#2330 Fisetin supplement ameliorates aging related changes in the kidney

Abstract

Abstract Background and Aims As the ageing population continues to grow worldwide, aging-related diseases are becoming an excessive burden on the global healthcare system. The kidney is one of the organs most affected by aging, which undergoes changes of decreased glomerular filtration rate (GFR), alterated renal blood flow, increased inflammation and fibrosis that increase the susceptibility to developing acute kidney injury (AKI) and chronic kidney disease (CKD). To date, the mechanisms underlying the changes of aged kidneys has not been fully elucidated and therapeutic strategies are still under exploration. Fisetin is a natural flavonol that has been shown to be beneficial to many age-related disorders, as well as increase lifespan in preclinical animal models. However, whether and how fisetin protects against kidney aging remains unclear. In the present study, we assessed the efficacy of fisetin as a senolytic to reduce cell senescence and SASP factors and improve renal function in old mice. Method 18 month-old C57BL/6 mice were randomly divided into the model group (n = 6), the fisetin low-dose group (100 mg/kg/d B.W., n = 6), fisetin high-dose group (100 mg/kg/d B.W., n = 6) and the rapamycin group (14 ppm, positive control, n = 6). The control group (n = 6) was composed of wild-type C57BL/6 mice of 4 month age. The fisetin and rapamycin were given in the diet for 4 months. Mice of model and treatment group were sacrificed at the age of 22 month and the blood and kidney samples were collected. The GFR of mice in each group was detected and the pathological morphology, lipid accumulation, collagen deposition of the kidneys were assessed. Additionally, the expressions of senescence markers including p53, p21,p16, and SASPs within the kidneys were analyzed. Results Fisetin treatment effectively restored the decline in GFR of old mice. Moreover, administration with fisetin significantly reduced age-related pathology including lipid accumulation and collagen fiber deposition in mice kidneys. The expression of aging markers of p53, p21,p16 and SASPs was remarkably upregulated in the kidneys of model mice, which was suppressed by fisetin treatment. Moreover, the kidney inflammation and oxidative stress as observed in aged kidneys was alleviated in mice of fisetin treatment group. Conclusion The natural product fisetin has senotherapeutic activity in mice kidneys. Intervention with fisetin is a promising therapy for clinical translation to target excess cell senescence to treat age-related kidney dysfunction.