Thymus Atrophy and Other Changes in the Aging Immune System
... likely method would be to reverse the age-associated thymic involution. A current hypothesis is that age-associated thymic atrophy is caused by defects in the thymic microenvironment, which leads to a deficiency in interleukin-7 and that the provision of interleukin-7 can reverse thymic atrophy. This hypothesis is based on several studies, one of which tested mice, which were treated with anti-interleukin-7. The study showed that the mice treated with anti-interleukin-7 had thymus atrophy resembling that of old age. Interleukin-7 has also been shown to be a vital cytokine for T cell development. In another study aged mice were given interleukin-7 to see whether it affected their thymus condition [2]. Five days later the mice were examined and the treatment had dramatic effects on both thymic weight and the number of thymocytes. Thymic weight increased in the mice that were treated with interleukin-7 due to an approximate doubling in the total number of thymocytes. However by the sixth day the boost given to the thymus wore out. This suggests that to maintain the boost the treatment requires the continued presence of interleukin-7. Another study showed that the surface receptor Fas may have something to do with age-related thymic involution [13]. Fas is expressed in varius tissues including thymus, spleen, heart, lung, liver and ovary. High levels of Fas are also expressed on T and B lymphocytes. In the study the role of Fas in age-related thymic involution in mice was analyzed. Fas-/- mice, which were Fas-deficient, and wild-type mice, which had the same genetic background but were not Fas-deficient, were used for the study. The results supported the hypothesis that Fas is involved in thymic involution. At the age of 12 months the Fas-/- mice had normal thymi and did not show any accumulation of fatty substances. However wild-type mice of the same age had a greatly reduced thymus and a considerable amount of fatty tissue where the thymus used to be. Not only was the thymus retained in Fas-/- mice, the mice also had a normal intra-thymic structure. There was also a significant difference in the number of thymocytes in the thymus. Fas-/- mice has considerably larger numbers of thymocytes than their wild-type counter parts. Malnutrition can also play a very large role in the involution of the thymus. The correlation is so strong that the thymus can be used to measure the extent of malnutrition in a person. The involution of the thymus due to malnutrition is due to changes in the lymphoid compartment of the thymus [11]. Thymocyte depletion is a common result of acute and chronic malnutrition. This depletion results is a decreased number of immature CD4+CD8+ cells, a result similar to that of age-related thymic involution. This overall depletion has been shown to result from increases thymocyte death by apoptosis and decreased thymocyte proliferation. These changes in the thymus may be caused by a hormonal imbalance. Changes to the thymic microenvironment also occur during malnutrition. The overall volume of the epithelial tissue in the cortex and in the medulla is decrease. A study on mice associated the apoptosis and proliferation pattern described above with age [5]. The study measured this pattern in mice as they aged from 1 month to 7 months. They determined the proliferation index of the different parts of the thymus. The proliferation index of the peripheral cortex was 3.6 times higher in the younger mice and the proliferation index of the deep cortex was 5.8 times higher. The apoptotic index of the thymic cortex of the old mice was 66% higher than the younger mice. This data shows that with age the ratio of apoptosis and proliferation of thymocytes in the thymus change. As one ages the rate of proliferation decreases while the rate of apoptosis increases thereby causing the decrease of naïve T cells produced by the thymus. Thymus atrophy may also explain why females have a long life expectancy. A study in mice showed that in C57BL/10 animals, the thymus appeared to atrophy faster in males than in females [4]. This conclusion was derived by measuring the number of CD4+CD8+ immature thymocytes. Females had greater numbers of CD4+CD8+ immature thymocytes so one could conclude that their thymus has a greater output and had atrophied less. A study on humans compared 46 healthy volunteers [9]. In the study 21 males and 25 females, aged up to 62 years, provided peripheral blood. The study successfully showed that thymic output is prolonged at higher levels in females compared to males. However the difference becomes less apparent with age. Thymic output of both males and females eventually converge at similar values. The study also compared mortality rates over the age range of the study. They found that more males died of influenza and pneumonia than females, which followed the hypothesis of thymic output. A probable reason for faster atrophy in the thymus of males is due to testosterone. This also explains why the difference in thymic atrophy between males and females decline with age, since testosterone also declines with age in men. It is hard to distinguish age related changes to the humoral immune system because most of the functions of B cells are mediated by T cells. So it is unclear if the changes occur in the T cells or the B cells. However there is evidence that points to changes in the humoral immune system. B cells produce antibodies and display them on the surface. Antibodies on the surface act as receptors for a specific antigen. When an antigen binds, it goes through endocytosis and is degraded. The antigenic peptides are then displayed with the help of Class II MHC proteins. Helper T cells recognize this and stimulate B cells to proliferate and become antibody-secreting cells. With age the antibodies that are produced are less protective against foreign antigens and more likely to recognize self-antigens. This is the reason why vaccines do not induce the same response in the elderly as they do with younger patients. Even though the elderly have antibodies with lower affinity for foreign antigens, the number of antibodies produced by the elderly during an immune response is high. So even though the overall quantity of antibodies produced do not change, the quality of the antibodies are significantly diminished with age. The innate immune system also goes through some changes as the body ages. Dendritic cells are antigen presenting cells for CD4+ T-helper lymphocytes. They take up antigen and display it with class II MHC proteins. Studies have shown that dendritic cells migrate from the blood stream to the peripheral organs as the body ages [10]. This can reduce the ...