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Grant Abstract: Role of cellular senescence in cardiovascular aging

Grant Number: 3R01AG055822-04S1
PI Name: Melov
Project Title: Role of cellular senescence in cardiovascular aging

Abstract: Aging is the primary risk factor for cardiovascular diseases (CVD). Increased CVD risk with aging is mediated primarily by arterial dysfunction, including impaired vascular endothelial and increased large elastic artery (e.g., aorta) stiffening. These changes in vascular function are largely due to excess reactive oxygen species (ROS), which reduces the bioavailability of the vasodilatory molecule nitric oxide (NO) and induces structural changes in arteries. However, the upstream events regulating these processes are incompletely understood. A mechanism thought to underly age-related arterial dysfunction is cellular senescence, a largely permanent cell cycle arrest which leads to the secretion of pro-inflammatory molecules, collectively referred to as the senescence-associated secretory phenotype (SASP). Indeed, cellular senescence contributes to vascular aging and therefore represents a novel therapeutic target for reducing the risk of CVD with aging. We have shown that genetic- and pharmacological-based senescent cell clearance (senolysis) in aged animals improves arterial function; however, the translational potential of senolytic therapies studied to data is hindered by their toxicity to non-senescent cells and/or unfavorable safety profiles. Therefore, it is biomedically relevant to develop novel and safe senolytics. Natural, food-derived compounds represent highly promising approaches to accomplish this goal. Fisetin is a flavonoid with proposed senolytic properties found in a variety of commonly consumed foods such as cucumbers and strawberries. Due to the content variations in food, fisetin-rich diets are not feasible; however, fisetin is available as a dietary supplement with a favorable safety profile in humans. Moreover, short-term (1-2 months), high dose fisetin administration in an intermittent manner is emerging as a promising, non-pharmacological, senotherapeutic strategy. As such, fisetin is an excellent candidate for clinical translation. The purpose of this administrative supplement, through the NIH Office of Dietary Supplements, is to determine the efficacy of the food-derived senolytic fisetin for treating age-related arterial dysfunction in old mice and to establish senolysis as the primary mechanism underlying the beneficial effects. This study represents a critical step for the eventual clinical translation of this dietary supplement to humans. Hypothesis 1: Oral supplementation with fisetin will improve arterial function in old mice. The improvements will be similar to those observed with in vivo genetic clearance of senescent cells. Hypothesis 2: Improvements in arterial function with fisetin will be driven by reductions in cellular senescence. Hypothesis 3: Fisetin-associated alterations in the circulating milieu/the SASP will improve endothelial cell function and these effects will be mediated via reductions in cellular senescence. PUBLIC HEALTH RELEVANCE: The risk of developing cardiovascular diseases increases with aging largely due to age-related declines in the function of arteries (arterial dysfunction), which are influenced by cellular senescence. This study will investigate the potential of a novel natural dietary supplement, fisetin, for treating age-related arterial dysfunction by targeting cellular senescence. Overall, this research has the potential to identify a new therapeutic strategy – with great promise for development as a dietary supplement and the translation to humans – preventing age-related arterial dysfunction and thereby reducing risk of cardiovascular diseases.

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