Fisetin is a natural flavonoid that possesses antioxidant, anti-inflammatory, anti-senescence, and neuroprotective effects in preclinical studies. This double-blind randomized clinical trial investigated the effects of two fisetin dosing regimens on senescent gene expression in peripheral blood mononuclear cells (PBMCs) in elderly humans (> 55 years old). Participants were randomized to Daily dose (100mg/day, N = 41) or Bolus dose (20mg/kg for two consecutive days on and 28 days off, N = 40) for 60 days. Blood draw, PBMC isolation, RNA extraction and quantitative polymerase chain reaction (Q-PCR) for 5 target genes were performed at baseline, and days 15, 35, 45 and 60. At the primary endpoint, day 45, both fisetin dosing regimens significantly decreased galactosidase beta 1 (GLB1) and P16 ^INK4A (P16) gene expression. Bolus dose also significantly reduced macrophage migration inhibition factor (MIF) and alpha-L-fucosidase 1 (FUCA1) compared to baseline and decreased MIF compared to daily dose. Further, Bolus dose significantly decreased GLB1 and MIF at days 15, 35, 60, and P16 at days 15, 35 as well as FUCA1 at day 35 compared to baseline. Hence, Bolus dosing of fisetin is more effective than Daily dosing for reducing cellular senescent genes in PBMCs isolated from elderly human blood.