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Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in i

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#1 VP.

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Posted 18 September 2019 - 09:27 PM


Abstract
Background

Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans.

Methods

In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68·7 ± 3·1 years old; 2 female; BMI:33·9 ± 2·3 kg/m2; eGFR:27·0 ± 2·1 mL/min/1·73m2). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed.

Findings

D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated β-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16INK4A+ and p21CIP1+ cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and −12.

https://www.ebiomedi...0591-2/fulltext

 


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#2 Daniel Cooper

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Posted 18 September 2019 - 09:41 PM

Thanks for posting this.  

 

This is getting to be very interesting.

 

 



#3 Rocket

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Posted 19 September 2019 - 12:24 AM

Reminds me I am out. Take it every 6 months but in about double those doses. I am convinced it has improved my egfr numbers as seen in blood tests. I don't think the Q does anything and have omitted early on.

#4 William Sterog

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Posted 19 September 2019 - 02:05 PM

Any news about the effectivity of Fisetin in humans?

#5 Daniel Cooper

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Posted 19 September 2019 - 05:47 PM

Reminds me I am out. Take it every 6 months but in about double those doses. I am convinced it has improved my egfr numbers as seen in blood tests. I don't think the Q does anything and have omitted early on.

 

I apologize for not having the reference on hand, but I thought that the evidence was that the D and the Q each targeted different cell types for elimination.  If I recall muscle cells vs. endothelial cells?  

 

I'm in a facility that blocks access to sci-hub at the moment so I can't look it up.



#6 Mind

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Posted 19 September 2019 - 06:04 PM

Any news about the effectivity of Fisetin in humans?

 

No results from human trials yet, but here is a review of what is known so far. https://www.longecit...-23#entry879240


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#7 Daniel Cooper

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Posted 19 September 2019 - 06:45 PM

No results from human trials yet, but here is a review of what is known so far. https://www.longecit...-23#entry879240

 

 

We really need a senolytic forum to keep this all in one place.


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#8 VP.

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Posted 19 September 2019 - 06:51 PM

I think senolytics have advanced enough to have their own forum like resveratrol, C60 etc. A separate thread for results is needed in the forum too. I usually head to the Reverse Ageing forum because posts are better organized there. 


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#9 OP2040

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Posted 19 September 2019 - 07:37 PM

I'll third that senolytics forum idea.  

 

I would like to know where everyone's getting Dasatinib.  If possible, can someone PM me about it?  And if you can also hold my hand and allay my fears about the riskines sof this substance, that would be great too. Thanks.

 

As for this study, I share the frustration of some people.  I've definitely wondered why they don't just push faster and harder with some of these potentially groundbreaking interventions. 

 

On the other hand, it's a sign of how well things are going that a study like this comes out and we're all like "oh, that's cool, <shrug>.  Just two or three years ago, this would have blown our minds.  D+Q has an almost unbroken record of positive interventions from planaria to people now.  Senolytics are not like most of the other interventions people focus on, because the result isn't simply tweaking metabolism.  It should translate to humans quite nicely.  

 

My senolytic protocol was/is Q+F+C, once a year for a few weeks, but now I want to add in the :D  

I may also do a before and after test next time I do this protocol. A before and after skin test (galactose) should be feasible and someone just needs to do it.

 

 



#10 Daniel Cooper

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Posted 19 September 2019 - 07:52 PM

OP2040 - PM sent

 

As to why more research isn't being done - the pharmaceutical have a real problem with treatments that actually fix underlying disease causes. 

 

This isn't something necessarily nefarious.  We haven't had much luck in addressing underlying causes and fixing them till lately.  So we've done bandaid treatments that require continuous pharmacological intervention.  So all of our pharmaceutical companies are built on a model of making drugs that you are on for life basically.  They don't know how to exist on something that is a one time or perhaps once per year treatment.

 

This is going to be something that will have to be resolved going forward if medical advancement is to continue.

 

 

   


Edited by Daniel Cooper, 19 September 2019 - 07:56 PM.

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#11 OP2040

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Posted 19 September 2019 - 08:21 PM

Totally agree Daniel.  I don't necessarily see it as nefarious, just built into the system we have.  There have been a lot of good government reforms in the last decade that should help, including new health care bills, right to try and clinical trials tweaks.  But even the big corps are starting to get in on the act, the biggest thing being the development of a subscription model for high cost cures.  At the end of the day, it will have to be a political solution and whole new markets will likely need to be created to reflect the changing reality.   All the pieces are there, they just need to be put together.

 

One thing I'm shocked hasn't happened yet at the university level is a strong multiple intervention study in mice.  We now have very good interventions for all the hallmarks of aging in mice.  It could be done quite easily.  And after that we would have a much better idea of our theoretical grasp of the situation, and how many "known unknowns" may be lurking out there. 

 

Of course this is another system problem though, right.  Scientists are too specialized.  David Sinclair worked on Sirtuins primarily for most of his career and only recently even addressed epigenetics in a separate paper.  CNIO has a great telomere group with Blasco, et al, but that's what they work on, telomeres and not much else. Each of these groups is touching a part of the elephant, but they won't see it until there is some cross-pollination.

 


Edited by OP2040, 19 September 2019 - 08:27 PM.


#12 VP.

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Posted 19 September 2019 - 08:40 PM

The Age Reversal Forums has lots of info on dosing, sources and some results. 

https://forum.age-reversal.net/

 

 

As for risk that is something you have to decide. Don't take it unless you are at least 50 and try a small dose first to see if you have a reaction.. Yesterdays study has this to say about the safety of Dasatinib:

 

This finding of a sustained decline in senescent cell burden means that D + Q is not likely to exert its effects through off-target mechanisms of the type involving continuous occupancy of a receptor or from modulating an enzyme, but rather it is more likely that D + Q kills slowly-reappearing, non-dividing senescent cells. Such intermittent administration of senolytics could reduce side effects. For example, D is usually administered continuously with a tolerable side effect profile at 100 mg/day (the dose used here for only a total of 3 days) for years or even over a decade in patients with chronic leukemias [61]. Most potential side-effects of D can be avoided though intermittent administration and, generally, serious side effects of D reverse upon temporary discontinuation [62,63], increasing the value of the opportunity to administer D intermittently, yet still benefit from its senolytic effects.

 

 


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#13 OP2040

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Posted 19 September 2019 - 09:11 PM

I'm only 45, but I think that's plenty old enough.  Whether we want to believe it or not, senescence starts at least as early as 40 by most measures. 

 

I did see that in the study, so maybe short term dosage is quite safe.  I was reading the wiki article with things like PAH and edema.  Sometimes I wonder about these longs lists of side effects.  If they are coming mostly from people who are already quite sickly, for example leukemia, the it probably is quite skewed.


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#14 Rocket

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Posted 20 September 2019 - 12:15 AM

OP2040 - PM sent

As to why more research isn't being done - the pharmaceutical have a real problem with treatments that actually fix underlying disease causes.

This isn't something necessarily nefarious. We haven't had much luck in addressing underlying causes and fixing them till lately. So we've done bandaid treatments that require continuous pharmacological intervention. So all of our pharmaceutical companies are built on a model of making drugs that you are on for life basically. They don't know how to exist on something that is a one time or perhaps once per year treatment.

This is going to be something that will have to be resolved going forward if medical advancement is to continue.


Yes!!
Original zicam wiped out colds in 2 or 3 days. Lawyers took it away.
When I had bad dermatitis that was not responding to prescriptions i did topical since and wiped it out. Told my doctor and he lectured me it was impossible.

Off topic I know.

#15 OP2040

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Posted 20 September 2019 - 06:48 PM

ok, I guess I'm not done with this.  Here is the full text from wikipedia for Dasatinib side effects:

 

 

Neutropenia and myelosuppression were common toxic effects. Fifteen people (of 84, i.e. 18%) in the above-mentioned study developed pleural effusions, which was a suspected side effect of dasatinib. Some of these people required thoracentesis or pleurodesis to treat the effusions. Other adverse events included mild to moderate diarrhea, peripheral edema, and headache. A small number of people developed abnormal liver function tests which returned to normal without dose adjustments. Mild hypocalcemia was also noted, but did not appear to cause any significant problems. Several cases of pulmonary arterial hypertension (PAH) were found in people treated with dasatinib.[6]

On October 11, 2011 the U.S. Food and Drug Administration (FDA) announced that dasatinib may increase the risk of a rare but serious condition in which there is abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension, PAH). Symptoms of PAH may include shortness of breath, fatigue, and swelling of the body (such as the ankles and legs). In reported cases, people developed PAH after starting dasatinib, including after more than one year of treatment.

Information about this risk has been added to the Warnings and Precautions section of the Sprycel drug label.[7]

 

 

What I find bizarre is the following.  I am on a forum where I participated in 20 pages of debate about the safety of Fisetin, a natural substance with absolutely no history of safety concern or toxicity.   Then I see almost everywhere else people nonchalantly taking Dasatinib or other concerning ones like Rapamycin.  I can't explain this discrepancy at all.  Nor can I explain the discrepancy that many people here have taken it with no problem reported at all. 

 

It can't be explained by the duration, because apparently some of the side effects do happen right after you start taking it.  Could it be dose size?  Is the dose for senolytic use much smaller than for cancer/other use?



#16 Engadin

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Posted 20 September 2019 - 07:29 PM

OP2040 - PM sent

 

As to why more research isn't being done - the pharmaceutical have a real problem with treatments that actually fix underlying disease causes. 

 

This isn't something necessarily nefarious.  We haven't had much luck in addressing underlying causes and fixing them till lately.  So we've done bandaid treatments that require continuous pharmacological intervention.  So all of our pharmaceutical companies are built on a model of making drugs that you are on for life basically.  They don't know how to exist on something that is a one time or perhaps once per year treatment.

 

This is going to be something that will have to be resolved going forward if medical advancement is to continue.

 

 

The following article seems to show, in Goldman Sachs words, the dilemma traditional big pharma is somehow facing these days: Are they already prepared for the 'one shot cure' era? What will their bussiness model look like when this new era arrives? In other words: 

 

 

 

 

“The potential to deliver ‘one shot cures’ is one of the most attractive aspects of gene therapy, genetically-engineered cell therapy and gene editing. However, such treatments offer a very different outlook with regard to recurring revenue versus chronic therapies,”

 

 

CNBC: Goldman Sachs asks in biotech research report: ‘Is curing patients a sustainable business model?’

 

 

 

 

.



#17 VP.

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Posted 20 September 2019 - 08:59 PM

ok, I guess I'm not done with this.  Here is the full text from wikipedia for Dasatinib side effects:

 

 

 

What I find bizarre is the following.  I am on a forum where I participated in 20 pages of debate about the safety of Fisetin, a natural substance with absolutely no history of safety concern or toxicity.   Then I see almost everywhere else people nonchalantly taking Dasatinib or other concerning ones like Rapamycin.  I can't explain this discrepancy at all.  Nor can I explain the discrepancy that many people here have taken it with no problem reported at all. 

 

It can't be explained by the duration, because apparently some of the side effects do happen right after you start taking it.  Could it be dose size?  Is the dose for senolytic use much smaller than for cancer/other use?

Toxicity is all about dose. Look at the bottom of this page to see someone who is taking probably at least 100 mg a day of Tasigna. He works full time as a fire fighter. For a 175 pound male you need one 200 mg dose a year of Dasatinib. The same goes for Rapamycin, the risk is small and doses are a fraction of organ rejection doses. I consider the risk but I believe it's low and worth the possible benefits. If you don't feel that way don't do it and wait 5-15 years for the studies. 

 

 

http://www.rajeun.net/Senolytics.html



#18 Daniel Cooper

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Posted 20 September 2019 - 09:13 PM

ok, I guess I'm not done with this.  Here is the full text from wikipedia for Dasatinib side effects:

 

 

 

What I find bizarre is the following.  I am on a forum where I participated in 20 pages of debate about the safety of Fisetin, a natural substance with absolutely no history of safety concern or toxicity.   Then I see almost everywhere else people nonchalantly taking Dasatinib or other concerning ones like Rapamycin.  I can't explain this discrepancy at all.  Nor can I explain the discrepancy that many people here have taken it with no problem reported at all. 

 

It can't be explained by the duration, because apparently some of the side effects do happen right after you start taking it.  Could it be dose size?  Is the dose for senolytic use much smaller than for cancer/other use?

 

 

You're talking about taking a medication for 3 days when you have people that are essentially on that particular medication for life in some cases.  Yes, if you have to take dasatinib for months and months to clear cancer cells then you certainly should worry about the side effects.  And I'm not saying not to worry at all about the side effects from using it as a senolytic.  But there is an ocean of difference between taking a drug for three days versus taking it for an extended period.


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#19 Rocket

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Posted 20 September 2019 - 11:57 PM

Well said Dan Cooper. People have no problem drinking liquor on a weekend night, but drink it all day and night for years and you got health issues.

Everything that is good for the body is also poison to the body, including purified water in too high a dose.

#20 OP2040

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Posted 24 September 2019 - 12:20 PM

So the usual/typical dose for senolytic use is 100 mg for 3 days?  I know this has probably been covered many times, but the usual problem of not wanting to go through many pages to find the information.  


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#21 roguereason

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Posted 24 September 2019 - 07:52 PM

Notice that the title says "decrease senescent cells".  I wouldn't consider D+Q at these levels to be a "do it once" and forget about it kind of therapy. A future senolytic might.

 

If I remember correctly they talked about different senescent cell types in two different tissues.  Fat and Skin. 

 

They also talked about some additional tissue specific cell types and structures that accumulate around those senescent cells (SAβgal-expressing macrophages for example).

 

I think senescent cell clearance was like 17-35% depending on cell type and tissue.  Please correct me if I'm wrong.  

 

I'd love to see a future report when this process is repeated.  Say 3 days a month for a few months.  How cumulative will the clearance levels be?

 

 



#22 OP2040

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Posted 25 September 2019 - 01:54 PM

apropos to the discussion about reform, Japan has been going in the right direction for  a while, as a couple papers in Nature reference today.  Unfortunately, the papers bring out the usual hyperactive safety concern trolling.  But the Japanese are saying basically what drug reformers are saying.  Legalize, regulate and advance through the system, because literally everyone wants the product and will go to great lengths to get it.  Unfortunately for us in the United States, civilization advances westward, and Japan, China and India are all moving in this direction.  Unless the U.S. reforms its archaic system, it will be left in the dust even with its current monumental lead in health technology.  Here is the more positive of  the two articles:

 

https://www.nature.c...586-019-02847-3



#23 aribadabar

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Posted 01 October 2019 - 08:32 PM

 

My senolytic protocol was/is Q+F+C, once a year for a few weeks, but now I want to add in the :D  

 

Which compound does C stand for in your protocol?



#24 OP2040

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Posted 02 October 2019 - 03:21 PM

Which compound does C stand for in your protocol?

 

Curcumin, which is also noted as a surprisingly strong senolytic.  Since curcumin is also an anti-inflammatory, some people will argue not to use it as it may enhance survival of cells.  I don't buy that argument, but I respect the opinion.



#25 OP2040

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Posted 02 October 2019 - 07:13 PM

Found a fairly cheap senescence assay here:

http://www.emdmillip...ay,MM_NF-KAA002

 

As usual for what I've been seeing there is always a nice clear protocol on how to use these things and usually less than 10 assorted pieces of adjunct lab equipment needed. None of the other lab equipment is all that difficult to get either.

 

So that leaves the biopsy as the only remaining barrier to doing this.  



#26 bhangchai

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Posted 13 October 2019 - 10:45 PM

Reminds me I am out. Take it every 6 months but in about double those doses. I am convinced it has improved my egfr numbers as seen in blood tests. I don't think the Q does anything and have omitted early on.

"By definition, the target of senolytics is senescent cells, not a molecule or a single biochemical pathway. The first senolytic drugs, Dasatinib (D) and Quercetin (Q), were discovered using a mechanism-based approach instead of the random high-throughput screening usually used for drug discovery [32]. Through a bioinformatics strategy that leveraged proteomic and transcriptomic data, we discovered networks of senescent cell anti-apoptotic pathways (SCAPs) that enable senescent cells to survive despite their own SASP. We verified this role of these networks in senescent cells by using RNA interference to show that targeting SCAP nodes, such as BCL-xL in the case of human umbilical vein endothelial cells, kills senescent cells. Using a priori knowledge about their molecular targets and mechanisms of action, D and Q were identified as being potentially senolytic based upon their predicted ability to transiently disable these SCAP networks [32]. The senolytic activity of D and Q was first verified in human senescent vs. non-senescent cells. We found that 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. Indeed, we found that D, which was selected based on the specific tyrosine kinases and other key SCAP elements that it targets, is senolytic in the case of human adipocyte progenitors, as predicted from the particular SCAPs these cells depend on. We found that the flavonoid Q, which was specifically selected because it targets BCL-2 family members as well as HIF-1α and particular nodes in PI3-kinase and p21-related anti-apoptotic pathways, is senolytic in the case of human endothelial cells, again as predicted. Q does not target senescent human adipocyte progenitors efficiently and D does not target senescent human endothelial cells. To extend the range of senescent cells targeted, in subsequent mouse in vivo studies and in the clinical trial reported here, we used the combination of D + Q."

 

https://www.ebiomedi...0591-2/fulltext


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