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

Abstract

AbstractINTRODUCTIONSenescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimer’s disease (AD). We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APPNL-F/NL-Fmice.METHODSMale and female APPNL-F/NL-Fmice were treated monthly with vehicle, 5 mg/kg Dasitinib (D) + 50 mg/kg Quercetin (Q), or 100 mg/kg Fisetin. Blood glucose levels, energy metabolism, spatial memory, and senescent cell markers were assayed.RESULTSD+Q treatment in female APPNL-F/NL-Fmice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue content was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble Aβ42and SA-β-gal activity leading to improved spatial memory.DISCUSSIONConsidering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine.Research in ContextSystematic reviewPubMed and Google Scholar were used to conduct literature reviews. Previous publications have shown senolytics improve cognition in tau and amyloid AD models. However, these studies were conducted at later disease stages when pathology was pronounced, do not examine effects in non-neuronal cell types, nor consider sex as a biological variable. We hypothesized senolytics could be used as a primary prevention against AD.InterpretationOur findings indicate Dasitinib plus Quercetin intervention acts in a sexually dimorphic manner that benefits female APPNL-F/NL-Fmice when administered before overt signs of cognitive decline.Future directionsThe manuscript proposes a framework for the generation of new hypotheses and the conduct of additional studies. Examples include further understanding: (a) the lack of Dastinib + Quercetin efficacy in male APPNL-F/NL-Fmice; (b) sex-dependent factors that contribute to adiposity changes after senolytic administration; and (c) changes in estrogen across the AD continuum and its potential role in modulating senolytic treatment.Graphical AbstractMonthly Dasatinib plus Quercetin administration in female APPNL-F/NL-Fmice, but not males, led to improvements in multiple physiological parameters including increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue content was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglyceride levels. In the brain senescence markers and SASP were reduced along with soluble and insoluble Aβ42and SA-β-gal activity leading to improved spatial learning.