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Dasatinib group buy from Nyles

dasatinib senolytic senescent scenescent cells sasp senolytics group buy

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#271 Logic

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Posted 01 March 2017 - 09:23 PM

Rasagiline
Offers neuroprotection via stimulation of PKC phosphorylation; upregulation of PKCepsilon mRNA; induction of Bcl-X(L), Bcl-w, and BDNF mRNAs; and downregulation of PKCgamma, Bad, and Bax mRNAs. http://www.ncbi.nlm....pubmed/16179541

 

Gene expression analysis revealed that EGCG prevented the QUIN-induced expression of the proapoptotic gene, caspase-9, and increased that of the antiapoptotic genes, Bcl-XL, Bcl-2, and Bcl-w. Further examination about potential cell signaling candidate involved in this neuroprotective effect showed that immunoreacitivity of PI3K was significantly increased in the cells treated with EGCG.

https://www.ncbi.nlm...pubmed/20025854

 

Lithium up-regulates the cytoprotective protein Bcl-2 in the CNS in vivo: a role for neurotrophic and neuroprotective effects in manic depressive illness.

https://www.ncbi.nlm...pubmed/10826666

 

NB that low dose lithium: 1-5 mg is recommended here.  Circadian rhythm should be considered to enhance autophagy.

 

I note that one needs more of these BCls for neurogenesis and other growth.
Upping them cyclically, after getting rid of the senescent/pre cancerous? stem cells may help to reverse the negative effects of Nav. 

 

 

 


Edited by Logic, 01 March 2017 - 09:34 PM.

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#272 Longevitarian

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Posted 02 March 2017 - 03:39 AM

May be I am playin here satan"s advocate, but It is worth to mention that Nav/ABT263

action can be considerably enhanced by 2-Deoxy-D-glucose, at least in vitro.

 

2011 article follows.

 

We initiated this project in order to search for agents that can increase the efficacy of ABT.

When we co-treated human tumor cell lines with ABT and drugs that interfere with cancer

specific cellular metabolism, we found that 2DG pre-treatment vastly improved the efficacy

of ABT without harming healthy cells. We show that 2DG-ABT induces apoptosis without

altering Mcl-1 levels in ABT-resistant cells. When cancer cells resistant to ABT are

pre-treated with 2DG, the protein levels of Mcl-1 remain the same, but Bak-Mcl-1 association

is lost, sensitizing cells for ABT-induced apoptosis. How 2DG treatment of cancer cells

disrupts Bak-Mcl-1 is not known. Thus, cancer cell sensitivity to ABT seems to be

determined not only by the protein levels of Mcl-1, but also by how much Bak is

sequestered by its association with Mcl-1.

http://journals.plos...al.pone.0024102

 

I am posting this is only as a reference, not to be tried until in vivo, preferably human

trials establish safety of this combination...and its efficacy.


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#273 Vantika

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Posted 02 March 2017 - 04:58 AM

May be I am playin here satan"s advocate, but It is worth to mention that Nav/ABT263

action can be considerably enhanced by 2-Deoxy-D-glucose, at least in vitro.

 

[...]

 

I am posting this is only as a reference, not to be tried until in vivo, preferably human

trials establish safety of this combination...and its efficacy.

 

Nice find.
 
Along those lines, co-administration with Rapamycin or Everolimus might also potentiate Navitoclax:
 
 
Breast cancer cells possess a deregulated apoptotic pathway with increased expression levels of anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins and ribosomal S6 kinase 1 (S6K1) protein activity. Therefore, combined interference of anti-apoptotic Bcl-2 family and S6K1 protein expression may be a reasonable therapeutic strategy for the treatment of patients with breast cancer. In the present study, it was identified that the administration of a combination of ABT263 [navitoclax; a Bcl-2/Bcl-extra large (Bcl-xL) inhibitor] and PF4708671 (an S6K1 inhibitor) markedly increased apoptotic cell death in the BT474 breast cancer cells compared with the administration of either agent alone. Furthermore, the downregulation of Bcl-2/Bcl-xL and S6K1 with small interfering RNA induced a significant increase in cell death compared with RNA interference of either agent alone. Notably, combination treatment with ABT263 and PF4708671 decreased the expression level of survivin protein, with this ectopic expression of survivin attenuating cell death. Thus, the present study determined that the combined inhibition of Bcl-2/Bcl-xL and S6K1 may be a good strategy for treating patients with breast cancer.
 
 
S6K is the canonical downstream target of mTORC1, which both Rapamycin and Everolimus inhibit.
 
(Out of safety and bioavailability concerns, I wouldn't recommend using an experimental direct S6K inhibitor like that mentioned in the article (PF4708671, in this case), which has likely never even been tested in vivo.)
 
The same caveats mentioned above by Longevitarian apply here.


#274 Longevitarian

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Posted 02 March 2017 - 05:53 AM

Hi Vantika"

 

I am very cautious with the rapalogs such as Rapamycin and Everlolimus.There is a reason

for this. 15 months ago in clinical trial of Everolimus i did some "improvements" to boost its

action. Half a year later I returned to my regular maintenance therapy with supplements,

which within a month induced severe overactivity of the immune system. This resulted in

extreme cholinergic hives which lasted for 3 months. This has never happened before ....

I was completely locked in at home , suffering from several stages of the disorder which

included severe itchiness, severe dermatitis , severe angioedema,severe cold hives,

severe sweat hives ....e.t.c.  Extreme suffering at each stage....Complete disability over

that time

 

I found out that some animals normally undergo this process during molting ....including

some mammals such as African Spiny Mice.

https://en.wikipedia...iki/Spiny_mouse

In 3 months I literally I shed old and regrew new skin all over the body with exception of

head and face.

From the doctors , I found out that this kind of hives and of this severity happen very

rarely , and only in young patients, less that 20 years old. It is usually harmless long

term and has pretty strong rejuvenating effect all over the body, including the internal

organs as well.

 

Still working on theory how it happened and the physiological mechanisms involved.

 

Was it dangerous ....Yes ...It could end up in anaphylactic shock.

Was it worth it ....I think so.... :-D

Would I repeat it ....NO WAY!!!!!. :excl:

 


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#275 Longevitarian

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Posted 02 March 2017 - 06:38 AM

More about the African Spiny Mouse From NATURE article:

 

African Spiny Mouse Can Regrow Lost Skin

http://www.nature.co...st-skin-1.11488

 

"Two species of African spiny mouse have been caught at something no other

mammal is known to do — completely regenerating damaged tissue. The work

could help improve wound healing in humans."

AND I KNOW HOW TO DO IT IN HUMANS!!!!! :-D



#276 ClarkSims

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Posted 04 March 2017 - 10:38 PM

Wish I could fast like you guys but I could barely make it half a day without going insane, literally. My brain can't handle it and I can't function at all without food. Every time I've tried to fast it's been the most miserable thing I've ever put myself through, ever. You guys have a real tolerance for self-torture. Here's to hoping that not only do I get benefits from D+Q but that scientists find more and more fasting mimetics.

 

I would guess that you have a carbohydrate based metabolism. I fast once per month. I don't even feel hungry. IMHO, the way to ease the pain of fasting it to switch to a low carb diet, that is high in plant and animal fats before the fast. That way the body is in ketosis before the fast begins, and simply switches from dietary fats, to body fat.


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#277 sthira

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Posted 04 March 2017 - 11:30 PM

Wish I could fast like you guys but I could barely make it half a day without going insane, literally. My brain can't handle it and I can't function at all without food. Every time I've tried to fast it's been the most miserable thing I've ever put myself through, ever. You guys have a real tolerance for self-torture. Here's to hoping that not only do I get benefits from D+Q but that scientists find more and more fasting mimetics.


I would guess that you have a carbohydrate based metabolism. I fast once per month. I don't even feel hungry. IMHO, the way to ease the pain of fasting it to switch to a low carb diet, that is high in plant and animal fats before the fast. That way the body is in ketosis before the fast begins, and simply switches from dietary fats, to body fat.

Yes, same for me. And it also helps to ease into fasting, no rush, no hurry, no panicky-must-master-this-now mentality. By ease into it I mean simply lengthening the time between meals. If you eat three meals a day, try skipping a meal sometimes.

Everyone is different, of course. Nate reports that he has trouble mentally focusing while working because of the hunger. I have the exact opposite experience, and when fasting I almost feel too alert, too energetic, sometimes bordering on mania. Everyone else seems to be moving in slow motion.
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#278 TaiChiKid

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Posted 05 March 2017 - 06:25 AM

Having studied the theory behind the use of senolytics such as the D&Q combination on this thread, I was wondering if anyone could contribute to the reports I see from people using this combination frequently?

 

For example, your body's cells accumulate the senesence associated secretory phenotype over a long, long period of time.  Presumably a session of one or several doses of the senolytic wipes out the senescent cells.

 

Surely your body cannot re-accumulate the senescent cells in a limited time scale:  eg a year.

 

So why do many of you do the senolytic therapy every other week?  Can you tell me your reasoning, please?


Edited by TaiChiKid, 05 March 2017 - 06:27 AM.

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#279 Nate-2004

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Posted 05 March 2017 - 06:26 AM

 

 

Wish I could fast like you guys but I could barely make it half a day without going insane, literally. My brain can't handle it and I can't function at all without food. Every time I've tried to fast it's been the most miserable thing I've ever put myself through, ever. You guys have a real tolerance for self-torture. Here's to hoping that not only do I get benefits from D+Q but that scientists find more and more fasting mimetics.


I would guess that you have a carbohydrate based metabolism. I fast once per month. I don't even feel hungry. IMHO, the way to ease the pain of fasting it to switch to a low carb diet, that is high in plant and animal fats before the fast. That way the body is in ketosis before the fast begins, and simply switches from dietary fats, to body fat.

Yes, same for me. And it also helps to ease into fasting, no rush, no hurry, no panicky-must-master-this-now mentality. By ease into it I mean simply lengthening the time between meals. If you eat three meals a day, try skipping a meal sometimes.

Everyone is different, of course. Nate reports that he has trouble mentally focusing while working because of the hunger. I have the exact opposite experience, and when fasting I almost feel too alert, too energetic, sometimes bordering on mania. Everyone else seems to be moving in slow motion.

 

 

I do know the brain depends on glucose for will power and focus. Perhaps you guys have some gene that makes your bodies create more glucagons than insulin, resulting in a naturally high glucose level without food. I doubt I could ever achieve that.



#280 Andey

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Posted 05 March 2017 - 07:50 AM

 

 

 

Wish I could fast like you guys but I could barely make it half a day without going insane, literally. My brain can't handle it and I can't function at all without food. Every time I've tried to fast it's been the most miserable thing I've ever put myself through, ever. You guys have a real tolerance for self-torture. Here's to hoping that not only do I get benefits from D+Q but that scientists find more and more fasting mimetics.


I would guess that you have a carbohydrate based metabolism. I fast once per month. I don't even feel hungry. IMHO, the way to ease the pain of fasting it to switch to a low carb diet, that is high in plant and animal fats before the fast. That way the body is in ketosis before the fast begins, and simply switches from dietary fats, to body fat.

Yes, same for me. And it also helps to ease into fasting, no rush, no hurry, no panicky-must-master-this-now mentality. By ease into it I mean simply lengthening the time between meals. If you eat three meals a day, try skipping a meal sometimes.

Everyone is different, of course. Nate reports that he has trouble mentally focusing while working because of the hunger. I have the exact opposite experience, and when fasting I almost feel too alert, too energetic, sometimes bordering on mania. Everyone else seems to be moving in slow motion.

 

 

I do know the brain depends on glucose for will power and focus. Perhaps you guys have some gene that makes your bodies create more glucagons than insulin, resulting in a naturally high glucose level without food. I doubt I could ever achieve that.

 

 

Ketone bodies are also associated with increase in mental capacity, that`s why things like bulletproof coffee exits.

Think about giving it another go, I am under impression that you had just caught first hunger moment and gave up. Everybody get more stress first day of fasting, especially when your body awaits scheduled meal and dont get it. "WTF" ! )

Its not necessary to full fast, you  could do fast mimicking diet by dr Longo. I would say its more tolerable approach psychologically and socially. If you brain crave for sugar too much you could use Tim Ferris advice and take few grams of BCAA. Liver would convert it carbohydrates but no more than brain actually needs.

Genes are not indulgence. It would be a very rare mutation if you really can not tolerate 2 day fast. It also should be somewhere in basic pathways, so it could stop such complex thing as fast (which involves by itself 1000s of genes), means that you you would have huge problems to survive even during childhood.


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#281 sthira

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Posted 05 March 2017 - 10:15 AM

Having studied the theory behind the use of senolytics such as the D&Q combination on this thread, I was wondering if anyone could contribute to the reports I see from people using this combination frequently?

For example, your body's cells accumulate the senesence associated secretory phenotype over a long, long period of time. Presumably a session of one or several doses of the senolytic wipes out the senescent cells.

Surely your body cannot re-accumulate the senescent cells in a limited time scale: eg a year.

So why do many of you do the senolytic therapy every other week? Can you tell me your reasoning, please?


My guess would be since D+Q appears to kill only a limited percentage of certain select cells, then people are thinking more might be better. Dunno. Maybe people expect to feel and look younger, and when they immediately do not, may feel nothing was achieved. It's hard to know if what you're playing around with has benefits or detriments (or likely both) without some indication.

For me, it'll be interesting to combine a short five day water only fast with one round of D+Q. The quandary, of course, remains whether fasting helps, hinders, or is neutral regarding the targeted death of senescent fat and endothelial cells. Measuring inflammatory blood markers might be one crude clue; but fasting alone reduces these numbers, so what is gained by adding potentially dangerous, self-administered D+Q?

I do know the brain depends on glucose for will power and focus. Perhaps you guys have some gene that makes your bodies create more glucagons than insulin, resulting in a naturally high glucose level without food. I doubt I could ever achieve that.


I love Dr. Sapolsky and have learned so much about primates -- particularly about baboon biology and culture -- but I'm not a subscriber to WSJ so can't access his writing in your link. But I'm familiar with his great work. One key difference you may note between us and many of our near relative primate species (like for example our nearest cousins pan bonobo chimps) is that we humans are adapted to undergo a metabolic shift that's kicked into action by food deprivation that they cannot.

I've learned a lot from George Cahill's wonderful work, and here's a nice lay introduction: http://www.asbmb.org...pective/Cahill/

"...The fact that the brain, which normally uses glucose as its fuel of choice, would switch its fuel preference to ketone bodies, which are synthesized from fatty acids in the liver, provided a major insight into the control of energy metabolism. As Cahill pointed out on many occasions, a 70-kilogram human has 141,000 kilocalories of triglyceride and only 900 kilocalories of carbohydrate stored as glycogen, mainly in the liver and skeletal muscle; glycogen in the liver is depleted after about 12 hours of fasting, after which the major source of glucose is gluconeogenesis from amino acids. If tissues such as the brain and skeletal muscle continued to use glucose as a primary fuel, the depletion of muscle protein would be accelerated, greatly impeding our ability to survive a prolonged fast. Thus, the utilization of fatty acids, or fatty acid-derived ketone bodies, is at the heart of fuel sparing. As an example, fatty acids block both glucose uptake and oxidation via glycolysis and the citric acid cycle in skeletal muscle, a major adaptation to fasting..."

Of course this one adaptation is only one of many other understudied processes kicked into drive by fasting. Is fasting conducive to senescent cell killing with D+Q experiments in healthy humans? No one knows.
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#282 aribadabar

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Posted 05 March 2017 - 04:16 PM

Having studied the theory behind the use of senolytics such as the D&Q combination on this thread, I was wondering if anyone could contribute to the reports I see from people using this combination frequently?

 

For example, your body's cells accumulate the senesence associated secretory phenotype over a long, long period of time.  Presumably a session of one or several doses of the senolytic wipes out the senescent cells.

 

Surely your body cannot re-accumulate the senescent cells in a limited time scale:  eg a year.

 

So why do many of you do the senolytic therapy every other week?  Can you tell me your reasoning, please?

 

I think D+Q does not kill ALL senescent cells at first pass so people do subsequent D+Q intakes to remove the remaining (and newly turned) senescent cells which somehow managed to survive the previous interventions.

That being said, every other week taken continuously does seem excessive. Depending on age, it should be several daily intakes as the initial onslaught the first month repeated by once monthly or quarterly "sweep" to keep the house clean.

That's how I plan to use it anyways.


Edited by aribadabar, 05 March 2017 - 04:18 PM.

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#283 DareDevil

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Posted 06 March 2017 - 01:38 PM

I'd agree that when you try a substance or in this case a combination of substance which produce noticeable positive results, one tends to think that more is better. I agree that while the frequency and dosages of most self-experimenters are usually lower than those of cancer patients taking Dasatinib, it may not be necessary or particularly useful to take D+Q frequently.

 

However, I did notice positives, and the youthening is something which has persisted even after stopping taking D+Q. I think that its action goes beyond the immediate intake. While I am probably the last person here to explain how these substances work, my latest theory is that after treatment it takes your body a while to regenerate brand new replacement cells where the senescent ones were eliminated. If so this would explain the lag between initial intake and the end of the positive effects of D+Q.

 

I plan to take some more, but I still feel the benefits from my last run. My only negative side effets where flu-like symptoms, namely a deep mucus-laden cough, another member here says this might be an expression of the presence of interferon generated by the treatment. Unless there is a depletion of red blood cells, my doctor tells me that nothing too serious could come from occasional intake. So once I feel the benefits aren't as present, I will try another run for several days.

 

There is also something I wanted to share. I think I may have unwillingly done things backwards. I stared with a run of Epitalon before taking D+Q. This may not be very smart. After all one wishes one's senescent cells to remain as senescent as possible prior to taking D+Q so that they are successfully targeted and eliminated. Taking Epitalon might lenthen the telomeres of senescent cells, making them more middle aged than old, sparing them from the D+Q purge?

 

So you'd wind up going from Old to Middle-Aged instead of from Old to Young !

 

Therefore I'd recommend first starting with D+Q or other methods of eliminating senescent cells before taking Epitalon or using other cell rejuvenation methods. FWIW.

 

DareDevil


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#284 Rocket

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Posted 06 March 2017 - 04:21 PM

I plan on running 1x monthly at 200-300mg D + corresponding Q per the mouse study. I have a good results from my 2 day cycle of 300mg/day, except for the flu symptoms. I was supposed to take a blood test last week but had to move to this week. I wonder if the test would show high white cells counts this long after the experiment.



#285 sthira

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Posted 10 March 2017 - 04:10 PM


Regarding dosage, starting from “The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs” (2015) http://onlinelibrary.wiley.com/doi/10.1111/acel.12344/full
A single dose of D+Q (D: 5 mg kg−1 body weight and Q: 50 mg kg−1 by oral gavage here and in the following studies), a drug ratio that was most effective in senescent MEFs (data not shown), reduced SA-βgal+ cells (Fig. 3C) and p16 mRNA (Fig. 3D) in fat from old mice within 5 days. D+Q also reduced p16-positive cells in liver from old mice (Fig. 3E-F). As with AP20187, the drug that activates selective killing of cells expressing p16 in transgenic INK-ATTAC mice (Baker et al., 2011), not all senescent cells were removed by D+Q.

A direct scaling of this 5 mg/kg body weight dose of dasatinib to my weight gives (5 mg/kg)(70 kg) = 350 mg.
This dose is twice the “escalation dose” recommended for cancer treatment in humans and is unsafe.

The Human Equivalent Dose (HED) scaling from mice to 70 kg adult humans is
http://www.fasebj.org/content/22/3/659.full.pdf+html
(5 mg/kg)(3/37)(70 kg) = 28.4 mg

I did not see much if any benefit at 70 mg Dasatinib + 6400 mg Quercetin dihydrate.

Increasing the dose to 120 mg Dasatinib + 6400 mg quercetin and adding 2000 mg honokiol cleared some of the sun/age damage to my skin.

For further confirmation, from the plasma concentration-time profile shown in Figure 1 of “Metabolism and Disposition of Dasatinib after Oral Administration to Humans” (2008) http://dmd.aspetjour...t/36/7/1357.ful, a 100 mg dose of Dasatinib results in a peak serum concentration of 104.5 ng/ml after 0.5 hr with a half-life of 3.6 hours. Converting to moles/liter, this peak concentration is calculated to be
= (104.5 ng/ml)/(488.01 ng/nMol)
= 0.214 nM/ml
= 214 nM/l, which is close to a reasonable target of 200 nM/L taken from Figure 2A of “The Achilles’ Heel”


Here is what I currently take: on an empty stomach I ingest

  • 120 mg Dasatinib
  • 2000 mg Quercetin phytosome
  • 2000 mg Honokiol (Magnolia bark extract)
  • 500 mg Pterostilbene
  • 600 mg Sodium butyrate every 15 minutes, 8 total, starting 15 minutes before taking anything else

I am certain that there is a strong apoptotic effect from this combination since my skin has gotten progressively smoother with repeated doses and some keratoses have either disappeared or been greatly reduced.

The major side effects I experience is fatigue and less mental clarity, which lasts maybe 5 days. On two occasions there was diarrhea.

Dasatinib is a powerful drug that is not without side effects or interactions.
Side effects and contraindications include

  • Do not take dasatinib if you are sick. Dasatinib increases the risk of getting an infection from a drop in white blood cells – it is harder to fight infections and you can become very ill. You may have headaches, aching muscles, a cough, a sore throat, pain passing urine, or you may feel cold and shivery.

  • 30% develop diarrhea

  • 30% experience headaches

  • 20% develop a rash or red, dry, itchy skin

  • 20% experience fluid buildup in the body

  • 20% experience a feeling of being sick

  • 20% experience fatigue

  • 10% feel bone and muscle pain

I've kept up with the different experimental routes you've posted after this one regarding senescent cell attacking. And I'm wondering how you're doing currently? Overall, was this a worthwhile and beneficial exercise for you?

#286 Nate-2004

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Posted 10 March 2017 - 04:27 PM

Any new update on the lab results and shipments?



#287 sthira

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Posted 10 March 2017 - 06:30 PM

Any new update on the lab results and shipments?


Natives getting restless?
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#288 Nate-2004

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Posted 10 March 2017 - 06:34 PM

 

Any new update on the lab results and shipments?


Natives getting restless?

 

 

I suppose, it's been a couple weeks or so, just wondering.



#289 Logic

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Posted 10 March 2017 - 07:58 PM

Dasatinib Group Buy progress report:
 
The lab contacted me asking for the postage list around monday or Tuesday.
I sent it and asked for the test results, but have not heard anything back yet.
I dont like to bother them as they are actually doing us a huge favour by aliquoting and posting the D and $600 for Mass Spectrography testing is also a very good price.
I sent of a quick Email asking for the lab results yesterday as normally they send then when asking for the Postage list, but have not yet heard back from them.
I can only think that they are very busy (with customers that pay full price) and will contact them again on Monday.

Thx everyone for your patience.
This buy has taken an awfully long time and I will work to rectify that if I do another.
 

Navitoclax:
The lab is researching making this and the minimum order is 500 grams.
​I have not looked at what the dosage and schedule would be for senescent cell clearance so hope we can reach that target when they get back to me.
 
In the meantime I have been looking at other suppliers and vetting them to make sure they are legit.
Vetting is following this time consuming procedure, more or less, as one cant take chances!
http://www.longecity...ndpost&p=763608

 

Concomitant Dasatinib and Navitoclax is not a good idea!?
 

BH3 mimetics such as ABT-737 and navitoclax bind to the BCL-2 family of proteins and induce apoptosis through the intrinsic apoptosis pathway...


We discuss how the expression of BCL-2 family proteins regulates the sensitivity to ABT-737. One of these, MCL-1, has been widely described as contributing to resistance to ABT-737 which might suggest a poor response in patients with cancers that express levels of MCL-1...

Dasatinib also reduces the expression of MCL-1 by inhibiting the SRC-family kinase LYN which suppresses the expression of miR-181. This microRNA recognizes the MCL-1 3’ UTR [67], decreasing expression of MCL-1 and contributes to the synergy between dasatinib and ABT-737 in [chronic lymphocytic leukemia] CLL cells.

https://www.ncbi.nlm...les/PMC3477050/

 
NB that ABT-737 is not Navitoclax = ABT-263, but it's close and more bioavailable.
How to interpret this info when considering senescent cells is a very good question that I am unqualified to do.
I will say that synergism means the effect was greater than the sum of its parts, so it may be a good or a bad thing for senescent cell clearance and one now has to have a good look at the MCL-1 gene in relation to senescence.
 

To find out whether broad inhibition of BCL-2 family members by a different inhibitor also results in increased elimination of senescent cells, we treated IMR-90 cells with obatoclax, an inhibitor of BCL-W, BCL-XL, BCL-2, and relatively selective inhibitor of MCL-1 (ref. 26). Surprisingly, obatoclax induced significantly more death of control cells than of senescent cells...

The reduction in viability of OIS cells in response to ABT-199 treatment might be attributable to lower levels of BCL-2 in these cells (Fig. 1d), to the oncogenic context that increases dependence on BCL-2, or to both. ABT-199 had no effect, however, on the viability of either senescent or growing MEFs (Supplementary Fig. 2a). These results indicated that BCL-W and BCL-XL account for most of the resistance of senescent cells to apoptosis.

siRNA mixtures directed against either BCL-W or BCL-XL efficiently reduced their protein levels, but silencing of these genes individually resulted in only minor reductions in DIS cell viability (Fig. 2c,d). In contrast, combined knockdown of BCL-W and BCL-XL had a synergistic effect, leading to a dramatic reduction (53%) in cell viability (Fig. 2c), comparable to that induced by ABT-737 treatment.

Similarly, inhibition of BCL-2 by ABT-199 reduced cell viability when the inhibitor was combined with siRNAs against BCL-W (by 14%), against BCL-XL (by 16%) or against both (by 13%). However, this additional effect was only additive, not synergistic as observed in the case of combined inhibition of BCL-W and BCL-XL. Thus, while all three family members contribute to the viability of DIS cells, Similarly, inhibition of BCL-2 by ABT-199 reduced cell viability when the inhibitor was combined with siRNAs against BCL-W (by 14%), against BCL-XL (by 16%) or against both (by 13%). However, this additional effect was only additive, not synergistic as observed in the case of combined inhibition of BCL-W and BCL-XL. Thus, while all three family members contribute to the viability of DIS cells, BCL-W and BCL-XL play a more prominent role than BCL-2.

http://www.nature.co...les/ncomms11190

(A very good read for anyone interested in senescent cell clearance!)

 

From the above it would seem that downregulation of BCL-W and BCL-XL are most important and synergistic for senescent cell clearance while BCL-2 only plays a minor additive role.
Most importantly, while Obatoclax is not Dasatinib + Navitoclax, it seems that downregulation of BCL-W, BCL-XL, BCL-2 and MCL1, as would happen with concomitant use of Navitoclax and Dasatinib may result in more healthy cell death than senescent cell death..!??

 


Edited by Logic, 10 March 2017 - 08:02 PM.

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#290 Longevitarian

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Posted 10 March 2017 - 08:29 PM

Hi Logic'

 

Minimum 50g of Nav (or whatever close relative) for me ....may be more....



#291 sthira

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Posted 10 March 2017 - 08:45 PM

Thx everyone for your patience.


Patiently waiting feels like a blessing in disguise to me, and we'd be smart to continue the group-think before this drug's arrival (one day: an envelope: via the postal service: open to a powder...).

In that spirit, I'm re-linking Reason's post from his site because I think these words are helpful as we attempt -- whatever --regarding this experimental, internet-delivered purchase potently aimed for riddance:

https://www.fightagi...ake-navitoclax/

"...The question here is one that is only now starting to be useful to ask: should we all be running out today to obtain and take a drug (such as navitoclax) or drug combination (such as dasatinib and quercetin) that were shown to clear some fraction of senescent cells in rodents? Certainly there have been no shortage of people chasing after whatever the current hype of the day was in past years; I'm sure you all recall resveratrol and other alleged calorie restriction mimetics or telomere length enhancers. All a waste of time and effort. The difference between the science behind those and the science behind senescent cell clearance is considerable, however. The items of the past have all been associated with altering metabolism so as to modestly slow aging, at best, and we have the very good examples of calorie restriction and exercise to show us the immediate bounds of the plausible on that front in our species. Senescent cell clearance on the other hand is legitimately and actually a form of rejuvenation, turning back one facet of the aging of your tissues to an earlier time. You probably don't have to keep taking the treatment, unlike those that slightly slow aging. An efficient senescent cell clearance treatment is something that you would undergo once every few years, perhaps. These first attempts won't be efficient, of course, but they should certainly have a sizable effect in comparison to most of the nonsense that gets peddled to the credulous.

"It is helpful to look at the question of whether you and I should jump on this bandwagon through the lens of navitoclax, or ABT-263, which is a likely candidate for UNITY Biotechnology to choose for their trials. The people involved with UNITY Biotechnology have worked with it, and it has been used in a range of clinical trials for cancer, which makes it harder for the FDA to mount their usual expensive objections and requests for more data. Navitoclax can be purchased, and dosages can be established from the human cancer studies and the senescent cell clearance rodent studies (there is a fairly standard method of going from mouse or rat dosage to human dosage). There is comprehensive human safety and side-effect data to look at, but only rodent data for its effects on senescent cells - no-one was looking at that in the cancer studies, which is entirely understandable, but a pity. The current methods of senescent cell clearance with published rodent data show a degree of clearance for fairly short treatments varying from negligible to more or less 50% by tissue type, with different drugs having different profiles. So from a technical point of view, the open question is whether or not it works in people to a useful degree. It is entirely reasonable to expect some drugs to do well in mice and terribly in people when it comes to killing senescent cells, and vice versa. The only real way to find out is to try it. Since clinical trials are coming up soon, from my perspective you would have to be something of an enthusiast to jump in ahead of that right now; a year or two seems a fine amount of time to wait for more certainty.

"If taking the leap now, you would have to establish the degree of effect yourself. To do that rigorously you'd need a friendly lab capable of a biomarker assay in a skin sample before and after, say, which isn't impossible to find, just quite specialized. The necessary equipment for those who know how to use it is certain readily available for sale. But without that, you might want to try before and after comprehensive bloodwork to look at markers of inflammation, or even simpler assessments such as blood pressure, given the recent suggestions that senescent cell clearance might help with tissue elasticity, and loss of elasticity in blood vessel walls drives age-related increase in blood pressure. There are other possible options to consider. The point being, don't just run the experiment and feel good about it. Prove to yourself that something happened..."
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#292 jmorris

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Posted 10 March 2017 - 10:18 PM

The point being, don't just run the experiment and feel good about it. Prove to yourself that something happened..."

 

 

 

YES!

 

I'm happy someone said this and I hope everyone starts thinking along these lines. I've seen many posts on this site where people are mixing up a witch's brew of supplements and just kind of hoping. The level of wishful thinking around here is at an unhealthy level and IMHO harmful to making progress. With respect, "I feel so much younger!" or "My skin feels tighter." or "People have been commenting on how good I look." just doesn't cut it as proof. These incredibly subjective self-assigned measures of success suffer from confirmation bias and post-purchase rationalization. They should be considered worthless or nearly so.

 

Let's put our heads together and figure out a solution to this.


Edited by jmorris, 10 March 2017 - 10:19 PM.

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#293 sthira

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Posted 10 March 2017 - 11:42 PM

The point being, don't just run the experiment and feel good about it. Prove to yourself that something happened..."


Let's put our heads together and figure out a solution to this.

Reason's idea is "...a biomarker assay in a skin sample before and after, say, which isn't impossible to find, just quite specialized. The necessary equipment for those who know how to use it is certain (sic) readily available for sale."

Any longevity enthusiasts here with skills and equipment and time and patience and...?

Alternatively: "...[Y]ou might want to try before and after comprehensive bloodwork to look at markers of inflammation, or even simpler assessments such as blood pressure, given the recent suggestions that senescent cell clearance might help with tissue elasticity, and loss of elasticity in blood vessel walls drives age-related increase in blood pressure..."

This seems simple enough. Get a basic blood panel, take a hit of D+Q (at educated-guessed upon rodent dosages) wait awhile, then get the same blood panel again. Daily record at home blood pressure readings, heart rates, blood glucose, whatever subjective feelings, are you crying, are you leaping in joy, what's up?

More targeted inflammation markers were beginning to be discussed earlier here in this thread, then that was fizzled out by distraction. It was fizzled to distraction probably because no one knows which biomarkers would be best to measure before and after. Or do you?

That's why we're "enthusiasts" and we're sorta wannabe "senescent cell clearance pioneers" attempting to jump ahead of the science that ain't there yet. And so what if the trials show the stuff we're contemplating is great for clearing senescent cells in rodents, but not so effective in healthy, normally aging people?

Again here's Reason: "These first attempts won't be efficient, of course, but they should certainly have a sizable effect in comparison to most of the nonsense that gets peddled to the credulous."

Nonsense to the credulous like the currently fashionable supplements rounding the bends on these fora that allege to "alter metabolism so as to modestly slow aging, at best..."
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#294 Logic

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Posted 11 March 2017 - 12:49 AM

Patiently waiting feels like a blessing in disguise to me, and we'd be smart to continue the group-think before this drug's arrival (one day: an envelope: via the postal service: open to a powder...).


In that spirit, I'm re-linking Reason's post from his site because I think these words are helpful as we attempt -- whatever --regarding this experimental, internet-delivered purchase potently aimed for riddance:

 

I think it might be a blessing in disguise too Sthira.
If the senescent cell you are taking out are replaced by stem cells; taking out the senescent stem cells 1st makes sense!
Possibly followed by telomerase activators as their action is pretty much limited to stem and progenitor cells IIRC.

Also as the senescent cell is no longer attached to the ECM; neither are any AGEs that were attached to it..?
Perhaps the upregulated immune system can be coaxed into taking some of them away with the dead cell..?
There are also some interesting leads involving cell signalling I have been looking at and will post about when I have my ducks in a row.

 

In the skin, we have previously shown that p14ARF expression leads to the accumulation of senescent cells in the epidermis, and that these cells are retained for weeks36. Here we show that treatment with ABT-737 eliminates most of these senescent cells, indicating that an anti-apoptotic signal is central to their retention in the tissue. In addition, p14ARF activation causes hair-follicle stem cells to arrest irreversibly, preventing follicle growth 36. We show here that ABT-737 allows re-entry of some of these bulge stem cells into the cell cycle, leading to an increase in overall stem cell numbers. The relevance of these observations to different tissues and conditions is strongly supported by similar recent observations in the haematopoietic system42. We did not observe, however, prominent regrowth of hair in these mice during the time frame of our experiment, suggesting that the overall numbers of activated stem cells accumulated during this time are not sufficient to execute this task, or that additional damage to the hair follicle prevents their regrowth. Overall, these findings suggest that the clearance of senescent cells can lead to tissue renewal and improved fitness, a possibility consistent with the recent finding that elimination of senescent cells via transgenic techniques and combinatorial treatments improves aging-associated phenotypes 14,43.

http://www.nature.co...les/ncomms11190

 

I'm wondering if Navitoclax has the same effect!? Or would some ABT-737 be nice too?
There are some supps that downregulate p14ARF, p21, p65...  in vivo!!!
These flavonoids often get eaten by gut bacteria as well as cleared by the liver before they get anywhere near cells.
I'm looking at that too.
Ducks ducks everywhere!   :)


 

 

 


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#295 Fafner55

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Posted 11 March 2017 - 12:51 AM

I've kept up with the different experimental routes you've posted after this one regarding senescent cell attacking. And I'm wondering how you're doing currently? Overall, was this a worthwhile and beneficial exercise for you?

 

 

My current protocol is, no more than once per month take

  1. 120 mg Dasatinib

  2. 100 mg  Mebendazole

  3. 300 mg EMIQ quercetin or quercetin phytosome

  4. 500 mg Pterostilbene

  5. 1500 mg Honokiol

 

I weigh 70 kg. Doses should be scaled down for lower weight individuals, and I recommend that they not increased much for heavier.

 

After 8 treatments of 120 mg dasatinib with various combinations of other drugs and supplements that operate in the same pathways, this is about the limit of what I can take. In one of my treatments, similar to the above except honokiol was 3000 mg, my skin thinned noticeably. That was a warning sign that I was probably killing too many healthy cells. I recovered, but it was obvious that I had gone too far.

 

A more prudent approach might be to reduce dosages and take more treatments, such as

  1. 100 mg Dasatinib

  2. 100 mg  Mebendazole

  3. 300 mg EMIQ quercetin or quercetin phytosome

  4. 500 mg Pterostilbene

  5. 1000 mg Honokiol

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#296 jmorris

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Posted 11 March 2017 - 01:06 AM

 

Or would some ABT-737 be nice too?

 

Have you seen the IC-50 of ABT-737 vs Navitoclax?

 

ABT-737: Bcl-xl, Bcl-2,Bcl-w: 78.7nM, 30.3 nM, 197,8 nM

 

Navitoclax:  Bcl-xl, Bcl-2,Bcl-w: <0.5nM, <1nM, <1nM

 

Meaning, (pharmacodynamics aside) you would need ~160 - 200 times as much ABT-737 to get the same effect as Navitoclax. That sounds expensive.

 

http://www.selleckch...ts/ABT-737.html

http://www.selleckch...ts/ABT-263.html

 

Oh yeah, and it's not orally available.


Edited by jmorris, 11 March 2017 - 01:07 AM.


#297 TaiChiKid

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Posted 11 March 2017 - 07:02 AM

The new protocols for cancer treatment have changed in last few years.  A friend of mine who administers experimental protocols at the BC Cancer Agency with whom I discuss the progression of treatments, and the use of immunotherapeutics told me that almost all the treatments recently are predominantly immunotherapeutic in nature:  partly due to the higher specificity of targeted conjugated antibodies/immunoglobulins, and a lot fewer nasty side effects.  Nonetheless, it would be prudent to 'tone down' repeated self-treatment in the hope of clearing our own senescent cells until more information emerges.

 

If you have a sympathetic physician, or lab facilities, one could measure senescent clearing markers in the blood such as CBC, sedimentation rate (measure of cleared cells), white blood cell counts, and immunoglobulin panels before, during, and after a course of D&Q.

 

After deleting your senescent cells, follow a course using both your stem cell activators and telomerase enhancers and give both of them a long chance to do their work.

 

IMHO one should also limit the use of a senolytic combination such as D&Q to no more than once or twice a year until more long term studies emerge from labs.


Edited by TaiChiKid, 11 March 2017 - 07:23 AM.

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#298 Longevitarian

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Posted 11 March 2017 - 07:46 AM

Before I get into details I will mention My Girlfriends favourite pet,Caucassian HUMster,

whose age is 58,weighting 74 and having BMI of around 24 ....Sedentary lifestyle for

last 3 years, to avoid false positives on the antiaging therapy due to physical exercise.

HUMster also practices form of CR, which involves 16 hours fasting and 8 hours ad libitum

feeding each day (typically one meal, rarely snacks) as well as bloodletting of between

200-500 ml of blood every month for last 14 years. No supplements nor other medication

for the duration of the experiment which started in November and ended 4 weeks ago.

 

The D used in the experiment has been produced by major Pharmafia extorting from naive

and desperate $360 for each pill. The Q has been phamaceutical grade offered by AOR.

Fasting (F) was free of charge.

 

HUMster's greatest marker is the blood pressure, which showed dramatic reduction

within few weeks after dosing with D+Q+F and holding stable at youthful level of around

120/72 since then, for last half a year.

Here is the historical perspective: The HUMster's blood pressure had been raising

steadily for last 5 years. About 2 years ago it reached levels which became seriously

worrysome.HUMster could see levels of over 150/80 more and more often since then

and HUMster seriously considered starting beta blockers.....but never went so far.

4 doses of D+Q (100 ,6) , each dose week apart , with fasting 2 days before each dosing

did the job ....Also importantly , HUMster had been preloading 3g of Q a day for 2 weeks

before starting D+Q experiment.

 

HUMster's physician  is speechless, wondering what happened.......

 

It would be not delussional to expect that this dramatic improvement in the

cardiovascular health could be also accompanied with commensurate level of

improvement in adipose tissue....and even muscular and liver function as

published elsewhere, citing experiments on mice.

However , since HUMster is quite slim and never had any problems with liver,and

the muscles are in pristine order,those improvements are not as obvious and visible

as it is the case of his vascular health.

 

Obviously this is one of the first cases (if not first) seing major marker (cardiovascular

system health) showing in HUMster similar improvement to that observed in the experiments

with mice.

The gains are so impressive and permanent that  D+Q+F should be considered a cure

for the artherosclerosis......a major scourge of old age.

The experiment indicates that the D+Q+F is likely all what you need to achive dramatic antiaging

effect. No exotic mixes are needed.

 

Imagine the economic impact on the Pharmafia , which has been relaying on the maintenance

of disease as model for their profit making......Not any more .......but this is another topic...

 

Cheers

 

 


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#299 sthira

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Posted 11 March 2017 - 07:54 AM

This is helpful (Nathaniel David from Unity):

#300 sthira

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Posted 11 March 2017 - 08:21 AM

Before I get into details I will mention My Girlfriends favourite pet, Caucassian HUMster, whose age is 58,weighting 74 and having BMI of around 24 ....Sedentary lifestyle for last 3 years..


You didn't mention any joint problems like perhaps osteoarthritis. Were you sedentary prior to your D+Q+F experiment because your joints were causing you pain during motion? If so, did you feel any improvements in joint pain after your self trial?





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