Immunosenescence

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 [ cite journal|title=Local and systemic immune response in nursing-home elderly following intranasal or intramuscular immunization with inactivated influenza vaccine|journal=Vaccine|date=2003|first=M|last=Muszkat|coauthors=E. Greenbaum, A. Ben-Yehuda, M. Oster, E. Yeu'l, S. Heimann, R. Levy, G. Friedman, and Z. Zakay-Rones|volume=21|issue=|pages=1180–1186|id= |url=|format=|accessdate=|doi=10.1016/S0264-410X(02)00481-4 ] . 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 [ cite journal|title=Immunosenescence and infectious diseases|journal=Microbes and Infection|date=2001|first=L.|last=Ginaldi|coauthors=M.F. Loreto, M.P. Corsi, M. Modesti, and M. de Martinis|volume=3|issue=|pages=851–857 |id= |url=|format=|accessdate=|doi=10.1016/S1286-4579(01)01443-5 ] . 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 [ cite journal|title=Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load|journal=Experimental gerontolgy|date=1999|first=C.|last=Franceschi |coauthors=S. Valensin, F. Fagnoni, C. Barbi and M. Bonafe|volume=34|issue=|pages=911–921|id= |url=|format=|accessdate=|doi=10.1016/S0531-5565(99)00068-6 ] . 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 [ cite journal|title=Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space|journal=Vaccine|date=2000|first=C.|last=Franceschi|coauthors=M. Bonafè and S. Valensin|volume=18|issue=|pages=1717–1720|id= |url=|format=|accessdate=|doi=10.1016/S0264-410X(99)00513-7 ] .

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 [ cite journal|title=Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells|journal=Nature|date=2004|first=K|last=Ito|coauthors=A. Hirao, F. Arai, S. Matsuoka, K. Takubo, I. Hamaguchi, K. Nomiyama, K. Hosokawa, K. Sakurada, N. Nakagata, Y. Ikeda, T. W. Mak, and T. Suda.|volume=431|issue=|pages=997–1002 |id= |url=|format=|accessdate=|doi=10.1038/nature02989 ] 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 [ cite journal|title=Neutrophil ageing and immunesenescence|journal=Mech Ageing Dev|date=2001|first=J.M.|last=Lord|coauthors=S. Butcher, V. Killampali, D. Lascelles, and M. Salmon|volume=122|issue=|pages=1521–1535|id= |url=|format=|accessdate=|doi=10.1016/S0047-6374(01)00285-8 ] [ cite journal|title=Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes|journal=Immunol Rev|date=2005|first=R.D.|last=Strout|coauthors=J. Suttles.|volume=205|issue=|pages=60–71|id= |url=|format=|accessdate=|doi=10.1111/j.0105-2896.2005.00260.x ] .
* The cytotoxicity of Natural Killer (NK) cells and the antigen-presenting function of dendritic cells is known to diminish with old age [ cite journal|title=Decreased natural killer cell activity is associated with atherosclerosis in elderly humans|journal=Exp Gerontol|date=2001|first=H.|last=Bruunsgaard|coauthors=A. N. Pedersen, M. Schroll, P. Skinhoj, and B. K. Pedersen.|volume=37|issue=|pages=127–136|id= |url=|format=|accessdate=|doi=10.1016/S0531-5565(01)00162-0 ] [ cite journal|title=NK and NKT cell functions in immunosenescence|journal=Aging Cell|date=2004|first=E|last=Mocchegiani|coauthors=M. Malavolta|volume=3|issue=|pages=177–184|id= |url=|format=|accessdate=|doi=10.1111/j.1474-9728.2004.00107.x ] [ cite journal|title=The frail elderly: role of dendritic cells in the susceptibility of infection|journal=Mech Ageing Dev|date=2002|first=K.|last=Uyemura|coauthors=S. C. Castle, and T. Makinodan|volume=123|issue=|pages=955–962|id= |url=|format=|accessdate=|doi=10.1016/S0047-6374(02)00033-7 ] . 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 [ cite journal|title=Enhanced differentiation of splenic plasma cells but diminished long-lived high-affinity bone marrow plasma cells in aged mice|journal=J Immunol|date=2003|first=S.|last=Han|coauthors=K. Yang, Z. Ozen, W. Peng, E. Marinova, G. Kelsoe, and B. Zheng|volume=170|issue=|pages=1267–1273|id= |url=|format=|accessdate= ] .

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 and autoimmunity [ cite journal|title=Immunosenescence: deficits in adaptive immunity in elderly|journal=Tissue antigens|date=2007|first=F.T.|last=Hakim|coauthors=R.E. Gress|volume=70|issue=|pages=179–189|id= |url=|format=|accessdate=|doi=10.1111/j.1399-0039.2007.00891.x ] . 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 [ cite journal|title=Immunosenescence and infectious diseases|journal=Microbes and Infection|date=2001|first=L.|last=Ginaldi|coauthors=M.F. Loreto, M.P. Corsi, M. Modesti, and M. de Martinis|volume=3|issue=|pages=851–857 |id= |url=|format=|accessdate=|doi=10.1016/S1286-4579(01)01443-5 ] . 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 [ cite journal|title=Inflamm-aging: An Evolutionary Perspective on Immunosenescence|journal=Annals of the New York Academy of Sciences|date=2000|first=C.|last=Franceschi|coauthors=M. Bonafe, S. Valensin, F. Olivieri, M. de Luca, E. Ottaviani and G. de Benedictis|volume=908|issue=|pages=244–254|id= |url=|format=|accessdate= ] . 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 [ cite journal|title=Immunosenescence : a problem of lymphoiesis, homeostatis, microenvironment and signalling|journal=Immunological reviews|date=2005|first=J.|last=Cambier|coauthors=|volume=205|issue=|pages=5–6|id= |url=|format=|accessdate=|doi=10.1111/j.0105-2896.2005.00276.x ] .

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 [ cite journal|title=T cell function in the aged: Lessons learned from animal models|journal=Clinical and Applied Immunology Reviews|date=2006|first=P.-J|last=Linton|coauthors=J. Lustgarten, and M. Thoman|volume=6|issue=|pages=73–97|id= |url=|format=|accessdate=|doi=10.1016/j.cair.2006.06.001 ] . 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/exhausion on the number of thymocytes (i.e. pre-mature T-cells), thus reducing output of peripheral naïve T-cells [ cite journal|title=Thymic involution in aging|journal=J Clin Immunol|date=2000|first=R.|last=Aspinall|coauthors=D. Andrew|volume=20|issue=|pages=250–256|id= |url=|format=|accessdate=|doi=10.1023/A:1006611518223 ] [ cite journal|title=Reduction in the developmental potential of intrathymic T cell progenitors with age|journal=J Immunol|date=2004|first=H.|last=Min|coauthors=E. Montecino-Rodriguez, and K. Dorshkind|volume=173|issue=|pages=245–250|id= |url=|format=|accessdate= ] . 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 [ cite journal|title=Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space|journal=Vaccine|date=2000|first=C.|last=Franceschi|coauthors=M. Bonafè and S. Valensin|volume=18|issue=|pages=1717–1720|id= |url=|format=|accessdate=|doi=10.1016/S0264-410X(99)00513-7 ] . T-cell components associated with immunosenescence include:
* deregulation of intracellular signal transduction capabilities [ cite journal|title=Age-related impairment of p56lck and ZAP-70 activities in human T lymphocytes activated through the TcR/CD3 complex|journal=Exp Gerontol|date=1999|first=T., Jr.|last=Fulop|coauthors=D. Gagne, A. C. Goulet, S. Desgeorges, G. Lacombe, M. Arcand, and G. Dupuis|volume=34|issue=|pages=197–216|id= |url=|format=|accessdate=|doi=10.1016/S0531-5565(98)00061-8 ]
* diminished capacity to produce effector lymphokines [ cite journal|title=Impaired immune response to Candida albicans in aged mice|journal=J Med Microbiol|date=2006|first=C.|last=Murciano|coauthors=E. Villamon, A. Yanez, J. E. O'Connor, D. Gozalbo, and M. L. Gil|volume=55|issue=|pages=1649–1656|id= |url=|format=|accessdate=|doi=10.1099/jmm.0.46740-0 ] [ cite journal|title=Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1)|journal=Blood|date=2002|first=D.|last=Voehringer|coauthors=M. Koschella, and H. Pircher|volume=100|issue=|pages=3698–3702|id= |url=|format=|accessdate=|doi=10.1182/blood-2002-02-0657 ] [ cite journal|title=Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1)|journal=Exp Gerontol|date=2003|first=Q.|last=Ouyang|coauthors=W. M. Wagner, D. Voehringer, A. Wikby, T. Klatt, S. Walter, C. A. Muller, H. Pircher, and G. Pawelec|volume=38|issue=|pages=911–920|id= |url=|format=|accessdate=|doi=10.1016/S0531-5565(03)00134-7 ]
* shrinkage of antigen-recognition repertoire of T-cell receptor (TcR) diversity [ cite journal|title=The influence of age on T cell generation and TCR diversity|journal=J Immunol|date=2005|first=K.|last=Naylor|coauthors=G. Li, A. N. Vallejo, W. W. Lee, K. Koetz, E. Bryl, J. Witkowski, J. Fulbright, C. M. Weyand, and J. J. Goronzy|volume=174|issue=|pages=7446–7452|id= |url=|format=|accessdate= ] [ cite journal|title=Aging of the immune system: how much can the adaptive immune system adapt?|journal=Immunity|date=2006|first=N. P. |last=Weng|coauthors=|volume=24|issue=|pages=495–499|id= |url=|format=|accessdate=|doi=10.1016/j.immuni.2006.05.001 ]
* cytotoxic activity of Natural Killer T-cells (NKTs) decreases [ cite journal|title=NK and NKT cell functions in immunosenescence|journal=Aging Cell|date=2004|first=E|last=Mocchegiani|coauthors=M. Malavolta|volume=3|issue=|pages=177–184|id= |url=|format=|accessdate=|doi=10.1111/j.1474-9728.2004.00107.x ]
* impaired proliferation in response to antigenic stimulation [ cite journal|title=Impaired immune response to Candida albicans in aged mice|journal=J Med Microbiol|date=2006|first=C.|last=Murciano|coauthors=E. Villamon, A. Yanez, J. E. O'Connor, D. Gozalbo, and M. L. Gil|volume=55|issue=|pages=1649–1656|id= |url=|format=|accessdate=|doi=10.1099/jmm.0.46740-0 ] [ cite journal|title=The influence of age on T cell generation and TCR diversity|journal=J Immunol|date=2005|first=K.|last=Naylor|coauthors=G. Li, A. N. Vallejo, W. W. Lee, K. Koetz, E. Bryl, J. Witkowski, J. Fulbright, C. M. Weyand, and J. J. Goronzy|volume=174|issue=|pages=7446–7452|id= |url=|format=|accessdate= ] [ cite journal|title=Aging of the immune system: how much can the adaptive immune system adapt?|journal=Immunity|date=2006|first=N. P. |last=Weng|coauthors=|volume=24|issue=|pages=495–499|id= |url=|format=|accessdate=|doi=10.1016/j.immuni.2006.05.001 ] [ cite journal|title=Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1)|journal=Blood|date=2002|first=D.|last=Voehringer|coauthors=M. Koschella, and H. Pircher|volume=100|issue=|pages=3698–3702|id= |url=|format=|accessdate=|doi=10.1182/blood-2002-02-0657 ]
* the accumulation and the clonal expansion of memory and effector T-cells [ cite journal|title=Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1)|journal=Blood|date=2002|first=D.|last=Voehringer|coauthors=M. Koschella, and H. Pircher|volume=100|issue=|pages=3698–3702|id= |url=|format=|accessdate=|doi=10.1182/blood-2002-02-0657 ] [ cite journal|title=Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load|journal=Experimental gerontolgy|date=1999|first=C.|last=Franceschi |coauthors=S. Valensin, F. Fagnoni, C. Barbi and M. Bonafe|volume=34|issue=|pages=911–921|id= |url=|format=|accessdate=|doi=10.1016/S0531-5565(99)00068-6 ]
* hampered immune defences against viral pathogens, especially by cytotoxic CD8+ T cells [ cite journal|title=Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1)|journal=Exp Gerontol|date=2003|first=Q.|last=Ouyang|coauthors=W. M. Wagner, D. Voehringer, A. Wikby, T. Klatt, S. Walter, C. A. Muller, H. Pircher, and G. Pawelec|volume=38|issue=|pages=911–920|id= |url=|format=|accessdate=|doi=10.1016/S0531-5565(03)00134-7 ]
* changes in cytokine profile e.g. increased pro-inflammatory cytokines "milieu" present in the elderly [ cite journal|title=Aging and the skin immune system|journal=Archives of dermatology|date=1997|first=C.|last=Suderkotter|coauthors=H. Kalden|volume=133|issue=|pages=1256–1262 |id= |url=|format=|accessdate=|doi=10.1001/archderm.133.10.1256 ]

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