Interactions between your drugs
Applies to: acarbose and sirolimus
Sirolimus may interfere with blood glucose control and reduce the effectiveness of acarbose and other diabetic medications. Monitor your blood sugar levels closely. You may need a dose adjustment of your diabetic medications during and after treatment with sirolimus. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.
Some good news on senolytics:
Results: Here, we demonstrate that D+Q alleviate LPS-induced senescence in HUVECs via inhibiting autocrine and paracrine of the senescence-associated secretory phenotype (SASP). We further confirm that D+Q alleviate HUVECs senescence via the TNF receptor-associated factor 6 (TRAF6)-MAPK pathway. Mechanically, this study validates that D+Q suppress SASP by upregulating m6A reader YTHDF2. Besides, YTHDF2 regulates the stability of MAP2K4 and MAP4K4 mRNAs. Conclusion: Collectively, we first identified that D+Q alleviate LPS-induced senescence in HUVECs via the TRAF6-MAPK-NF-κB axis in a YTHDF2-dependent manner, providing novel ideas for clinical treatment of age-related cardiovascular diseases.
Do you have a longevity opinion on senolytics so far, and if so, what protocol would you suggest (not asking for medical advice, but a science based opinion of efficacy in longevity)
My opinion is to “wait and see”.
Won’t get deep in the weeds, but exercise and rapamycin to suppress SASP are enough for my age to buy time on clarity for the complexity involving senescence cells.
I’ll also add there could be unanticipated off-targets (i.e. see wound healing and tissue regen, particularly in the liver). I have a feeling the anti-aging community at large generally is going down the “XYZ = bad = must destroy” mindset and I prefer to wait on the gaps in the literature.
Lustgarten’s take on SASP is that the inflammation helps your immune system fight off microbial burden. As you get older, microbial burden gets greater and the senescent cells’ constant production of SASP helps keep them in check.
I wonder if the magic in Rapa is just it’s ability to reduce microbial burden? Too simple.
Yeah, he’s going much more in-depth and I had a few other speculative theories on direct vs indirect effects, but basically, way too many people are eating up the “senescence cells are bad zombie cells that must be destroyed” story without actually reading papers beyond the abstract.
Similar to the groupthink that goes on with “mTORC2 inhibition = bad”. It’s just not clear and there’s enough to go off that suggests otherwise.
It’s not just anti-aging forums. I’ve seen enough scientists and medical professionals that are not immune to thinking one way, but not the other. It boils down to my main heuristic - if you can’t think of the strongest argument of the other side, you probably don’t understand it enough.
BTW, there are multiple potential natural MEK inhibitors in the traditional Okinawan diet with IC50 at bioavailable amounts
Bicep, you’ve got a good point there. It’s something that has occurred to me more than once over the last year or so.
I am taking only 3 mg of Rapa but I also take a Life Extension 3 pill per week protocol Only on my Third dose of both so too soon to tell outcome. Recently read an article of a trial called UBX1325 , injecting Senolytic into eyes with AMD and results are very positive , I have AMD . Apparently it is the senescent cells that are damaging the rods and cones . Maybe the Rapamycin is sufficient to destroy the scenescent cells ?
There are some people I just greatly admire and Dr. Blagosklonny is one of them. I think he is brilliant.
There are so many conflicting opinions on which drugs, supplements, etc that it is hard for a layman to tell who is right.
Since I do not have a medical or biological background, I have to choose someone to follow. I have chosen to follow Dr. B’s advice on rapamycin protocols and I try to keep up with his blogs.
If doctor Blagosklonny thinks “senolytics” works by slightly suppressing mTORC1, then I think I can safely drop them from my list of supplements and rely on rapamycin for mTORC1 suppression.
It has not been proven that senolytics such as fisetin can selectively induce the death of senescent cells and improve health in humans.
I am trying to reduce, not add to my many supplements. So, it appears that there is not enough research to prove fisetin is a selective senolytic. I will now be dropping it from my list of supplements.
Mikhail Blagosklonny is a scientist who studies cancer and aging and has an M.D. in internal medicine and a Ph.D. in experimental medicine and cardiology. He is a professor of oncology at Roswell Park Comprehensive Cancer Center.
“By the strict definition given by Kirkland , the existence of senolytics has not yet been proven. Although F and D+Q decrease the number of SA-β-gal and p16-positive cells in some tissues, there is no proof that this decrease is due to the killing of senescent cells in the organism. It could be due to reduction of these markers per cell, or even cell rejuvenation. In fact, rapamycin, which does not kill senescent cells, decreases expression of SA-β-gal and p16”
[Anti-aging: senolytics or gerostatics (unconventional view) | Oncotarget]
Senescent cells can arise throughout the lifespan and, if persistent, can have deleterious effects on tissue function due to the many proteins they secrete. In preclinical models, interventions targeting those senescent cells that are persistent and cause tissue damage have been shown to delay, prevent or alleviate multiple disorders. In line with this, the discovery of small-molecule senolytic drugs that selectively clear senescent cells has led to promising strategies for preventing or treating multiple diseases and age-related conditions in humans. In this Review, we outline the rationale for senescent cells as a therapeutic target for disorders across the lifespan and discuss the most promising strategies—including recent and ongoing clinical trials—for translating small-molecule senolytics and other senescence-targeting interventions into clinical use.
Cellular senescence and senolytics: the path to the clinic
Below is a different view. Authors are from Mayo Clinic, and Scripps Research Institute. James Kirkland is a co-author:
“Fisetin selectively induces apoptosis in senescent but not proliferating human umbilical vein endothelial cells (HUVECs).”
“Fisetin induces apoptosis in senescent HUVECs. HUVECs were treated with fisetin for 12h and then caspases-3&7 were assayed using a luminescent substrate. Fisetin (500 nM) induced apoptosis in senescent cells by caspase 3/7 assay.”
Unfortunately the tests were not done on mice, rats, humans etc.
Fisetin in vitro is a far cry from the human digestive tract.
I’m not saying for anyone not to take fisetin, it’s just that there is no proof it does anything in humans.
If there is proof that fisetin does anything in human, I would be glad to hear about it.
“We found that fisetin and the BCL-XL inhibitors, A1331852 and A1155463, are senolytic in vitro, inducing apoptosis in senescent, but not non-senescent HUVECs.”
“performed or taking place in a test tube, culture dish, or elsewhere outside a living organism.”
There was a study done on progeroid mice,
later confirmed with naturally aged mice.
Good find. Fisetin is relatively cheap to take as a supplement.
I was using the high pulse periodic, once monthly dose.
I still have some left so I probably take it again. Nice to find anything that seems to work for aged animals.
“Fisetin treatment extended the health and lifespan in WT mice even when treatment was initiated in aged animals”
would like to hear the dose and frequency of Fisetin that others are taking?
I take 10 grams, yes, that is 10 grams, on one day, once a month.
“Importantly, no adverse effects of fisetin have been reported, even when given at high doses . Thus, our results suggest that supplementation or even intermittent treatment with this safe, natural product could improve healthy aging, even in elderly individuals.”
This is the brand I have been using. This does not imply an endorsement:
Fisetin 500mg - 98% Pure Fisetin Supplement (Similar to Apigenin, Luteolin, Quercetin) Senolytic Activator - Sirtuin Activator - Bioflavonoid Polyphenols - Non-GMO, Vegan, Soy Free - by Humanx
There is a long thread of personal experiences that is two years long. There are tweaks, bloodworks before and after fisetin ingestion, and combo - fisetin + dasatinib and Quercetin.
Thanks for the info. Rationale for 10 grams one day a month?
For me the rationale is that a higher dose is more likely to work, then once dead they should not have to be treated again.
Like weeds in a field. Spray a dose toxic to the weeds, not to the crop, then go on to the next job.