The lymphatic system a part of the broader circulatory system and has many similarities to the cardiovascular system of blood vessels. The lymphatic system is also a network of vessels, transporting various necessary cells and substances, and subject to processes of aging that degrade function and thereby cause issues. While circulation of fluid is an important function of the lymphatic system, and conditions such as lymphedema arise when it runs awry, the role of lymphatic vessels in the function of the immune system is arguably far more vital.
Immune cells must be able to rapidly travel the body and locally coordinate with one another in order to mount an effective immune response. The lymphatic system links repositories of immune cells, such as those of the spleen and thymus with tissues throughout the body. Lymphatic vessels also link the numerous lymph nodes of the body, where immune cells gather to secrete and accept signals necessary to the correct function of the immune response.
With aging, lymph nodes in particular degenerate and become fibrotic, making it ever harder for immune cells to mount an acceptable defense against pathogens and cancers. The presence of senescent cells and the chronic inflammation they produce is thought to be important in this process, but it is likely one of a number of contributing factors. Further, lymphatic vessels suffer problems arising from loss of control over permeability, regarding what can pass through the vessel walls, as well as many of the same issues with stiffening that are seen in aged blood vessels. This latter problem results from processes such as cross-linking that reduces elasticity by restricting the motion of the complex molecules making up the extracellular matrix, and dysfunction of the smooth muscle tissue responsible for contraction and dilation. The latter degeneration is also in part a consequence of senescent cells and chronic inflammation, but mitochondrial dysfunction is also implicated - as demonstrated by the ability of NAD+ enhancement to improve matters in older patients.
The aging process induces changes in structure and function of lymphatic networks. Lymphatic-related diseases are prevalent in elderly, such as lymphedema. In 1960s, the specific "varicose bulges" in muscular lymphatic vessels were observed and this bulges were increased with age. Muscle cell atrophy, elastic elements destruction, and aneurysm-like formations were also found in aged lymphatic vessels. Aging associated alterations in lymphatic contractility decrease pump efficiency which result in excessive retention of tissue fluid within interstitial spaces.
Reduced responsiveness to inflammatory stimuli in aged lymphatic vessels decreases the normal capacity to react against foreign organisms. The occurrence of high permeability is caused by the loss of glycocalyx and the dysfunction of junctional proteins. In addition, increased caspase-3 activity, the dissociation of the VE-cadherin/catenin complex and the low expression of actin cytoskeleton that occur in aged blood vessels may also be seen in aged lymphatic vessels.
The lymphatic endothelial cell surface is covered by the glycocalyx layer on the lumen side. The glycocalyx functions as a barrier between lymphatic fluid and the endothelium to prevent immune cells and pathogens from adhering to the endothelium. A significant loss of glycocalyx with a reduction in thickness and destruction in continuity occurs in lymphatic endothelial membranes from aged rat. This observation was in contrast with the intact, continuous layer covering cell membranes from adult lymphatic vessels. The global proteomic analysis of ultrastructural changes of glycocalyx composition also demonstrated a dramatic difference between the adult and aged groups. The thin glycocalyx layer is impaired in its ability to limit certain pathogens from adhering to the endothelial cell membrane and becomes hyperpermeable in the lymphatic vessels from aged rats. Thus in aged lymphatic vessels, pathogens could escape more easily from the collectors into surrounding tissue, along with an increased leakage of lymph fluid and immune cells.
The effect of aging-related hyperpermeability is also observed in blood vessels. Adherens junctions consisting of vascular endothelial cadherin (VE-cadherin) and β-catenin maintain intercellular permeability in both blood vessels and lymphatic vessels. β-catenin, is an intracellular protein that links cadherin with the actin cytoskeleton. Studies have found that aging process may affect all of the adherens junctional proteins. First, global proteomic profiling of the lymphatic vessels from aged rats revealed a significant decrease in cadherins. The downregulation of cadherins expression results in a decreased number of adherens junction complexes. In contrast, β-catenin is a key regulator of barrier integrity and a known substrate for caspase 3, which is an effector caspase in the apoptotic signaling pathway.
Recent research found that increased activity of the intrinsic apoptotic signaling pathway in aged vessels leads to high expression of proapoptotic members (Bak, Bax). Caspase 3 is activated by Bak and mediates barrier dysfunction through the disruption of β-catenin. This series of reactions eventually causes dissociation of the VE-cadherin/β-catenin complex and results in vascular hyperpermeability.
In addition to adherens junctions, tight junctions are an equally important determinant of vascular permeability of blood vessels and lymphatic vessels. As part of the tight junction, occludin and claudin-5 showed significantly low expression level in senescent endothelial cells. We hypothesize that the mechanism of intercellular hyperpermeability caused by the disruption of endothelial cell-cell junctions in aged blood vessels may also exist in aged lymphatic collectors. Further investigations are needed to delineate the detailed mechanisms related to impaired barrier function in aged lymphatic vessels.