459 replies to this topic

[niner]

Low concentrations of flavonoids are protective in rat H4IIE cells whereas high concentrations cause DNA damage and apoptosis.  states that quercetin and fisetin induced cytotoxicity, DNA strand breaks, oligonucleosomal DNA fragmentation, and caspase activation at concentrations between 50 and 250 micromol/L …. Published data on quercetin pharmacokinetics in humans suggest that a dietary supplement of 1-2 g of quercetin may result in plasma concentrations between 10 and 50 micromol/L.   

 
 
When they say 1-2g doses provide 10-50 uM, they can't possibly be referring to the quercetin aglycone.  Probably they are talking about all quercetin metabolites, expressed as a quercetin equivalent.    On the other hand, all the scary cytotox, DNA issues etc is undoubtedly in vitro data using the aglycone.  In such systems, there isn't a bothersome liver waiting to destroy all the cool xenobiotics you manage to get your hands on...
 

PublishedDose PlasmaConcentration TargetConcentration TargetDose
8 mg    140 nM    15 uM    5240 mg
20 mg    220 nM    15 uM    3408 mg  
50 mg    290 nM    15 uM    2586 mg
80 mg    630 nM    15 uM    1905 mg
1000 mg 1500 nM    15 uM    9750 mg

 
 This table, on the other hand, appears to be talking about the aglycone, based on the nanomolar plasma concentrations they see.  None of these are remotely in the ballpark of the doses seen to cause cytotox in vitro.
 

The genotoxicity in vitro is also worrying to me.  No symptoms related to DNA damage has been observed in animal models, but in humans maybe in the very long term this might be a concern.

Based on the low concentrations of the aglycone that are achieved even from large doses of quercetin, I think that a problem is unlikely. We wouldn't be using quercetin long term for senescent cell clearance, so I'm not particularly concerned. Quercetin at dietary doses has very good epidemiology, FWIW.

Edited by niner, 26 March 2015 - 01:43 AM.

[pone11]

 

Another study, Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies and http://ajcn.nutrition.org/content/81/1/243S.full  shows various measures of plasma concentrations from ingesting quercetin, which I convert to target therapeutic doses.  It should be noted that that these studies showed a very high interindividual variability.  

 

 

Which table in these studies were you pasting data from?  I could not locate those data points anywhere in the study.

[nowayout]

The genotoxicity in vitro is also worrying to me.  No symptoms related to DNA damage has been observed in animal models, but in humans maybe in the very long term this might be a concern.

Based on the low concentrations of the aglycone that are achieved even from large doses of quercetin, I think that a problem is unlikely. We wouldn't be using quercetin long term for senescent cell clearance, so I'm not particularly concerned. Quercetin at dietary doses has very good epidemiology, FWIW.

 

 

What about the possible testicular toxicity claimed in the other study I posted? 

 

This, for me, would be a deal breaker. 
 

[LeeYa]

Brainstorming goes on in other related communites, too....

 

 

 

What do you think of this particular strategy, I've seen in a german forum?

 

Essentially, it consists of a 3 day fast for maximizing autophagy plus some (optional) autophagy-enhancing supplements ( i.e., resveratrol, curcumin, trehalose), with quercetin at day 3.

The therory behind day 4 is now to stop fasting, and induce autophagy inhibition with chloroquine, in combination with a 2nd round of quercetin plus nitrostress (arginine and citrulline). As far as I understand it, the idea is to catch additional senescent cells that are able to escape toxicity by their own activated autophagy mechanisms.

 

By the way, pulse wave velocity was suggested as biomarker for succesfull clearance of senescent endothelial cells.

 

Any opinions?

 

 

Edited by LeeYa, 26 March 2015 - 06:43 PM.

[niner]

Essentially, it consists of a 3 day fast for maximizing autophagy plus some (optional) autophagy-enhancing supplements ( i.e., resveratrol, curcumin, trehalose), with quercetin at day 3.
The therory behind day 4 is now to stop fasting, and induce autophagy inhibition with chloroquine, in combination with a 2nd round of quercetin plus nitrostress (arginine and citrulline). As far as I understand it, the idea is to catch additional senescent cells that are able to escape toxicity by their own activated autophagy mechanisms.
 
By the way, pulse wave velocity was suggested as biomarker for succesfull clearance of senescent endothelial cells.
 
Any opinions?

Thanks for that find, LeeYa. I'm not sure that fasting will do what we want here-- It will increase autophagy, but we're looking for apoptosis. In this paper looking at Dietary Restriction, they say:
 

As summarized above, the limited data available so far do not point to a single gene, pathway, or molecular mechanism underlying the benefits of short-term DR. Instead, these studies highlight a range of potential mechanisms. Three of these - altered metabolism allowing for differential or more efficient fuel usage (17, 24, 29), increased survival signaling resulting in less apoptotic cell death (30, 31) and upregulation of genes involved in cytoprotection (11) – are observed in the injured organs themselves, suggesting possible cell or organ autonomy.

It's possible that fasting is different enough from DR that these things wouldn't apply; I don't really know.  Since senescent cells ignore normal death signals, things that cause apoptosis in normal cells may or may not work with senescent cells.   It would really help to have solid markers.  Is PWV something that can be measured without sophisticated equipment?

[pone11]

It's possible that fasting is different enough from DR that these things wouldn't apply; I don't really know.  Since senescent cells ignore normal death signals, things that cause apoptosis in normal cells may or may not work with senescent cells.   It would really help to have solid markers.  Is PWV something that can be measured without sophisticated equipment?

 

 

They describe a non invasive technique to measure pulse wave velocity (PWV) here:

http://en.wikipedia....e_wave_velocity

 

The method is summarized as "The advantage of foot-to-foot PWV measurement is the simplicity of measurement, requiring only two pressure wave forms recorded with invasive catheters, or mechanical tonometers or pulse detection devices applied non-invasively to the pulse across the skin, where the site of the two measurements are a known distance apart."

 

But the question is who would do such measurements?   I kind of doubt my cardiologist would a) agree to do it; b) necessarily even understand what it is and how to do the measurement.

 

I'm trying to imagine the conversation with the doctor: "I want to measure my pulse wave velocity, then take some chemotherapy drug to clear senescent cells, then measure my pulse wave velocity again to establish efficacy."   

Edited by pone11, 27 March 2015 - 01:19 AM.

[LeeYa]

Niner,

 

thank you for your research on that topic!

Your considerations would argue for the autophagy inhibition (see above, day 4), right? Maybe one could skip day 1-3, then?

 

Pulse wave velocity seems to be more of a general marker for cardiovascular health. Ín my eyes, it lacks specifity for senescent cells but has a good correlation to aging:

 

http://www.atcormedi...ing_effect2.jpg

 

More about PWV:

http://circ.ahajourn...06/16/2085.long

 

pone11:

But the question is who would do such measurements? I kind of doubt my cardiologist would a) agree to do it; b) necessarily even understand what it is and how to do the measurement.

 

In europe, it seems to be a recommended routine measurement, it should be possible at least to get it once. (and maybe a second measurement from another doc "2nd opinion"?)

 

Edited by LeeYa, 27 March 2015 - 12:04 PM.

[Logic]

FWIW TLR has SENOLYTIX up on their site.
It consists of 100 doses of 300mg of Q with 30mg D which is the HED of the mouse dosage used in the study. 

http://teamtlr.com/a...arch-agent.html

 

There is a 25% discount on it for those that ordered GHK/GHK-Cu which I plan to take advantage of once its in stock and after the GHK arrives.

One dose of Dasatinib from a quack is $360.
So 100 doses at $75, plus Quercetin, is around 1/500th the price!

 

I will report back if/when I have taken a dose, but I suspect it may take a looooong while for enough pre orders to accumulate to get this made.

 

PS:  I would go on holiday to mexico to visit BioViva afterward if could afford it!

http://www.longecity...rapy-available/

Edited by Logic, 04 April 2015 - 03:10 AM.

[corb]

I suspect senolytics will gain popularity very fast and very soon.

 

 

Our data describe that differentiated cells, which are driven into senescence by an oncogene, use this senescence state as trigger for tumor transformation, giving rise to highly aggressive tumor-initiating cells. These observations provide the first experimental in vitro evidence for the evasion of oncogene-induced senescence on the cellular level and ensuing transformation.

http://www.ncbi.nlm....pubmed/25837487

 

 

[Fafner55]

Resveratrol is likely synergistic with Dasatinib in inducing apoptosis of preadipose cells.  

 

“Effect and underlying mechanism of resveratol on porcine primary preadipocyte apoptosis” (2010)

http://www.ncbi.nlm.nih.gov/pubmed/21090107

We demonstrated the effect of resveratrol on porcine primary preadipocytes apoptosis, to study the intracellular molecular mechanism. Porcine primary preadipocyte was treated with different concentration of resveratrol (0 micromol/L, 50 micromol/L, 100 micromol/L, 200 micromol/L, 400 micromol/L). We used optical microscope and fluorescence microscope to observe morphological changes during apoptosis after Hoechst 33258 Fluorescent dyes staining; and RT-PCR and Western blotting to measure the expression of apoptosis-associated gene sirt1, caspase-3, bcl-2, bax, p53, NF-kappaB. Primary preadipocyte apoptosis was apparent, accompanied by reduced cell volume, chromatin condensation, and nuclear shrinkage. Compared to the control and low concentration group, high dose group (200 micromol/L) significantly increased the ratio of primary preadipocyte apoptosis. The expression of sirt1, caspase-3, and bax was up-regulated markedly in response to resveratrol; in contrast, apoptotic inhibitor bcl-2, p53, NF-kappaB down-regulated. We further proved fact that resveratrol can specifically promote the activity of sirt1; moreover, activated sirt1 modulates the activity of caspase-3 and bcl-2 family, involving in transcriptional regulation of p53 and NF-kappaB through antagonizing factor-induced acetylation. Taken together, our data established resveratrol as new regulator in porcine primary preadipocyte apoptosis via activating the expression of sirt1, modulating activity of apoptotic-associated factor.

[Kalliste]

PLGA Quercetin might be good for this combo:

The use of nano-quercetin to arrest mitochondrial damage and MMP-9 upregulation during prevention of gastric inflammation induced by ethanol in rat.

Chakraborty S1, Stalin S, Das N, Choudhury ST, Ghosh S, Swarnakar S.

Author information

Abstract

Gastric ulcer is a multifaceted process that involves reactive oxygen species (ROS) generation, extracellular matrix degradation and mitochondrial damage. Mitochondria play a crucial role for homeostasis of ROS and cell survival. In our study, we investigated the efficacy and mechanism of polymeric nanocapsuled quercetin (NQC) over the free quercetin (QC) molecule in prevention of ethanol-induced gastric ulcer in rat. NQC possessed significantly higher efficacy (~20 fold) than free QC while preventing gastric ulcers. Our data show that prior administration of NQC and/or QC significantly blocked synthesis and secretion of matrix metalloproteinase (MMP)-9 as well as infiltration of inflammatory cells and oxidative damage in rat gastric tissues. As compared to free QC, NQC protected much better the mitochondrial integrity and size along with mitochondrial functions by controlling succinate dehydrogenase and NADH oxidase in rat gastric tissues. In addition, both free QC and NQC down regulated PARP-1 as well as apoptosis during protection against ethanol-induced gastric ulcer. Herein, the effect of NQC was greater than QC on expression of enzymes like cyclooxygenase and nitric oxidase synthase (NOS)-2. We conclude that NQC with greater bioavailability offers significantly higher potency in downregulating MMP-9 and NOS-2 as well as oxidative stress in blocking ethanol-induced gastric ulcer.

Edited by Cosmicalstorm, 05 April 2015 - 08:30 PM.

[zorba990]

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

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

lots more....

[pone11]

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

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

lots more....

 

I have tried taking the BodyBio brand of both Sodium  Butyrate and Sodium/Potassium Butyrate.   I cannot digest it and it runs straight through me.   I have heard the same complaint from many users of ketone salts, which are similar ingredients.

[Logic]

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

This does NOT sound good:
"...Sodium butyrate, a histone deacetylase inhibitor, has been shown to induce differentiation of many cancer cells and senescence-like state of human fibroblasts..."
As the authors are oriental; I suspect they misspoke and their paper is in dire need of correcting!?
 
 

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

lots more....

Thats better and more in line with other studies.

 

It seems that SB induces senescence in cancerous cells, which D+Q should then kill.

 

Niner has a valid concern about contra indications with mixing so many different substances with Dasatinib, but a google search seems to point to synergy between these 2 substances?

https://www.google.c...SODIUM BUTYRATE

 

So you may be onto something here.

 

Sodium Butyrate has a very short half life however and apparently smells worse than skunk ass! 
Tributyrin is the way to go IMHO, but a time release version of SB should also work.

In the mean time RS, FOS and Inulin are accessible, but apparently make you fart like crazy!  See skunk ref above!  

 

 

[pone11]

 

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

This does NOT sound good:
"...Sodium butyrate, a histone deacetylase inhibitor, has been shown to induce differentiation of many cancer cells and senescence-like state of human fibroblasts..."
As the authors are oriental; I suspect they misspoke and their paper is in dire need of correcting!?
 

 

Differentiated cancers spread at a slower rate and resemble normal cells (and therefore potentially better respond to apoptosis signals).   It is undifferentiated cancers that lack known function and structure and grow uncontrollably.

 

So if butyrate has the ability to take an existing cancer cell and make it differentiated, that would be a good thing.

[niner]

Resveratrol is likely synergistic with Dasatinib in inducing apoptosis of preadipose cells.  

 

“Effect and underlying mechanism of resveratol on porcine primary preadipocyte apoptosis” (2010)

http://www.ncbi.nlm.nih.gov/pubmed/21090107

We demonstrated the effect of resveratrol on porcine primary preadipocytes apoptosis, to study the intracellular molecular mechanism. Porcine primary preadipocyte was treated with different concentration of resveratrol (0 micromol/L, 50 micromol/L, 100 micromol/L, 200 micromol/L, 400 micromol/L). We used optical microscope and fluorescence microscope to observe morphological changes during apoptosis after Hoechst 33258 Fluorescent dyes staining; and RT-PCR and Western blotting to measure the expression of apoptosis-associated gene sirt1, caspase-3, bcl-2, bax, p53, NF-kappaB. Primary preadipocyte apoptosis was apparent, accompanied by reduced cell volume, chromatin condensation, and nuclear shrinkage. Compared to the control and low concentration group, high dose group (200 micromol/L) significantly increased the ratio of primary preadipocyte apoptosis. The expression of sirt1, caspase-3, and bax was up-regulated markedly in response to resveratrol; in contrast, apoptotic inhibitor bcl-2, p53, NF-kappaB down-regulated. We further proved fact that resveratrol can specifically promote the activity of sirt1; moreover, activated sirt1 modulates the activity of caspase-3 and bcl-2 family, involving in transcriptional regulation of p53 and NF-kappaB through antagonizing factor-induced acetylation. Taken together, our data established resveratrol as new regulator in porcine primary preadipocyte apoptosis via activating the expression of sirt1, modulating activity of apoptotic-associated factor.

 

I don't think that resveratrol will help much since they didn't see an effect at 50 uM.  It's essentially impossible to achieve a 50 uM resveratrol concentration in vivo, at least in humans.  In the Kirkland lab's Dasatinib paper (Yi et al.), they say:

 

By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells.

 

 

I'm not sure how much overlap there is between these proteins and the ones regulated by high-dose (in vitro only) resveratrol, or indeed in any system that effects normal cells.  Senescent cells might be a special case.

[Logic]

Differentiated cancers spread at a slower rate and resemble normal cells (and therefore potentially better respond to apoptosis signals).   It is undifferentiated cancers that lack known function and structure and grow uncontrollably.
 
So if butyrate has the ability to take an existing cancer cell and make it differentiated, that would be a good thing.

Thx Pone11

That leaves the "...senescence-like state of human fibroblasts..."?
http://en.wikipedia....wiki/Fibroblast

[Razor444]

Clostridium butyricum (probiotic) is a butyrate producing bacteria.

 

ProBIOTIC 3 is the brand I currently use.

[Logic]

For the sake of completeness; I am copying dosage info from:
http://www.longecity...buy-from-nyles/
here:

Me:
From the study:
"...A single dose of D+Q (D: 5 mg/kg body weight and Q: 50 mg/kg by oral gavage
here and in the following studies)..."
(Mice)
http://onlinelibrary.../acel.12344/pdf

HED (mg/kg) = Animal Dose (mg/kg) x [Animal Km / Human Km]*
Human Km = 37
Mouse Km = 3
Rat Km = 6
http://www.longecity...nimal-to-human/

So
HED for D is: 0.4054054054054054 mg/kg = 28.4mg/70kg human
HED for Q is: 4.054054054054054 mg/kg = 283.8 mg/70kg human

(I am ~ 110kg = 45 mg D & 446 mg Q)

Unless there are other factors to consider?
Differences in bioavailability between mice and humans?

Niner:
...The HED for Dasatinib is probably safe, but I worry about the bioavailability of quercetin in humans relative to rodents. It would be nice to know the concentrations that are considered necessary for quercetin to have an effect on the pro-survival pathways. It would also be nice to know if you needed the aglycone, or if a glucuronidated version would work. My inclination at this point would be to use the HED for Dasatinib, or maybe just go ahead and use a typical therapeutic dose like 70 mg, but take a lot more quercetin, like multiple grams, because of its poor bioavailabilty, and because it's well tolerated in most people.

Me:
Have you looked at the graphs in the study? (figure 2 at the bottom)
I worry that too high a dose of Q could kill off proliferating cells?

Niner:
In the quercetin-only plots, quercetin was pretty clean up to 10 uM, but showed some fall-off in proliferating cells after that. I wouldn't worry at all about this, since we'd never even see 10 uM in vivo. We'd have a hard time reaching 5, assuming that the aglycone is the active agent. If a glycoside or glucuronide were active, that would change the equation.

Me:
Thx
So we don't know if its the aglycone, glycoside or glucuronide which is active?

[nowayout]

I weigh about 70 kg, so by simple math the 50 mg/kg dose given to the mice comes to 3500 mg for me.  I couldn't be sure of the bioavailability or other factors, and my experience with lower doses quercetin didn't show any side effects, so I just went ahead and took the heavy dose I described using NOW brand quercetin dihydrate (800 mg) + bromelain (165 mg), 4 capsules twice per day.

 

I am not questioning your self-report, and I might try something similar. 

 

However, my sense is that if quercetin alone had a dramatic anti-aging effect on the average person, it would surely have been noticed before now, wouldn't it?  Quercetin is, after all, a common supplement and has been for a number of years. 
 

[niner]

 

I weigh about 70 kg, so by simple math the 50 mg/kg dose given to the mice comes to 3500 mg for me.  I couldn't be sure of the bioavailability or other factors, and my experience with lower doses quercetin didn't show any side effects, so I just went ahead and took the heavy dose I described using NOW brand quercetin dihydrate (800 mg) + bromelain (165 mg), 4 capsules twice per day.

 

I am not questioning your self-report, and I might try something similar. 

 

However, my sense is that if quercetin alone had a dramatic anti-aging effect on the average person, it would surely have been noticed before now, wouldn't it?  Quercetin is, after all, a common supplement and has been for a number of years.

 

Well, I can think of two reasons why this might not be the case.  The first is that I suspect we will need a fairly large dose of quercetin in order to have the effect, but more importantly, I doubt that anyone at all young is going to have enough senescent cells that losing a modest percentage of them would make an obvious difference.  If you need to take 3-5 grams and be over 85, the population of people who have done that is going to be pretty small.  If you only need a gram and to be over 65, that would be different, but I think the odds of that are small.

[Razor444]

Quercetin Phytosome

[nowayout]

 

I am not questioning your self-report, and I might try something similar. 

 

However, my sense is that if quercetin alone had a dramatic anti-aging effect on the average person, it would surely have been noticed before now, wouldn't it?  Quercetin is, after all, a common supplement and has been for a number of years.

 

Well, I can think of two reasons why this might not be the case.  The first is that I suspect we will need a fairly large dose of quercetin in order to have the effect, but more importantly, I doubt that anyone at all young is going to have enough senescent cells that losing a modest percentage of them would make an obvious difference.  If you need to take 3-5 grams and be over 85, the population of people who have done that is going to be pretty small.  If you only need a gram and to be over 65, that would be different, but I think the odds of that are small.

 

Well, I suspect a lot of people over 50 who have obvious signs and diseases of aging have indeed taken cumulative doses of 5 grams over the course of a week or two (consistent with typical labeling), typically repeated over the course of months.  Is your thinking that the effect would be nonlinear, necessitating a "shock dose"?  Or that it may not work without the "cocktail effect" with the other drug?  Or are signs of aging at 50 mostly due to etiologies other than senescent cells? 

Edited by nowayout, 08 April 2015 - 10:45 PM.

[niner]

 

 

I am not questioning your self-report, and I might try something similar. 

 

However, my sense is that if quercetin alone had a dramatic anti-aging effect on the average person, it would surely have been noticed before now, wouldn't it?  Quercetin is, after all, a common supplement and has been for a number of years.

 

Well, I can think of two reasons why this might not be the case.  The first is that I suspect we will need a fairly large dose of quercetin in order to have the effect, but more importantly, I doubt that anyone at all young is going to have enough senescent cells that losing a modest percentage of them would make an obvious difference.  If you need to take 3-5 grams and be over 85, the population of people who have done that is going to be pretty small.  If you only need a gram and to be over 65, that would be different, but I think the odds of that are small.

 

Well, I suspect a lot of people over 50 who have obvious signs and diseases of aging have indeed taken cumulative doses of 5 grams over the course of a week or two (consistent with typical labeling), typically repeated over the course of months.  Is your thinking that the effect would be nonlinear, necessitating a "shock dose"?  Or that it may not work without the "cocktail effect" with the other drug?  Or are signs of aging at 50 mostly due to etiologies other than senescent cells? 

 

Yes to all of these.  Quercetin is not very bioavailable in humans to begin with, and it's not clear that mouse results would translate to humans, as far as quercetin bioavailability goes, although there is a fair chance that they might.  If we're trying to use quercetin to inhibit a pro-survival / anti-apoptosis pathway, that sort of effect usually requires getting over a dose threshold.  It's not likely to work in a cumulative way, which is why I would use a large dose.  The cocktail effect appears to be a real thing with these compounds.  It does look like either one has activity with at least some cell types, but effects are larger with both.   I just saw a paper the other day that said senescent cells didn't become a serious problem until people were at advanced ages.  Of course, due to my senescent brain I don't remember where I read it...  At any rate, at ages as young as 50, I think most aging is likely to be caused by other things.   However, all these are just my best guesses at the moment.  Now that sources of Dasatinib are starting to materialize, we will probably see some experimentation among our intrepid crew.  Considering the number of people who have been dosed chronically with either of these compounds, I don't think that a single-dose treatment is likely to cause much trouble.  One thing to bear in mind is that quercetin and dasatinib are zeroeth generation senolytics.  They've hardly screened any compounds, much less worked up structure-activity relationships and optimized for senolytic activity.  There may well be other existing drugs or supplements that could be added to the cocktail to improve results, along with formulation and dosing optimization.  We need biomarkers for human senolytic activity.

[sthira]

Any guesses of how to increase quercetin's bioavailability?

[corb]

  We need biomarkers for human senolytic activity.

 

I don't think there's any sure method besides biopsy right now.

Since most of this type of research is done in the lab no one has had the need to create non invasive diagnostic procedures for it. I'm sure most people here realize it, I just like to reiterate.

 

 

Any guesses of how to increase quercetin's bioavailability?

 

Quercetin mixed with Beta Cyclodextrin. That way you can remove senescent cells and digest lipofuscin at the same time. Theoretically.

 

The enhancement of aqueous solubility of quercetin using this method was 2.2-fold

http://www.ncbi.nlm....les/PMC2663686/

 

 

Edited by corb, 09 April 2015 - 02:19 AM.

[pone11]

 

  We need biomarkers for human senolytic activity.

 

I don't think there's any sure method besides biopsy right now.

Since most of this type of research is done in the lab no one has had the need to create non invasive diagnostic procedures for it. I'm sure most people here realize it, I just like to reiterate.

 

 

Here is a study with biomarkers, but they don't look like anything that we can order:

http://circres.ahajo...t/111/1/97.full

 

This study suggests there is no unique biomarker:

http://jcb.rupress.o.../192/4/547.full

[corb]

 

 

  We need biomarkers for human senolytic activity.

 

I don't think there's any sure method besides biopsy right now.

Since most of this type of research is done in the lab no one has had the need to create non invasive diagnostic procedures for it. I'm sure most people here realize it, I just like to reiterate.

 

 

Here is a study with biomarkers, but they don't look like anything that we can order:

http://circres.ahajo...t/111/1/97.full

 

This study suggests there is no unique biomarker:

http://jcb.rupress.o.../192/4/547.full

 

 

That's an assay for a flow cytometer. It still requires a biopsy. And a flow cytometer.

And even according to the paper can be affected by other factors.

I'm pretty sure the only scientifically sound method of counting senescent cells is still ... physically counting senescent cells. I think I mentioned it once already further up the thread.
 

[Logic]

Pharmacology

Absorption

After oral ingestion of quercetin, it is taken up from the gut into the liver. The conjugate of quercetin influences its absorption rates.

quercetin glycosides (food source):  52+/-15% uptake,

quercetin rutinoside (tea):                 17+/-15% uptake,

quercetin aglycone (supplemental):  24+/-9% uptake.

 

One pharmacokinetic study in humans using QU995:

 

500mg Quercetin (as aglycone):                              Cmax 1051.9+/-393.1ug/mL - Tmax 3.66 hours

 

500mg Quercetin (as aglycone - Food bar format): Cmax 698.1+/-189.5μg/L - Tmax 2.3 hours

 

500mg Quercetin (as aglycone - juice suspension): Cmax 354.4+/-87.6μg/L - Tmax 4.7 hours

 

 

Due to enhanced lymphatic release of Quercetin following administration of Long-Chain Fatty acids (LCFAs), it is thought that the formation of micelles from LCFAs can enhance the apparent bioavailability of Quercetin.

 

 

Circulating Quercetin

 

2,000mg quercetin aglycone (in a food matrix): 4.76+/-2.56μM at one hour.

730mg quercetin (as aglycone): 1419+/-189nM.

 

50mg quercetin (as dihydrate): 92.2nM

100mg quercetin (as dihydrate): 171.8nM

150mg quercetin (as dihydrate): 316.2nM (large range: 240–1292nM)

 

 

Metabolism

After the liver, quercetin exists in the blood solely as quercetin glucuronides. Regardless of initial source, all forms of quercetin undergo hydrolysis and get glucuronidated in the liver before being released into systemic circulation.

 

http://examine.com/s...ents/Quercetin/

 

 

Optimal Q concentrations for inducing senescent preadipocyte and HUVEC cell death
were 20 and 10 μM, respectively.

 

D (200 nM)
plus Q (20 μM) resulted in 65% apoptotic cells (TUNEL assay) after 12 hours in senescent but
not proliferating, non-senescent preadipocyte cultures.

 

http://onlinelibrary.../acel.12344/pdf

 

 

Edited by Logic, 10 April 2015 - 12:50 PM.

[Logic]

(Sigh..!  Pressing the spacebar posted the above post and then Longecity decided I had run out of time for editing it and that I no longer wanted any of what I had written!   )

 

 

Proliferating and senescent preadipocytes and HUVECs were exposed to a fixed concentration of Q and different concentrations of D for 3 days. Optimal Q concentrations for inducing senescent preadipocyte and HUVEC cell death were 20 and 10 μM, respectively

 

2,000mg quercetin aglycone (in a food matrix) gave 4.76+/-2.56μM at one hour.

 

10 μM/4.76 X 2000mg = 4484 mg

20 μM/4.76 X 2000mg = 8403 mg

 

That gives a dose of between 4484 and 8403 mg for a 70kg? person assuming that concentration increases linearly with dosage?

Every hour for 3 days!??

 

Note that food seems to decrease concentration by about a third and that LCFA 'can enhance the apparent bioavailability of Quercetin'.

Edited by Logic, 10 April 2015 - 01:50 PM.