Senolytic (Entos/Oisin)

Aging is a primary risk factor for disease progression in multiple sclerosis (MS). Because of this, treatments that can reduce the consequences of molecular aging, like senescence, have been proposed as a strategy to address disease progression. However, the effects of senolytics, a class of drugs which selectively ablate senescent cells, on the central nervous system are largely unknown. Here, we examined the effects of senolytic treatment on myelination and oligodendrocyte function in vivo using C57BL6/J mice and in vitro using primary rat oligodendrocyte cultures. Initial data showed that naïve young (3 to 4 mo) and aged (22 mo) C57BL6/J mice treated with dasatinib and quercetin (D+Q) developed significant demyelination compared to vehicle-treated controls, though no cell death was observed in the brain. In vitro, oligodendrocyte progenitor cells treated with D+Q in differentiation media exhibited significantly reduced myelin basic protein protein and morphological complexity, also without inducing cell death. Bulk RNA sequencing and ingenuity pathway analysis of D+Q treated oligodendrocytes identified differentially expressed genes associated with endoplasmic reticulum stress. These data suggest that D+Q evokes the unfolded protein response in oligodendrocytes, causing oligodendrocyte dysfunction and myelination failure. Due to the resemblance between oligodendrocytes treated with D+Q and those found in MS lesions, D+Q treatment offers a potential method to model an aspect of oligodendrocyte dysfunction relevant to MS. Therefore, understanding the mechanism by which D+Q perturb oligodendrocyte function may provide insight into some of the pathological features contributing to disease progression in MS.

Tau protein accumulation induces cellular senescence in Alzheimer's disease (AD). Treating tau transgenic mice with the senolytic therapy, dasatinib plus quercetin (DQ), to clear senescent cells reduced brain pathology and improved structure and function. DQ has since been moved into clinical AD trials. Herein, we report results from a direct comparison of DQ to fisetin FIS, a senolytic with a potentially more favorable side‐effect profile.

Fourteen‐month‐old female and male wild type (WT) and tau transgenic (rTg4510) mice received 12 weeks of intermittent DQ, FIS or vehicle by oral gavage. Physical and cognitive assessments, and RNA sequencing analysis on brain tissue were performed.

Both senolytics significantly increased frailty in female and male rTg4510 mice ( p  < 0.05). There was no effect of senolytic on working memory measured with Y‐Maze, or hippocampal dependent nest building behavior in rTg4510 mice. Spontaneous alterations percentage increased in WT male mice treated with FIS. Both senolytics significantly improved nest building in WT females ( p  < 0.02). Grip duration was reduced by both senolytics in WT and rTg4510 female mice and by FIS in WT and rTg4510 treated males compared to vehicle treated controls ( p  < 0.03). FIS was protective against ventricular enlargement, indicative of neurodegeneration in rTg4510 females. RNA analysis revealed differential expression of 232 genes with senolytic treatment; with an overlap of 54 genes that were differentially expressed by both treatments.

Outcomes related to physical and cognitive function were largely unchanged by senolytic in rTg4510 mice, indicating our model may have been too advanced by the time of drug initiation to see benefits from the treatment. Subtle, functional changes observed after senolytic in WT mice and the RNA sequencing data highlight the need for additional studies to evaluate the appropriateness of selected senolytic, dose, and initiation timeline, for use in AD relevant populations.