The Aging of Lymphatic Vessels

All of the the body's systems are impacted by aging. Damage to cells and tissues occurs as a consequences of the normal operation of metabolism, and leads to a chain of cause and consequence that ultimately produces functional declines and age-related disease. While the root cause of aging consists of only a few different forms of damage, how that damage then spreads into dysfunction is very different for every tissue and organ. Aging may have simple causes, but its progression is enormously complex and still far from completely mapped. Here, researchers review what is known of the aging of the lymphatic system. That there was a lack of detailed information until quite recently is not an unusual state of affairs, and is also the case for many other important systems in the body:

Lymph flow is necessary for vital functions, such as fluid and macromolecule homeostasis, absorption of lipids and transport of immune cells. All of these functions require proper functioning of the lymphatic vessels - their phasic contractions that propel lymph forward to central veins, proper permeability and interaction with cellular elements of the surrounding tissue microenvironment. Aging affects all of these functions of lymphatic vessels. However, despite findings of the last decades, our understanding of key regulatory mechanisms that support lymphatic vessel functions is still far from complete. The field of lymphatic biology has historically encountered difficulties in the assessment of lymphatic vessel function in vivo and in obtaining lymphatic vessels for studies in vitro. These difficulties have overlapped with an underappreciation of the importance of the lymphatic vascular component of the pathogenesis of various disorders in the past. Therefore, the lymphatic-related components in the pathogenesis of many diseases of the elderly remain to a large degree unknown.

Until the last decade, there were no published reports of systematic studies on aging-associated changes in the lymphatic vasculature. One study, published more than two decades ago, examined aging-associated changes in the structure of human lymphatic vessels. These authors demonstrated that in older humans, the destruction of the elastic elements and atrophy of muscle cells in the thoracic duct wall resulted in the development of "duct sclerosis." Investigations of the human mesenteric lymphatic bed demonstrated that after the age of 65, the number of collecting lymphatic vessels in the human mesentery was significantly reduced, and the number of connections between lymphatic vessels was greatly diminished. In some preparations of collecting lymphatic vessels, aneurism-like formations containing only endothelial cells in their walls were found, primarily in the areas located downstream but close to the lymphatic valves. Due to the profound difficulty of measuring lymph flow in vivo, there are only a few reports demonstrating measurements of reduced lymph flow in aged animals. In particular, it was reported that aging significantly reduced lymph flow from the main mesenteric lymph duct in rats by ~60% when compared between 3-month-old and 22-month-old animals.

Over the last decade, our group has performed a wide spectrum of studies significantly expanding our knowledge on how and by which mechanisms aging alters the structure and function of lymphatic vessels. These recent findings have led to a better understanding of the regulatory mechanisms of interactions between lymphatic vessels and mast cells (MCs) located in perilymphatic tissues, and demonstrated their importance for the control of all lymphatic functions mentioned above. We believe that these new discoveries provide the groundwork for a better understanding of the pathogenesis of many diseases in the elderly that involve a lymphatic component.

Our studies during the last decade have demonstrated that aging alters the structure and contractile function of lymphatic vessels. These changes are complex and predispose aged lymphatic vessels to diminished lymphatic contractility and lymph flow, especially during edemagenic challenges in the event of overlapping acute inflammation in the elderly. In addition, aging creates conditions for the easier spread of pathogens from lymphatic vessels into perilymphatic tissues. Aging induces the basal activation of perilymphatic MCs, which, in turn, restricts the recruitment/activation of several types of immune cells in perilymphatic tissues. Activated MCs trigger NF-κB signaling through the release of histamine. The aging-associated basal activation of MCs limits acute histamine-driven inflammatory NF-κB activation in aged perilymphatic tissues. Therefore, aging-associated dysfunction of MCs critically affects all NF-κB-mediated reactions of aged tissues to acute inflammation. Proper functioning of the mast cell/histamine/NF-κB axis is essential for the regulation of lymphatic vessel transport and barrier functions, as well as for both the interaction and trafficking of immune cells near and within lymphatic collectors. Thus, this axis appears to play important roles in the pathogenesis of the alterations in inflammation and immunity associated with aging.


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