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.
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
I'll be reading this one closely... I'll need dosages and an idea of how frequently to do it.
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.
You are right there are no details on the clinical significance
@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.
"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.
"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.
"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.
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.
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.
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.
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!
@Reason, what is your opinion? It's a yawn effect or it has medical relevance? Thanks!
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.
"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.
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.
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."
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
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.
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.
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)
@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.
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 ?
@cuberat: How old are you? If you're in your 30s or 20s you're not likely to derive any benefit from senolytics.
@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.
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.
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.
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
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.
David, did you forget that D+Q significantly improves physical function in IPF patients?
@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.
In this study dose dasatinib was 100 mg x 3 days. That is @ $300. Reasonable cost, under consideration
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
A dose suggestion might be taken from this study
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.
Fisetin looks the best of a lot a recent article ...........lancet https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(18)30373-6/fulltext?fbclid=IwAR2kd4Qo11aIIehco_cZjH0X75eapBYMH7FjHmITNNPdjdkU51oVWpnEHqk
I want to buy fesetin and test it on myself but not find the dose for humans.
Rik, I've read that one of the Fisetin study protocols at Mayo Clinic is 2 grams x two days in a row every thirty days. I've been using somewhat lower doses myself and have also incorporated it into a "mixed regimen" provided as "Smoker's New Hope" for those addicted to cigarettes.
i've tried fisetin with no affect on my chronic, steroid resistant sinsusitis. I will soon try D+Q and report back on here if I get any positive effects.
Of course, senescent cells may not be a driver of steroid resistant asthma and sinusitis. But I hope they are so I can stop suffering.
Interesting thread. I just ordered India Dasatinib, 50 mg #60, for $125 with shipping. There is a service where you put in the medication you want and India pharmacies bid. I'm going to try the protocol I read about: 3 days of Dasatinib 100 mg per day plus Quercetin 1000 mg per day. Two week rest, repeat, two week rest, repeat. Obviously I have enough Dasatinib coming to do 30 days, which would translate into once a year for 3 years.
Interested in any comments on my plan. I am 73, and my mile time has dropped from 8 minutes in my 30s to 15+ minutes now. Some kidney dysfunction, some asthma. I'll measure kidney fx after the first cycle. So I imagine I have a fair load of senescent cells, but how to measure?
Did you already try fisetin?
How did you come with the one month protocol? Usually I find 2-4 days.
And please share your results.
I take dasatinib 100 mg daily for chronic myeloid leukaemia. The net effect of this miracle drug is that I am held in a non-leukaemic state currently without side effects. There remains the danger that in the future dasatinib could cause pleural effusion. I have added quercetin 1000 mg daily into the mix surmising that this will cause no additional harm but remaining hopeful that this could have a beneficial effect. I have seen my kidney GFR increase from 54 to 75. Is there any specific improvement but I should monitor?
Cancer is always a bad news. It is good that your leukemia us responding to Dasatinib.
Are you in remission? If so when you are supposed to stop taking Dasatinib?
Abd from Senolytic OOV, A Few things to look for are reversal of grey hair, improved blood pressure, reduced arthritis and less inflammation
I looked up patent expiration for Dasatinib and eureka!
Post patent expiry of BMS' Sprycel (dasatinib), Dr. Reddy's has launched the first branded generic for dasatinib under the brand name 'Invista' on 13 April 2020 in 50mg, 70mg and 100mg dose strengths. Shilpa Medicare is the first company to have launched dasatinib generic Dasashil in all strengths of 20mg, 50mg, 70mg and 100mg as branded drug.
96% drop in price
Yes. But even at 200 USD per dose it would be widely used in the OECED countries if we had the right human protocol. If course, now when it is cheaper it will be prescribed more often and there will be more metastudies.
In its current form it is quite a blunt tool, but there are second generation Senolytics where pro drugs enhance the specific targets. Those are much more specific and less harmful. Unfortunately, they are far from human trials
@Cuberat: I started my protocol of Q+D today. The India drug for Dasatinib took longer than expected to arrive.
I saw one protocol where one takes 3 days of Q+D then repeats 2 weeks later and again two weeks later. That will be the protocol I will report on.
I did not try Fisitin. I should have some report in two months.
I did my first 3 day D+Q protocol and what I can report is I lost 4#, without any effort or change of eating habits. I'll try to post a report after I finish the 6 week protocol and get kidney function tests.
@Lynn Johnson: Can you update us on the results of your D+Q protocol from last summer?
I see that everyone here are experts in this area of medicine/ science. I am relatively young (and clueless) about these topics. But from a young age, I have always been aware of the fact that human lifespan is still too short for human aspirations and desires, and hence I have been trying to find out what experts are doing (what treatments they are doing) to increase their lifespan/ healthspan.
So far my research has told me that:
1. Depleting amounts of telomerase enzyme decreases telomere caps at end of DNA chromosomes which causes DNA degeneration - causes DNA to change/ become non-functional. Telomerase supplements are available. Telomeres seem to decrease with bad lifestyle choices.
2. NMN (Nicotinamide mononucleotide) supplements can be eaten as it is a precursor to NAD+ which leads to more metabolic activity and less aging occurs as a result.
3. Cancer is an immortalized cell line - I inferred that this may be due to excessive telomerase expression and changed functionality to other cyclin-dependent kinases. I thought that there may be a possibility of developing cancer by consuming telomerase enzyme.
4. Senescent cells cause aging (and related diseases). Senescent cells produce cytokines and the enzyme CD38. CD38 is shown to increase with age, and is said to have a correlation with neurodegeneration and neuroinflammation. CD38 seems to be important for cADPR production, but does this through the hydrolyzation of NAD molecules. Less NAD molecules is correlated with aging as cellular NAD levels decline during the aging process. Hence, I thought that removing or neutralizing senescent cells will inhibit production of CD38, leading to more NAD molecules.
5. I saw that senescent cells can be killed by using a senolytic cocktail of dasatinib plus quercetin. Dasatinib seems to be used in chemotherapy and has bad side effects, but quercetin seems to be a beneficial pigment found in fruits and vegetables.
So with this in mind, I am curious as to what everyone else is using to prolong their healthspan/ lifespan.
Are you eating telomerase supplements? NMN supplements? Vitamin B3, B6 & B12 supplements? Doing self-genetic engineering to remove (ablate) genes that codes for enzymes which causes aging? Doing the senolytic therapy with D + Q? Genetically engineering bacteria to produce NAD precursors (like NMN) and placing them into animals/ humans so that they (bacteria + host) can benefit from a mutualistic relationship? Doing exercise, avoid eating "junk food", not smoking, and reducing stress in every lifestyle?
I am most curious as to what experts would do.