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New class of drugs "senolytics" extends healthspan

apoptosis scenescent cells sasp senolytics

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#301 pone11

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Posted 27 February 2016 - 09:18 PM

On a whim I searched "NAD depletion Senescence Apoptosis Autophagy" After scanning some of the results I'm wondering for those of us on a NAD boosting regimen if we might be helping to hold on to some of our cellular baggage? As I scan these articles NAD depletion seems to be a necessary condition in this multi staged process of cells moving into senescence and later cell death. If this NAD stress is necessary to weed out these zombie cells maybe part of our future plan to eliminate senescence cells might be a washout period where we stop any NAD boosting some days before taking our senolytic drugs.

 

This is speculation but I wouldn't want to rescue the same cells I was wanting to eliminate. Any opinions?

 

Okay, but don't you think you would want to measure your NAD+ / NADH ratio levels before you go off on grand experiments to manipulate it?!

 

Dr Joseph Baur - of Harvard resveratrol fame - was nice enough to share with me papers and ideas on how one could get an approximation of NAD+ / NADH by measurements of Pyruvate and L-Lactate, as well as making underlying assumptions about pH of H+ in the environment outside the mitochondria.   My level of science understanding was barely able to understand it, but I did come up with a spreadsheet that embedded the calculations, and then I tested my formulas by researching various studies showing measurements of lactate and pyruvate in humans in various conditions.    That gave me a very good sense of what ratios are normal and which are pathological, in humans.   

 

I found a test for lactate and pyruvate done by a private lab owned by Quest, but each of two times they did this for me the lab gathering the blood screwed it up and the test could not be run.   So taking care to research the preparation of the sample and finding a competent lab to gather the blood is critical.

 

If one of the super-scientists here like Niner wants to audit my work I would be happy to share it.   I view the spreadsheet as a long term resource that I want to improve on.

 

Random thoughts on manipulating NAD+:

 

* NAD+ is mostly a product of complex 1 of the electron transport chain (ETC), so a pathological NAD+ level might be evidence of failure in the ETC.

 

* You might want to research what ozone therapy does, because one of the speculated mechanisms of action of this form of oxidation therapy is that it results in a cascade that produces a huge amount of NAD+.    This may be why people with chronic fatigue seem to do so well with that therapy, particularly ozone infusions.

 

* You might be able to infer your NAD+ level indirectly by taking an exercise physiology test VO2Max (including CO2 data, which is not commonly provided).   This will clearly indicate if your aerobic metabolism in the mitochondria is broken (i.e., are you going into full on glycolysis at low levels of workload).   If aerobic metabolism is broken, you might be able to infer that your NAD+/NADH ratios are not great.

 

* The other side of the coin here is that if you manipulate your NAD+ to very high levels, are you manipulating your electron transport chain, and thereby increasing the amount of ROS you subject your mitochondria to?   It might feel incredibly great to have very high NAD+ levels, but you might actually be aging yourself faster.   Getting a proper balance between pathological fatigue (e.g., low NAD+/NADH) and super-energetic (e.g., high NAD+/NADH) would be important.

 

A personal frustration I have with Longecity - and most of the online blogs on nutrition and science and health - is that people are very anxious to do N=1 experiments where they manipulate multiple variables simultaneously, while at the same time measuring no metabolites before and after the experiment.   Manipulating too many variables at once means you lose the ability to establish even rough causality.   Failure to measure metabolites before and after means you have no real experiment and any subjective result is subject to placebo effects (which are extraordinarily difficult to overcome, even for a very disciplined and trained observer).

 

NAD+/NADH ratios are one of my favorite topics.  I would love to see people do N=1 experiments around that.   But have a measurement of that before and after, otherwise what exactly are you testing?   The person with a pathological low NAD+/NADH who further suppresses that ratio is going to feel miserable and fatigued (most likely).  The person with "pathological" high NAD+/NADH might actually feel better with lower NAD+ levels.   I don't think it is safe to make generalizations like "more NAD+ is better".


Edited by pone11, 27 February 2016 - 09:38 PM.

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#302 stefan_001

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Posted 02 March 2016 - 11:45 AM

 

On a whim I searched "NAD depletion Senescence Apoptosis Autophagy" After scanning some of the results I'm wondering for those of us on a NAD boosting regimen if we might be helping to hold on to some of our cellular baggage? As I scan these articles NAD depletion seems to be a necessary condition in this multi staged process of cells moving into senescence and later cell death. If this NAD stress is necessary to weed out these zombie cells maybe part of our future plan to eliminate senescence cells might be a washout period where we stop any NAD boosting some days before taking our senolytic drugs.

 

This is speculation but I wouldn't want to rescue the same cells I was wanting to eliminate. Any opinions?

 

I wondered about the same thing.

 

It isn't certain, but research suggests that nicotinamide riboside could inhibit the caspase cascade and suppress apoptosis.

  1. “Mitigation of gamma-radiation induced abasic sites in genomic DNA by dietary nicotinamide supplementation: metabolic up-regulation of NAD(+) biosynthesis.” (2013) http://www.ncbi.nlm.nih.gov/pubmed/23891603

  2. “NAD+ acts on mitochondrial SirT3 to prevent axonal caspase activation and axonal degeneration“ (2013) http://www.ncbi.nlm.nih.gov/pubmed/23975935

 

I took NR not the day of but the day before my experiment #8.

 

 

Would there be a possibility to test synolytics combinations by topical administration on wrinkled skin? Applying it on patches of skin multiple times a day may provide some more direct feedback as you can see the impact immediately. FOr example earlier we discussed using honokiol topically. I tried two mixes on skin tags:
1) Honokiol + Ptero

2) Honokiol + Ptero + NR

 

Mix 1) caused them to swollen, mix 2) is shrinking them. A somewhat interesting outcome.

 

 

 

 



#303 LeeYa

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Posted 02 March 2016 - 12:33 PM

 

NAD+/NADH ratios are one of my favorite topics.  I would love to see people do N=1 experiments around that.   But have a measurement of that before and after, otherwise what exactly are you testing?   The person with a pathological low NAD+/NADH who further suppresses that ratio is going to feel miserable and fatigued (most likely).  The person with "pathological" high NAD+/NADH might actually feel better with lower NAD+ levels.   I don't think it is safe to make generalizations like "more NAD+ is better".

 

 

Please keep in mind that NAD+/NADH ratio is dependent on the time of the day. Thus, timing of senolysis matters!
 



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#304 niner

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Posted 02 March 2016 - 09:02 PM

 

 

On a whim I searched "NAD depletion Senescence Apoptosis Autophagy" After scanning some of the results I'm wondering for those of us on a NAD boosting regimen if we might be helping to hold on to some of our cellular baggage? As I scan these articles NAD depletion seems to be a necessary condition in this multi staged process of cells moving into senescence and later cell death. If this NAD stress is necessary to weed out these zombie cells maybe part of our future plan to eliminate senescence cells might be a washout period where we stop any NAD boosting some days before taking our senolytic drugs.
 
This is speculation but I wouldn't want to rescue the same cells I was wanting to eliminate. Any opinions?

 
I wondered about the same thing.
 
It isn't certain, but research suggests that nicotinamide riboside could inhibit the caspase cascade and suppress apoptosis.

  • “NAD+ acts on mitochondrial SirT3 to prevent axonal caspase activation and axonal degeneration“ (2013) http://www.ncbi.nlm.nih.gov/pubmed/23975935

  • I took NR not the day of but the day before my experiment #8.
     
    Would there be a possibility to test synolytics combinations by topical administration on wrinkled skin? Applying it on patches of skin multiple times a day may provide some more direct feedback as you can see the impact immediately. FOr example earlier we discussed using honokiol topically. I tried two mixes on skin tags:
    1) Honokiol + Ptero
    2) Honokiol + Ptero + NR
     
    Mix 1) caused them to swollen, mix 2) is shrinking them. A somewhat interesting outcome.

 

This is very interesting.  I like the idea of using senolytics topically.  There might be a role for DMSO solutions here, or maybe some other formulation involving lipids.   It's interesting that NR addition is causing an apparent shrinkage; if there is really apoptosis happening, then maybe the concerns about NR interfering with apoptosis are unfounded, but I think we need more data to really say that.  One question, though:  Do skin tags have a senescence component?  Off hand, I wouldn't think so.  Would you happen to have any actinic (or sebhorrheic) keratoses? 
 

Please keep in mind that NAD+/NADH ratio is dependent on the time of the day. Thus, timing of senolysis matters!

 
Do you have any sense of the magnitude of this effect, and what time of day would be predicted to be best?


Edited by niner, 02 March 2016 - 09:06 PM.


#305 LeeYa

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Posted 03 March 2016 - 11:42 AM

Please keep in mind that NAD+/NADH ratio is dependent on the time of the day. Thus, timing of senolysis matters!

 
Do you have any sense of the magnitude of this effect, and what time of day would be predicted to be best?



f16t268p5182n2_frZFwLvk.jpg
Circadian fluctuations in NAD+ levels and SIRT1 activity drive oscillations of the transcriptionally activating H3K4 trimethyl mark at promoters of clock-controlled genes
http://www.nature.co.../nsmb.3004.html

Edited by LeeYa, 03 March 2016 - 11:43 AM.

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#306 ta5

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Posted 06 March 2016 - 05:12 PM

Wondering if rutin will work just as well. Bulk rutin is way cheaper than Quercetin (like 5x)
It does seem bioavailability of rutin may be less optimal, but still shows up as quercetin in the blood.
http://www.ncbi.nlm....pubmed/11151743

 

The bioavailability of rutin appears to be very poor.

Respective bioavailability of quercetin aglycone and its glycosides in a rat model.

[...]By contrast, the plasma concentrations of quercetin metabolites was quite low with the rutin meal (about 3 microM) and undetectable after the quercetin 3-rhamnoside meal.[...]

 

 

Journal of Health Science, 46(4) 229–240 (2000) 229
Effects of Quercetin and Rutin on Serum and Hepatic Lipid Concentrations, Fecal Steroid Excretion and Serum Antioxidant
Yumiko Nakamura,* Susumu Ishimitsu, and Yasuhide Tonogai
Division of Food Chemistry, National Institute of Health Sciences, Osaka Branch, 1–1–43, Hoenzaka, Chuo-ku, Osaka 540–0006, Japan
Effects of quercetin and rutin on serum and hepatic lipid concentrations, fecal steroid excretion and their antioxidant properties were investigated in rats by oral administration. No toxic symptom was observed even at the dose of 1.0 g/kg of quercetin or rutin. Serum and hepatic lipid concentrations and fecal steroid excretion was not influenced remarkably, but serum thiobarbituric acid reactive substances (TBARS) decreased dose-dependently with the administration of quercetin or rutin. The decrease of serum TBARS was significantly correlated with the increase of serum free flavonoids (p < 0.05–0.001). Serum flavonoid concentrations, especially free quercetin, were higher in rutin-administered rats than in quercetin-administered rats at doses of 1.0 g/kg for 10 d (p < 0.05– 0.001). When 1.0 g/kg of quercetin or rutin was administered in a single dose, they remained in the blood as aglycone or their conjugates of quercetin and isorhamnetin, even three days after administration. Recovered fla- vonoids were only 0.13% and 0.89% in urine for 3 d and 0.03% and 0.13% in serum on day 3 by administration of quercetin and rutin, respectively. Thus, some part of the administered quercetin or rutin was metabolized and showed antioxidant property, but had no remarkable influence on serum or hepatic lipid concentrations or fecal steroid excretion in rats.


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#307 ta5

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Posted 06 March 2016 - 11:00 PM

This study says the AUC for quercetin in rats administered rutin was 2.25-fold higher than in rats administered quercetin.

 

 

J Agric Food Chem. 2003 Apr 23;51(9):2785-9.
Absorption and urinary excretion of quercetin, rutin, and alphaG-rutin, a water soluble flavonoid, in rats.
Shimoi K1, Yoshizumi K, Kido T, Usui Y, Yumoto T.
Quercetin, rutin, alphaG-rutin (a water soluble flavonoid), and a mixture of rutin and alphaG-rutin were administered to rats by a single gastric intubation, and their absorption and urinary excretion were examined. The plasma and 24 h urinary levels of aglycons (quercetin and tamarixetin/isorhamnetin) were measured by HPLC after deconjugation with beta-glucuronidase/sulfatase treatment. alphaG-rutin was absorbed more rapidly than quercetin or rutin, and the plasma concentrations of quercetin and tamarixetin/isorhamnetin reached the highest peak level 30 min after dosing. Quercetin, rutin, and the mixture of rutin and alphaG-rutin showed the first peak level 8 h, 8 h, and 30 min after dosing, respectively. The area under the concentration-time curve (AUC) for quercetin in rats administered alphaG-rutin was approximately 4.5- and 2-fold higher than those in rats administered quercetin and rutin, respectively, and was almost the same as that in rats administered a mixture of rutin and alphaG-rutin. The highest 24 h urinary excretion was observed in alphaG-rutin-administered rats. These results suggest that alphaG-rutin is absorbed more efficiently than either quercetin or rutin and that a high plasma concentration can be maintained by supplying rutin and alphaG-rutin in combination.
PMID: 12696973


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#308 stefan_001

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Posted 07 March 2016 - 09:04 AM

So quercetin senolytic action may be like this?

 

A molecular docking study revealed that quercetin, a flavonoid constituent of Ginkgo biloba, showed a higher potential to interact with topoisomerase II (Topo II) than did the other Ginkgo biloba constituents; this in silico prediction was confirmed by using a biochemical assay to study Topo II enzyme inhibition. Moreover, as measured by the Comet assay and the induction of γ-H2A.X, quercetin, followed by keampferol and isorhamnetin, appeared to be the most potent DNA damage inducer in HepG2 cells. In Topo II knockdown cells, DNA damage triggered by Ginkgo biloba leaf extract or quercetin was dramatically decreased, indicating that DNA damage is directly associated with Topo II. DNA damage was also observed when cells were treated with commercially available Ginkgo biloba extract product. Our findings suggest that Ginkgo biloba leaf extract- and quercetin-induced in vitro genotoxicity may be the result of Topo II inhibition.

http://www.ncbi.nlm....les/PMC4588569/

 

Topoisomerase inhibitors are agents designed to interfere with the action of topoisomerase enzymes[1] (topoisomerase I and II), which are enzymes that control the changes in DNA structure[2] by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle.

In recent years, topoisomerases have become popular targets for cancer chemotherapy treatments. It is thought that topoisomerase inhibitors block the ligation step of the cell cycle, generating single and double stranded breaks that harm the integrity of the genome. Introduction of these breaks subsequently leads to apoptosis and cell death.

Topoisomerase inhibitors can also function as antibacterial agents.[3]Quinolones (including nalidixic acid and ciprofloxacin) have this function.[4] Quinolones bind to these enzymes and prevent them from decatenation replicating DNA.

 

Also raises some questions about the safety of mega dosing.  DNA repair is an energy-consuming process so makes me wonder about the idea to stop NR while megadosing. This study implicates other pathways that lead to cancer cell death:

Obviously, the mechanism by which antineoplastic drugs affect the glycolytic status of cancer cells seems to be a key component of tumor sensitivity in chemotherapy. Because the molecular inhibitors of DDR kinases and PI3K/Akt/mTor signaling administered in this study (particularly BEZ235) have been shown to disrupt the glucose supply and therefore to eradicate OPM-2 cells, we see a promising therapeutic potential in dual targeting of these pathways.

http://www.ncbi.nlm....les/PMC4497433/

 

 

 


Edited by stefan_001, 07 March 2016 - 09:21 AM.

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#309 pone11

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Posted 08 March 2016 - 05:11 AM

 

 

Please keep in mind that NAD+/NADH ratio is dependent on the time of the day. Thus, timing of senolysis matters!

 
Do you have any sense of the magnitude of this effect, and what time of day would be predicted to be best?

 



f16t268p5182n2_frZFwLvk.jpg
Circadian fluctuations in NAD+ levels and SIRT1 activity drive oscillations of the transcriptionally activating H3K4 trimethyl mark at promoters of clock-controlled genes
http://www.nature.co.../nsmb.3004.html

 

 

Do you have any specific average/median NAD+/NADH ratios at each extreme of the cycle?  The standard deviation may not be so great.



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#310 LeeYa

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Posted 09 March 2016 - 07:05 PM

Do you have any sense of the magnitude of this effect, and what time of day would be predicted to be best?


Do you have any specific average/median NAD+/NADH ratios at each extreme of the cycle?  The standard deviation may not be so great.

 
In a nutshell:

  • Fasting at night raises AMPK activity, leading to an oxidative metabolism and mitochondrial biogenesis.
  • Oxidative metabolism raises NAD+/NADH ratio.
  • NAD+/NADH ratio modulates SIRT1 activity

The amplitude of NAD+/NADH cycle is influenced by the time and the amount of calories of your meals.

worth a read, for example:

http://www.sciencedi...092867408000627
http://www.nature.co...ature07813.html

To draw a conclusion for senolysis:
Catching senescent cells in a time frame with low NAD+/NADH ratio is more likely to induce apoptosis.
Kill them when you are in an anabolic state during the day, i.e. shortly after your main meal!

P.S.: It doesn't matter which magnitude the standard deviation actually has. It's the metabolic effect that counts.


Edited by LeeYa, 09 March 2016 - 07:18 PM.


#311 corb

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Posted 09 March 2016 - 11:20 PM

 

Do you have any sense of the magnitude of this effect, and what time of day would be predicted to be best?


Do you have any specific average/median NAD+/NADH ratios at each extreme of the cycle?  The standard deviation may not be so great.

 
In a nutshell:

  • Fasting at night raises AMPK activity, leading to an oxidative metabolism and mitochondrial biogenesis.
  • Oxidative metabolism raises NAD+/NADH ratio.
  • NAD+/NADH ratio modulates SIRT1 activity

The amplitude of NAD+/NADH cycle is influenced by the time and the amount of calories of your meals.

worth a read, for example:

http://www.sciencedi...092867408000627
http://www.nature.co...ature07813.html

To draw a conclusion for senolysis:
Catching senescent cells in a time frame with low NAD+/NADH ratio is more likely to induce apoptosis.
Kill them when you are in an anabolic state during the day, i.e. shortly after your main meal!

P.S.: It doesn't matter which magnitude the standard deviation actually has. It's the metabolic effect that counts.

 

 

I've been thinking a bit about that.

You might think you'd want to induce the maximum amount of apoptosis - but the thing is - cells that are capable of maintaining a high amount NAD+ are probably healthy cells - according to the literature we have so far.

So that makes me think there's a chance it'd be better to use senolytics when the NAD+ levels are at their highest. That way you might spare the healthy cells and only remove the malignancies.



#312 Logic

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Posted 10 March 2016 - 01:42 AM

 

In a nutshell:

  • Fasting at night raises AMPK activity, leading to an oxidative metabolism and mitochondrial biogenesis.
  • Oxidative metabolism raises NAD+/NADH ratio.
  • NAD+/NADH ratio modulates SIRT1 activity

 

Is that a graph of human levels or rodents?

Rodents are active at night..?



#313 pone11

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Posted 13 March 2016 - 11:46 AM

 

Do you have any sense of the magnitude of this effect, and what time of day would be predicted to be best?


Do you have any specific average/median NAD+/NADH ratios at each extreme of the cycle?  The standard deviation may not be so great.

 
In a nutshell:

  • Fasting at night raises AMPK activity, leading to an oxidative metabolism and mitochondrial biogenesis.
  • Oxidative metabolism raises NAD+/NADH ratio.
  • NAD+/NADH ratio modulates SIRT1 activity

The amplitude of NAD+/NADH cycle is influenced by the time and the amount of calories of your meals.

worth a read, for example:

http://www.sciencedi...092867408000627
http://www.nature.co...ature07813.html

To draw a conclusion for senolysis:
Catching senescent cells in a time frame with low NAD+/NADH ratio is more likely to induce apoptosis.
Kill them when you are in an anabolic state during the day, i.e. shortly after your main meal!

P.S.: It doesn't matter which magnitude the standard deviation actually has. It's the metabolic effect that counts.

 

 

I think you are missing the point and I think you need to quantify the effect that you say is important.

 

If a "normal" person has an NAD+/NADH ratio of 700, and an extremely pathological person with - say - diabetes has the same ratio at 200, that defines endpoints for known conditions.   The person who is at 700 - using your examples of factors that can alter the ratio - probably does not swing more than maybe 500 to 800 due to factors you cite like exercise and diet.   That person is never going to enter a pathological range using the benign variables you are mentioning, and you do nothing to clarify this conversation by raising vague issues that you do not quantify.

 

Energy deficit diseases like diabetes and chronic fatigue syndromes that result from some kind of tissue hypoxia/ischemia create enormous depressions in the NAD+/NADH ratio.  You simply won't get a normal person into that pathological range with the variables you cite.

 

Remember the citric acid cycle and electron transport chain regulate each other.   Citric acid cycle is a continuous producer of NADH.   High NADH stimulates the electron transport chain to pick up its rate of action which then oxidizes NADH back to NAD+.   In a healthy individual, the body is going to seek a steady state range for NAD+/NADH.  Sure, if you run a marathon you will collapse the ratio.  If you go to 14K feet you will collapse the ratio.   But a jog around the block or a large meal are not going to significantly alter these things.  The cells are going to self-regulate these things to keep your energy levels appropriately high to run metabolism of the cell and fuel DNA/RNA replication and repair.

 

It's not clear why you mention that "Oxidative metabolism raises the NAD+/NADH ratio".    NADH is oxidized by complex 1 of the electron transport chain to NAD+.  That's by definition.  It's not like a person does something to make that happen.

 

The person I responded to wanted to tinker with his NAD+/NADH ratio.   I'm simply saying define what your ratio is before you mess with it otherwise you are generating random numbers.   If you observe your own ratio at a steady state - not in an extreme oxygen stress condition like marathon or high altitude - this will tell you plenty about your level of aerobic metabolism and about whether it is desirable to improve this ratio.   If your ratio is at 900 you are already way beyond a healthy range and your aerobic metabolism is in overdrive.  Does such a person need to raise  aerobic metabolism another 20% and run the harm caused by the additional ROS?   Why?    On the other hand, if you are suffering from some kind of tissue hypoxia and your ratio is 200, this is extremely dire and your body is not generating enough energy to do DNA/RNA replication and repair.  You are likely converting amino acids to fuel inefficient glycolysis, and losing lean body mass in the process.  Your body is in serious trouble.    That person probably benefits from safe experimentation around how to raise their NAD+/NADH ratio in order to fuel the bare minimum processes the body needs to stay healthy.  This should not be controversial.


Edited by pone11, 13 March 2016 - 12:16 PM.


#314 LeeYa

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Posted 13 March 2016 - 06:01 PM

You might think you'd want to induce the maximum amount of apoptosis - but the thing is - cells that are capable of maintaining a high amount NAD+ are probably healthy cells - according to the literature we have so far.
So that makes me think there's a chance it'd be better to use senolytics when the NAD+ levels are at their highest. That way you might spare the healthy cells and only remove the malignancies.

 
Good point. 
 
High NAD levels -> low toxicity for healthy cells, low senolytic effetivity
Low NAD levels -> higher toxicity for healthy cells, high senolytic effectivity.
 
It seems to be quite similar to fasting approches during cancer chemotherapy, by the way.
 
Maybe high NAD levels are more safe and if you don't see much side effects, you may carry on with the "armed version"`?
 

 

In a nutshell:

  • Fasting at night raises AMPK activity, leading to an oxidative metabolism and mitochondrial biogenesis.
  • Oxidative metabolism raises NAD+/NADH ratio.
  • NAD+/NADH ratio modulates SIRT1 activity
 
Is that a graph of human levels or rodents?
Rodents are active at night..?

 

 
This is an important point!

 

The graph shows the situation for rodents.  However, my "nutshell"-statment and the above mentioned timing are already adopted to the human situation ;)
 

I think you are missing the point and I think you need to quantify the effect that you say is important.[...]
It's not clear why you mention that "Oxidative metabolism raises the NAD+/NADH ratio".    NADH is oxidized by complex 1 of the electron transport chain to NAD+.  That's by definition.  It's not like a person does something to make that happen.

As you know, NAD/NADH ratio usually is measured indirectly by determination of the lactate/pyruvate ratio
(but there are some caveats for this method: http://journals.plos....pone.0034525).

As you already mentioned, there are big variations from individual to individual. For example, if you have a disrupted circadian rhythm, the standard deviation may be even non existent.

 

If you want precise values, you should measure your personal range (overnight fasting vs. postprandial).
 
It is quite easy to drive your organism into an oxidative state, if you know how. Given the mentioned connection,  you can influence your NAD+/NADH ratio. 

 

There will be a lot of contraindications for a senolytic therapy, that's for shure! At this time, senolysis is still highly experimental.


Edited by LeeYa, 13 March 2016 - 06:14 PM.


#315 pone11

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Posted 13 March 2016 - 11:58 PM

 

I think you are missing the point and I think you need to quantify the effect that you say is important.[...]
It's not clear why you mention that "Oxidative metabolism raises the NAD+/NADH ratio".    NADH is oxidized by complex 1 of the electron transport chain to NAD+.  That's by definition.  It's not like a person does something to make that happen.

As you know, NAD/NADH ratio usually is measured indirectly by determination of the lactate/pyruvate ratio
(but there are some caveats for this method: http://journals.plos....pone.0034525).

As you already mentioned, there are big variations from individual to individual. For example, if you have a disrupted circadian rhythm, the standard deviation may be even non existent.

 

If you want precise values, you should measure your personal range (overnight fasting vs. postprandial).
 
It is quite easy to drive your organism into an oxidative state, if you know how. Given the mentioned connection,  you can influence your NAD+/NADH ratio. 

 

There will be a lot of contraindications for a senolytic therapy, that's for shure! At this time, senolysis is still highly experimental.

 

 

That study is interesting but does anyone else find it disturbing that their tests were against human breast cancer cells?   Cancer hijacks the mitochondria and alters normal aerobic metabolism in favor of glycolysis.   I'm not sure why we would use such cells to establish baseline techniques for measuring healthy cells.

 

I would love to hear your ideas on how you can drive an organism into an oxidative state.   Keep in mind that most individuals with a bad NAD+/NADH ratio are diabetic or suffering from some kind of hypoxia.   Aerobic metabolism does not work simply because not enough O2 is getting to the cell to fuel the mitochondrial electron transport chain.

 

I have looked closely at therapies like major autohemotherapy of ozone, which supposedly results in a cascade of metabolites that create a flood of NAD+.   It's not clear to me however whether this is safe in the environment of hypoxia.   



#316 Wilberforce

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Posted 18 March 2016 - 05:48 PM

Has anyone found any positive effects from a personal trial yet?  I've searched through the forum and only found one story where someone had a skin condition flake off. I've got the Senolytix pack from TLR in the fridge but its looking like a waste of money ;-)



#317 stefan_001

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Posted 18 March 2016 - 09:11 PM

Has anyone found any positive effects from a personal trial yet? I've searched through the forum and only found one story where someone had a skin condition flake off. I've got the Senolytix pack from TLR in the fridge but its looking like a waste of money ;-)

Well I have started to play with topical use and took some mix to a real large mold instead of a flake applying morning and evening for two weeks. It is for sure that it has impact, becoming more smooth and lighter but it is not gone yet however still improving even now that I have stopped applying for a week or so. I am taking now and then a picture, will post those eventually.

I am taking the same supplements also orally for a longer time but oral use has no impact or then very slow.

So what did I learn from this. Topical application apparently is a method to reach much higher concentrations of serum level in skin cells than oral consumption. Topical experiments hence may be a safer way to test whether synolytics drugs have effect.

That next I will "attacks" a wrinkle with morning/evening application. Also I need to try to figure out whether each component dissolves well in the skin cream and is actually absorbed. It may still be just one component works.

Here is to suggestions what would be a good mix to try. As I have multiple wrinkles it's easy to test multiple variations :-)

Edited by stefan_001, 18 March 2016 - 09:12 PM.

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#318 zorba990

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Posted 18 March 2016 - 10:06 PM

Has anyone found any positive effects from a personal trial yet? I've searched through the forum and only found one story where someone had a skin condition flake off. I've got the Senolytix pack from TLR in the fridge but its looking like a waste of money ;-)

Well I have started to play with topical use and took some mix to a real large mold instead of a flake applying morning and evening for two weeks. It is for sure that it has impact, becoming more smooth and lighter but it is not gone yet however still improving even now that I have stopped applying for a week or so. I am taking now and then a picture, will post those eventually.

I am taking the same supplements also orally for a longer time but oral use has no impact or then very slow.

So what did I learn from this. Topical application apparently is a method to reach much higher concentrations of serum level in skin cells than oral consumption. Topical experiments hence may be a safer way to test whether synolytics drugs have effect.

That next I will "attacks" a wrinkle with morning/evening application. Also I need to try to figure out whether each component dissolves well in the skin cream and is actually absorbed. It may still be just one component works.

Here is to suggestions what would be a good mix to try. As I have multiple wrinkles it's easy to test multiple variations :-)

I am thinking of using phlogel for this, but wondering if things like quercetin will stain the skin permanently if it gets in deep enough...
http://jarpharmaceut...ultra-500g-jar/

#319 stefan_001

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Posted 20 March 2016 - 03:40 PM

So it is not only about the amount of scenescent cells but also the age:

 

http://www.jidonline...0371-7/fulltext

 

In addition the activity of complex II was examined in senescent and nonsenescent skin fibroblast cell populations, as senescent cells are thought to play a prominent role in the aging process, potentially via mitochondrial dysfunction. This study demonstrated that complex II activity decreases in an age-dependent manner in FACS-sorted senescent cells but not in FACS-sorted nonsenescent cells. This could suggest that the overall decrease in complex II activity observed in skin fibroblasts with age demonstrated in this study was due to the senescent cells only. Work investigating the differences in mitochondrial complex activity between senescent cells from older and senescent cells from younger individuals has not been previously reported. This study provides evidence that senescent cells from older individuals are less efficient in terms of mitochondrial complex II activity than senescent cells from younger individuals, which could have implications in terms of deciphering the causes of the overall decrease in cellular efficiency observed with age. Higher levels of ROS generation are present in senescent compared to nonsenescent cells (Passos et al., 2007), potentially resulting in increased mitochondrial DNA and nuclear DNA damage and mitochondrial dysfunction (Passos et al., 2007) and a possible decrease in complex II activity if damage becomes sufficiently high. Damage to senescent cells may be higher in the skin of older individuals because of the lower levels of antioxidants observed with age (Micallef et al., 2007), as well as the age-related decline of senescent cell removal systems such as the immune system (Rodier and Campisi, 2011) and the autophagy/lysosomal pathway (Dutta et al., 2012). These factors could result in lower complex II activity in senescent cells of older individuals. In conclusion, the rate of complex II activity within human skin fibroblasts was shown to be lower in older individuals in this study, specifically in their senescent cells. It is likely that a decrease in complex II activity, whether causal or consequential in terms of the aging process, is likely to be exacerbating mitochondrial dysfunction with age.

 

 


Edited by stefan_001, 20 March 2016 - 03:53 PM.

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#320 stefan_001

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Posted 21 March 2016 - 09:19 PM

 

 

Has anyone found any positive effects from a personal trial yet? I've searched through the forum and only found one story where someone had a skin condition flake off. I've got the Senolytix pack from TLR in the fridge but its looking like a waste of money ;-)

Well I have started to play with topical use and took some mix to a real large mold instead of a flake applying morning and evening for two weeks. It is for sure that it has impact, becoming more smooth and lighter but it is not gone yet however still improving even now that I have stopped applying for a week or so. I am taking now and then a picture, will post those eventually.

I am taking the same supplements also orally for a longer time but oral use has no impact or then very slow.

So what did I learn from this. Topical application apparently is a method to reach much higher concentrations of serum level in skin cells than oral consumption. Topical experiments hence may be a safer way to test whether synolytics drugs have effect.

That next I will "attacks" a wrinkle with morning/evening application. Also I need to try to figure out whether each component dissolves well in the skin cream and is actually absorbed. It may still be just one component works.

Here is to suggestions what would be a good mix to try. As I have multiple wrinkles it's easy to test multiple variations :-)

I am thinking of using phlogel for this, but wondering if things like quercetin will stain the skin permanently if it gets in deep enough...
http://jarpharmaceut...ultra-500g-jar/

 

 

Quercetin is included in some skin care products for its anti-inflamtory and anti- exidant qualities but I guess it doesn't do the miracles we would like to see because then we would have heard more about it. Possibly the amount of Quecetin in those creams is too low. The gel sounds like something I may try to buy.

 



#321 mikeinnaples

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Posted 24 March 2016 - 04:50 PM

Some of this discussion around senolytics is fascinating.

 

 

On that note, the discussion about ozone therapy made me think about the hyperbaric oxygen therapy combined with the test subjects being fully in ketosis and its impact on certain cancers. A 1-2 punch of sorts and pretty effective, I am wondering if adding senolytics into the mix at the right time could result in a 1-2-3 punch and knockout for certain cancers. In addition combining keto w/senolytics for a few months every year as a preventative. Might be off base with my reasoning, but it seems plausible.



#322 Logic

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Posted 25 March 2016 - 08:43 AM

Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: towards molecular targeted therapies

Systemic sclerosis (SSc) is a fibrosing connective tissue disease with significantly increased mortality. Therapeutic options to treat fibrosis are limited. The small molecule tyrosine kinase inhibitor imatinib and related drugs such as dasatinib and nilotinib target simultaneously two of the major profibrotic pathways, TGFβ- and PDGF- signaling. Imatinib, dasatinib and nilotinib inhibit collagen synthesis in cultured fibroblasts and have potent anti-fibrotic effects in animal models of different fibrotic diseases. Moreover, several case reports, case series and uncontrolled studies on patients with SSc, mixed connective tissue disease, nephrogenic systemic fibrosis and in particular sclerodermatous graft versus host disease (cGvHD) report regression of fibrosis and good tolerability. However, the results of larger controlled trials, which are currently ongoing, are needed before any conclusions on efficacy and tolerability can be drawn. Until the results of these trials are available, we discourage off-label use of Imatinib in single patients.

http://ard.bmj.com/c..._1/i48.abstract

 

NB That Nilotinib upregulates autophagy and mitophagy of ailing mitochondria only, as well as clears misfolded proteins from cells:

http://www.longecity...e-with-enzymes/

http://www.longecity...1-month-supply/

 


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#323 The Capybara

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Posted 26 March 2016 - 07:31 AM

Having nothing to do tonight, save for watching repeats of Family Guy, I mixed up 100mg of dasatinib in 20ml of distilled water.

Next I mixed up about a teaspoon of quercetin in 20ml of distilled water. I didn't expect the latter to mix well in distilled water, and it didn't.

Next I added 6 drops of Dr Bronner's Peppermint Pure Castile (liquid) Soap to the quercetin / 20ml distilled water slush and surprisingly the quercetin went into solution very quickly.

The reason for the Dr Bronner's was less to get the quercetin in solution than to facilitate absorption of the mixture into the deeper layers of the skin.

Next I took some veterinary OB gloves (SyrVet) and poured both the 20ml dasatinib solution and the 20ml quercetin / Dr Bronner's solution into one of them and mixed the solutions from the outside of the glove. I had used similar gloves previously while doing embryo transfer work on camels, and knew these gloves were largely inert and didn't leak or break. (As an aside, there is no more comfortable, warm, and well padded place to place your arm on a brisk winter morning than a camel's vagina). These gloves cover the entire length of the arm, which was useful in this preliminary test.

I washed my entire left arm with dish washing soap twice to remove as much natural body oils as possible and perhaps further facilitate diffusion of the solution into the exposed skin. I put the glove on my left arm, and used my untreated right arm as a control. I did have to slosh the solution around regularly inside the glove (after taping up the end of the glove near my armpit to prevent leakage) in order to get good coverage of my arm with the 40ml solution.

Since this was a first, and I didn't know how this would play out, I exposed the area for approximately 40 minutes (2 episodes of Family Guy without commercials) and then removed the gloves, shook off the excess liquid, and let the left arm dry for about 20 minutes (1 episode of Family Guy). I limited the exposure time of the direct contact with the liquid, figuring it was better to have aging skin rather than no skin if this all went south.

I left the dry residue on my skin for about 2 hours, and then rinsed briefly with a slightly soapy solution.

All went well and I have nothing to report since this all just occurred.

I suppose if NADH is really an issue (previously discussed above), I can add apocynin in a later trial.

 


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#324 stefan_001

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Posted 26 March 2016 - 06:39 PM

Having nothing to do tonight, save for watching repeats of Family Guy, I mixed up 100mg of dasatinib in 20ml of distilled water.

Next I mixed up about a teaspoon of quercetin in 20ml of distilled water. I didn't expect the latter to mix well in distilled water, and it didn't.

Next I added 6 drops of Dr Bronner's Peppermint Pure Castile (liquid) Soap to the quercetin / 20ml distilled water slush and surprisingly the quercetin went into solution very quickly.

The reason for the Dr Bronner's was less to get the quercetin in solution than to facilitate absorption of the mixture into the deeper layers of the skin.

Next I took some veterinary OB gloves (SyrVet) and poured both the 20ml dasatinib solution and the 20ml quercetin / Dr Bronner's solution into one of them and mixed the solutions from the outside of the glove. I had used similar gloves previously while doing embryo transfer work on camels, and knew these gloves were largely inert and didn't leak or break. (As an aside, there is no more comfortable, warm, and well padded place to place your arm on a brisk winter morning than a camel's vagina). These gloves cover the entire length of the arm, which was useful in this preliminary test.

I washed my entire left arm with dish washing soap twice to remove as much natural body oils as possible and perhaps further facilitate diffusion of the solution into the exposed skin. I put the glove on my left arm, and used my untreated right arm as a control. I did have to slosh the solution around regularly inside the glove (after taping up the end of the glove near my armpit to prevent leakage) in order to get good coverage of my arm with the 40ml solution.

Since this was a first, and I didn't know how this would play out, I exposed the area for approximately 40 minutes (2 episodes of Family Guy without commercials) and then removed the gloves, shook off the excess liquid, and let the left arm dry for about 20 minutes (1 episode of Family Guy). I limited the exposure time of the direct contact with the liquid, figuring it was better to have aging skin rather than no skin if this all went south.

I left the dry residue on my skin for about 2 hours, and then rinsed briefly with a slightly soapy solution.

All went well and I have nothing to report since this all just occurred.

I suppose if NADH is really an issue (previously discussed above), I can add apocynin in a later trial.

 

 

Now this sounds like a serious approach to test the topical route. Very curious to hear whether you will note anything. Hope you are less experimental with the Camel's though.....

 



#325 Fafner55

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Posted 27 March 2016 - 03:19 PM

Experiment #11  

This experiment is nearly the same as experiment #8 except for the addition 100 mg  mebendazole.

 

2016-03-18, late afternoon   Starting at 5:30 in the afternoon on an empty stomach I ingested

120 mg Dasatinib

6400 mg Quercetin dihydrate

350 mg Liposomal quercetin

600 mg Sodium butyrate every 15 minutes, 8 total, starting 30 minutes before taking anything else

500 mg Pterostilbene

2000 mg Longvida curcumin

800 mg Honokiol (Magnolia bark extract)

400 mg Grape seed extract

1000 mg Green tea extract

100 mg  Mebendazole

2016-03-18, evening   The skin all over my body is slightly flushed.  I didn’t notice flushing in experiment #8.

2016-03-19   Woke with slight muscle ache.  Otherwise I feel and look normal.  Unlike experiment #8, there is no sensation of fever.

2016-03-20   Small, raised, scaly patches of skin on my head appear to be gone or greatly reduced.  I have had these bumps for years.  This improvement supports the idea that mebendazole contributes to this apoptotic mix.

2016-03-27  Three keratoses on my thigh sloughed off on 3-20 or 3-21 (I didn’t note the day).  Two appear to be healed and replaced by normal skin.  The third is reduced in size.  Like the bumps on my head, I have had these small  keratoses for years.  Since experiment #8 did not clear them, the addition of mebendazole to this experiment most likely increased the apoptotic effect of this treatment.

 

I have only a small amount of dasatinib and no source for getting more.  I would appreciate it if anyone could point me to a source.

 

Fafner55


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#326 nbourbaki

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Posted 28 March 2016 - 03:09 AM

This is the supplier I've been using:

 

https://teamtlr.com/...arch-agent.html



#327 stefan_001

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Posted 28 March 2016 - 06:58 AM

Experiment #11  

This experiment is nearly the same as experiment #8 except for the addition 100 mg  mebendazole.

 

2016-03-18, late afternoon   Starting at 5:30 in the afternoon on an empty stomach I ingested

120 mg Dasatinib

6400 mg Quercetin dihydrate

350 mg Liposomal quercetin

600 mg Sodium butyrate every 15 minutes, 8 total, starting 30 minutes before taking anything else

500 mg Pterostilbene

2000 mg Longvida curcumin

800 mg Honokiol (Magnolia bark extract)

400 mg Grape seed extract

1000 mg Green tea extract

100 mg  Mebendazole

2016-03-18, evening   The skin all over my body is slightly flushed.  I didn’t notice flushing in experiment #8.

2016-03-19   Woke with slight muscle ache.  Otherwise I feel and look normal.  Unlike experiment #8, there is no sensation of fever.

2016-03-20   Small, raised, scaly patches of skin on my head appear to be gone or greatly reduced.  I have had these bumps for years.  This improvement supports the idea that mebendazole contributes to this apoptotic mix.

2016-03-27  Three keratoses on my thigh sloughed off on 3-20 or 3-21 (I didn’t note the day).  Two appear to be healed and replaced by normal skin.  The third is reduced in size.  Like the bumps on my head, I have had these small  keratoses for years.  Since experiment #8 did not clear them, the addition of mebendazole to this experiment most likely increased the apoptotic effect of this treatment.

 

I have only a small amount of dasatinib and no source for getting more.  I would appreciate it if anyone could point me to a source.

 

Fafner55

 

This study is pessimistic on the oral use of Pterostilbene and Quercitin for cancer treatment. In particular negative for Q:

 

Bioavailable concentrations of PTER and QUER, measured in plasma after oral administration, failed to inhibit B16M-F10 cell growth (even when concentrations of these polyphenols were constant along the culture time; see Inhibition of B16 Melanoma Cell Growth In Vitro section). However, bioavailable concentrations of PTER and QUER, measured in plasma after intravenous administration (Figure 1), inhibited tumor growth up to ∼ 56% (even when both polyphenols were present only for 60 minutes for each 24 hours of culture) (Figure 2) without increasing the rate of cell death (cell viability remained > 95%, as in controls, in all cases).

http://www.ncbi.nlm....les/PMC1490314/
 


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#328 Logic

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Posted 28 March 2016 - 10:26 AM

Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively?

  • Curcumin has been shown to have differential effects on normal cells such as endothelial cells, lymphocytes, hepatocytes, fibroblasts, thymocytes, and mammary epithelial cells (78,96,110–115,163,172,173,224).
  • Why curcumin kills tumor cells and not normal cells is not fully understood, but several reasons have been suggested. First, absorption and fluorescence spectroscopic methods showed that cellular uptake of curcumin is higher in tumor cells than in normal cells (256). The studies also showed that curcumin was maximally distributed in the cell membrane and the nucleus. Second, the glutathione levels in tumor cells tend to be lower than normal cells, thus enhancing the sensitivity of tumor cells to curcumin (172). Third, most tumor cells, but not normal cells, express constitutively active NF-κB and mediate their survival (150). Curcumin can suppress the survival and proliferation of tumor cells by suppressing NF-κB-regulated gene products.
  • Apart from this, human epidermal keratinocytes have been shown to undergo apoptosis when exposed to curcumin through the inhibition of AP-1 (104).
  • Low concentrations of curcumin may protect hepatocytes by reducing lipid peroxidation and cytochrome c release. Conversely, higher concentrations provoke glutathione depletion, caspase-3 activation, and hepatocytotoxicity (96). Interestingly, curcumin had no effect on normal rat hepatocytes, which showed no superoxide generation and therefore no cell death (172).
  • Primary cultures of human dermal fibroblasts were less sensitive to lower doses of curcumin (78). Studies have shown that curcumin causes fibroblast apoptosis and that this could be inhibited by co-administration of antioxidants N-acetyl-l-cysteine , biliverdin or bilirubin, suggesting that ROS are involved (221).
  • In endothelial cells, curcumin inhibited MAP kinase activity and enhanced TNF-induced apoptosis (218). Studies suggests that curcumin induces the apoptosis in human retinal endothelial cells by the regulation of intracellular ROS generation, VEGF expression and release, and VEGF-mediated PKC-beta II translocation (257).
  • Curcumin can induce cell death in both quiescent and proliferating normal human lymphocytes, without oligonucleosomal DNA degradation, which is considered a main hallmark of apoptotic cell death (258). Curcumin induces cell death in lymphocytes that can be classified as apoptosis-like cell death (220).

http://www.ncbi.nlm....les/PMC2758121/

 

The effects in bold are not ​desirable!?

It seems 'The devil is in the dosage!' and perhaps the new bioavailable formulations are something to be wary of?

 

http://www.longecity...damage-and-atm/

 

http://www.longecity...gvida-curcumin/

 

http://www.longecity...ndpost&p=720190

 



#329 The Capybara

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Posted 30 March 2016 - 10:55 PM

This is a continuation of my topical dasatinib, quercetin experiment dated March 26th (above)

 

There were no side effects from the first trial.

I did have a fair amount of superficial skin flaking, but figuring my skin was washed with detergent prior to being soaked in 100mg of disatinib and a teaspoon of quercetin with some Dr Bronner's soap for 40 minutes, I can't say that the flaking was due to the removal of senescent cells.

 

Last night I ran the same experiment, but did add a smidgen (that's metric, isn't it?) of apocynin in the mixture to lower NADH for no good reason other than the speculative dialog above discussing NADH levels.

 

This time I soaked my arm (as previously described), but instead of a 40 minute soak, I went for 2 hours.

I took a shower after the 2 hour soak rather than let the solution dry on my skin.

As before, there were no issues while soaking, and the following day (today), there were no signs of skin flaking or anything else positive or negative so far.

 

I'll continue this experiment every few days. Any insightful ideas are appreciated, as are critiques of something I may be missing such as skin permeability to any of the components as well as skin diffusion.


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#330 niner

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Posted 31 March 2016 - 03:25 AM

I did have a fair amount of superficial skin flaking, but figuring my skin was washed with detergent prior to being soaked in 100mg of disatinib and a teaspoon of quercetin with some Dr Bronner's soap for 40 minutes, I can't say that the flaking was due to the removal of senescent cells.

 

If you made up a solution of the vehicle minus the drugs, you could have a pretty good control.  You could use one arm for the active and the other for the control, or split one or both arms.  If you wanted to go nuts, you could even get someone to blind it for you, if they were sufficiently similar.







Also tagged with one or more of these keywords: apoptosis, scenescent cells, sasp, senolytics

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