Nalakrats has in two major posts shared fascinating insights on senescence and senolytics, drugs that selectively clear senescent cells. I am most grateful to him for this, which set me off on a journey the results of which I sum up in this post. Senescence has also recently been well reported on by TA and Mateo Beach.
Senescent cells cause much illness. For many of us on this Forum, senescent prostate cancer cells lurk undetected and are ready to strike at the right moment.
Crucially, a leap, albeit tenuously and tentatively, has been made from in vitro/vivo to two small completed and fairly successful open-label clinical trials for the senolytics combo Dasatinib (D) + Quercetin (Q) on patients with two disparate illnesses. ncbi.nlm.nih.gov/pmc/articl... ,and Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease - EBioMedicine (thelancet.com) with a corrigendum of the latter largely confirming the results with the main conclusion unchanged: a decrease in cells with markers of senescence and a reduction in senescent cell burden. The first study showed clinically meaningful improvement in physical function in IPF-disease patients: “These findings constitute preliminary proof-of-concept evidence that interventions designed to target senescent cells may alleviate functional consequences of aging-related diseases in humans, as is the case in mice”
I have tried to penetrate what conclusions that can be drawn from these and other studies for my own decision on starting senolytics.
The following is largely taken from those two studies and from “Senolytic drugs: from discovery to translation” onlinelibrary.wiley.com/doi... with dr Kirkland of the Mayo Clinic as lead author. He and others have initiated an array of clinical trials on D+Q plus an additional senolytic also highlighted by Nalakrats, Fisetin.
From the latter article, which is an overview and makes for powerful reading together with the articles above: “Thus, as in mice, D+Q can successfully decrease senescent cell burden in humans”.
An important caveat: Each article cautions that the senolytic drugs should not be used outside of carefully monitored clinical trials. Although the research has been conducted in compliance with Mayo Clinic Conflict of Interest policies, the authors have a financial interest related to the research and patents on senolytic drugs are held by the Mayo clinic.
In a nutshell, D+Q appear to transiently disable networks of senescent cell anti-apoptotic pathways (SCAPs) that enable senescent cells to survive despite their own apoptotic environment “inflammatory senescence-associated secretory phenotype” SASP, which can target neighboring healthy cells. Stated simply, targeting the SCAP nodes kills senescent cells.
The target
The target of senolytics is senescent cells in general, not a molecule, a single biochemical pathway or a single disease. This is congruent with the in vitro/vivo studies and indicated by the two highly disparate illnesses targeted in the first reports from clinical trials. The second clinical trial states that oral administration of D + Q decreases overall senescent cell burden, as opposed to targeting senescent cells within a single organ or structure.
The illnesses targeted in these two clinical trials are far from cancer, let alone prostate cancer. But if the hype holds up, many diseases including cancer will be targeted . The therapeutic effects of one of the substances, Q, have been assessed in a wide array of illnesses and diverse cancers including prostate cancer in preclinical trials, as shown in a recent review reported on this Forum by to23456 “Emerging impact of quercetin in the treatment of prostate cancer” sciencedirect.com/science/a...
Different types of senescent cells use different SCAPs or even redundant combinations of SCAPs to evade apoptosis, meaning that agents targeting a single SCAP would only be expected to eliminate a subset of senescent cells. It has been found that D targets senescent human adipocyte progenitors efficiently but not senescent human endothelial cells, whereas the opposite is the case for Q; . D+Q combined appear to more comprehensively disable SCAP networks. For this reason the combo D+Q is used in the preclinical and clinical trials.
With targeting of senescent cells being a systemic therapy not limited to a particular disease, with the leap to humans tentatively done for two disparate illnesses, and with a large array of preclinical studies showing effects on prostate cancer, my hunch, without any science to back it up, is that the odds of a leap to humans for prostate cancer are dramatically improved for the combo D+Q, although very far from proven.
Any self-experiment on a potentially far-reaching but unproven drug combo is in my view contingent upon a likely low risk of serious side effects.
Side effects
There is a daunting list of serious side effects given for D, with low blood cell counts, severe bleeding and fluid retention given as the most common in sprycel.com/side-effects-in.... A total of 13 side effects are stated as common – occurring in more than 10 % of patients using chronic D 100 mg/day – in cancerresearchuk.org/about-... See also mayoclinic.org/drugs-supple... and drugs.com/sfx/dasatinib-sid...
The risks in using D for senolytic purposes are reduced by senolytic dosage being intermittent. In the second clinical trial, a single 3-day oral treatment regimen with D 100 mg daily and Q 1000 mg total daily (500 mg twice daily) was administered to all participants on Study Days 1 to 3, after which nothing more was given. This is because if and when senescent cells have been killed, they take weeks to reaccumulate including the time required to form a SASP. There is no apparent need for new senolytic medication until that is estimated to have happened.
From the second clinical trial of D+Q: “D has been used for 20 years to treat certain cases of chronic myelogenous leukemia and acute lymphoblastic leukemia. D is usually administered continuously with a tolerable side effect profile at 100 mg/day (the dose used in the trial for only a total of 3 days) for years or even over a decade in patients with chronic leukemias. While D can sometimes cause transient and reversible platelet deficiency, this is uncommon. Even with hematological malignancies that themselves can cause platelet depletion, significant (class 3/4) bleeding occurs in <1% of patients on continuous D treatment. This usually only occurs after months of uninterrupted D administration, unlike the intermittent D regimen used in the clinical trials”.
As for Q, it is a substance found in some foods and is used at much higher dosages for therapeutic reasons including, I believe, by many on this Forum, with chronic use of 500 - 1000 mg a day mentioned. TA and Phil S reported on evidence indicating that (chronic) Q may reduce serum ferritin. Senolytic use of Q is intermittent.
How to do it
If one chooses to take a calculated risk with an uncertain but potentially great benefit in trying D+Q, how would one do it?
The same dosage of the second trial, 100 mg D and 1000 mg Q daily for three days, is used in the one other D+Q trial that I could find dosage info on, for haematopoiatic stem cell transplant survivors, with estimated study completion date in December. In the one animal trial that I checked a 3.5 times higher dosage for each of D and Q was used, on a per kilo weight basis. The multiday trials I checked for mice were between 3 and 5 days. Perhaps the researchers are conservative when determining the dose for humans in the first trials, or perhaps they have simply used the typical dosage apparently used for D for its clinically approved purpose, and what is often used by humans in taking Q for other therapeutic purposes. Intuitively it seems reasonable to use the same three day 100/1000 mg dosage for initial self-experimenting.
Underlying the research is an implicit assumption that D+Q needs to be taken again at some point. From one of the studies: “Because senescent cells can take weeks to months to develop and do not divide, and because even eliminating only 30% of senescent cells can be sufficient to alleviate dysfunction in preclinical studies,D + Q is as effective in mice if administered intermittently, for example every 2 weeks to a month, as continuously, even though D and Q have elimination half-lives of only 4 and 11 h, respectively”. “From initiation to the attainment of a completed state of cellular senescence takes from 10 days to 6 weeks”. The latter is followed by “at least in cell culture, depending on the cell type and the inducers driving the cell into the senescent fate”. I have not been able to find anything on (estimated) time for reemergence of senescent cells with SASP for humans.
In the second clinical trial, key markers of senescent cell burden were decreased in biopsies taken from patients 11 days after completing the 3-day course of D + Q i.e. 14 days from the start. Based on that and on the bold assumption that the maximum time before development of new senescent cells is similar in humans to human cell culture and mice, the frequency of a 3-day regimen would be between 14 days and 6 weeks. To minimize side effect risks, something close to the latter or even longer would be chosen with the risk of missing reemerging senescent cells by a few weeks or not rapidly retargeting senescent cells not killed by the first 3-day regimen. A more aggressive approach, in the absence of noticeable side effects, would be closer to the shorter time frame, and/or following up with 4 or 5-day regimens.
Quercetin
Q has poor bioavailability. With a tip from a fellow member on the Forum, I am (initially) using Tesseract´s QuerciSorb. According to the statement of the manufacturer, the relevance of which I cannot evaluate: “Tesseract’s proprietary and patent-pending science ….isolates individual molecules of an active ingredient to achieve nano-level scale. Second, CyLoc technology then encases each molecule of the active ingredient in its own dextrin delivery cage, thus eliminating the issue of unpalatable taste and smell. And third, Tesseract’s one-of-a-kind, proprietary DexKey technology accompanies the molecule and breaks the cage at the desired release point in the intestinal tract, thus resolving the problem of poor absorption and further enhancing proprietary absorption mechanisms already in place and supplementing the body’s own efforts”
A related question is whether to go for chronic, rather than intermittent, Q, together with intermittent D. There is a variety of possible benefits for chronic Q. On Q alone, without D, I found one clinical trial on cancer, from 1996, with infusions of Q leading to “evidence of anti-tumor activity”. pubmed.ncbi.nlm.nih.gov/981... From one review from 2015 reported on by to23456 on this Forum: “Meanwhile, epidemiologic studies have demonstrated a negative association between quercetin intake and prostate cancer incidence and have suggested a chemopreventive effect of quercetin on prostate cancer…”. There is promising evidence of chronic Q for other illnesses e.g. Covid-19, with anti-inflammatory action stated as the reason in e.g. nutritionaloutlook.com/view...
I suspect some on this Forum may already be using D+Q, or thinking of starting. From them and any others I welcome feed-back, here or by messaging.
I end by paradoxically restating the caution from the researchers that the drugs are not to be used outside carefully monitored clinical trials.
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