Investigating the Aging of the Lymphatic System
This open access paper describes detrimental age-related changes in the lymphatic system that involve disruption of the extracellular matrix and inflammation-associated biochemistry, something that suggests the involvement of senescent cells. Like old blood vessels, lymph vessels become leaky and less capable with age:
The lymphatic system comprises blunt-ended lymphatic capillaries, collecting lymphatic vessels, lymph nodes, and the thoracic duct. The role of lymphatic vessels is to transport fluid, soluble molecules, and immune cells to the draining lymph nodes. Here, we analyze how the aging process affects the functionality of the lymphatic collectors and the dynamics of lymph flow. Our ultrastructural and proteomic analysis indicated a loss of the basal membrane and the extracellular matrix supporting the lymphatic endothelial cells as well as the proteins related to GAP junction formation. Functionally, the aged lymphatic vessels were impaired in their ability to actively support lymph flow. Significant reduction in pumping indices, including amplitude, frequency, and fractional pump flow, were observed. Under resting conditions these changes can generate low level of tissue edema, particularly when associated with increased vessel permeability as also observed in this study. However, in pathological conditions, such as acute and chronic inflammation, the increased volumetric loads imposed on the lymphatic collectors could further enhance their impaired ability to support the lymph flow.A reduced thickness in the glycocalyx, with increased protein glycation and oxidation, was also observed. These modifications help explain the increased permeability observed in the aged collectors. Functionally, these modifications translate into apparent hyperpermeability of the lymphatics with pathogen escaping from the collectors into the surrounding tissue and a decreased ability to control tissue fluid homeostasis. Microvascular dysfunction with hyperpermeability was also previously observed in aged blood vessels and was attributed to oxidative stress, inflammation, and activation of apoptotic signaling. Likely, the same mechanism contributes to the hyperpermeability observed in the aged lymphatic collectors. Indeed, analysis confirmed the presence of posttranslational modifications associated with oxidative stress. These modifications can alter proteins half-life, increase protein degradation, and decrease cellular functionality. Indeed, several of the collagen proteins as well as cadherins and GAP junction proteins were decreased in aging collectors. Disruption of these proteins was previously observed to be associated with paracellular permeability in blood capillaries. Similarly, we observed endothelial cells barrier dysfunction and increased permeability in aged lymphatic collectors. Functionally, the ability of pathogens to more readily escape the aged lymphatic collectors would contribute to the decreased ability of the immune system to control infections in aging. Indeed, decreased lymph transport to the lymph nodes is associated with an increase in the number of tissue colony-forming units.