Fisetin - The Mayo Clinic Senolytics Protocol?

[RapAdmin]

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

Highlights from the 2023 Longevity Summit

More updates from the conference: Rubedo Life Sciences Rubedo is doing extremely interesting things in the Senolytics market, and they are raising a round of funding right now (so if you’re a serious investor/venture capitalist interested in Senolytics, I recommend you give them a call). The reason I think Rubedo is interesting to the people here in the forum is because of their message on how the understanding of senescent cells and senolytics has changed over the past few years; since the early days and early research done by James Kirkland. In fact this was the key Message Marco spent most of his presentation covering. Now the researchers realize that the hope for a universal marker for senescent cells, and therefore a universal senolytic (or mix of senolytics, as Kirkland has done) is really seen as a historical fantasy. We’ve seen many instances of the problems companies have had in developing senolytic therapies, as demonstrated most recently by Unity Biotech, which has …

[Engadin]

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.

[Vlasko]

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.”

Intermittent supplementation with fisetin improves arterial function in old...

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

[DeStrider]

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…

[RapAdmin]

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.

Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in...

[RapAdmin]

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

[WJ_PhD]

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!

Fisetin as a senotherapeutic agent: Evidence and perspectives for age-related...

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