Grant Abstract: Changes in senescent cells and SASP from bone marrow, synovial fluid, and peripheral blood after senolytic treatment

Grant Number: 3UG3AR077748-01
PI Name: Huard
Project Title: Changes in senescent cells and SASP from bone marrow, synovial fluid, and peripheral blood after senolytic treatment

Abstract: Cellular senescence is thought to be a fundamental driver of aging and major contributor to age-associated decline and loss of physiological reserve. Cell senescence is a mechanism by which cells are metabolically active but cease dividing and undergo distinct phenotypic changes, including upregulation of p16Ink4a, significant secretome changes, telomere shortening, and etc. Senescent cell accumulation is not only a fundamental property of aging, but also promotes several age-related morbidities such as osteoarthritis (OA), through the production of the Senescence Associated Secretory Phenotype (SASP). SASP factors include pro-inflammatory cytokines/chemokines, tissue degrading proteases, and reactive oxygen species (ROS) inducing signals responsible for paracrine induction and potentiation of inflammation and systemic senescence. Thus, understanding the spatiotemporal dynamics of senescent cell accumulation at the tissue and peripheral level, including cognate SASP production, is paramount to devise strategies to target senescence for the treatment of age associated chronic conditions. The recent discovery of dietary supplements such as Fisetin with demonstrated senolytic effects offers a potentially powerful and safe approach to promote healthy aging and delay age-related disease by selectively targeting and eliminating senescent cells without affecting quiescent or proliferating cells. Our studies have shown that senolytic treatment (Fisetin) can delay articular cartilage degeneration in a murine model of OA and based on these promising pre-clinical data, we are conducting a phase-I/2 clinical trial to investigate the efficacy of senolytic agents to reduce senescent cells and SASP factors to consequently improve therapeutic approaches for OA patients. For this proposal, we aim to characterize senescent cells and SASP production locally and systemically in human synovial fluid, bone marrow, and peripheral blood that will be collected as part of an ongoing NIH-funded clinical trial (NIAMS UG3/UH3 AR077748-01 RMIP) investigating the efficacy of senolytic (Fisetin) and anti-fibrotic therapies in combination with bone marrow concentrate to treat knee OA. In response to a current Program Announcement (PA-20-227: Administrative Supplement for Research on Dietary Supplements), we propose to collect and compare clinical samples for senescent cells and SASP from three different compartments including peripheral blood, synovial fluid and bone marrow. We also propose to analyze changes in senescent cell content and senescence biomarkers in these 3 compartments, with and without senolytic treatment with the dietary supplement Fisetin. Collecting samples in conjunction with a concurrent clinical trial allows for an efficient and economical yet robust assessment of senescence indices in unique tissue compartments that can be difficult to obtain in healthy human patients (namely synovial fluid and bone marrow). Overall, the ability to utilize existing patient samples from this RMIP clinical trial will allow us to generate additional analyses to characterize the effects of Fisetin on cellular senescence in peripheral blood, bone marrow and synovial fluid.

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