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Immunosenescence is the gradual deterioration of the immune system, brought on by natural age advancement. Generally, it is believed 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. This age-associated immune deficiency is found in both long- and short-living species as a function of their age relative to life expectancy rather than chronological time.[2] It has been studied in various animal models such mice, marsupials and monkeys.[3][4][5] It is considered a major contributory factor to the increased frequency of morbidity and mortality among the elderly. Besides anergy and T-cell exhaustion, immunosenescence belongs among the major immune system dysfunctional states. However, while T-cell anergy or exhaustion are reversible condition, immunosenescence is believed to be a state that can not be reversed.[6][7]

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.[8] 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.[9]

Age-associated decline in immune function[edit]

Aging of the immune system is a controversial phenomenon. Senescence in the term immunosenescence 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 eventually degenerate in their functional properties.[10] However, an immunological term "immunosenescence" generally means a robust shift in both the structural and functional parameters of the immune cells that has a clinically relevant outcome.[10] Thymus involution is probably the most relevant factor responsible for immunosenescence. Involution of the thymus is common in most mammals and in humans it begins after puberty, as the immunological defense against most of the novel antigens is necessary mainly during infancy and childhood.[11]

The major characteristic of the immunosenescent phenotype is a shift in the T-cell subpopulation counts. As the thymus involutes with advanced age, the number of naive T cells (especially CD8+) decreases, thus naive T cells homeostatically proliferate into a late-stage (memory) T cells as a compensation for the cell loss.[5] It is believed that the progression of the conversion to memory phenotype can be accelerated by restimulation of the immune system by persistent pathogens causing lifelong infections 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 it seems that the CD8+ T-cell precursors, specific for the most rare and less frequently present antigens do shed the most.[5] However, such shift in T-cell counts leads to the increased susceptibility to non-persistent infection, cancer, autoimmune diseases, cardiovascular health conditions and many others.[12][13]

Nevertheless, 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.[23] 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.[24]

T-cell biomarkers of age-dependent dysfunction[edit]

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.[25] 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 the decrease of IL-2 production[26][27] and reduction/exhaustion on the number of thymocytes (i.e. pre-mature T cells), thus reducing output of peripheral naïve T cells.[28][29] 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.[9]

Research challenges of immunosenescence[edit]

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.[2] This causes problems in diagnosis and treatment.

Vaccination in the elderly[edit]

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 function of dendritic cells.[46] Therefore, the immunization with novel antigens in an earlier life stages seems to be more reasonable but, on the other hand, the lifetime of the established memory differ from a pathogen to the other one.[47][10]

Rescue of the advanced-age phenotype[edit]

As mentioned above, immunosenescence is a complex and spontaneous process, in which various cell subtypes participate. However, the reduced T cell output resulting from involution of the thymus seems to carry the greatest importance.[28] Therefore, 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 to aged or defective thymus.[48] Clinically important seems to be an antidiabetic drug Metformin that has been proven to moderate aging in preclinical studies.[49] Its aging protective effect is probably caused primarily by impaired mitochondria metabolism, particularly decreased reactive oxygen production[50] or increased AMP:ATP ratio[51] and lower NAD/NADH ratio. Also coenzyme NAD+ has shown to be reduced in various tissues in age-dependent manner, and thus redox potential associated changes seems to be critical in process of aging,[52] and NAD+ including supplements may have a protective effects.[53] Similarly works an antitumor and immunosuppressive substance Rapamycin.[54]


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