An overly simplistic view of the lymphatic system is that it is network of highways and collaboration centers for the cells of the immune system. Immune cells use lymphatic vessels to travel about the body, while the hundreds of lymph nodes scattered throughout the lymphatic system are important locations at which immune cells exchange information about signatures of infection and damage, managing the immune response. Like all tissues, lymph nodes are structured in certain ways, and that structure is degraded by the processes of aging. Lymph nodes become fibrotic, for example, and these changes impede the activities of immune cells.
There is evidence to suggest that the degenerative aging of lymph nodes places limits on the ability of the immune system to respond effectively to threats, distinctly from other causes of immune aging. For example, a study of thymic regrowth in very old animals showed that the additional T cells produced in a regrown thymus did not lead to an improved immune response to infectious disease. That work implicated lymph node dysfunction as the cause of this undesirable outcome. Interestingly, cellular senescence is implicated in the fibrosis found disrupting the structure of aged lymph nodes; a study on whether senolytic treatments, aimed at removing those senescent cells, could help to reverse some of the detrimental changes that take place in lymph nodes might produce interesting results.
Even during healthy aging, the functions of the immune system may be weakened by a process known as immunosenescence. Immunosenescence and inflammaging are responsible for the increasing incidence of infections, autoimmune diseases, and neoplasms in the population over 65. Older adults also show weaker responses to vaccination than younger ones. Aging causes adverse changes in the innate and adaptive parts of the immune system, the microenvironment of lymphoid organs where immune cells develop and reside, and the equilibrium of soluble chemokines and cytokines, all responsible for the functioning and homeostasis of the immune system. Aging-associated changes in the primary lymphoid organs, i.e., bone marrow and thymus, have been thoroughly characterized; however, data on aging of the secondary lymphoid organs, e.g., lymph nodes, is still incomplete and requires extensive discussion.
Lymph nodes play a pivotal role in the innate and adaptive immune response to natural antigens and vaccines. Lymphatic vessels direct lymph from the tissues to the lymph nodes scattered throughout the body. As lymph passes through the lymph node parenchyma, antigens come into contact with the effector cells of the adaptive immune system, initiating a cascade of immune processes that enable the recognition and neutralization of foreign antigens and pathogens. Immune cell migration to the lymph node in response to self or foreign antigens exposure relies on the coordinated functioning of adhesion molecules on the surface of leukocytes and venule endothelial cells. Such migration plays a fundamental role in regulating physiological processes, e.g., wound healing and angiogenesis, and pathological phenomena, e.g., inflammation and tumor cell filtration.
The number of lymph nodes in the human body ranges from 300 to 500, and their total weight is about 100 grams. Studies have shown that the number of nodes decreases with age, and aging-associated degenerative features emerge in the lymph nodes, such as fibrosis, lipomatosis, a reduction in the number of postcapillary vessels, and changes in the morphology and function of the specialized endothelial cells lining the venous capillaries. Consequently, the amount of lymphoid tissue in the cortical and medullary zones of lymph nodes is reduced, as is the number and size of germinal centers in lymphoid follicles. These changes result in a reduced reactivity to antigen challenge. The number of follicular dendritic cells also decreases, and the ability to uptake and retain immune complexes is significantly impaired. These deficits result in decreased humoral immunity associated with impaired antibody production in the elderly and an increased susceptibility to infections, one of the leading causes of morbidity and mortality in people over 65
The aging of lymph nodes results in decreased cell transport to and within the nodes, a disturbance in the structure and organization of nodal zones, incorrect location of individual immune cell types and impaired intercellular interactions, as well as changes in the production of adequate amounts of chemokines and cytokines necessary for immune cell proliferation, survival and function, impaired naïve T-cell and B-cell homeostasis, and a diminished long-term humoral response. Understanding the causes of these stromal and lymphoid microenvironment changes in the lymph nodes that cause the aging-related dysfunction of the immune system can help to improve long-term immune responses and the effectiveness of vaccines in the elderly.
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