Researchers here provide evidence for 5 days of injections with 25-hydroxycholesterol to be senolytic in the vasculature of mice, reducing the harmful burden of senescent cells to reduce age-related aortic stiffness. There may be other mechanisms involved, but the researchers focused on clearance of senescent cells and the potential pathways by which this occurs in response to increased levels of 25-hydroxycholesterol. The comparison with the genetic model of senescent cell clearance is particularly interesting. Whether this treatment also provokes programmed cell death of senescent cells meaningfully in other tissues is an open question left unexamined in this short paper, though earlier work did test the senolytic capacity of 25-hydroxycholesterol in a number of different cell types in vitro.
Stiffening of the aorta is a key antecedent to cardiovascular diseases (CVD) with aging. Age-related aortic stiffening is driven, in part, by cellular senescence - a hallmark of aging defined primarily by irreversible cell cycle arrest. In this study, we assessed the efficacy of 25-hydroxycholesterol (25HC), an endogenous cholesterol metabolite, as a naturally occurring senolytic to reverse vascular cell senescence and reduce aortic stiffness in old mice.
Old (22-26 months) p16-3MR mice, a transgenic model allowing for genetic clearance of p16-positive senescent cells with ganciclovir (GCV), were administered vehicle, 25HC, or GCV to compare the efficacy of the experimental 25HC senolytic versus genetic clearance of senescent cells. We found that short-term (5 day) treatment with 25HC reduced aortic stiffness in vivo, assessed via aortic pulse wave velocity to a similar extent as GCV. Ex vivo 25HC exposure of aorta rings from the old p16-3MR GCV-treated mice did not further reduce elastic modulus (measure of intrinsic mechanical stiffness), demonstrating that 25HC elicited its beneficial effects on aortic stiffness, in part, through the suppression of excess senescent cells.
Improvements in aortic stiffness with 25HC were accompanied by favorable remodeling of structural components of the vascular wall (e.g., lower collagen-1 abundance and higher α-elastin content) to a similar extent as GCV. Moreover, 25HC suppressed its putative molecular target CRYAB, modulated CRYAB-regulated senescent cell anti-apoptotic pathways, and reduced markers of cellular senescence. The findings from this study identify 25HC as a potential therapy to target vascular cell senescence and reduce age-related aortic stiffness.
Link: https://doi.org/10.1111/acel.70118
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