459 replies to this topic

[pone11]

How dangerous would it be to do this in a human? Looking at some cancer forums people seems to be eating this day in and day and while complaining about prices and so on. I guess there would be some side-effects, I know cytostatica can be a real boring thing for many.

But both Q and D seems like nothing that would be too bad in one single dosing.

 

Why isn't this forum going crazy over trying this? It's the dream of all supplements so far IMO. A

 

It's too early in the research process for it to be clear what the effect will be in humans.   But the idea itself is absolute gold.

[Sanhar]

It was already mentioned in this thread that the biggest benefit of the new "senolytics" is that it's going to spur real interest in progressing the science of killing senescent cells.  As I see it, this will lead to better drugs sure, but also a more widepsread look into the whole process and what other approaches could be done.  I am also encouraged by the fact that this at least partly validates the SENS approach which is probably going to give them more traction.  Additionally, I have been hearing across the web how some people are now questioning if life extension should really entirely be approached as a life rejuvenation concept - which is what SENS is all about.  This is important because a lot of money is being wasted on lines of treatment that aren't going to lead to indefinite lifespan.  Rejuvenation will.

 

Thus I'd garner that unless you can't afford to wait a few more years, it might be better to watch how things develop so as to avoid any problems with the current drugs that aren't *really* designed for this purpose.

Edited by Sanhar, 13 March 2015 - 09:44 PM.

[Logic]

How dangerous would it be to do this in a human? Looking at some cancer forums people seems to be eating this day in and day and while complaining about prices and so on. I guess there would be some side-effects, I know cytostatica can be a real boring thing for many.

But both Q and D seems like nothing that would be too bad in one single dosing.

 

Why isn't this forum going crazy over trying this? It's the dream of all supplements so far IMO. A

 

 

I agree!  

 

Its strange that people post that this is still 10 years out and are disappointed that his isn't the one available therapy to save them when everybody knows full well that there is no 'one pill'.
If they don't; they should by now!??

Quercetin  is easy to find and I'm sure TLR or similar can find Dasatinib or have some made at a reasonable price.

(sold under the trade name Sprycel®) 

 

This is a practical therapy that is available now!

We just have to figure out dosages and schedule.

 

I have a contact here that may be able to to get hold of some Dasatinib.

If he can and is willing to share; I will try it too.

Probably with some vasodilators to get it thoroughly dispersed and as close to the skin's surface as possible.

[ceridwen]

It would be nice if we could have a group buy of Dasatinib

[Logic]

It would seem that taking telomerase activators at the same time as you are killing off senescent cells may be a good idea?

• "...Quercetin was also synergistic with Resveratrol in protection of blood vessels..."
• http://examine.com/s...ts/Resveratrol/
•  
• "...Resveratrol has been shown to activate telomerase in human ... endothelial (vein/artery wall) progenitor cells..."
• http://www.ncbi.nlm....les/PMC3251731/
•  
• "...quercetin was more effective (at killing off) senescent human endothelial cells..."
• http://www.scienceda...50309144823.htm

Now increasing telomere length may reverse senescence in some cells....
So.... You're trying to save senescent cells and kill them off at the same time... and thats synergistic!??

[niner]

I think it's edgy enough to try Dasatinib and quercetin on our own today; I'd rather not mix a bunch of other chemicals with them.   The bioavailability of quercetin is atrocious.  It's possible that it's better in mice than in humans.  If we need to hit 10 uM of the quercetin aglycone, that is a tall order.  We might be able to kinda sorta approach that with a megadose of a sophisticated formulation and something to suppress phase 2 metabolism.  There's also the question of whether or not a glucoside would show the activity.  If it does, quercetin glucosides (not glucuronides!) are actually quite bioavailable because they hitch a ride on a glucose transporter and present fewer targets to phase 2 enzymes.   If quercetin is known for helping blood vessels, and it has been shown to kill senescent endothelial cells, then maybe that's the mechanism.  It would sure be cool if all you had to do was have a meal of fried onions every now and then in order to have healthy vessels.  (Onions are high in quercetin glucoside)  That's probably not going to cut it, though...

 

It occurs to me that there have been thousands of middle-aged or older people who have used dasatinib.  I wonder what their ratio of senescent to normal cells is?  Someone should look at that.

 

I'll bet that there are people all over the world who are hatching plans to try out dasatinib and quercetin.  I hope some of them check in here and let us know how it's going.

[Kalliste]

A single megadose of Quercetin can't be that bad? Not like it's going to cause fulminant liver or something?

 

Trying it along with a solid five day faste would be neat. But maybe that would be counterproductive? At least fasting makes chemo a lot more bearable according to Valter Longo.

It would make it harder to see if this D+Q thing worked though since fasting probably has health benefits on it's own.

 

Some of those cancer-types must be combining Quercetin with their treatment and that did not seem to kill them.

[pone11]

I think it's edgy enough to try Dasatinib and quercetin on our own today; I'd rather not mix a bunch of other chemicals with them.   The bioavailability of quercetin is atrocious.  It's possible that it's better in mice than in humans.  If we need to hit 10 uM of the quercetin aglycone, that is a tall order.  We might be able to kinda sorta approach that with a megadose of a sophisticated formulation and something to suppress phase 2 metabolism.  There's also the question of whether or not a glucoside would show the activity.  If it does, quercetin glucosides (not glucuronides!) are actually quite bioavailable because they hitch a ride on a glucose transporter and present fewer targets to phase 2 enzymes.   If quercetin is known for helping blood vessels, and it has been shown to kill senescent endothelial cells, then maybe that's the mechanism.  It would sure be cool if all you had to do was have a meal of fried onions every now and then in order to have healthy vessels.  (Onions are high in quercetin glucoside)  That's probably not going to cut it, though...

 

It occurs to me that there have been thousands of middle-aged or older people who have used dasatinib.  I wonder what their ratio of senescent to normal cells is?  Someone should look at that.

 

I'll bet that there are people all over the world who are hatching plans to try out dasatinib and quercetin.  I hope some of them check in here and let us know how it's going.

 

Niner, I did some research to help you here:

 

http://www.ncbi.nlm....pubmed/11053503

 

I think you can do a better job of interpreting this study result than I can, but it is surprising because the glucoside form was hydrolyzed in the gut and then rapidly absorbed.

 

As I understand it, this doesn't overcome your concern, because you think the quercetin without glucoside is likely to be grabbed by liver before it can get into cells?

 

Would you be able to do a liposomal formulation of the glucoside form, or would the liposome by itself be sufficient to gain entry into the cell?

[Kalliste]

Wow one dose of Datasinib is $360! Seems you can get it for $4 in India.

 

Here some on Q

 

 

Due to its potentially beneficial impact on human health, the polyphenol quercetin has come into the focus of medicinal interest. However, data on the bioavailability of quercetin after oral intake are scarce and contradictory. Previous investigations indicate that the disposition of quercetin may depend on the sugar moiety of the glycoside or the plant matrix. To determine the influence of the sugar moiety or matrix on the absorption of quercetin, two isolated quercetin glycosides and two plant extracts were administered to 12 healthy volunteers in a four-way crossover study. Each subject received an onion supplement or quercetin-4′-O-glucoside (both equivalent to 100 mg quercetin), as well as quercetin-3-O-rutinoside and buckwheat tea (both equivalent to 200 mg quercetin). Samples were analyzed by HPLC with a 12-channel coulometric array detector. In human plasma, only quercetin glucuronides, but no free quercetin, could be detected. There was no significant difference in the bioavailabilityand pharmacokinetic parameters between the onion supplement and quercetin-4′-O-glucoside. Peak plasma concentrations were 2.3 ± 1.5 μg•mL⁻¹ and 2.1 ± 1.6 μg•mL⁻¹ (mean ± SDJ and were reached after 0.7 ± 0.2 hours and 0.7 ± 0.3 hours, respectively. After administration of buckwheat tea and rutin, however, peak plasma levels were—despite the higher dose—only 0.6 ± 0.7 μg•mL⁻¹ and 0.3 ± 0.3 μg•mL⁻¹, respectively. Peak concentrations were reached 4.3 ± 1.8 hours after administration of buckwheat tea and 7.0 ± 2.9 hours after ingestion of rutin. The terminal elimination half-life was about 11 hours for all treatments. Thus, the disposition of quercetin in humans primarily depends on the sugar moiety. To a minor extent, the plant matrix influences both the rate and extent of absorption in the case of buckwheat tea administration compared with the isolated compound. The site of absorption seems to be different for quercetin-4′-O-glucoside and quercetin-3-O-rutinoside. The significance of specific carriers on the absorption of quercetin glycosides, as well as specific intestinal b-glucosidases, needs to be further evaluated.

 

 

Might be good to get some from natural sources and some through supplements:

 

 

Red onions and low doses of the flavonoid, quercetin, increase insulin sensitivity and improve glucose tolerance. We hypothesized that dietary supplementation with red onion extract (RO) would attenuate high fat diet (HFD)-induced obesity and insulin resistance similar to quercetin supplementation by increasing energy expenditure through a mechanism involving skeletal muscle mitochondrial adaptations. To test this hypothesis, C57BL/6J mice were randomized into four groups and fed either a low fat diet (LF), HFD (HF), HFD + quercetin (HF + Q), or HFD + RO (HF + RO) for 9 weeks. Food consumption and body weight and composition were measured weekly. Insulin sensitivity was assessed by insulin and glucose tolerance tests. Energy expenditure and physical activity were measured by indirect calorimetry. Skeletal muscle incomplete beta oxidation, mitochondrial number, and mtDNA-encoded gene expression were measured. Quercetin and RO supplementation decreased HFD-induced fat mass accumulation and insulin resistance (measured by insulin tolerance test) and increased energy expenditure; however, only HF + Q showed an increase in physical activity levels. Although quercetin and RO similarly increased skeletal muscle mitochondrial number and decreased incomplete beta oxidation, establishing mitochondrial function similar to that seen in LF, only HF + Q exhibited consistently lower mRNA levels of mtDNA-encoded genes necessary for complexes IV and V compared to LF. Quercetin- and RO-induced improvements in adiposity, insulin resistance, and energy expenditure occur through differential mechanisms, with quercetin—but not RO-induced energy expenditure being related to increases in physical activity. While both treatments improved skeletal muscle mitochondrial number and function, mtDNA-encoded transcript levels suggest that the antiobesogenic, insulin-sensitizing effects of purified quercetin aglycone, and RO may occur through differential mechanisms.

 

 

Q can be spun with Amaranth proteins to possibly increase availability

 

 

Highlights •

Quercetin and ferulic acid were encapsulated using electrospinning.

•

Blends of amaranth protein isolate and pullulan were used as encapsulating matrices.

•

Sustained release of the antioxidants from the electrospun fibers was observed.

•

Encapsulation improved antioxidant capacity of bioactives during in-vitro digestion.

Abstract

Two bioactive compounds, quercetin and ferulic acid, were encapsulated using the electrospinning technique within hybrid amaranth protein isolate (API):pullulan ultrathin fibers. Initially, the composition of the encapsulation structures was optimized, both in terms of matrix components ratio and to maximize the bioactive loading. The morphology and thermal stability of the developed encapsulation structures were evaluated, as well as the encapsulation efficiency and distribution within the fibers of both antioxidant compounds. Moreover, the release characteristics and protection ability of the encapsulation structures during an in-vitro digestion study were investigated. Smooth ultrathin electrospun fibers were obtained in which the antioxidants were homogeneously distributed. Through this methodology, it was possible to incorporate within the API:pullulan fibers up to 10 and 20% (by weight) of quercetin and ferulic acid, respectively, which were released in a sustained manner during in-vitro digestion, keeping to a greater extent their antioxidant capacity in comparison with the non-encapsulated compounds.

 

Some studies use Quercetin Dihydrate

 

 

Abstract

Objectives

The flavonoid quercetin holds promise as an anti-tumor agent in several preclinical animal models. However, the efficacy of oral administration of quercetin in a pancreatic cancer mouse model is unknown.

Methods

The anti-proliferative effects of quercetin alone or in combination with gemcitabine were tested in two human pancreatic cancer cell lines using cell count and MTT assays. Apoptosis was evaluated by flow cytometry. Tumor growth in vivo was investigated in an orthotopic pancreatic cancer animal model using bioluminescence. Quercetin was administered orally in the diet.

Results

Quercetin inhibited the growth of pancreatic cancer cell lines, which was caused by an induction of apoptosis. In addition, dietary supplementation of quercetin attenuated the growth of orthotopically transplanted pancreatic xenografts. The combination of gemcitabine and quercetin had no additional effect compared to quercetin alone. In vivo quercetin caused significant apoptosis and reduced tumor cell proliferation.

Conclusions

Our data provide evidence that oral administration of quercetin was capable of inhibiting growth of orthotopic pancreatic tumors in a nude mouse model. These data suggest a possible benefit of quercetin in patients with pancreatic cancer.

 

[pone11]

 

Wow one dose of Datasinib is $360! Seems you can get it for $4 in India.

 

Here some on Q

 

Might be good to get some from natural sources and some through supplements:

 

Q can be spun with Amaranth proteins to possibly increase availability

 

Some studies use Quercetin Dihydrate

 

 

The Indian pharma business is a zoo.  There is very little quality control and labeling practices are poor.  You never know whether they are giving you a clone, or some chemical that simply looks similar to the target chemical, without any double blind studies to prove it works.   If I couldn't test what I was buying there for quality and purity, I would not take it.   I also can't believe people here are seriously thinking about taking a regulated chemotherapy drug.   

 

Could you include references for all of those studies?   Some were worth following up on.

 

The one study you had on Quercetin absorption was interesting.  It suggests the glucoside versions were better absorbed.   Combine that with the study I posted that shows the glucoside version is apparently hydrolyzed and absorbed as Quercetin without the glucoside.  It's a mystery.  Maybe niner can make sense of the chemistry to reconcile those two results.

[Kalliste]

Sorry dropped the links in private mode. Google the articles and you should find them

I have to question if we really need to get it exactly right dose wise as they did in the study. Maybe you simply need a pretty large dose to get close enough. Maybe you need smaller dosages.

 

A personal setup might look like this:

 

1. Get ahold of a few days worth of Datasinib

 

2. Get ahold of Quercetin, lets say you buy three different supplemental forms and one combination of foods rich in the,

 

3. Once every 30 days (to minimize toxicity) you take one daily dose of Datasinib, I don't know how to scale it up to humans. And you take a fist of Quercetin pills.

Lets say you do this 3-5 times, each time with a different source of Quercetin, i.e some different supplements plus one or two occasions when you binge in on red onions, capris, apples and what not.

 

Does this sound crazy? I can't imagine that this little trial would have some horrible side-effects?

[Decimus]

This company claims to have a form of quercetin with good bioavailability:

http://www.pureencap...ewscap-10-30-13

For the dieharders, you might be able to find an unadulterated form of quercetin and inject it intravenously. If you only have to inject a few days once every couple of months it would probably be manageable, if you could find the proper dose. Then you would have 100% bioavailability.

[corb]

Does this sound crazy? I can't imagine that this little trial would have some horrible side-effects?

 

Anything can have horrible side effects.

 

But more importantly what would be your way of knowing whether it works or not?
I don't question the ability of Dasatinib to clear out senescent cells, lots of cancer drugs developed in the last decade activate cellular suicide. What I'm asking is how would you know it's doing something good for your health?

 

That's the biggest problem with "trials" like that. I don't have a problem with anyone doing them but at least think of way of proving it does something for aging beforehand - this drug in itself shouldn't be a significant lifespan increaser so you'd be doing yourself and everyone else much more good if we can get some data out of your adventure.

[nowayout]

 The bioavailability of quercetin is atrocious.

 

Quercetin is a small enough molecule that transdermal of sublingual formulations seem like they should be absorbed well. 

 

Although - a problem may be that quercetin appears to be water- and alcohol-soluble rather than fat-soluble - maybe someone who knows more about this can comment.  
 

Edited by nowayout, 14 March 2015 - 02:49 PM.

[Kalliste]

Im too lazy and poor that I wont be tge first to try it. But seriously people take all kinds of horrible poisons for years to get in shape. Someone has to try this and tab valuable healthparameters before and after. If the improvement is big it should be noticable.

[david ellis]

. . .

Probably with some vasodilators to get it thoroughly dispersed and as close to the skin's surface as possible.

 

 

I was hoping that the endothelial cells lining the cardiovascular system would also be rejuvenated.   

[niner]

http://www.ncbi.nlm....pubmed/11053503

 

I think you can do a better job of interpreting this study result than I can, but it is surprising because the glucoside form was hydrolyzed in the gut and then rapidly absorbed.

 

As I understand it, this doesn't overcome your concern, because you think the quercetin without glucoside is likely to be grabbed by liver before it can get into cells?

 

Would you be able to do a liposomal formulation of the glucoside form, or would the liposome by itself be sufficient to gain entry into the cell?

 

I think what this paper is telling us is that much of the quercetin glucoside was absorbed,  probably as the glucoside, and the rest was hydrolized in the gut.  It at least suggests that the glucoside gets in pretty well, but it's not clear whether or not it would have the effect we want. 

 

If I were to do a micellar formulation, I'd use straight quercitin.  I think that would do a pretty fair job of getting into the system, although I have to say, the glucoside is pretty impressive, without even needing any special formulation.

[pone11]

 

Does this sound crazy? I can't imagine that this little trial would have some horrible side-effects?

 

Anything can have horrible side effects.

 

But more importantly what would be your way of knowing whether it works or not?
I don't question the ability of Dasatinib to clear out senescent cells, lots of cancer drugs developed in the last decade activate cellular suicide. What I'm asking is how would you know it's doing something good for your health?

 

That's the biggest problem with "trials" like that. I don't have a problem with anyone doing them but at least think of way of proving it does something for aging beforehand - this drug in itself shouldn't be a significant lifespan increaser so you'd be doing yourself and everyone else much more good if we can get some data out of your adventure.

 

 

I strongly agree with the last paragraph here.   An aggressive therapy that actively kills some of your cells demands proof that it has benefit.   

 

As a group, we should be exerting at least as much effort in establishing some before-and-after objective tests for metabolites or performance that each person participating in the experiment can do to help establish there is a benefit.   Having such tests will then additionally help to set best dosing and frequency.

[niner]

 

. . .

Probably with some vasodilators to get it thoroughly dispersed and as close to the skin's surface as possible.

 

I was hoping that the endothelial cells lining the cardiovascular system would also be rejuvenated.   

 

I suspect the major site of action would be the epithelial lining of the vasculature.  It might help skin some, but there's still all the other forms of damage, like glycation and other forms of ECM damage that are so prevalent in skin.

[pone11]

Here is a study suggesting that curcumin might degrade mitochondria and cause increased apoptosis:

http://www.febslette...2376-6/abstract

 

If anyone has access to full text on that study please post the URL.

[Logic]

 

. . .

Probably with some vasodilators to get it thoroughly dispersed and as close to the skin's surface as possible.

 

 

I was hoping that the endothelial cells lining the cardiovascular system would also be rejuvenated.   

 

 

Yep; As Niner said above.  

I was just thinking out load there:

If the Quercetin is killing of the endothelial cells lining the cardiovascular system; a vasodilator may be a good idea to get Quercetin into the microvasculature where circulation is at its lowest.

That would include all organs, but I was wondering if it would improve skin as that would be a good, easily examined, sign that it worked..

 

Quercetin which kills off senescent  endothelial etc? cells is proven to be synergistic with Resveratrol which activates telomerase in endothelial progenitor cells.

I would have no problem taking another telomerase activator and vasodilator like Gingko Biloba at the same time as Quercetin and Resveratrol.

 

The dark horse is Dasatinib.

Is it synergistic with Quercetin, or do they just have an additive effect by killing of different senescent cell types?

Who knows how it will interact with Resveratrol and Gingko Biloba.

 

 

This Patent may sched some light and Dasatinib's MOA:

 

...Cells with inactive BRAF undergo senescence in the presence of dasatinib....

 

...In the present study, dasatinib induced senescence in HI 666 and Call2T cells but induced apoptosis in H661 cells into which were transfected kinase impaired BRAF mutations. Possible reasons for this discrepancy are that the absolute level of endogenous w BRAF, the level of mutant BRAF, or the w mutant BRAF ratio may influence the outcome of dasatinib- based treatment...

 

...The mechanism by which dasatinib induces senescence in NSCLC cells with kinase-deficient BRAF is unknown. It was hypothesized that dasatinib induces senescence by affecting CRAF function (8). Although it was found that dasatinib did not directly affect CRAF or BRAF kinase activity at relevant concentrations...

 

...Oncogene-induced senescence occurs after activation of oncogenes such as RAS and RAF. Classically, it is mediated by activation of the p^^/Rb and/or pi 4ARF/p53 tumor suppressor pathway. Senescence also can be induced and mediated by other pathways, such as those involving c-Src, STAT3, c-Myc, FOX04, Chk2, and c-Jun-N-terminal-kinase. In the present study, dasatinib induced senescence in HI 666 and Call2T cells but induced apoptosis in H661 cells into which were transfected kinase impaired BRAF mutations. Possible reasons for this discrepancy are that the absolute level of endogenous wtBRAF, the level of mutant BRAF, or the w mutant BRAF ratio may influence the outcome of dasatinib- based treatment. The level of mutant BRAF expression was higher in the transfected cells, which also harbored a full complement of endogenous "'BRAF, than in non-trans fected cells. [0081] Occasionally, spontaneous tumor regression occurs in melanoma and renal cell carcinoma cases and is thought to be immune mediated. Also, the activating V600EBRAF mutation in melanoma may induce an immune response. Although such a possibility cannot be excluded in the case of PX, spontaneous tumor regression is very rare in NSCLC cases. Instead, the dasatinib sensitivity of NSCLC cell lines with kinase impaired BRAF mutations is consistent with the patient having experienced a direct antitumor effect of dasatinib rather than an immune-mediated mechanism....

http://www.google.co...3155077A1?cl=en

 

 

...Dasatinib inhibited cell viability with an IC(50) in the submicromolar range in 7 of 10 tested cell lines. In sensitive cells, Dasatinib reduced anchorage-independent growth and, in some instances, induced senescence and apoptosis. In HTLA-230 cells, Dasatinib treatment caused down-regulation of c-Kit and c-Src phosphorylation in conjunction with strong inhibition of Erk1/2 and Akt activity...

http://www.pubfacts....n-orthotopic-mo

[pone11]

 

 

. . .

Probably with some vasodilators to get it thoroughly dispersed and as close to the skin's surface as possible.

 

 

I was hoping that the endothelial cells lining the cardiovascular system would also be rejuvenated.   

 

 

Yep; As Niner said above.  

I was just thinking out load there:

If the Quercetin is killing of the endothelial cells lining the cardiovascular system; a vasodilator may be a good idea to get Quercetin into the microvasculature where circulation is at its lowest.

That would include all organs, but I was wondering if it would improve skin as that would be a good, easily examined, sign that it worked..

 

 

I have a good solution to that problem.   Most aging adults have low nitric oxide.  Recent studies are highlighting that nitric oxide (NO) has a key role in maintaining the health of the endothelial lining:

http://www.ncbi.nlm....les/PMC2617738/

 

and one of the specific mechanisms of this is that NO maintains smooth muscle relaxation and dilation.   It is believed that the lowering of nitric oxide levels as we age allows susceptible individuals to begin an inflammatory process in the endothelial lining that leads to heart disease.

 

You can test your nitric oxide levels indirectly by using nitrite test strips such as those sold by BerkeleyTest (I buy their 3 for 2 50 packs on Amazon).   Sure enough, my nitric oxide levels were like a corpse.  I set out to improve on that, and after much deliberate experimentation and testing I discovered that eating a few meals a day of high nitrate foods significantly affected my nitric oxide levels in a very positive way.   I have a head of butter lettuce in morning as part of a smoothie that includes berries and lots of coconut milk.   At night I have a huge salad that is about half arugula.   Arugula is particularly high in nitrates.

 

There is research suggesting nitrates raise your risk of stomach cancer, but the link looks weak to me, and the benefits of endothelial lining health are overwhelmingly positive.   So I weigh the high probability of maintaining endothelial lining against the remote risk of - maybe - increasing my stomach cancer risk less than 5%.

 

Exercise also releases nitric oxide and forces dilation, which of course is an appropriate response to exercise because the tissues involved in exercise want to be fed a lot of oxygen and nutrients to help recovery.

 

Combining these elements together, you could do the following:

 

1) Nitrate meal in morning

2) Two hours of very low intensity exercise, preferably in your fat burning range and nowhere close to your aerobic threshold.   The idea is to do sustainable low intensity exercise that doesn't leave you loaded with lactic acid.   This will force you to start releasing a lot of nitric oxide.

3) Nitrate meal for dinner

4) Take your quercetin before bed

 

The nitrate meals and exercise should leave your vascular extremely dilated, and you should be getting that effect deep into your body tissues.    If your hypothesis is that quercetin is going to target marginal senescent cells in the endothelial lining, then the above procedure should maximize delivery of whatever bioavailable quercetin you can get into your bloodstream.

 

Autophagy is upregulated during fasting, so it is probably a good idea to fast at least 12 hours on the night you take the quercetin.

Edited by pone11, 15 March 2015 - 06:42 AM.

[niner]

Here is a study suggesting that curcumin might degrade mitochondria and cause increased apoptosis:

http://www.febslette...2376-6/abstract

 

If anyone has access to full text on that study please post the URL.

 

It's open access.  Here's the full text.  From a cursory look, I don't think it's going to be a huge problem.  It's an in vitro experiment, and they first see the problem in a significant way at 10 uM curcumin.  It's reversed by ubiquinone, or at least some aspects of it are, and thus people using mitochondrial antioxidants are probably ok.

[resveratrol_guy]

As has been pointed out above, none of this is very useful if most candidates for senolytic therapy are unwilling to take dasatinib, even if we can manage to enhance quercertin bioavailability (Longvida-style, perhaps?). I wonder if we could avoid the problem by supplanting dasatinib with everolimus, which appears to be better pharmacologically characterized and accomplishes similar autophagic responses in vivo. It's a rapamycin derivative which has been used in chemotherapy sessions spanning a number of months, which affords a considerable margin of safety compared to the acute loading doses in question here. Nilotinib also comes to mind for these reasons. For its part, lipidated curcumin could assist with apoptosis. My point is that it's better to have mediocre senolytic therapy with relatively well understood pharmacokinetics, than  cutting-edge therapy that few are willing to attempt.

 

Moreover dasatinib enhances differentiation of acute myeloid leukemia cells even though it also upregulates autophagy (which sounds bad, but maybe I've misunderstood) and autophagizes liver cells poisoned by its own action (moot senolyticism).

 

I'm also leery of single-dose senolytic therapies which might kill too many senescent-yet-semifunctional cells, inducing a sort of tumor lysis syndrome if done too quickly (due to both lost functionality and the ensuing BUN spike); careful hematologic monitoring would well advised, in any event.

 

Backing up your stem cells in the freezer would also be prudent, in case the resulting replacement of senescent cells with newly differentiated stem cells causes replication or telomere stress of some sort, which could remain hidden until it became a life-threatening problem, especially if as we presume to be the case, senolytic therapy will become a periodic maintenance event. You don't need to be young to expose yourself to the benefits of such insurance, and in fact it's not necessarily optimal. (There is a tradeoff between stem cell senescence, finances, and freezer facility fidelity which is worth analyzing but beyond the scope of this thread.)

 

Edited by resveratrol_guy, 15 March 2015 - 05:04 PM.

[pone11]

As has been pointed out above, none of this is very useful if most candidates for senolytic therapy are unwilling to take dasatinib, even if we can manage to enhance quercertin bioavailability (Longvida-style, perhaps?). I wonder if we could avoid the problem by supplanting dasatinib with everolimus, which appears to be better pharmacologically characterized and accomplishes similar autophagic responses in vivo. It's a rapamycin derivative which has been used in chemotherapy sessions spanning a number of months, which affords a considerable margin of safety compared to the acute loading doses in question here. Nilotinib also comes to mind for these reasons. For its part, lipidated curcumin could assist with apoptosis. My point is that it's better to have mediocre senolytic therapy with relatively well understood pharmacokinetics, than  cutting-edge therapy that few are willing to attempt.

 

Moreover dasatinib enhances differentiation of acute myeloid leukemia cells even though it also upregulates autophagy (which sounds bad, but maybe I've misunderstood) and autophagizes liver cells poisoned by its own action (moot senolyticism).

 

I'm also leery of single-dose senolytic therapies which might kill too many senescent-yet-semifunctional cells, inducing a sort of tumor lysis syndrome if done too quickly (due to both lost functionality and the ensuing BUN spike); careful hematologic monitoring would well advised, in any event.

 

Backing up your stem cells in the freezer would also be prudent, in case the resulting replacement of senescent cells with newly differentiated stem cells causes replication or telomere stress of some sort, which could remain hidden until it became a life-threatening problem, especially if as we presume to be the case, senolytic therapy will become a periodic maintenance event. You don't need to be young to expose yourself to the benefits of such insurance, and in fact it's not necessarily optimal. (There is a tradeoff between stem cell senescence, finances, and freezer facility fidelity which is worth analyzing but beyond the scope of this thread.)

 

 

Quercetin and dasatinib acted on totally different tissues.    Quercetin worked on endothelial lining and dasatinib on fat cells.   So why would you need to take both?

 

I'm quite confused on the issue of killing senescent cells, versus the potential apoptosis of healthy cells that function marginally.    The study we are commenting on in this thread apparently found that quercetin focused its killing action on senescent cells and left marginally healthy cells alone.    The study I posted on curcumin suggests it might cause apoptosis in tumor cells, but how can we be so sure it is not killing marginally healthy cells that we want to preserve (e.g., neurons)?   When you read the description of how curcumin works, it seems like a very tricky minefield of effects that no one completely understands.

 

Regarding stem cells, what good does it do to store these when there is no existing therapy to re-apply them and have them correctly differentiate where you want them to?   Is it just hope for the future?

[resveratrol_guy]

 

Quercetin and dasatinib acted on totally different tissues.    Quercetin worked on endothelial lining and dasatinib on fat cells.   So why would you need to take both?

 

I'm quite confused on the issue of killing senescent cells, versus the potential apoptosis of healthy cells that function marginally.    The study we are commenting on in this thread apparently found that quercetin focused its killing action on senescent cells and left marginally healthy cells alone.    The study I posted on curcumin suggests it might cause apoptosis in tumor cells, but how can we be so sure it is not killing marginally healthy cells that we want to preserve (e.g., neurons)?   When you read the description of how curcumin works, it seems like a very tricky minefield of effects that no one completely understands.

 

Regarding stem cells, what good does it do to store these when there is no existing therapy to re-apply them and have them correctly differentiate where you want them to?   Is it just hope for the future?

 

 

Why take both? Because the benefits are potentially greater (and conveniently, orthogonal). But obviously the risks are compounded as well, particularly with the comparatively unknown dasatinib. So you raise a good question whose answer is dependent upon disease state and risk tolerance.

 

Yes, stem cell freezing is mainly just an optimistic policy which presumes that therapies will improve in the future, and be able to utilize the particular cell species which one preserves. I actually think this is a good bet, though, as there are even some FDA approved therapies which already use these cells, in addition to many nonapproved ones. It's a personal optimization question. But it needs to be taken seriously by anyone considering jumping on the senolytic drug bandwagon. We do certainly need some heroes to try these approaches and report back, if we've ever to learn anything useful about their effects.

 

And I completely appreciate your concerns about wanting to kill severely senescent cells, while not killing slightly faulty cells that are still doing more help than harm. I don't think it's possible to sit back and design a drug which hits the threshold right where you want it. But that's precisely why I fall back on curcumin: it literally has centuries of safety profiling. Observationally, it may well be the case that it overenthusiastically destroys muscle mitochondria and thus muscle cells, if we look at the distribution of muscle mass among Indian males vs. world averages (although other factors clearly influence that), but mitochondrial antioxidants might help. Then again, I personally wouldn't mind being quite thin if it meant that I could avoid dementia.

 

A brilliant website providing dementia statistics by country is here. (Sorry I can't vouch for the numbers, but it does look credible, and India is close to the bottom while the US is unsurprisingly near the top. Most disturbing are the Scandanavian nations, which one would think would have tons of omega 3 and vitamin D from cold water fish. Other better sources are invited.)

[niner]

As has been pointed out above, none of this is very useful if most candidates for senolytic therapy are unwilling to take dasatinib, even if we can manage to enhance quercertin bioavailability (Longvida-style, perhaps?). I wonder if we could avoid the problem by supplanting dasatinib with everolimus, which appears to be better pharmacologically characterized and accomplishes similar autophagic responses in vivo. It's a rapamycin derivative which has been used in chemotherapy sessions spanning a number of months, which affords a considerable margin of safety compared to the acute loading doses in question here. Nilotinib also comes to mind for these reasons. For its part, lipidated curcumin could assist with apoptosis. My point is that it's better to have mediocre senolytic therapy with relatively well understood pharmacokinetics, than  cutting-edge therapy that few are willing to attempt.

 

Why would people not want to use dasatinib?  It's used by thousands of CML patients, on a daily basis, and they aren't dropping like flies.  I think the main problem is that people don't see a very sensible way to get some.  Make friends with an insured CML patient?  Go talk to you doctor?  "Hey doc, would you mind writing me a prescription for a single dose of a chemotherapy agent?  It made some mice healthier..."  I can't see that going over very well.  Not with my doctor, anyway.  Stick up a pharmacy?  Hmm. Probably not.    It's ~$367 a pill, at least in the States.  Undoubtedly less everywhere else in the world.    I looked at the structure, and it's not that complicated.  I bet we could have some made for a lot less than the thousands they want for a gram of it.  Better yet, Here.  Generic Dasatinib, courtesy of the grey market.  Probably dark grey, but whatever...  I have no idea if these guys are legit, but if a bunch of us wanted to check it out, we'd only be out a few bucks each at worst.  We'd want to analyze it ourselves, but that's not a stopper.

 

I wouldn't be too anxious to substitute everolimus; while it may encourage apoptosis in certain types of cells, it's not clear to me that it would work in the particular anti-apoptotic mechanism of senescent cells.

 

For people who are under 60 (or maybe 65?) I'm not sure I'd be in a huge rush to jump on this train.  For one thing, if you have few senescent cells, you may not be able to tell if the treatment did any good.  For another thing, In a couple years, I think that we will understand this a whole lot better, and we will very likely have more effective agents. 

 

This seems like a project that the SENS guys could get behind.  I wonder what they think of it?

[Kalliste]

Wonder if me taking 5ml of c60 a day would mess with the effect?

Btw: Here in Scandinavia we do not get enough sunlight and it's correlated to the amount of some diseases of neurodegeneration. We also eat a lot of dairy which MIGHT increase our IGF-1 levels.
Lots of red meat. Lots of junkfood everywhere.

[corb]

A brilliant website providing dementia statistics by country is here. (Sorry I can't vouch for the numbers, but it does look credible, and India is close to the bottom while the US is unsurprisingly near the top. Most disturbing are the Scandanavian nations, which one would think would have tons of omega 3 and vitamin D from cold water fish. Other better sources are invited.)

 

Looking at the low prevalence of dementia deaths on the Balkans and I can't help but think of all those 70-80 year olds living alone in the countryside taking care of their little gardens and raising chickens, sheep and the random pig, haha.

I have to wonder if it's our diet, or some other factor. They do spend their free time in the village libraries as well, so it might be a side effect of stimulation.

Or it could be curcumin, though I doubt we eat it nearly as much as the Indians do, so the connection is dubious at best.

 

Anyway, I'm with you, stem cell therapies will definitely pan out in the future. Though I'm not so sure if freezing tissues will be an important factor, in my reading at least in the lab the best therapies seem to make use of somatic -> ipsc -> progenitor reprogramming, and as we know even a centenarian somatic cell can become an ipsc.

 

 

Why would people not want to use dasatinib?  It's used by thousands of CML patients, on a daily basis, and they aren't dropping like flies.  I think the main problem is that people don't see a very sensible way to get some.  Make friends with an insured CML patient?  Go talk to you doctor?  "Hey doc, would you mind writing me a prescription for a single dose of a chemotherapy agent?  It made some mice healthier..."  I can't see that going over very well.  Not with my doctor, anyway.  Stick up a pharmacy?  Hmm. Probably not.    It's ~$367 a pill, at least in the States.  Undoubtedly less everywhere else in the world.    I looked at the structure, and it's not that complicated.  I bet we could have some made for a lot less than the thousands they want for a gram of it.  Better yet, Here.  Generic Dasatinib, courtesy of the grey market.  Probably dark grey, but whatever...  I have no idea if these guys are legit, but if a bunch of us wanted to check it out, we'd only be out a few bucks each at worst.  We'd want to analyze it ourselves, but that's not a stopper.

 

I wouldn't be too anxious to substitute everolimus; while it may encourage apoptosis in certain types of cells, it's not clear to me that it would work in the particular anti-apoptotic mechanism of senescent cells.

 

For people who are under 60 (or maybe 65?) I'm not sure I'd be in a huge rush to jump on this train.  For one thing, if you have few senescent cells, you may not be able to tell if the treatment did any good.  For another thing, In a couple years, I think that we will understand this a whole lot better, and we will very likely have more effective agents. 

 

This seems like a project that the SENS guys could get behind.  I wonder what they think of it?

 

 

Well since Dasatinib works on fat cells ... wouldn't there be a better way of getting rid of senescent fat cells for a non-geriatric anyway? *nudge nudge wink wink* Adipokines alone are a good enough reason to get rid of all of your "excess" fat, not just the senescent fat cells. And the side effect of chemo like nausea, Dasatinib supposedly induces is a detriment on it's own.

 

I can't disagree with the rest of your post though, I already said it myself, if someone wants to try a DQ cocktail they better have a plan to show the results, in at the very least, semi scientific manner. It's the least they can do for the incredible pleasure of puking their guts after that nice dose of D at least.

 

And I'm with you on the last paragraph completely. The SENSF should be the ones to organize a follow up study.

Edited by corb, 16 March 2015 - 10:05 PM.

[ceridwen]

Am I right in thinking that there are no deaths from dementia in Monaco. Do they know something the rest of us don't? I wouldn't be surprised if I am wrong though but if not...