#63

I recommend anyone interested in senolytics to review the Rubbed presentation and commentary:

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#65

As Dr. George Church, fabulous genetist from Nebula recently stated in a video, ‘it is always too soon to say something’s impossible’. 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 don’t know about these secretory phenotypes leaving some sort of protein or marker over the emitting cell’s 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 I’ll be on time yet to enjoy their benefits in the coming years.

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#66

Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence

“Overall, 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.”

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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#67

It kind of makes sense why it didn’t 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 however…

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#68

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 Alzheimer’s 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 Aβ42 and SA-β-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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#69

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.

…
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 Biotechnology’s 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

#70

Fairly recent (Dec) summary paper of Fisetin. Mostly in vitro and in vivo animals models but Includes summary of 4 completed human studies and also lists the 20 ongoing clinical trials.
It’s open access too! :slight_smile:

https://www.sciencedirect.com/science/article/pii/S0047637424000952?via%3Dihub

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#71

There are so many fisetin threads I don’t know which one to post this to, so I’ll post it here:

This is a new preprint from people at the University of Colorado, Boulder, and then also people at the National Institute on Aging (with people from the University of Maryland):

Senolytic treatment with fisetin reverses age-related endothelial dysfunction partially mediated by SASP factor CXCL12

https://www.biorxiv.org/content/10.1101/2025.08.13.670216v1

Note that it’s a mouse study:

Results Senescent endothelial cells exhibited elevated expression of SASP factors, particularly Cxcl12, which was reversed by fisetin supplementation, with responses also reflected in circulating CXCL12 concentrations. Plasma from old mice impaired endothelial function by inducing vascular cell senescence, reducing NO, increasing mitochondrial oxidative stress, and promoting endothelial-to-mesenchymal transition—effects partially driven by CXCL12 and prevented by fisetin.

Conclusions These results identify the SASP and CXCL12 as drivers of age-related endothelial dysfunction and establish mechanisms of senolytic intervention with fisetin supplementation.

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