#1
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"Lock In" Rapamycin Gains with Higher Doses
#2

Fisetin is a dud as expected. When Kirkland went all quiet for more than a year I suspected there was some issues about this. Better to give the money to charity then to waste it on this.

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#3

ā€œIn conclusion, we found that senescent cells were widely present in the cerebral brain cortex and cerebellum and non-CA area of the hippocampus of old sheep. Fisetin treatment significantly decreased senescent neurons, astrocytes, and microglia in both gray and white matter of the cerebral brain cortex and non-CA area of the hippocampus. In addition, fisetin treatment decreased senescent gene expressions and inflammasomes in other organs, such as the lung and the liver. Fisetin treatment represents a promising therapeutic strategy for age-related diseases.ā€

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#4

The study you cite is from Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657 with self-interest attached to the study.
The study is not convincing and is probably used by them to sell their services. In addition, all of the authors are from the same institute that sells medical services.

The study cited by ā€œImitation_Blackā€ has a more diverse authorship and the citation is more of a Cochrane-type review.

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#5

Full article below:

  1. It is a preprint; not peer reviewed.
  2. Sample size is 19 individuals.
  3. Seems to be more a critique of the tests, than of Fisetin.

Together, our findings suggest that 1st generation clocks are insufficient tools to quantify the impact of senolytic therapies. Additionally, second generation clocks still remain largely unchanged with Dasatinib and Quercetin use and other markers are needed to measure the physiologic impact of senolytic treatments. In either instance, our findings reemphasize the importance of developing new biomarkers which can quantify senescence and impact to aging phenotypes.

Addition of fisetin seems to mitigate the negative effects of DQ.

Significant increases in epigenetic age acceleration were observed in first-generation epigenetic clocks and mitotic clocks at 3 and 6 months, along with a notable decrease in telomere length. However, no significant differences were observed in second and third-generation clocks. Building upon these findings, a subsequent investigation evaluated the combination of DQ with Fisetin (DQF), a well-known antioxidant and antiaging senolytic molecule. After one year, 19 participants (including 10 from the initial study) received DQF for 6 months, with DNAm assessed at baseline and 6 months. Remarkably, the addition of Fisetin to the treatment resulted in non-significant increases in epigenetic age acceleration, suggesting a potential mitigating effect of Fisetin on the impact of DQ on epigenetic aging.

Overall, our findings indicate that the administration of senolytic drugs Dasatinib and Quercitin significantly increases biological age measured by first generation clocks. The only 2nd generation clock to show an increase was DNAmPhenoAge. However, we see no significant change in second and third-generation clocks such as GrimAge and DunedinPACE or any significant changes with the addition of Fisetin to the protocol (DQF treatment).

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#6

Not really. One of eight authors said they received some kind of royalty.

Since you read through the full text and studied and critiqued the methodologies and findings, maybe you could explain how you arrived at that determination and why.

Do you say the same about Cleveland Clinic studies?

All except one.

His study isnā€™t even in direct contradiction to the one I referenced. I posted it in response to someone who was disappointed that Fisetin is a dud. This was just the latest paper with evidence that fisetin does work as intended as a senolytic. It adds more weight because it examined sheep organs where previous studies were in rodents. It provides evidence of its in vivo senolytic effects in a longer-lived mammal.

There is also a new study showing it likely works in skin.

Regardless, the ITP Fisetin studies unfortunately did not find that it extended lifespan with the protocols they used. There was also a murine quercetin lifespan study from the 80ā€™s and it may have shortened lifespan.

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#7

There is no compelling evidence for fisetin or quercetin supplementation.
There are many factors in question, such as actual absorption.
The number of doubters is increasing.

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#8

Agee. Canā€™t find a good reason to take these.

The study by the op is a pre-publish and not peer reviewed right?

#9

I agree that the evidence for the use of fisetin is not compelling. The Mayo Clinic (Kirkland) was spearheading this research. The data was supposed to be out about a year ago. It hasnā€™t arrived. Therefore, itā€™s probably not worth pursuing further.

Quercetin is a senolytic booster. It doesnā€™t do much on its own, but I have read from several other sources that when used with senolytics (such as Dasatinib), it enhances their effectiveness. Supposedly, Rapamycin is a senomorphic, but when paired with Resveratrol becomes a senolytic.

I guess Rapamycin + Resveratrol makes the cells not want to repair themselves and just commit suicide instead (apoptosis).

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#10

This is a fascinating topic, and I was going to start a fresh item on this.

I love this review ā€¦ with so much caution ā€¦ but with this degree of caution, Iā€™m sure theyā€™d also advise strongly against Rapamycin.
https://longevity.technology/news/avoid-the-use-of-dq-as-a-senolytic-therapy/

However, I have a series of articles that I really like on this topic, including human trials. Especially in the area of neurodegenerative decline.

I have an increasing number of patients with early Parkinsonā€™s Disease (or genetics likely to lead to this) or with 1 or 2 copies of ApoE4 and concerns in regard to Alzheimerā€™s Disease.

Nature Article

Life Extension Article

https://pubmed.ncbi.nlm.nih.gov/35042834/

https://pubmed.ncbi.nlm.nih.gov/31542391/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9924942/

https://pubmed.ncbi.nlm.nih.gov/30762245/

Iā€™m really interested in hearing from folks with neurodegenerative risk/decline/fear and whether they are doing this, if so, how often, what their experience has been.

Iā€™m also really interested in another topic in this same space, have individuals been using any of the ketoneaid products, especially with Alzheimerā€™s concerns and seeing marked improvement?

Same question with experience on stabilizing these same issues, or reversing with Rapamycin?

The space of neurocognitive decline is widely feared and it seems to me like these 3 treatments Rapamycin, Ketones, Dasatinib/Quercetin or Fisetin, in addition to health optimization for lipids, optimal HBA1C (~4.7%), blood pressure optimal management and a nutrient rich diverse diet that optimizes gut health is really the combination needed.

Anyway, would really enjoy hearing what people on the forum are doing in this space and what their experiences have been if utilizes these agents.

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#11

I have taken some KE4. I have tried lots of interventions and in the round they help with the way my body functions. However, it is hard at times to identify which intervention is key. I cannot say that anything particularly changed from KE4. I initially used it when having sleep maintenance issues. It is a bit of an odd taste and more expensive than malt whisky (the cheaper malts). I donā€™t know if I will buy any more, but I will use up that which I have. I take 5ml at a time.

It may help me sleep, but I tended to use melatonin at the same time and I know that gets me back to sleep (and how to use it).

I have no quantitive mechanism by which I can say my cognition has improved. My sleep has improved and I think my cognition has improved. I think part of the cognition improvements came from melatonin hectodosing.

I am of the view that there is not a proper understanding that the nocturnal concentration of melatonin in CSF is many times that in serum. This means the brain is used to being washed in high concentrations of one of the best anti-oxidants.

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#12

Very interesting - Iā€™ve done their Hard Ketones in place of having some wine for the last couple of weeks, and it has been a good thing in regard to HRV, Resting Heart Rate and Sleep parameters on Oura. Itā€™s different - but also isnā€™t the KE4 product which is a different ketone generator that isnā€™t intoxicating.
Yes the melatonin is interesting - on some patients I combine this with the salivary testing for cortisol curve, a spot check of DHEA and then multiple point melatonin. It does seem like this testing does correlate nicely with dysfunction - it is more complicated as to how to address that dysfunction.

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#13

Melatonin is complicated because it
A) is injected into the CSF first (either entirely or mainly by the pineal)
B) Has a signalling effect at the start of the HPA cycle

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