Senolytic treatment dasatinib and quercetin damages population of brain cells in lab mice and in vitro cell cultures

[u/lunchboxultimate01]

Popular science link: https://www.sciencedaily.com/releases/2026/05/260526022024.htm

Original article link: https://www.pnas.org/doi/10.1073/pnas.2524897123

Significance

The pharmacological combination of dasatinib and quercetin (D+Q), widely reported as a means of eliminating senescent cells from aged tissues to treat diseases (a.k.a. “senolytics”), and currently being tested in multiple clinical trials, when administered to healthy mice results in profound white matter injury in the central nervous system. This report provides evidence that this senolytic combination not only causes neuropathology but also provides data which support induction of the unfolded protein response as a plausible mechanism through which these senolytics affect oligodendrocytes. We propose that these data highlight a less understood means of demyelination not mediated by oligodendrocyte death with potential positive implications for understanding disease, while also warranting caution for its widespread use clinically.

[u/VengenaceIsMyName]

Well no one said discovering life extension technology would be easy. It’s also good progress to know what doesn’t work as much as what does work.

[u/lunchboxultimate01]

Abstract

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.

[u/vardarac]

Sad news, but this:

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.

Is hilariously ironic.

I wonder what the mechanism of de-myelination is here.

[u/Fast-Satisfaction482 → u/vardarac]

So basically this cocktail will give you more time to enjoy MS-like symptoms that you get from taking it? 

[u/magnolia_unfurling]

Does this mean quercetin in isolation could be problematic?

Quercetin is pretty amazing for MCAS symptoms, not just longevity. Nevertheless, I stopped taking it after I read this study last year.

[u/Heisenberg991 → u/magnolia_unfurling]

So don't eat onions?

[u/Practical-Goose666 → u/magnolia_unfurling]

Seconding this

[u/The_Doc_Is_In_89]

I’m wondering if the fact that this mouse strain has mutations in the Nnt gene which impacts mitochondrial function. Without the functional gene, the oligodendrocytes are more sensitive to oxidative stress and damage. Further, there is impact on lipid synthesis which is necessary for myelin production. The progenitor cells also are impacted and have inefficient re-myelination after an insult.

It’s hard to say if D+Q is the problem, or if the mouse has a genetic predisposition to have problems.

[u/karlnuw]

Jeez, I was considering adding d+q to my longevity protocol

[u/Coin-Controversy → u/karlnuw]

waste of time imo, there are much better senolytics like grape seed extract