Abstract
Aging is associated with cognitive decline and accumulation of senescent cells in various tissues and organs. Senolytic agents such as dasatinib and quercetin (D+Q) in combination have been shown to target senescent cells and ameliorate symptoms of aging-related disorders in mouse models. However, the mechanisms by which senolytics improve cognitive impairments have not been fully elucidated particularly in species other than mice. To study the effect of senolytics on aging-related multifactorial cognitive dysfunctions we tested the spatial memory of male Wistar rats in an active allothetic place avoidance task. Here we report that 8 weeks treatment with D+Q alleviated learning deficits and memory impairment observed in aged animals. Furthermore, treatment with D+Q resulted in a reduction of the peripheral inflammation measured by the levels of serum inflammatory mediators (including members of senescent cell secretome) in aged rats. Significant improvements in cognitive abilities observed in aged rats upon treatment with D+Q were associated with changes in the dendritic spine morphology of the apical dendritic tree from the hippocampal CA1 neurons and changes in the level of histone H3 trimethylation at lysine 9 and 27 in the hippocampus. The beneficial effects of D+Q on learning and memory in aged rats were long-lasting and persisted at least 5 weeks after the cessation of the drugs administration. Our results expand and provide new insights to the existing knowledge associated with effects of senolytics on alleviating age-related associated cognitive dysfunctions.
Highlights
Aging is the major risk factor for cancer, cardiovascular disease, diabetes, and neurodegenerative disorders associated with multiple cognitive impairments that lead to significant disabilities and lower quality of life.According to the UN estimates, the world population of people above 65 years old will double in the 30 years and is expected to exceed 1,5 billion worldwide by 2050 (UN, 2019)
To study the effect of dasatinib and quercetin (D+Q) on aging-associated cognitive impairment, we designed an experiment in which allothetic spatial memory was tested in young and aged male Wistar rats (GROUP 1) in the active allothetic place avoidance task (AAPAT)
It www.aging‐us.com consisted of two place avoidance trainings, 5 training days each spaced by 8 weeks of vehicle or D+Q treatment period
Summary
Aging is the major risk factor for cancer, cardiovascular disease, diabetes, and neurodegenerative disorders associated with multiple cognitive impairments that lead to significant disabilities and lower quality of life.According to the UN estimates, the world population of people above 65 years old will double in the 30 years and is expected to exceed 1,5 billion worldwide by 2050 (UN, 2019). Aging is associated with cognitive changes that have been well described in both humans and laboratory animals. Since normal aging has not been associated with significant changes in the number of brain cells [3], the accompanying cognitive impairments are believed to result from alterations in the cellular and molecular mechanisms of brain plasticity. One of the mechanisms that allow rapid changing of the accessibility of genes to the transcriptional machinery is post-translational modification of histones such as methylation. Methylation of histone H3 has been implicated in age-associated cognitive decline in mice. It has been shown that the decrease in the H3K9me by systemic administration of an inhibitor of the principal enzyme responsible for the trimethylation of H3K9 (histone methyltransferase SUV39H1) improved memory performance in aged, but not young mice [9]
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