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 ^[1]. 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 ^[2]. It is considered a major contributory factor to the increased frequency of morbidity and mortality among the elderly.

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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 ^[3]. 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 ^[4].

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 ^[5] 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 ^[6][7].
• The cytotoxicity of Natural Killer (NK) cells and the antigen-presenting function of dendritic cells is known to diminish with old age ^[8][9][10]. 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 ^[11].

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 ^[12]. 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 ^[13]. 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 ^[14]. 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 ^[15].

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 ^[16]. 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 ^[17][18]. 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 ^[19]. T-cell components associated with immunosenescence include:

• deregulation of intracellular signal transduction capabilities ^[20]
• diminished capacity to produce effector lymphokines ^[21][22][23]
• shrinkage of antigen-recognition repertoire of T-cell receptor (TcR) diversity ^[24][25]
• cytotoxic activity of Natural Killer T-cells (NKTs) decreases ^[26]
• impaired proliferation in response to antigenic stimulation ^{[27][28][29][30]}
• the accumulation and the clonal expansion of memory and effector T-cells ^[31][32]
• hampered immune defences against viral pathogens, especially by cytotoxic CD8+ T cells ^[33]
• changes in cytokine profile e.g. increased pro-inflammatory cytokines milieu present in the elderly ^[34]

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