Senolytic Treatment with Dasatinib and Quercetin Confirmed to Reduce the Burden of Senescent Cells in Human Patients

Setting aside the mice genetically engineered to destroy senescent cells, the combination of dasatinib and quercetin is the oldest of the senolytic treatments used in animal studies. Senolytic therapies are those that selectively destroy senescent cells in old tissues in order to produce rejuvenation, turning back the progression of numerous age-related conditions. Unusually for early stage research, these initial senolytics are actually quite effective, considered in the grand scheme of things. Thus they have moved directly to human trials in some cases. The first data on their ability to produce the same outcomes in humans as in mice emerged this year, and more data will continue to roll out over the next few years as the first trials run and complete. The results reported in today's open access paper provide an important demonstration for those not yet convinced that the animal data is relevant.

Meanwhile, the older members of the self-experimentation community have been using dasatinib, quercetin, and a few other senolytics for a few years now on the strength of the animal data and the whisper network of positive outcomes. Further, groups such as the Age Reversal Network are attempting to build physician networks and support for off-label use of senolytics.

While senescent cells are important in a range of beneficial processes, from cancer suppression, to the Hayflick limit, to wound healing, their presence is temporary in all such cases. Near all are destroyed, either by programmed cell death or by the immune system. Lingering senescent cells, on the other hand, are an entirely different story: they are in fact an important cause of aging and age-related dysfunction. They secrete a potent and inflammatory mix of signals that rouses the immune system to destructive chronic inflammation, degrades surrounding tissue structure and function, and encourages other cells to also become senescent.

The more lingering senescent cells present in the body, the worse the outcome for health, and their numbers steadily and inexorably grow with age. The silver lining here is that senescent cells actively maintain a degraded, aberrant state of metabolism, regeneration, and tissue function. If they are removed, rejuvenation takes place quite rapidly. In some cases, surprising levels of rejuvenation, with features of aging that might have been thought irreversible, and that no existing medicine can much affect, vanishing as the tissue environment becomes less aged and dysfunctional. The world at large will begin to wake up to the true potential here as trials continue, but it remains a tragedy that hundreds of millions of people worldwide could have their quality of life significantly improved overnight, if they only knew. But it isn't happening. Dasatinib and quercetin are both mass produced and cheap, easily obtained, easily used. Too little is being done to bring this treatment to the masses who could benefit.

Mayo researchers demonstrate senescent cell burden is reduced in humans by senolytic drugs

In a small safety and feasibility clinical trial, researchers have demonstrated for the first time that senescent cells can be removed from the body using drugs termed "senolytics". The result was verified not only in analysis of blood but also in changes in skin and fat tissue senescent cell abundance. Senescent cells are malfunctioning cells that accumulate with aging and in organs affected by chronic diseases. Senescent cells can remain in the body and contribute to multiple diseases as well as features of aging, ranging from heart disease to frailty, dementias, osteoporosis, diabetes, and kidney, liver, and lung diseases.

For three days the nine participants received a combination dose of dasatinab and quercetin. Though the drugs cleared the body in a couple of days, effects on reducing senescent cells were evident for at least 11 days. The researchers say this shows the senolytic drug combination significantly decreases senescent cell burden in humans. Senescent cells are characteristic in end-stage kidney failure as well as diabetes-related kidney disease. By removing the cells from mice, researchers had previously found that senolytics alleviate insulin resistance, cell dysfunction, and other processes that cause disease progression and complications. While more research is needed on the impact of senolytics on diseases and disorders of aging, the researchers say the results of occasional dosing reduces risks from having to give drugs continuously.

Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease

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. 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 hours, respectively. This is consistent with the point that, since the target of senolytics is senescent cells, these drugs do not need to be continuously present in the circulation in the same way as drugs whose mechanism of action is to occupy a receptor, modulate an enzyme, or act on a particular biochemical pathway, at least in mice. Intermittently administering D + Q effectively circumvents any potential off-target effects due to continuous receptor occupancy or modulation of an enzyme or biochemical pathway.

Based on the many promising studies of D + Q in mice, the experience gained from the use of D in humans for over 20 years, and the fact that Q is a natural product present in many foods such as apples, we initiated clinical trials of these agents. The first-in-human clinical trial of senolytics was a brief course of D + Q for patients with idiopathic pulmonary fibrosis, which resulted in statistically significant improvements in physical function in 14 subjects with this relentlessly progressive, debilitating, and ultimately fatal cellular senescence-driven disease. Although alleviation of this cellular senescence-related phenotype was demonstrated in that pioneering trial in tandem with trends for decreased senescence-associated secretory phenotype (SASP) factors, and others found decreased SASP factors in a trial of continuous D administration in the skin of subjects with systemic sclerosis, so far, there has been no direct demonstration of senescent cell clearance by senolytic drugs in peer-reviewed published human clinical trials.

To test whether intermittent D + Q is effective in targeting senescent cells in humans, we administered a single 3 day course of oral D + Q and assayed senescent cell abundance 11 days after the last dose in subjects with diabetic kidney disease, the most common cause of end-stage kidney failure and which is characterized by increased senescent cell burden. We found D + Q alleviates insulin resistance, proteinuria, and renal podocyte dysfunction caused by high fat diet-induced or genetic obesity in mice. We also found that even Q alone can prevent high fat diet-induced increases in markers of senescence, renal fibrosis, decreases in renal oxygenation, and increased creatinine in mice, although Q alone did not prevent insulin resistance. Diabetes and chronic kidney disease (CKD) in humans therefore represent conditions that may benefit from D + Q therapy-induced alleviation of tissue dysfunction and disease progression, which is being tested as the clinical trial reported here continues. In this interim report of findings from that trial, we found the single brief course of D + Q attenuated adipose tissue and skin senescent cell burden, decreased resulting adipose tissue macrophage accumulation, enhanced adipocyte progenitor replicative potential, and reduced key circulating SASP factors.

Comments

The issue is not about animal study relevance

It's about therapeutic relevance

And again, like the Unity trial before, this is still a yawn effect, heavily based on biomarkers and cell load, and has a long way to go to prove any therapeutic relevance in aging

Posted by: David Permisov at September 18th, 2019 4:16 PM

I'll be reading this one closely... I'll need dosages and an idea of how frequently to do it.

Posted by: Mark Borbely at September 18th, 2019 4:45 PM

The source article doesn't mention how exactly was the SC measured. The effects were visiting l measurable for at least 13 days, but no mention on how much SC reappeared. We don't even know what is the half live and for how long they cold linger under normal conditions.

@David Permisov
You are right there are no details on the clinical significance

Posted by: Cuberat at September 18th, 2019 6:32 PM

@Cuberat: They explain quite clearly their methodology of how they measured senescent cells (hint, its the title of one of the sections, "2.3. Immunohistochemistry, imaging of biopsies, and counting"), what biomarkers they used, where the biopsies they took came from, and then they also went ahead and looked at the cells ability to proliferate in vitro.

Posted by: Dylan Mah at September 18th, 2019 6:57 PM

"The issue is not about animal study relevance

It's about therapeutic relevance

And again, like the Unity trial before, this is still a yawn effect, heavily based on biomarkers and cell load, and has a long way to go to prove any therapeutic relevance in aging"

What exactly does a non-yawn effect look like to you? These kinds of studies are part of the overall process of demonstrating that a proposed intervention is safe and shows results consistent with the mechanistic hypothesis being advanced. On the second ppint, how do you propose to measure therapeutic relevance in aging? Lifespan studies are totally impractical in humans, and will get more and more impractical the longer we're able to extend human lifespan.

Posted by: Dylan Mah at September 18th, 2019 7:02 PM

"On the second ppint, how do you propose to measure therapeutic relevance in aging? Lifespan studies are totally impractical in humans, and will get more and more impractical the longer we're able to extend human lifespan."

A sufficient number of sufficiently old people will give you lifespan results in 5 years. Clearance of senescent cells doesn't need to be started in childhood, so it's just about having enough money (and political / strategic will) to design the right study.

Starting senolytics at age 50 may yield better results than initiating treatment at age 70, but at 70+ mortality rates are high enough for a relatively short study to show effect (or lack thereof) on remaining life expectancy, which is what rejuvenation is all about anyway.

We won't know the best clinical protocol straight away, but this isn't needed to open the floodgates to real funding and a domino-like change in public attitude.

Posted by: Barbara T. at September 18th, 2019 9:07 PM

"A sufficient number of sufficiently old people will give you lifespan results in 5 years. Clearance of senescent cells doesn't need to be started in childhood, so it's just about having enough money (and political / strategic will) to design the right study."

That's potentially the case, but to get your drug approved you need to show that it's modifying the risk of a disease or the disease state itself.

Posted by: Dylan James Mah at September 18th, 2019 9:34 PM

It will be fairly easy to show whether eliminating SCs have an impact on some aspects of aging by noting improvements in specific conditions and diseases such as type 2 diabetes and diabetes-related kidney disease. For this current Phase 1 trial, this will be reported later as change in frailty and more importantly, change in kidney function. Although they'd be nice to do, human lifespan studies are not even necessary. And the same logic applies to any other aging intervention.

https://clinicaltrials.gov/ct2/show/results/NCT02848131

Posted by: Florin at September 18th, 2019 10:33 PM

I'm one of those "older members of the self-experimentation community". I did a dose of D&Q in April and I am convinced this is not a "yawn" result for me or this study. You can read about results in Age Reversal Forums or Reddit.

Posted by: Larry at September 18th, 2019 10:36 PM

I'm confused about the supposed value of limiting the dosing to only three days, for Quercetin anyway. I've been taking ProstaQ with Quercetin twice daily for one or two years.

Posted by: NY2LA at September 18th, 2019 11:37 PM

@Dylan Mah

The did not measure GFR, creatinine, uric acid, albumin, various makers of podocyte destruction, etc., etc. etc....all the things that you need to prove therapeutic relevance in DKD to regulators

They did this in mice, but not humans, wanting you to get excited about the tolerability and cell burden only - we know D&Q is tolerable!

It's a yawn

For now it is only slight of hand trying - just like Unity - awesome in animals, lackluster in humans until you show clinical significance!

Posted by: David Permisov at September 19th, 2019 4:40 AM

@Reason, what is your opinion? It's a yawn effect or it has medical relevance? Thanks!

Posted by: Josep at September 19th, 2019 5:11 AM

Could someone post links for self experimentation with senolytics?

I searched through Age Reversal and Reddit forums and came with nothing explicit or dramatic. There is a huge amount on content on where to get dasanitib and related matters but little else. Not even under Self Experimentation.

Posted by: Eighthman at September 19th, 2019 7:09 AM

"The did not measure GFR, creatinine, uric acid, albumin, various makers of podocyte destruction, etc., etc. etc....all the things that you need to prove therapeutic relevance in DKD to regulators".

True, but the clincher if we are talking about life extension is a reduction in mortality at each given (advanced) age because lowering markers still says nothing about whether the intervention is truly rejuvenating.

For example, my creatinine may drop to normal levels but this does not necessarily mean that I will live longer: for all we know it can dive and then raise threefold three months later, with unknown consequences in the context of changes in other components of the system.

On the other hand, a x% mortality reduction at age 75, 76, 77 etc. will push up median life expectancy at least until the end of the observed sequence. Even if this stops at, say, age 85 and everyone taking senolytics then drops dead (pretty unlikely), in a population whose life expectancy is 82 the mortality reduction will have extended LE by 3 years.

Also, 99%+ of the population doesn't understand the significance of obscure biomarkers, so it's unlikely that people will get very excited about a drug that improves them. But "This drug will make you live 3 years longer" is a whole different story.

Posted by: Barbara T. at September 19th, 2019 8:46 AM

Maybe a naive question but does a combination of Dasatinib/Quercetin/Fisetin can fit into a let's say $100/month budget ? I don't know the prices and where to get them at the right dose.

Posted by: Jonathan Weaver at September 19th, 2019 9:12 AM

@Barbara T.
100% agree.

I hope that for the purpose of the study they have concentrated on the markers to avoid potentially charged subjects of life extension. it is more "hey look, we are trying to fix the kidney disiease, no rejuvenation is happening."

Posted by: cuberat at September 19th, 2019 9:33 AM

I've been through and around the ringer on trying to get an off-label Dasatinib prescription. I even called and emailed the maker of Sprycel. 1) I couldn't find a doctor willing to give me one, and whats more, they never even heard of the longevity effects. Even the so-called "Princeton Longevity Center" wouldn't even talk to me about it.

I wrote a letter to the former FDA head, requesting an emergency order/note that would allow doctors to prescribe it off-label for longevity. No response.

=======================
From: Tom Schaefer
Sent: Monday, January 7, 2019 2:49 PM
To: CommissionerFDA@fda.hhs.gov
Cc: carol.torgan@nih.gov
Subject: Approve Dasatinib for Off-Label Treatment of Senescent Cells
Mon 1/7/2019, 2:49 PM
Dear Commissioner Gotlieb,

For the past 8 months, I have been undertaking 4-day water fasts to trigger autophagy and release stem cells. There is little doubt that Dasatinib (brand name Sprycel) combines with quercetin (a readily available herbal) to attack malfunctioning "senescent" cells, with the longevity research community now referring to the combination as "DQ". Do you know how hard, in fact nearly impossible your rules make it to get a doctor to prescribe Dasatinib off-label?

I sincerely request that the FDA put out an announcement stating that an exception is being made to your off-label rules in the case of Dasatinib. It is particularly outrageous that doctors in the research community can give prescriptions to themselves and their friends to rejuvenate themselves, but those of us without such connections must find far more expensive alternatives. As for me, I will be traveling to Russia this summer to obtain and use Dasatinib (over the counter) combined with quercetin during a 4-day fast. It is unfair to the "little people" like me, who you should support, that I have to pursue "medical tourism" to get state-of-the-art rejuvenation therapies.

Thank you,
Tom Schaefer
=================

The makers of Sprycell give you the run-around and take 30 minutes putting your information and request into their system and then never get back to you.

The moral of the story is: If you are not among the elite/powerful, or don't have a doctor friend, you are not going to get it. I was referred to one reader here to an Indian company who would international mail it to you, but they wanted $400 to $800 for it. I cheap it out doing my 4 day water fasts monthly (just ended one) and taking a lot of fisetin (tastes horrible). The general pain this causes prevents sleep during the last 2 days.

I know about Phalidomide, and the FDAs conservative nature re: drugs as a result. But they are obstructing my pursuit of life, liberty, and happiness at this point on this issue.

Posted by: Tom Schaefer at September 19th, 2019 9:40 AM

@Jonathan Weaver
Depending on your sources Qercetin and Fisetin can be obtained more or less cheaply. Besides the dosage is about 2 grams of Fisetin per treatment (probably as much QC), and you are supposed to do it only sporadically (say 2-3 days every 2-6 months). Dasatinib is expensive per dose (100-$250 USD per daily pill) but it is only because it is patent protected, and the patents expire in US in just a couple of years. Production costs could be a few dollars per dose. In the OECED countries, the problem is that it is a prescription drug and getting the prescription requires a highly paid professional. That alone can dwarf the costs of the compounds. And of course, the biggest problem is that we don't know for sure whether it causes more harm than good.

If you can get D at 100$/pill and use it once in 3 months than it will not break the bank. I would pay much more if i was sure it is helping. On the other hand, you can do fasting (CR in its ultimate form) for free (as like not paying money, but it requires quite a motivation)

Posted by: cuberat at September 19th, 2019 9:44 AM

@David Permisov: "The did not measure GFR, creatinine, uric acid, albumin, various makers of podocyte destruction, etc., etc. etc....all the things that you need to prove therapeutic relevance in DKD to regulators"

And if they were doing a phase 2 trial they would want to be looking at this, but it's also very important to establish the treatment is having the underlying mechanistic effect they think its having; that wasn't established for the Unity Biotechnology trial. If all those biomarkers are changing favorably and you don't see evidence of senescent cell ablation, that would also be a serious problem because that means your drug doesn't work the way you think it does mechanistically.

Meanwhile, if this fails to show therapeutic relevance now (and none of the studies to date have been large enough to do that), you are seriously calling into question the relevance of senescent cells in human aging and disease.

Posted by: Dylan Mah at September 19th, 2019 10:08 AM

@Tom Schaefer
You wen much further then I did. The doctors I know outright refuse to prescribe Dasatinib and call me crazy. And honestly, I understand them.

Btw, do you feel any benefits of Fisetin ? Do you take it before or after fasting ?

Posted by: cuberat at September 19th, 2019 10:12 AM

@cuberat: How old are you? If you're in your 30s or 20s you're not likely to derive any benefit from senolytics.

Posted by: Dylan James Mah at September 19th, 2019 10:39 AM

@cuberat: I clean out on day 1 of 4. Morning and evening on days 2 to 4, I take 5 grams of fisetin. As I've said before, I'm in execelent shape for a 58yo (50bpm resting heart rate, 40 sleeping, ~3 breaths per minute (carry over from deep breathing exercises/meditation), and 110/70 blood pressure. But I'm doing so many things to fight aging it is impossible for me to attribute any of this to the fisetin or fasting. What I'm pretty certain of is that the endocrine-enhancing stack I take (equivalent to ~5 doses of Nugenix/day for 1/5th the price, but the macca root extract makes it taste HORRIBLE compared to their pills I'm sure) is giving me uncanny strength greater than in my youth when I was a lanky runner type.

Posted by: Tom Schaefer at September 19th, 2019 11:04 AM

@Dylan James

[offtopic]
I might sound immature at times but I am not in my 20s or even 30s. I am 43, and I do feel how every year or two my body deteriorates. Not by much but if the trend goes like that at 75 I will be totally decrepit, if not dead.
[/offtopic]

I might be too young (yay) to feel any benefits from senolytics. For sure , NAD,NAD+ has zero effect on me, for example, but having lingering senescent cells is not good at any age. And since there is measurable aging (in the sense of degradation) I would say that one of the root causes might be SC. Of course, i can afford to wait 10 or even 20 years , but if I can slow the rate of the damage now, I would rather do it. Besides, my parents are still alive, albeit not in a good shape(over 70), so I am personally interested in a faster progress in this area.

Posted by: cuberat at September 19th, 2019 11:06 AM

@Dylan Mah

They could easily measure these items in Phase I also

As far as whether the senolytic story has any "legs" per clinical relevance, that is a whole other matter

We don't know at all yet if this will be the case

Posted by: David Permisov at September 19th, 2019 1:22 PM

Dasatinib is cheap if you source it from India. If you dose once a year, which I think is all you need, you can get a 7 year supply for $207 including shipping. My results are posted in the comments in a number of threads. Go to Josh's site and look at comments from Larry near the end of the list from Sep 15. That's my results. It's N=1 but I am about 90% certain that the effects are real. Unfortunately, the easiest person to fool is yourself. If you do try D&Q get as much pre-dosing data as you can. I will do post-lab work early next year including an epigenetic redo test.
https://joshmitteldorf.scienceblog.com/2019/09/07/1st-age-reversal-results-is-it-hgh-or-something-else/

Posted by: Larry at September 19th, 2019 2:39 PM

@David Permisov: Yes, and I wish they had looked at bloodwork, but I don't think there's intent to deceive here, or in the case of Unity, where the endpoint they're looking at is osteoarthritis, not aging. Unity has far less of an excuse for not measuring every possible biomarker, because they have a much bigger budget than a trial working with drugs that are already approved for use in humans.
In the case of this research, you'd probably get an answer if you emailed the study authors about why they didn't measure the parameters you wanted; it may simple come down to budget; they're mostly interested here in establishing the mechanism of action of the drug in humans.

Posted by: Dylan Mah at September 20th, 2019 10:40 AM

In this study dose dasatinib was 100 mg x 3 days. That is @ $300. Reasonable cost, under consideration

Posted by: alan green at September 22nd, 2019 8:53 PM

@alan green
The maximum dosage I have found was 180 mg/day for longer periods ("until disease progression or intolerance"). It might turn out that the optimal protocol is 200 mg/day for 3-5 days. Even with the current prices it is nothing compared to the doctor's and nursing costs. Besides the bulk of the dasatinib patents expire on 2020. There are some for 2025 and 2026. But the later ones are rather for production optimization than the compound itself. The projected cost can go as low as 4 USD per dose/pill. Therefore, if proven useful , in 10 years it will be widely affordable

Posted by: Cuberat at September 24th, 2019 7:19 AM

A dose suggestion might be taken from this study
https://www.sciencedirect.com/science/article/pii/S2352396419305912

3 days of oral D 100 mg and Q 1000mg
Hit-and-run" treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans.

Posted by: August at October 16th, 2019 9:26 PM

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