I recommend anyone interested in senolytics to review the Rubbed presentation and commentary:
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As Dr. George Church, fabulous genetist from Nebula recently stated in a video, āit is always too soon to say somethingās impossibleā. With this in mind, I wish there is already some group of scientists around looking for a biomarker to tell pro-aging senescent cells from those with an unrelated to age way of action (i.e. wound healing), regardless their celullar type. At first sight, SASPs could be one, but I donāt know about these secretory phenotypes leaving some sort of protein or marker over the emitting cellās membrane to identify any age related senescent cell as their source, and therefore become a positive target for senolitics as fisetin or any other in the pipeline. Those scientists at Rubedo are a guaranty of future for efficient senolytics. Hope Iāll be on time yet to enjoy their benefits in the coming years.
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Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence
āOverall, our findings provide the first evidence that oral intermittent fisetin supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness through the suppression of excess cellular senescence, inflammation, and oxidative stress.ā
Mahoney SA, Venkatasubramanian R, Darrah MA, et al. Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence. Aging Cell. Published online December 7, 2023. doi:10.1111/acel.14060
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It kind of makes sense why it didnāt increase mouse life expectancy then. Mice die of cancer not heart attacks. Any cardiovascular improvement probably would not move the needle on lifespan. For humans howeverā¦
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Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APPNL-F/NL-F Mice.
Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimerās disease (AD). We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APPNL-F/NL-F mice.
METHODS: Male and female APPNL-F/NL-F mice were treated monthly with vehicle, 5 mg/kg Dasitinib (D) + 50 mg/kg Quercetin (Q), or 100 mg/kg Fisetin. Blood glucose levels, energy metabolism, spatial memory, and senescent cell markers were assayed.
RESULTS: D+Q treatment in female APPNL-F/NL-F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue content was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble AĪ²42 and SA-Ī²-gal activity leading to improved spatial memory.
DISCUSSION: Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine.
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The quest to turn back the clock
Approaches to slow or reverse aging have gained momentum in recent years, but the field is still in its infancy with hurdles to overcome, as illustrated by efforts to develop therapies that clear senescent cells.
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As such companies progress with their diverse approaches to target senescence, they will encounter the challenges of running pivotal trials that contributed to the failure of Unity Biotechnologyās pioneering program, including identifying a suitable indication where their drugs result in meaningful improvements in a clinical endpoint that could provide the basis for approval. As the momentum and investment in the field of aging builds though, it is becoming increasingly likely that a breakthrough candidate will emerge. If so, there will be intense competition from larger companies to gain access to therapeutics that may indeed turn back the clock on aging.
Full article: The quest to turn back the clock