Sexual Dimorphic Metabolic and Cognitive Responses of C57BL/6 Mice to Fisetin or Dasatinib and Quercetin Cocktail Oral Treatment

Abstract Senolytic treatment in aged mice clears senescent cell burden leading to functional improvements. However, less is known regarding the effects of these compounds when administered prior to significant senescent cell accumulation. From 4-13 months of age, C57BL/6 male and female mice received monthly oral dosing of either 100 mg/kg Fisetin or a 5 mg/kg Dasatinib (D) plus 50 mg/kg Quercetin (Q) cocktail. During treatment, several aspects of healthy aging were assayed including glucose metabolism using an insulin and glucose tolerance test, cognitive performance using Morris water maze and novel object recognition, and energy metabolism using indirect calorimetry. Afterwards, mice were euthanized for plasma and tissue specific markers of senescence(definition)-associated secretory phenotype (SASP) and white adipose tissue accumulation (WAT). Sexually dimorphic treatment effects were observed. Fisetin treated male mice had reduced SASP, enhanced glucose and energy metabolism, improved cognitive performance, and increased mRNA expression of adiponectin receptor 1 and glucose transporter 4. D+Q treatment had minimal effects in male C57BL/6 mice, but was detrimental to females causing increased SASP expression along with accumulation of WAT depots. Reduced energy metabolism and cognitive performance were also noted. Fisetin treatment had no effect in female C57BL/6 mice potentially due to a slower rate of biological aging. In summary, the senolytic treatment in young adulthood, has beneficial, negligible, or detrimental effects in C57BL/6 mice dependent upon sex and treatment. These observations should serve as a note of caution in this rapidly evolving and expanding field of investigation. Graphical Abstract Male and female C57BL/6 mice were treated with once monthly oral doses of either Dasatinib (D) + Quercetin (Q) or Fisetin from 4-13 months of age. Females treated with D+Q had increased adiposity and SASP markers (red spheres) along with decreased metabolism (blue flame) and cognitive performance. Males treated with Fisetin had reduced SASP markers (blue spheres) as well as improved metabolism (red flame) and cognition. No effects were observed in females treated with Fisetin or males treated with D+Q.