4049/jimmunol.1500598. PMID 26459351. S2CID 24146051.
  49. ^ Fuertes Marraco SA, Soneson C, Cagnon L, Gannon PO, Allard M, Abed Maillard S, et al. (April 2015). "Long-lasting stem cell-like memory CD8+ T cells with a naïve-like profile upon yellow fever vaccination". Science Translational Medicine. 7 (282): 282ra48. doi:10.1126/scitranslmed.aaa3700. PMID 25855494. S2CID 21394251.
  50. ^ Chambers ES, Akbar AN (2020). "Can blocking inflammation enhance immunity during aging?". The Journal of Allergy and Clinical Immunology. 145 (5): 1323–1331. doi:10.1016/j.jaci.2020.03.016. PMID 32386656.
  51. ^ Kim MJ, Miller CM, Shadrach JL, Wagers AJ, Serwold T (May 2015). "Young, proliferative thymic epithelial cells engraft and function in aging thymuses". Journal of Immunology. 194 (10): 4784–4795. doi:10.4049/jimmunol.1403158. PMC 4481326. PMID 25870244.
  52. ^ Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA (June 2016). "Metformin as a Tool to Target Aging". Cell Metabolism. 23 (6): 1060–1065. doi:10.1016/j.cmet.2016.05.011. PMC 5943638. PMID 27304507.
  53. ^ Kane DA, Anderson EJ, Price JW, Woodlief TL, Lin CT, Bikman BT, et al. (September 2010). "Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats". Free Radical Biology & Medicine. 49 (6): 1082–1087. doi:10.1016/j.freeradbiomed.2010.06.022. PMC 2921476. PMID 20600832.
  54. ^ El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X (January 2000). "Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I". The Journal of Biological Chemistry. 275 (1): 223–228. doi:10.1074/jbc.275.1.223. PMID 10617608.
  55. ^ Madiraju AK, Qiu Y, Perry RJ, Rahimi Y, Zhang XM, Zhang D, et al. (September 2018). "Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo". Nature Medicine. 24 (9): 1384–1394. doi:10.1038/s41591-018-0125-4. PMC 6129196. PMID 30038219.
  56. ^ Rajman L, Chwalek K, Sinclair DA (March 2018). "Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence". Cell Metabolism. 27 (3): 529–547. doi:10.1016/j.cmet.2018.02.011. PMC 6342515. PMID 29514064.
  57. ^ Popovich IG, Anisimov VN, Zabezhinski MA, Semenchenko AV, Tyndyk ML, Yurova MN, Blagosklonny MV (May 2014). "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. doi:10.4161/cbt.28164. PMC 4026081. PMID 24556924.
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