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, tissue specific markers of senescence-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. Males treated with Fisetin had reduced SASP markers (blue spheres) as well as improved metabolism (red flame) and cognition. Females treated with D + Q had increased adiposity and SASP markers (red spheres) along with decreased metabolism (blue flame) and cognitive performance. No effects were observed in females treated with Fisetin or males treated with D + Q.

Repurposing Drugs for Senotherapeutic Effect: Potential Senomorphic Effects of Female Synthetic Hormones

“…We found differences in SAB positivity, expression of splicing factors and expression of mRNAs encoding SASP proteins between male and female cells in response to female sex hormones. Sex differences in drug responses are not uncommon, and a sexual dimorphism has been reported in mice in response to senotherapeutics [ 65 , 66 ]. Recently, the NIA Interventions Testing Program in mice has revealed sex differences in effects on longevity in response to 17-α-estradiol and aspirin [ 67 , 68 ].…”

Exploring the effects of Dasatinib, Quercetin, and Fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions

“…While the link between cellular senescence and aging is indisputable [ 51 ], the differential analysis of these clocks limits our interpretation of their clinical significance. However, the advantages of senolytic treatments have shown greater nuances, as detrimental and sex-based effects have been seen in mice [ 52 ]. Indeed, previous literature has shown varied benefits among mice models and human trials with the application of senolytics [ 53 , 54 ].…”

Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APPNL-F/NL-FMice

“…In a separate study, D+Q treatment has been shown to overcome negative effects of estrogen-deficiency, such as postmenopausal osteoporosis [41]. We previously discussed a possibility of D+Q treatment leading to low estrogen levels in normal aging C57BL/6 mice [20], however, data support the sometimes contradictory differential effects of early intervention between normal aging and mouse models of AD [31]. This, combined with the general lack of characterization of estrogen levels across disease progression in APP NL-F/NL-F mice, makes it difficult to determine if the effects of D+Q treatment in APP NL-F/NL-F mice are mediated through modulating estrogen levels.…”

“…Senotherapeutic concentrations and dosing strategy were based on previous publications [20, 43, 45]. APP NL-F/NL-F mice were dosed with 100 mg/kg of Fisetin while a cocktail of 5 mg/kg of D + 50 mg/kg of Q, or vehicle (2% DMSO in canola oil) by oral administration [45].…”