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Effect of peripheral cellular senescence on brain aging and cognitive decline
Vivekananda Budamagunta1,2,3, Ashok Kumar1, Asha Rani1
1Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA.
Aging Cell
|March 24, 2023
Summary
Two senolytic treatments, dasatinib + quercetin (D+Q) and ABT-263, preserved cognition and brain health in aging rats by reducing inflammation and improving synaptic function. Both treatments showed benefits, with some distinct effects on gene expression and cellular markers.
Area of Science:
- Gerontology
- Neuroscience
- Pharmacology
Background:
- Aging is associated with cognitive decline and increased senescence.
- Senescent cells contribute to age-related diseases through the senescence-associated secretory phenotype (SASP).
- Senolytic therapies aim to clear senescent cells to mitigate aging effects.
Purpose of the Study:
- To compare the effects of two senolytic treatments, dasatinib + quercetin (D+Q) and ABT-263, on cognition and aging markers.
- To investigate the impact of these senolytics on peripheral senescence, blood-brain barrier (BBB) integrity, and brain aging markers.
- To explore the differential effects of D+Q and ABT-263 on gene expression in the hippocampus.
Main Methods:
- Male F344 rats were treated with D+Q, ABT-263, or vehicle from 12 to 18 months of age.
- Cognitive function, BBB integrity, and hippocampal N-methyl-D-aspartate receptor (NMDAR) function were assessed.
- Plasma SASP and inflammatory markers, spleen senescence genes, and dentate gyrus (DG) gene expression were analyzed.
Main Results:
- Both D+Q and ABT-263 rescued memory, preserved BBB integrity, and prevented NMDAR decline.
- Senolytic treatments reduced plasma SASP and inflammatory cytokines, with differential responses to D+Q and ABT-263.
- ABT-263 was more effective in reducing spleen senescence genes, while D+Q affected more DG genes.
- Both treatments decreased immune and oxidative stress genes and increased synaptic genes in the DG.
- D+Q showed greater reduction in microglial activation markers compared to ABT-263.
Conclusions:
- Senolytic treatments can preserve cognitive function in aging rats by reducing peripheral senescence and systemic inflammation.
- Both D+Q and ABT-263 demonstrate efficacy, but with distinct effects on central gene expression and cellular markers.
- Differential central effects may be due to variations in drug penetration or targets, suggesting tailored senolytic strategies may be beneficial.
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