Reversing aging-induced lymphatic dysfunction to improve immune function

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One significant problem with aging is a reduced ability to generate immune responses to bacterial, viral and fungal infections, leading to more hospitalizations and putting elderly people at greater risk of death from common infections. This problem has been starkly demonstrated by the greater rates of hospitalization and death from SARS-CoV-2 infections in older people. Older people also have lower rates of generating immunity after vaccination, leaving them vulnerable to common infectious diseases. Thus, there is a need to improve the function of the immune system in elderly people in order to lower rates of infections and their associated burdens. The lymphatic system—consisting of lymph nodes and lymphatic vessels—plays a central role in generating immune responses, which depend on lymph flow to carry antigens from the pathogen to lymph nodes to activate immune cells. We, and others, have shown that lymphatic function and lymph flow are reduced in aged animals. The reduced lymph flow limits antigens from getting to lymph nodes and initiating an immune response. Thus, poor lymphatic function can be one potential factor that contributes to reduced immune function in the elderly. The mechanisms behind reduced lymphatic function in aged mice are not well characterized. Further, there are no FDA approved drugs indicated to improve lymphatic function. The overall goal of the proposed project is to define the mechanisms that drive the aging-related reduction in lymphatic function in order to target these mechanisms to boost both lymphatic and immune function in aged mice. Lymphatic muscle cells (LMCs) are a natural target cell to boost lymphatic function as they drive lymph flow by causing rapid lymphatic vessel contractions. LMCs however have not been well characterized and are often considered vascular smooth muscle cells, despite clear phenotypic differences in the behavior of these cell types. Building on our recently generated transcriptome of LMCs, we will compare the transcriptomes of LMCs from freshly isolated collecting lymphatic vessels from young and old mice in the proposed work. These data will identify mechanistic pathways to target in order to boost lymphatic function in aged animals. Further, we will determine whether the transcriptional changes are dictated by age-related microenvironmental differences. We will also test the causal relationship between poor immune function and poor lymphatic function in aged mice by increasing lymphatic pumping pharmacologically. Long-term, we will validate our findings in human tissue and develop therapeutic approaches to boost lymphatic function in elderly people. This work will form the basis for the first FDA approved drugs to improve lymphatic function. Our novel therapeutic concept would lead to fewer hospitalizations and deaths due to infections in elderly people as well as better vaccine efficacy, which will prevent common viruses, such as influenza or SARS-CoV-2, from driving mortality in elderly people. This work will be carried out by a world-class team of experts in lymphatic vessel biology, immunology, single cell RNAseq data analysis, intravital lymph flow measurements and clinical care of patients with lymphatic diseases.