Ways in Which the Failing Lymphatic System Contributes to Age-Related Disease

The lymphatic system is a parallel circulatory system responsible for moving fluid, immune cells, and a range of vital molecules around the body. It is of particular importance to immune function, allowing components of the immune system to carry messages from place to place in the body, and communicate and coordinate the immune response at the hubs known as lymph nodes. Like all tissues in the body, the lymphatic system is negatively impacted by aging, and this has widespread detrimental effects throughout the body and brain.

For example, lymph nodes become disrupted in structure and function by the presence of senescent cells and consequent fibrosis as tissue maintenance runs awry in the face of the senescence-associated secretory phenotype. The consequences of this are well demonstrated in a recent paper: very old mice and primates suffering from immunosenescence, an immune system with a poor response to pathogens, cannot benefit from the addition of new, functional immune cells. Their lymph nodes are too structurally impacted to allow the new cells to coordinate an effective immune response. Given that fibrosis in a number of tissues has been reversed in animal models via use of senolytics to clear senescent cells and their inflammatory signaling, it is possible that lymph node aging might be reversed to some degree. If the structure cannot be regenerated, however, then there are efforts underway to produce artificial lymph nodes that can be transplanted to integrate with the lymphatic system.

It isn't just a matter of lymph nodes, of course. Lymphatic vessels actively pump their contents, and this pumping function declines and becomes erratic with advancing age. Other forms of degeneration also take place, impairing the ability of immune cells and their signals to move about the body. This is a harder problem to solve, given its distributed nature, and that it probably arises due to contributions from most of the underlying forms of molecular damage that cause aging. It is important for the research community to keep working on means of repair for all forms of damage, not just focus on the approaches, like senolytics, that are closest to practical clinical use.

Reduced lymphatic function contributes to age-related disease

The diverse etiologies of age-related diseases, from osteoarthritis to Alzheimer's disease, all share an impairment, or slow loss, of tissue function. Aging tissue homeostasis shifts towards progressive, low-grade inflammation and a dampened immune response. The lymphatic vasculature is the key regulator of tissue homeostasis in health and disease. Lymphatics transport antigens and other macromolecules, excess interstitial fluid, and activated immune cells during inflammation. Here we highlight how reduced lymphatic function is a key component regulating several age-related diseases.

Lymphatic vessels are structurally quite different from blood vessels, beginning with blind-ended capillaries possessing leaf-like cell junctions that lead to large, unidirectionally-valved collecting vessels. These larger vessels are surrounded by lymphatic muscle cells that provide intrinsic pumping to maintain lymph flow. A recent review focused on lymphatic collecting vessels found that lymphatic muscle contractions are reduced in amplitude and frequency and can become irregular with age. Other researchers have demonstrated altered muscle coverage and function, decreased ion channel activity, limited nitric oxide responsiveness, and reduced antigen trafficking in aged lymphatic vessels: all leading to an impairment of the immune response. They identified that increased mast cell investiture and elevated histamine levels cause heightened basal NF-kB activity in aged lymphatic vessels. This resulted in a blunted inflammatory response both in reduced vessel contractility and limited NF-kB activation. Tissue homeostasis depends on lymphatics and the structural and physiologic decline in lymphatic vessel function likely contributes to age-associated pathologies.

Chronic tissue degeneration is a common feature of age-associated disorders like osteoarthritis (OA). A series of collaborative studies have extensively detailed lymphatic involvement in several models of arthritis. Inflammatory lymphangiogenesis and increased pumping initially facilitate the removal of immune cells and fluid to the draining lymph nodes, but that over time lymphatics regress and collecting lymphatic vessels lose contractility. In their recent study of OA, blocking lymphangiogenesis accelerated joint tissue loss. The team identified increased pro-inflammatory macrophages in the knee joint and increased inflammatory markers expressed by lymphatic endothelial cells. Treatment with the proteasome inhibitor bortezomib significantly improved lymphatic drainage and reduced cartilage loss. The group's arthritis research portfolio has clearly identified that maintaining effective lymphatic drainage reduces inflammation through fluid clearance and immunomodulatory mechanisms. Further elucidating these mechanisms may make modulating lymphatics a strategy to slow OA progression.

Cardiovascular (CV) disease and diabetes are progressive pathologies whose diagnoses increase with age, and the side effects, treatment, and recovery are more difficult to manage in older patients. Lymphatic vessels have demonstrated a critical role and therapeutic potential in several CV pathologies including atherosclerosis, myocardial infarction, hypertension, and diabetes. Atherosclerosis is characterized by chronic cholesterol-rich plaque accumulation and macrophage foam cell residency in the arterial wall. Preventing lymphangiogenesis worsened lesions while increasing lymphatics reduced macrophage numbers and cholesterol content, highlighting the lymphatic route of immune cell and macromolecule. Similarly, following myocardial infarction, functional lymphangiogenesis reduced fluid accumulation and inflammatory fibrosis. We recently demonstrated that the therapeutic induction of lymphangiogenesis specifically in the kidney may target the chronic renal inflammation characteristic of hypertension and prevent an elevation in blood pressure. Similarly, we found that inducing lymphangiogenesis in adipose tissue reduced adipose-associated macrophage accumulation and improved glucose homeostasis in an obese mouse model of diet-induced diabetes. Age-related lymphatic impairment may therefore provide a target to slow the functional decline of CV tissues.

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