Immunosenescence refers to the gradual deterioration of the immune system brought on by natural age advancement. It involves both the host’s capacity to respond to infections and the development of long-term immune memory, especially by vaccination. This age-associated immune deficiency is ubiquitous and found in both long- and short-living species as a function of their age relative to life expectancy rather than chronological time. It is considered a major contributory factor to the increased frequency of morbidity and mortality among the elderly.
Immunosenescence is not a random deteriorative phenomenon, rather it appears to inversely repeat an evolutionary pattern and most of the parameters affected by immunosenescence appear to be under genetic control. Immunosenescence can also be sometimes envisaged as the result of the continuous challenge of the unavoidable exposure to a variety of antigens such as viruses and bacteria.
Overview of the age-associated decline in immune function
Immunosenescence is a multifactorial condition leading to many pathologically significant health problems in the aged population. Some of the age-dependent biological changes that contribute to the onset of immunosenescence are listed below:
- Hematopoietic stem cells (HSC), which provide the regulated lifelong supply of leukocyte progenitors that are in turn able to differentiate into a diversity of specialised immune cells (including lymphocytes, antigen-presenting dendritic cells and phagocytes) diminish in their self-renewal capacity. This is due to the accumulation of oxidative damage to DNA by aging and cellular metabolic activity and the shortening of telomeric terminals of chromosomes.
- There is a notable decline in the total number of phagocytes in aged hosts, coupled with an intrinsic reduction of their bactericidal activity.
- The cytotoxicity of Natural Killer (NK) cells and the antigen-presenting function of dendritic cells is known to diminish with old age. The age-associated impairment of dendritic Antigen Presenting Cells (APCs) has profound implications as this translates into a deficiency in cell-mediated immunity and thus, the inability for effector T-lymphocytes to modulate an adaptive immune response (see below).
- A decline in humoral immunity caused by a reduction in the population of antibody producing B-cells along with a smaller immunoglobulin diversity and affinity.
As age advances, there is decline in both the production of new naive lymphocytes and the functional competence of memory cell populations. This has been implicated in the increasing frequency and severity of diseases such as cancer, chronic inflammatory disorders, breakthrough infections and autoimmunity. A problem of infections in the elderly is that they frequently present with non-specific signs and symptoms, and clues of focal infection are often absent or obscured by underlying chronic conditions. Ultimately, this provides problems in diagnosis and subsequently, treatment.
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. It should be further noted that changes in the lymphoid compartment is not solely responsible for the malfunctioning of the immune system in the elderly. Although myeloid cell production does not seem to decline with age, macrophages become dysregulated as a consequence of environmental changes.
T-cell functional dysregulation as a biomarker for immunosenescence
The functional capacity of T-cells is most influenced by the effects of aging. In fact, age-related alterations are evident in all stages of T-cell development, making them a significant factor in the development of immunosenescence. After birth, the decline of T-cell function begins with the progressive involution of the thymus, which is the organ essential for T-cell maturation following the migration of precursor cells from the bone marrow. This age-associated decrease of thymic epithelial volume results in a reduction/exhaustion on the number of thymocytes (i.e. pre-mature T-cells), thus reducing output of peripheral naïve T-cells. Once matured and circulating throughout the peripheral system, T-cells still undergo deleterious age-dependent changes. Together with the age-related thymic involution, and the consequent age-related decrease of thymic output of new T cells, this situation leaves the body practically devoid of virgin T cells, which makes the body more prone to a variety of infectious and non-infectious diseases. T-cell components associated with immunosenescence include:
- reduction in the CD4+/CD8+ ratio
- impaired development of CD4+ T follicular helper cells, which are specialized in facilitating peripheral B cell maturation, and the generation of antibody-producing plasma cells and memory B cells
- deregulation of intracellular signal transduction capabilities
- diminished capacity to produce effector lymphokines
- shrinkage of antigen-recognition repertoire of T-cell receptor (TcR) diversity
- cytotoxic activity of Natural Killer T-cells (NKTs) decreases
- impaired proliferation in response to antigenic stimulation
- the accumulation and the clonal expansion of memory and effector T-cells
- hampered immune defences against viral pathogens, especially by cytotoxic CD8+ T cells
- changes in cytokine profile e.g. increased pro-inflammatory cytokines milieu present in the elderly
- Muszkat, M; E. Greenbaum; A. Ben-Yehuda; M. Oster; E. Yeu'l; S. Heimann; R. Levy; G. Friedman; Z. Zakay-Rones (2003). "Local and systemic immune response in nursing-home elderly following intranasal or intramuscular immunization with inactivated influenza vaccine". Vaccine. 21 (11–12): 1180–1186. doi:10.1016/S0264-410X(02)00481-4. PMID 12559796.
- Ginaldi, L.; M.F. Loreto; M.P. Corsi; M. Modesti; M. de Martinis (2001). "Immunosenescence and infectious diseases". Microbes and Infection. 3 (10): 851–857. doi:10.1016/S1286-4579(01)01443-5. PMID 11580980.
- Franceschi, C.; S. Valensin; F. Fagnoni; C. Barbi; M. Bonafe (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.
- Franceschi, C.; M. Bonafè; S. Valensin (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.
- High frequency electromagnetic waves such as gamma and xrays can penetrate and damage DNA. Ito, K; A. Hirao; F. Arai; S. Matsuoka; K. Takubo; I. Hamaguchi; K. Nomiyama; K. Hosokawa; K. Sakurada; N. Nakagata; Y. Ikeda; T. W. Mak; T. Suda (2004). "Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells". Nature. 431 (7011): 997–1002. doi:10.1038/nature02989. PMID 15496926.
- Lord, J.M.; S. Butcher; V. Killampali; D. Lascelles; M. Salmon (2001). "Neutrophil ageing and immunesenescence". Mech Ageing Dev. 122 (14): 1521–1535. doi:10.1016/S0047-6374(01)00285-8. PMID 11511394.
- Strout, R.D.; J. Suttles (2005). "Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes". Immunol Rev. 205: 60–71. doi:10.1111/j.0105-2896.2005.00260.x. PMC 1201508. PMID 15882345.
- Bruunsgaard, H.; A. N. Pedersen; M. Schroll; P. Skinhoj; B. K. Pedersen (2001). "Decreased natural killer cell activity is associated with atherosclerosis in elderly humans". Exp Gerontol. 37 (1): 127–136. doi:10.1016/S0531-5565(01)00162-0. PMID 11738153.
- Mocchegiani, E; M. Malavolta (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.
- Uyemura, K.; S. C. Castle; T. Makinodan (2002). "The frail elderly: role of dendritic cells in the susceptibility of infection". Mech Ageing Dev. 123 (8): 955–962. doi:10.1016/S0047-6374(02)00033-7. PMID 12044944.
- Gibson, KL; Wu, Y-C; Barnett, Y; Duggan, O; Vaughan, R; Kondeatis, E; Nilsson, BO; Wikby, A; Kipling, D; Dunn-Walters, DK (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.
- Han, S.; K. Yang; Z. Ozen; W. Peng; E. Marinova; G. Kelsoe; B. Zheng (2003). "Enhanced differentiation of splenic plasma cells but diminished long-lived high-affinity bone marrow plasma cells in aged mice". J Immunol. 170 (3): 1267–1273. doi:10.4049/jimmunol.170.3.1267. PMID 12538685.
- Hakim, F.T.; R.E. Gress (2007). "Immunosenescence: deficits in adaptive immunity in elderly". Tissue Antigens. 70 (3): 179–189. doi:10.1111/j.1399-0039.2007.00891.x. PMID 17661905.
- Haq, Kamran; McElhaney, Janet E (2014). "Immunosenescence: influenza vaccination and the elderly". Current Opinion in Immunology. 29: 38–42. doi:10.1016/j.coi.2014.03.008. PMID 24769424.
- Franceschi, C.; M. Bonafe; S. Valensin; F. Olivieri; M. de Luca; E. Ottaviani; G. de Benedictis (2000). "Inflamm-aging: An Evolutionary Perspective on Immunosenescence". Annals of the New York Academy of Sciences. 908: 244–254. doi:10.1111/j.1749-6632.2000.tb06651.x. PMID 10911963.
- Cambier, J. (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.
- Linton, P.-J; J. Lustgarten; M. Thoman (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.
- Aspinall, R.; D. Andrew (2000). "Thymic involution in aging". J Clin Immunol. 20 (4): 250–256. doi:10.1023/A:1006611518223. PMID 10939712.
- Min, H.; E. Montecino-Rodriguez; K. Dorshkind (2004). "Reduction in the developmental potential of intrathymic T cell progenitors with age". J Immunol. 173 (1): 245–250. doi:10.4049/jimmunol.173.1.245. PMID 15210781.
- Hadrup SR, Strindhall J, Køllgaard T, Seremet T, Johansson B, Pawelec G, thor Straten P, Wikby A (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.
- Lefebvre JS, Maue AC, Eaton SM, Lanthier PA, Tighe M, Haynes L (2012). "The aged microenvironment contributes to the age-related functional defects of CD4 T cells in mice". Aging Cell. 11 (5): 732–40. doi:10.1111/j.1474-9726.2012.00836.x. PMC 3444657. PMID 22607653.
- Fulop, T., Jr.; D. Gagne; A. C. Goulet; S. Desgeorges; G. Lacombe; M. Arcand; G. Dupuis (1999). "Age-related impairment of p56lck and ZAP-70 activities in human T lymphocytes activated through the TcR/CD3 complex". Exp Gerontol. 34 (2): 197–216. doi:10.1016/S0531-5565(98)00061-8. PMID 10363787.
- Murciano, C.; E. Villamon; A. Yanez; J. E. O'Connor; D. Gozalbo; M. L. Gil (2006). "Impaired immune response to Candida albicans in aged mice". J Med Microbiol. 55 (Pt 12): 1649–1656. doi:10.1099/jmm.0.46740-0. PMID 17108267.
- Voehringer, D.; M. Koschella; H. Pircher (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.
- Ouyang, Q.; W. M. Wagner; D. Voehringer; A. Wikby; T. Klatt; S. Walter; C. A. Muller; H. Pircher; G. Pawelec (2003). "Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1)". Exp Gerontol. 38 (8): 911–920. doi:10.1016/S0531-5565(03)00134-7. PMID 12915213.
- Naylor, K.; G. Li; A. N. Vallejo; W. W. Lee; K. Koetz; E. Bryl; J. Witkowski; J. Fulbright; C. M. Weyand; J. J. Goronzy (2005). "The influence of age on T cell generation and TCR diversity". J Immunol. 174 (11): 7446–7452. doi:10.4049/jimmunol.174.11.7446. PMID 15905594.
- Weng, N. P. (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.
- Suderkotter, C.; H. Kalden (1997). "Aging and the skin immune system". Archives of Dermatology. 133 (10): 1256–1262. doi:10.1001/archderm.133.10.1256. PMID 9382564.