459 replies to this topic

[Fafner55]

Thorne has a new quercetin phytosome.

 

https://shop.thorne....cetin-phytosome

 

Is there a way to estimate the dosage compared to other forms of quercetin?

[Fafner55]

What about sodium butyrate?
http://www.sciencedi...006291X97971588

http://www.nrcresear...9/bcb-2014-0022

lots more....

 

Sodium butyrate does seem to have the potential for enhancing the effects of dasatinib as does valproic acid.  

 

From Dasatinib Accelerates Valproic Acid-Induced Acute Myeloid Leukemia Cell Death by Regulation of Differentiation Capacity,

We also found the dasatinib-mediated induction of p21Cip1 to be blocked by combination treatment with VPA, which is consistent with previous reports [42], [43] indicating that p21Cip1induction decreases following co-treatment with dasatinib and such histone deacetylase inhibitors as sodium butyrate [42] and vorinostat [43]. We also observed the interruption of dasatinib-induced p21Cip1 via VPA-potentiated apoptosis, as shown in Figure 4. The inhibitory effect of VPA on dasatinib-induced p21Cip1 may contribute to the synergistic apoptotic effects of the combination treatment observed in the HL60 and primary AML cells. It remains unknown whether the inhibitory mechanism of Src and HDAC leads to AML cell death, although there is considerable evidence to suggest that HDAC interference with p21CIP1 induction contributes to the potentiation of Src inhibitor-mediated apoptosis, at least in part. In contrast, the loss of p21CIP1 has been found to sensitize cells to cytotoxic drugs [44], low doses of cytarabine [45]and various differentiation-inducing agents such as phorbol esters [44]. Given these findings, it is tempting to propose that the interruption of p21CIP1 induction in Src inhibitor-treated cells may contribute to enhanced lethality. Direct evidence is lacking at present, however.

[veblen]

I took 25mg of dasatinib with 500mg of quercetin today. I used the FDA dose conversion as a rough guide (I could have taken less quercetin).

I'll report back in a few days, even if I don't notice anything (which I fully expect). Unfortunately, I won't be able to offer much of a scientific evaluation. It'll be purely anecdotal.

One dose is enough for me, though. I don't plan on taking more in the near future.

[nowayout]

I took 25mg of dasatinib with 500mg of quercetin today. I used the FDA dose conversion as a rough guide (I could have taken less quercetin).

I'll report back in a few days, even if I don't notice anything (which I fully expect).

 

Please do.  Even if you don't notice benefit, any info on side effects (or lack thereof) would be useful. 
 

[veblen]

It's been four days since I took 25 mg of dasatinib with 500 mg of quercetin.

 

Nothing really to report. The day after taking this dose, I felt pretty tired the next morning, and had a slow start. Since then, I haven't noticed any difference.

 

I'm in my early forties, am in good health, and am moderately active. Perhaps for this reason one wouldn't expect a noticeable change.

[Decimus]

I took 40mg of dasatinib and 1500mg of quercetin this morning.  Dasatinib is definitely a heavy drug.  I could feel it in my system.  I had a headache, my head felt fuzzy and I was lethargic for a few hours, but most of it passed around the fifth hour or so.  I don't expect that the results of this drug combination will be particularly noticeable.  I plan on repeating the above dose every 6 months (as this was the outer time limit of efficacy in the mouse study) until a more effective senolytic comes out.  

[Decimus]

So I woke up this morning and I felt an unexpected effect.  My breathing feels easier and my lungs feel lighter.  It has led to a few peculiar coughs.  It feels like the type of cough and breathing you get when you go outside into freezing air and the first breath in overwhelms your lungs and you cough a bit, but it feels good.  I have no idea if that is a side effect of the drug or whether or not the senolytic cleared out some senescent cells in my lungs.  I'm not sure if lung tissue is among the tissues affected by this drug combination, but there you go; that's what I've noticed.  

Edited by Decimus, 28 April 2015 - 08:48 PM.

[niner]

So I woke up this morning and I felt an unexpected effect.  My breathing feels easier and my lungs feel lighter.  It has led to a few peculiar coughs.  It feels like the type of cough and breathing you get when you go outside into freezing air and the first breath in overwhelms your lungs and you cough a bit, but it feels good.  I have no idea if that is a side effect of the drug or whether or not the senolytic cleared out some senescent cells in my lungs.  I'm not sure if lung tissue is among the tissues affected by this drug combination, but there you go; that's what I've noticed.  

 

Interesting.  Approximately how old are you, Decimus?  I suspect that you'd need to be pretty old to feel an effect from this, but maybe I'm wrong on that.  Senescent cells don't become "a problem" until pretty late in the game.  Getting rid of them should be beneficial, but if you don't have enough to feel, then you probably aren't going to notice when they go.

[Decimus]

Niner, I am 38. I smoked for 10 years. I quit in my late 20's. I would strongly assume that smoking creates a lot of senescent cells in the lungs, but like I said, it could just be an odd side effect from the senolytic.

[corb]

I would strongly assume that smoking creates a lot of senescent cells in the lungs,

 

http://www.pnas.org/...12/16/5099.long

 

 

Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with short telomeres to support alveolar organoid colony formation and found that type 2 alveolar epithelial cells (AEC2s), the stem cell-containing population, were limiting. When telomere dysfunction was induced in adult AEC2s by conditional deletion of the shelterin component telomeric repeat-binding factor 2, cells survived but remained dormant and showed all the hallmarks of cellular senescence. Telomere dysfunction in AEC2s triggered an immune response, and this was associated with AEC2-derived up-regulation of cytokine signaling pathways that are known to provoke inflammation in the lung. Mice uniformly died after challenge with bleomycin, underscoring an essential role for telomere function in AEC2s for alveolar repair. Our data show that alveoloar progenitor senescence is sufficient to recapitulate the regenerative defects, inflammatory responses, and susceptibility to injury that are characteristic of telomere-mediated lung disease. They suggest alveolar stem cell failure is a driver of telomere-mediated lung disease and that efforts to reverse it may be clinically beneficial.

[Fafner55]

Here is an excerpt from my log documenting my experiment with dasatinib and quercetin.

I am nearly 60 years old, in good health and weigh 70 kg.

To remove the influence of other factors from this experiment I have not not taken any other supplement since April 5th.

 

2015-04-23  Took reference pictures of both arms.

 

2015-04-24  Began treatment.  

15:15  Took 70 mg dasatinib and 6400 mg quercetin dihydrate all at once.

16:30  No side effects observed.

17:40  No side effects observed.

17:50  Very slight headache and slight muscle ache.

19:15  Slight muscle ache.

21:15  No side effects.

 

2015-04-25  After a good night’s sleep awoke feeling normal.

7:30  Took 100 mg dasatinib and 6400 mg quercetin dihydrate all at once.

9:30  No side effects.

11:30  No side effects.

13:00 Diarrhea after lunch.

21:00 Fatigue, otherwise no side effects.  Went to bed early.

 

2015-04-26  Awoke feeling normal.

 

2015-04-29  Compared the skin on my arms and hands to my 4/23 reference pictures.  There is no change to my skin.  I am not aware of any change to my body or health. 

 

In about a month I plan to do another experiment with the same doses of dasatinib and quercetin plus a TBD dose of sodium butyrate.

[Fafner55]

Honokiol is a bio-available substance that could be synergistic with dasatinib.  It would be worthwhile to test this combination.

 

Honokiol induces caspase-dependent apoptosis in a TRAIL-mediated manner, and potentiates the pro-apoptotic effects of doxorubicin and other etoposides. So potent is honokiol's pro-apoptotic effects that it overcomes even notoriously drug resistant neoplasms such as multiple myeloma and chronic B-cell leukemia. Honokiol also acts on the PI3K/mTOR pathway in tumor cells while maintaining pathway activity in T cells.  http://en.wikipedia.org/wiki/Honokiol

 

 

The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells

 

Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis

 

Down-modulation of Bcl-XL, release of cytochrome c and sequential activation of caspases during honokiol-induced apoptosis in human squamous lung cancer CH27 cells

 

Honokiol Suppresses Survival Signals Mediated by Ras-Dependent Phospholipase D Activity in Human Cancer Cells

[xEva]

Interesting. And so how do you take this honokiol?

[Fafner55]

Interesting. And so how do you take this honokiol?

 

Honokiol is taken orally.  It is readily available on Amazon.  I don't know what dose is appropriate in combination with dasatinib for senolytic purposes but there is a wealth of literature on its apoptotic effects on various cancers. 

 

More on honokiol is found at  http://examine.com/s...ia officinalis/

[sthira]

Interesting. And so how do you take this honokiol?

Honokiol is taken orally. It is readily available on Amazon. I don't know what dose is appropriate in combination with dasatinib for senolytic purposes but there is a wealth of literature on its apoptotic effects on various cancers.

More on honokiol is found at http://examine.com/s...ia officinalis/

"Things to Note

Enemas of magnolia officinalis bark appear to result in higher circulating levels of bioactives than oral ingestion..."

[xEva]

Interesting. And so how do you take this honokiol?

 
More on honokiol is found at  http://examine.com/s...ia officinalis/

The problem with this site is that it's speaking of dosages without any mention of the form the preparation is supposed to be, i.e. is it just bark? (don't think so), it must be extract, but then standardized to what %?

When I looked, I also saw this magnolia bark extract in combination with Phellodendron amurense (bark), a 'proprietary blend' for weight loss called Relora. I'm interested not so much in weight loss as in appetite suppressors (I assume this is one -?). Do you think this combo would be even more synergic?

Plain magnolia bark extract standardized to 90% honokiol, how much would you take?

[PWAIN]

Gave my pet rat around 20 to 40mg of Dasatinib and around 2 to 2.5 grams of Quercetin night before last. No sign of any changes so far but was more of a safety test. Will up dose tonight probably doubling both. Will report back later. Anyone else doing this?

[Florian Xavier]

apparently, Honokiol act like rapamycin ? but only on tumors. too bad.

 

it would still be interesting to know the effect of honokiol on mouse lifespan

 

https://www.google.c...q=Honokiol mtor

Edited by Florian Xavier, 03 May 2015 - 09:46 AM.

[mrvontar]

SIRT4 is activated by quercetin and ECGC, which you can uptake ECGC of green tea by taking quercetin...can you see how this would be good? I can't provide references, too lazy, but look it up if you're interested. I've been taking Quercetin daily at 800 mg usually morning/mid-day. Can't say I've noticed much of a difference although it is confounded with the variety of other things I take, which obfuscate the results. I should also be drinking green tea more often along with it. I think Quercetin has a relatively long half-life too.

[Florian Xavier]

maybe intravenous Quercetin ?

[Logic]

I am keen on adding some of TLR's 'Senolytix' to my GHK parcel.

Senolytix is based on the HED of the doses used in the mouse study that started this thread.  That works out to 300 mg of Q with 30 mg D for a 70 kg human.

http://www.longecity...ndpost&p=722225

 

 

It would seem that there is a big difference in the bioavailability of Q between 'mice and men' however?

My previous research on this indicated doses of around 8000 mg of Q being required for humans (70 kg)?

 

http://www.longecity...ndpost&p=722696

and

http://www.longecity...ndpost&p=722703

 

What is the general consensus here? Are my calculations correct?  Or should I just go with the HED dose?

 

I plan to test Senolytix on myself and my parents.  The 'Fossils' should give a better indication than myself to effectiveness of this treatment.

[Fafner55]

If radiation-induced senescence is inhibited by sodium dichloroacetate (DCA), presumably by inducing normal glucose oxidation in the mitochondria, does anyone have an idea if DCA might improve the apoptotic effects of senolytics on senescent cells?

 

Part 4 of the NAD world: the NQ01 gene, the Warburg effect, SIRT 1 and inflammation, and possible interventions

 

Radiation induces senescence and a bystander effect through metabolic alterations

 

The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway

 

[corb]

Quercetin protects necrotic insult and promotes apoptosis by attenuating the expression of RAGE and its ligand HMGB1 in human breast adenocarcinoma cells.

Dhumale SS1, Waghela BN1, Pathak C1.

Abstract

The receptor for advanced glycation end-products (RAGE) is a multiligand member of the immunoglobulin superfamily, which plays an important role in maintaining cellular homeostasis. It is normally expressed on immune cells, including macrophages, monocytes, dendritic cells and T cells to maintain homeostasis, but highly upregulated at sites of vascular pathology. Accumulating evidence suggest that the elevated expression of RAGE and its ligand HMGB-1 was found in various types of cancer. The accumulation of RAGE and its ligand high-mobility group box proteins-1 (HMGB1) activates complex signaling network for cell survival and evades apoptosis. Therefore, targeting the RAGE-mediated signaling could be the promising strategies for the therapeutic potential of cancer. This study was aimed to examine the biological potential of quercetin on the regulation of RAGE- and HMGB1-mediated activation of NF-κB and induction of apoptotic cell death in MCF-7 cells. Our findings demonstrate that quercetin inhibits the expression of RAGE and HMGB1 in MCF-7 cells. In addition, quercetin protects necrotic insult and augments apoptosis in MCF-7 cells. Taken together, these results suggest that quercetin plays an important role in modulating RAGE and HMGB1 signaling and induces apoptotic cell death in MCF-7 cells.

 

http://www.ncbi.nlm....pubmed/25983116

 

Now I'm going to make a sweeping generalization that might turn out to be wrong BUT - maybe every drug used in the fight against cancer is also a drug that could be used in treating senescent cells. And vice versa.

 

Maybe there is a benefit in exploring some safe mild cancer drugs for interaction with senescent cells.

Imagine if cancer and other age related pathologies could be prevented by a cheap cocktail of watered down cancer drugs, I doubt big pharma would be particularly happy about it but everyone else would rejoice.

[Kalliste]

 

Quercetin protects necrotic insult and promotes apoptosis by attenuating the expression of RAGE and its ligand HMGB1 in human breast adenocarcinoma cells.

Dhumale SS1, Waghela BN1, Pathak C1.

Abstract

The receptor for advanced glycation end-products (RAGE) is a multiligand member of the immunoglobulin superfamily, which plays an important role in maintaining cellular homeostasis. It is normally expressed on immune cells, including macrophages, monocytes, dendritic cells and T cells to maintain homeostasis, but highly upregulated at sites of vascular pathology. Accumulating evidence suggest that the elevated expression of RAGE and its ligand HMGB-1 was found in various types of cancer. The accumulation of RAGE and its ligand high-mobility group box proteins-1 (HMGB1) activates complex signaling network for cell survival and evades apoptosis. Therefore, targeting the RAGE-mediated signaling could be the promising strategies for the therapeutic potential of cancer. This study was aimed to examine the biological potential of quercetin on the regulation of RAGE- and HMGB1-mediated activation of NF-κB and induction of apoptotic cell death in MCF-7 cells. Our findings demonstrate that quercetin inhibits the expression of RAGE and HMGB1 in MCF-7 cells. In addition, quercetin protects necrotic insult and augments apoptosis in MCF-7 cells. Taken together, these results suggest that quercetin plays an important role in modulating RAGE and HMGB1 signaling and induces apoptotic cell death in MCF-7 cells.

 

http://www.ncbi.nlm....pubmed/25983116

 

Now I'm going to make a sweeping generalization that might turn out to be wrong BUT - maybe every drug used in the fight against cancer is also a drug that could be used in treating senescent cells. And vice versa.

 

Maybe there is a benefit in exploring some safe mild cancer drugs for interaction with senescent cells.

Imagine if cancer and other age related pathologies could be prevented by a cheap cocktail of watered down cancer drugs, I doubt big pharma would be particularly happy about it but everyone else would rejoice.

 

 

My mind also drifted out there while reading about this. There must be a million different combinations of signaling pathways used by various mutant CSC's.

I have been waiting for mature high throughput biological experimental equipment that can be used to make a comprehensive list to screen for goodies. It would be curious if it turned out that almost every effective part of chemotherapy has an influence somewhere inside the tree of cellular senescence. Maybe you could use a combination of mitochondrial antioxidants to protect healthy cells and nanoparticles like Nanogold, nanoceria, nanosilver, nanodiamonds and combine that with whole body radiation therapy, powerful light therapy, magnetic therapy, Proton beams or some such to ablate senescent cells.

 

It would be a good poster for anti aging therapies to have something that could be used in a Hollywood movie

Edited by Cosmicalstorm, 30 May 2015 - 03:01 PM.

[niner]

I think this generalization is a bit too sweeping.  Most conventional chemotherapy works through the induction of oxidative stress, to which cancer cells are more susceptible than normal cells.  Anything that helps apoptosis-resistant cells to finally pull the trigger would be a good candidate for testing as a senolytic, since senescent cells are apoptosis-resistant.  This would include some compounds thought of as "anti-cancer", but it probably wouldn't be very many conventional chemotherapeutics.

[Fafner55]

I am keen on adding some of TLR's 'Senolytix' to my GHK parcel.

Senolytix is based on the HED of the doses used in the mouse study that started this thread.  That works out to 300 mg of Q with 30 mg D for a 70 kg human.

http://www.longecity...ndpost&p=722225

 

 

It would seem that there is a big difference in the bioavailability of Q between 'mice and men' however?

My previous research on this indicated doses of around 8000 mg of Q being required for humans (70 kg)?

 

http://www.longecity...ndpost&p=722696

and

http://www.longecity...ndpost&p=722703

 

What is the general consensus here? Are my calculations correct?  Or should I just go with the HED dose?

 

I plan to test Senolytix on myself and my parents.  The 'Fossils' should give a better indication than myself to effectiveness of this treatment.

 

 

 

The pharmacokinetics of dasatinib have been extensively studied.  From Metabolism and Disposition of Dasatinib after Oral Administration to Humans, a standard 100 mg dose resulted in a peak serum concentration of 104.5 ng/ml after 0.5 hr with a half-life of 3.6 hours.  Converting this oral dose to a moles/liter concentration, this peak concentration is calculated to be  

= (104.5 ng/ml)/(488.01 ng/nM) (Dasatinib has a molecular weight of 488.01 g/mol.)

= 214 nM/l, very close to a target of 200 nM/l taken from Figure 2 of  The Achilles’ Heel of Senescent Cells...

 

Determining the appropriate oral dose of quercetin for a target plasma concentration of 30 uM/l is not so straightforward as there is a wide range of published results on its pharmacokinetics. There appears to be a long plasma half-life of its glucosides (6 to 16 hr is reported by various articles) and relative safety. My best estimate is that a 6000 to 8000 mg dose is likely about right for a 70 kg adult.

[LeeYa]

@corb

 

 

Now I'm going to make a sweeping generalization that might turn out to be wrong BUT - maybe every drug used in the fight against cancer is also a drug that could be used in treating senescent cells. And vice versa.

 

This was my thirst thought, too!

 

If we look at "translational" therapy options for senolysis from cancer therapy, we should keep in mind that cancer therapy includes both Induction of senescence and induction of apoptosis. The latter only is needed for senolysis!

[corb]

@corb

 

 

Now I'm going to make a sweeping generalization that might turn out to be wrong BUT - maybe every drug used in the fight against cancer is also a drug that could be used in treating senescent cells. And vice versa.

 

This was my thirst thought, too!

 

If we look at "translational" therapy options for senolysis from cancer therapy, we should keep in mind that cancer therapy includes both Induction of senescence and induction of apoptosis. The latter only is needed for senolysis!

 

I have considered it for another reason as well, if cancer drugs can be used for prophylaxis as well that means greater quantities will need to be produced and they'll become cheaper. It has an added humanitarian benefit.

[Fafner55]

 

Here is an excerpt from my log documenting my experiment with dasatinib and quercetin.

I am nearly 60 years old, in good health and weigh 70 kg.

To remove the influence of other factors from this experiment I have not not taken any other supplement since April 5th.

 

2015-04-23  Took reference pictures of both arms.

 

2015-04-24  Began treatment.  

15:15  Took 70 mg dasatinib and 6400 mg quercetin dihydrate all at once.

16:30  No side effects observed.

17:40  No side effects observed.

17:50  Very slight headache and slight muscle ache.

19:15  Slight muscle ache.

21:15  No side effects.

 

2015-04-25  After a good night’s sleep awoke feeling normal.

7:30  Took 100 mg dasatinib and 6400 mg quercetin dihydrate all at once.

9:30  No side effects.

11:30  No side effects.

13:00 Diarrhea after lunch.

21:00 Fatigue, otherwise no side effects.  Went to bed early.

 

2015-04-26  Awoke feeling normal.

 

2015-04-29  Compared the skin on my arms and hands to my 4/23 reference pictures.  There is no change to my skin.  I am not aware of any change to my body or health. 

 

In about a month I plan to do another experiment with the same doses of dasatinib and quercetin plus a TBD dose of sodium butyrate.

 

 

 

My next experiment included sodium butyrate in addition to dasatinib and quercetin.

 

2015-05-24

13:45  Begin a regimen of 600 mg of sodium butyrate every 15 minutes because of its rapid clearance.  Sodium butyrate has a plasma half-life of only 6.1 minutes.

14:15 Took 100 mg dasatinib and 6400 mg quercetin dihydrate all at once.

15:45 Took 9th and final sodium butyrate capsule for 9 total (5400 mg).  No side effects.

18:00 No side effects.

20:00 No side effects.

 

2015-05-25  Awoke with slight muscle aches.

 

2015-05-29  I don't feel or see any benefit.

 

2015-06-05  Compared the skin on my arms and hands to my 4/23 reference pictures.  There is no change to my skin.  I am not aware of any change to my body or health.

 

My expectation is that the treatments I have taken so far should have cleared at least 40% of my senescent preadipose cells and 70% of my endothelial cells, enough that there should be measurable changes.  Some way of measuring this clearance or its benefits is needed.

[niner]

There is no change to my skin.  I am not aware of any change to my body or health.

 

My expectation is that the treatments I have taken so far should have cleared at least 40% of my senescent preadipose cells and 70% of my endothelial cells, enough that there should be measurable changes.  Some way of measuring this clearance or its benefits is needed.

 

Fafner55, thanks for your careful reports.  That's a nice contribution to our knowledge.  There's one missing element here, which is the fraction of your cells that are senescent.  It's possible that you just don't have enough of them to see an obvious effect.  You're right, we need better ways to quantify these things.