Senolytic intervention improves cognition, metabolism, and adiposity in female APP NL -F/NL-F mice.
Yimin FangMackenzie R PeckKathleen QuinnJenelle E ChapmanDavid MedinaSamuel A McFaddenAndrzej BartkeErin R HascupKevin N HascupPublished in: GeroScience (2024)
Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimer's disease (AD). The APP NL-F/NL-F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue and the hippocampus before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APP NL-F/NL-F mice. Thus, 4-month-old male and female APP NL-F/NL-F mice were treated monthly with vehicle, 5 mg/kg dasatinib + 50 mg/kg quercetin, or 100 mg/kg fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + quercetin treatment in female APP NL-F/NL-F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass 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 amyloid-β (Aβ) 42 and senescence-associated-β-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APP NL-F/NL-F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine.
Keyphrases
- blood glucose
- adipose tissue
- cognitive decline
- high fat diet induced
- mild cognitive impairment
- dna damage
- insulin resistance
- randomized controlled trial
- endothelial cells
- induced apoptosis
- mouse model
- type diabetes
- stress induced
- glycemic control
- coronary artery disease
- working memory
- high fat diet
- single cell
- cell cycle arrest
- mesenchymal stem cells
- pregnant women
- cognitive impairment
- wild type
- endoplasmic reticulum stress
- cell death
- blood brain barrier
- cerebral ischemia
- body mass index
- weight loss
- resting state
- signaling pathway
- pi k akt