Fisetin experimentation one year (reposted as topic for info purposes)

Fred Cloud thank you for the helpful information. That encourages me continue taking it as I do enjoy the boost in athletic performance as I like my pulse to be at least in the 150s when working on the bicycle.

Fred Cloud s

Allen DeLaney 

Fred, So, if I umderstand you correctly, The Mayo Climic studies got it all wrong w their senolytic dosing intervals because the senolytic effects dissapate or resolve after 2 weeks, & the senolytic celks really weren't killed... 

Fred Cloud 

Fred, could you please supply a reference or article  for 'the known effect of boost in performance' from ingesting a senolytic'  I haven't come across any science supporting this purported immediate effect..  I must be looking in the wrong place... 

Allen DeLaney It looks like you are dealing with some personal struggles Allen, I wish you the best.

Fred Cloud Thanks for sharing your anecdotal evidence, Fred.  I should share mine as well, so here goes.  

My own anecdote is different in that I haven't yet been able to clearly correlate (without highly suspecting intervening variables) any boosts in performance with my ingestion of senolytics, which is typically at least a monthly double strength dose of Life Extension's Senolytic Activator along with relatively high doses of a few other possibly senolytic (by preliminary evidence) supplements such as grape seed extract, gingko biloba, etc.

An example of something that I have more clearly correlated, not surprisingly, is the lowering of my resting heart rate with my increased number of daily minutes of vigorous exercise (at roughly 90% [?] of my maximum heart rate).  I controlled as much as reasonably possible for confounding variables. 

We're all different, of course, which could be one explanation.  I'm a quite healthy semi-retired 72 year old, but no doubt have (or had?) a fair number of senescent cells.  Perhaps I'll eventually see a senolytic ingestion/performance boost correlation in myself.  Or maybe not!

Allen DeLaney Brian Valerie We may be assuming the wrong action of Fisetin. People have written since 2011 about Fisetin "killing" senescent cells by making them targets of the cell cleanup machinery. But what if fisetin simply shuts down the production of the harmful SASP that those cells secrete?

I just read this at FightAging.org about fisetin: "Fisetin has the potential to reduce senescence markers in multiple tissues in murine and human subjects." The bold type is mine. So maybe these researchers found that the Markers of senecence were reduced  but did not go looking for individual senecent cells (which is probably very difficult).

This would go a long way to explain why several people here seem to get almost immediate results from Fisetin and seem to need to repeat the treatments every 2 to 3 weeks.

Dean W. 

    As I recall, the Mayo Clinic work identified Fisetin and D+Q as senolytics, i.e., senescent cell killers, in part by observing cultures of human cells that had been made senescent by X-rays and then killed by applying a test senolytic to the cell culture.  (There are other things that suppress SASP, but Fisetin and D+Q do not.)  That cell culture test on many possible molecules is how they identified Fisetin as a senolytic in the first pace.

    Further, there is the subjective evidence that those of us who do periodic senolytic sessions experience symptoms for a day or so that resemble coming down with the flu.  Shutting off SASP would not be expected to produce those, while dumping the residue of killed cells into the bloodstream should.

JGC All good info. Personally, I have not read about anyone getting flu-like symptoms and I have experienced zero change after completing 3 days of fisetin at 30 mg/kg a day. For the past 3 years, twice a year. I am old enough to have senecent cells too.

Dean W. You might need to do it once a month to really get results. Many people when they first start out do get flu-like symptoms or it just feel weirded out. I'm not sure if flu like symptoms is actually what you would call it. But definitely something where you feel a little off center. Now I just feel better with less pain in my joints and I can do a better yoga with more bending etc lots of little things that show a difference

Dean W. 

Dean W. Also you might try the dasatinib combined with a question which was the original Mayo study. I mix that into the mix. I do that first and then a couple 3 hours later I do the fisetin large doses like you...

You can start off with 50 mg of dasatinib but always get approval from your doctor first,.... Hopefully they'll come out with a special with something that is not a cancer drug although this is a relatively mild one and well researched as people use this one for many years when they have leukemia so it's one of the more benign ones but you never know everybody's reaction can be different

garland woops u mix the dasatinib with the quercetin to start off with.... You might try the ones from Life extension as they stay in the system a lot longer

garland Yes, as part of my senolytic protocol I use the Life Extension Senolytic Activator, which they say contains "ultra-absorbable" forms of quercetin and fisetin, along with apigenin, and substitutes relatively benign tea leaf extract theaflavins for the dasatinib, but only provides references to what seems to me rather less than particularly meaningful preliminary evidence that these theaflavins, while evidently senolytic, are as effective to use with quercetin as is dasatinib. 

garland Thanks for the suggestions. I will try it once every 2 months for awhile. I am a bit leary because a recent study found a slight increase in epigenetic age after taking fisetin with or without D+Q. (see  https://www.fightaging.org/archives/2024/03/human-data-on-epigenetic-age-following-senolytic-treatment/  )

My doctor will not prescribe dasatinib for me. She is very worried about any off-label prescription writing. I need a new doctor and so I am looking for a  doc who keeps up with the latest science.

Dean W. In defense of your doctor, very, very few doctors will prescribe off-label dasatinib (or rapamycin).  It's not because they're necessarily unaware of the research either, which most of them (and I) see as still in a rather preliminary stage, but many no doubt fear that a future malpractice lawsuit may actually have legal merit.  I'm okay with waiting what may well be only another year or two for further evidence from the significant amount of currently ongoing research.  In the case of rapamycin, some of its analogs ("rapalogs") that are being researched have given hope of potentially being more effective and/or safe for long-term use than rapamycin itself.

Brian Valerie I forgot to mention that I use 24 mgs of fisetin about 3 hours after I do the dasatinib quercetin combo. i use the one from Life Extension which stays in your system for many more hours.....I like the Fisetin more than the other combo.... seems to add a sparkle to my life... 

IMPORTANT DASATINIB SUBSTITUTES UPDATE!  Just published: Meiners, et al., "Computational identification of natural senotherapeutic compounds that mimic dasatinib based on gene expression data", Scientific Reports, 14, 6286 (2024). I quote from lifespan.io: "Unfortunately, dasatinib activity frequently leads to adverse side effects, such as skin irritation, fluid retention, reduction in blood cell production, and diarrhea....the authors used computational approaches to identify natural senotherapeutic candidates that have similar properties to dasatinib....these included piperlongumine, parthenolide, curcumin, and phloretin, with piperlongumine [found in long pepper] being the most promising candidate."  I find it interesting that Life Extension's Senolytic Activator's (which I use and which garland  suggested to  Dean W. ) substitute for dasatinib, black tea theaflavins, was not identified.   

Brian Valerie Thanks, Brian. Good to know someone has looked into this. I always wondered why Life Extension thought black tea theaflavins would be a substitute for dasatinib. There is nothing in the literature that I could find which supports it. I tried one bottle a while ago with no noticable effects.

Brian Valerie I see that Amazon sells one pound jars of Long Pepper seeds for about $25. I found that an extract of the seeds with methanol yields 99.3% piperlongumine:

"Together with their analytical characteristics, the P. longum fruit extract analytically characterized to contain 1.75% piperine (PLE) and almost pure piperlongumine (99.33%) isolated from P. longum roots used in this study were generously supplied by Sami Labs Limited, Bengaluru, India. The extract PLE is a methanolic extract of dried and powdered fruits of P. longum fruits and purity of piperlongumine and piperine contents of the PLE sample were established by HPLC using acetonitrile and water as mobile phase."

Dean W. That quote is from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067934/

Dean W. Thanks for sharing that, Dean.  Another alternative on Amazon is CellFend brand fermented (to increase bioavailability) long pepper extract capsules, with 10 mg of piperlongumine per two capsule serving.  I have a subscription from Amazon for this product for which I pay $22.91 for a bottle of 60 capsules.

Brian Valerie Piperlongumine is fascinating.

Piperlongumine promotes autophagy via inhibition of Akt/mTOR signalling and mediates cancer cell death - PMC (nih.gov)

Discovery of piperlongumine as a potential novel lead for the development of senolytic agents - PMC (nih.gov)

"PL is a natural product that is reported to have many pharmacological effects, including anti-tumor activity. We show here that PL preferentially killed senescent human WI-38 fibroblasts when senescence was induced by ionizing radiation, replicative exhaustion, or ectopic expression of the oncogene Ras. PL killed SCs by inducing apoptosis, and this process did not require the induction of reactive oxygen species. In addition, we found that PL synergistically killed SCs in combination with ABT-263"

Piperlongumine induces rapid depletion of the androgen receptor in human prostate cancer cells - PMC (nih.gov)

"Androgen receptor (AR) signaling is regarded as the driving force in prostate carcinogenesis" 

"RESULTS
The results of our experiments demonstrate that PL rapidly reduces AR protein levels in PC cells via proteasome-mediated ROS-dependent mechanism. Moreover, PL effectively depletes a modified AR lacking the ligand-binding domain, shedding light on a new paradigm in the treatment approach to prostatic carcinoma that expresses mutated constitutively active AR. Importantly, PL effectively depletes AR in prostate cancer cells at low micromolar concentrations, while concurrently exerting a significant inhibitory effect on AR transcriptional activity and proliferation of prostate cancer cells.

CONCLUSIONS
Our investigation demonstrates for the first time that PL induces rapid depletion of the AR in prostate cancer cells. As such, PL may afford novel opportunities for both prevention and treatment of prostatic malignancy."

Staffan Olsson Thanks for sharing this truly fascinating info, Staffan.  My best guess is that PL will also prove to have fewer side effects than dasatinib.