The Atrophy of Lymph Nodes with Age Negatively Impacts Immune Function
The lymphatic system allows rapid transit of large numbers of immune cells throughout the body. Scattered through this system of lymphatic vessels are the lymph nodes. Lymph nodes are vital to the function of the immune system, acting as meeting places where immune cells can communicate to effectively coordinate the response to pathogens. With age, lymph node structure begins to break down, however, becoming fibrotic, or the active tissue replaced by fat. Researchers have shown that this is an obstacle to rejuvenation of the adaptive immune system; one can regrow the atrophied thymus to provide a supply of new T cells, but without a fully functioning lymphatic system, the immune response is not properly coordinated.
Replacement of lymph nodes is a possibility, and it has been demonstrated that suitable organoids or other structures will produce new lymph nodes when implanted into the body. It is an open question as to whether this would work well in older individuals, in an aged tissue environment, however. Forms of regenerative therapy based on adjusting the signals controlling growth in lymphatic tissue, analogous to the approaches that can be used to regrow an atrophied thymus in animal studies, may be the better way forward. Little work has taken place in this part of the field, however. It is only comparatively recently that a broader recognition of the importance of lymph node aging has emerged.
How fat takes over the lymph nodes as we age
As we age, the normal tissue in the lymph nodes (the stroma) is gradually replaced by adipose tissue (fat). The phenomenon is known as lymph node lipomatosis. Although lipomatosis is very common and increases with age, researchers have previously devoted very little discussion and research to it. By careful analysis of more than 200 lymph nodes, researchers have demonstrated that lipomatosis begins in the central part of the lymph node, known as the medulla, and presents evidence linking lipomatosis to the transformation of the supporting cells of lymph nodes (fibroblasts) into adipocytes (fat cells). They also show that specific types of fibroblasts located in the medulla are more prone to become adipocytes.
The study shows that even at early stages of lipomatosis, negative changes arise that impair the ability of the lymph node to provide effective immunity. Among other observations, they note that the specialised blood and lymphatic vessels that normally provide channels for immune cells to enter and leave the lymph node are destroyed in the parts of the node where fat has formed. Lipomatosis of lymph nodes, even at early stages, may therefore be one important factor behind the poorer response to vaccinations observed in elderly people. Ultimately, the fat completely takes over the lymph node and it loses its ability to function.
Lymph node (LN) lipomatosis is a common but rarely discussed phenomenon associated with aging that involves a gradual exchange of the LN parenchyma into adipose tissue. The mechanisms behind these changes and the effects on the LN are unknown. We show that LN lipomatosis starts in the medullary regions of the human LN and link the initiation of lipomatosis to transdifferentiation of LN fibroblasts into adipocytes. The latter is associated with a downregulation of lymphotoxin beta expression. We also show that isolated medullary and CD34+ fibroblasts, in contrast to the reticular cells of the T-cell zone, display an inherently higher sensitivity for adipogenesis.
Progression of lipomatosis leads to a gradual loss of the medullary lymphatic network, but at later stages, collecting-like lymphatic vessels are found inside the adipose tissue. The stromal dysregulation includes a dramatic remodeling and dilation of the high endothelial venules associated with reduced density of naïve T-cells. Abnormal clustering of plasma cells is also observed. Thus, LN lipomatosis causes widespread stromal dysfunction with consequences for the immune contexture of the human LN. Our data warrant an increased awareness of LN lipomatosis as a factor contributing to decreased immune functions in the elderly and in disease.