459 replies to this topic

[Sanhar]

As must have been pointed out by now, this is one of the seven "pillars" of SENS.  By itself it will help but it must be combined with the other six approaches to achieve indefinite lifespan (plus any other tweaks we may discover).

 

As of this moment, other than these new senolytic drugs the only option you have that I know of is exercise to keep your mitochondria situation strong.  Killing old senescent cells stops them from poisoning you (removes harm) and improving mitochondria situation keeps you healthy and strong (increases good).  Together, once optimized, this should increase healthspan but won't stop the other five pillars from killing you, but will probably help with the escape velocity concept.

 

I just hope you biohackers don't cause yourself irreparable harm.  Good luck :P

[thedarkbobo]

This is interesting, but I am wondering at what age should you take it? Does it make any sense <30? Are there any information (data or estimates) about the rate/number of those cells in different group ages?

 

 

Edited by thedarkbobo, 21 March 2015 - 05:44 PM.

[Kalliste]

I might try it once. Seems pretty safe for a one time test. I might faste a few days before so Im resistant to the chemo so that will ruin most measurements I could make.

[pone11]

 

As for an hypothesis. Let's for the arguments sake assume that most cells can only divide about 50 times before their telomeres get so short they are no longer able to replicate. If you kill of all senescent cells as well as the "soon-to-be senescent but working quite well at the moment" cells, the remaining cells are likely to start replicate faster, taking the recently died off cells places. The first times you kill off these older cells you are likely to get organs and a body which work better because all the old cells have been eliminated. However, for each time you repeat the process, the remaining cells will get shorter telomeres and will themselves get closer to the point where they will no longer be able to work or replicate. My hypothesis is that if you repeat this process too many times, your cells will age rapidly to the point where most of the cells will go into apoptosis, making the organs they are part of to fail. You should be able to test this hypothesis by repeatedly administrating the drugs on people which are not suffering from accelerated aging. I expect the results to be people with greater average health span but with shorter average life span.

 

This method of attacking the problem of aging reminds me of one described in the Hugo Award Novella Fountain of Age. It describes a method of rejuvenation which upon administration turns the subject back to being young again, giving them an additional almost perfect health span of twenty years. The unfortunate side effect of this administration is that they will also have an expected remaining life span of the same twenty years. Many people in the novella did however prefer to end their life with a period of 20 years being young again and with perfect health, rather than living on for perphaps another 40 years as old and with a failing body.

 

 

The counter argument would be the senescent cells poison healthy cells around them and increase their rate of decline.    So you have at least two competing theories of what might happen if senescent cells suddenly disappear, and these are highly non trivial processes to understand and unwind.   But if effective senolytics are developed it will be about the empirical result on lifespan, and we can figure out the underlying theory later.

[pone11]

 

Mathematically the first organ capable of reaching the Hayflick limit in your body is the thymus. At age 125. No one has reached even close to that age so we can't know if it's a real possibility for all cells of an organ to go into senescence. And even if it happens, well, there's always transplantation.

 

Most people die from pathologies caused by chronic inflammation and impaired cellular turnover, so removing senescent cells gives the people who were going to die in their 60s and 70s from a CVD or cancer a bit of extra time - or maybe a lot of extra time, we'll see.

It's very straightforward, I'd even say it's in line with the mainstream medical thinking - which is good, it will be incorporated into medicine faster than most other proposed anti aging therapies.

 

 

Do you have any references on Hayflick limit in different organ types?   

 

So based on that you do not believe that telomere shortening currently has much effect on human aging, but will start to have an effect as maximum lifespan exceeds 125 years?

[corb]

 

 

Mathematically the first organ capable of reaching the Hayflick limit in your body is the thymus. At age 125. No one has reached even close to that age so we can't know if it's a real possibility for all cells of an organ to go into senescence. And even if it happens, well, there's always transplantation.

 

Most people die from pathologies caused by chronic inflammation and impaired cellular turnover, so removing senescent cells gives the people who were going to die in their 60s and 70s from a CVD or cancer a bit of extra time - or maybe a lot of extra time, we'll see.

It's very straightforward, I'd even say it's in line with the mainstream medical thinking - which is good, it will be incorporated into medicine faster than most other proposed anti aging therapies.

 

 

Do you have any references on Hayflick limit in different organ types?   

 

So based on that you do not believe that telomere shortening currently has much effect on human aging, but will start to have an effect as maximum lifespan exceeds 125 years?

 

 

For the Hayflick limit of the thymus in particular I read it in a japanese longitudinal study of organ wasting during aging. There were a couple of other organs mentioned but it was mostly a comparison of organ mass at different ages, and how much of the organ was functional cells or otherwise - fat, senescent cells, lesions, etc.

It was couple of months back and I don't remember the exact source anymore.

 

As far as how much of a problem senescent cells are, I don't think anyone can tell you right now.
Our best way of measuring how much of them are in a tissue is by looking at a stained slide with a microscope and hoping the concentration is the same throughout the organ - which is probably not the case. I remember reading somewhere they don't exceed about 10%, but don't quote me on this.

[niner]

There aren't any real effects to report yet.  I feel groggy and fuzzy but slept decently last night.  I only had that remaining 75mg and *someone* recommended boosting it with grapefruit juice which based on dosage could have between a 1.5 - 2x effect in theory.

 

Grapefruit juice might help.  Dasatinib is extensively modified by 3A4.  The major metabolites are active, but generally not as good as the parent.  There is 3A4 in both the gut and the liver, but only the gut enzyme is modified by fruit juices, so the magnitude of the effect is hard to predict.  See Table 3 here for relative activities.

[niner]

This is interesting, but I am wondering at what age should you take it? Does it make any sense <30? Are there any information (data or estimates) about the rate/number of those cells in different group ages?

 

 

I wouldn't dream of trying this before 30.  I don't think that you would have enough senescent cells to make a difference, and the science will be much more settled in a few years.   The question gets more interesting if you're over 60 (-ish).

 

I might try it once. Seems pretty safe for a one time test. I might faste a few days before so Im resistant to the chemo so that will ruin most measurements I could make.

 

 

I think we should avoid calling dasatinib "chemo".  That brings to mind the old cytotoxic poisons that killed all rapidly dividing cells, made you barf and made your hair fall out.  This isn't that at all.  It's a very specific tyrosine kinase inhibitor that addresses a gene defect known as "The Philadelphia Chromosome" that's active in certain cancers. 

 

Fasting is adding something new to the equation.  If you're trying to get certain cells to undergo apoptosis, maybe it would be better not to fast.  Low nutrient availability tends to put cells in a maintenance mode.  You'd get more autophagy, which isn't necessarily what you you want here, and probably less apoptosis, which is.

[Kalliste]

Since I'm 30 now it might be best to wait.

 

Wonder if C60 might interfer with the effect somehow? Is there any obvious reason to think so?

Edited by Cosmicalstorm, 22 March 2015 - 06:28 AM.

[albedo]

I wish someone could enlighten us.  The HED conversion has been a long-standing area of concern.  I worry a lot about differences in xenobiotic metabolism between humans and mice causing errors here.  I think dasatinib is less of a problem, because it was designed to avoid xenobiotic metabolism.  Quercetin, on the other hand, is very heavily metabolized.  It's a sufficiently benign compound that I'd be inclined to use a larger dose than the HED predicts, but the only way to really know what's right is a dose-ranging experiment.  We would need to have a ton of people randomized to different doses, and do before/after biopsies and a lot of other tests.  If enough people do n=1 experiments on themselves, it might be possible for real effects to emerge, but placebo effects are going to be a big problem. 

 

Yes, fully agree. My 150mg today quercetin dose (included in my LEF's t-resveratrol (250mg formula - I recollect also lot of discussion on that relatively low dose too)) is maybe ridiculously low and do not expect to grasp much benefit from it. I am considering adding 500mg after these recent studies and until a better HED is determined. In the meantime I keep eating also apples and onions ... :-)

 

I much agree dasatinib is less of a problem.

 

[Kalliste]

When does senescent cells start to cause havoc? I was of the impression that they do no good. Just barf SASP. Why would I as a 30 year want senescent cells?

[Fafner55]

In The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs, the mechanism for apoptotic clearance of senescent cells appears to be sufficient activation of the caspase cascade.  This begs the question of whether other supplements that activate the caspase cascade might be synergistic with quercetin to induce apoptosis, or might clear senescent cells in more types of cells.  It seems reasonable to speculate that the combination of quercetin, pterostilbene, resveratrol , curcumin,  genistein and other flavonoids might be taken together synergistically.  This thesis might be useful in selecting some.  INVESTIGATION OF THE ROLE OF DIETARY FLAVONOIDS ON CELL DEATH: EVIDENCE TO SUPPORT A NON-CLASSICAL APOPTOTIC MECHANISM

 

Other supporting references are

Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondrial pathway in human breast cancer MCF-7 cells.

 

Curcumin and Quercetin Combined with Cisplatin to Induce Apoptosis in Human Laryngeal Carcinoma Hep-2 Cells through the Mitochondrial Pathway

 

Caspase-8 has an essential role in resveratrol-induced apoptosis of rheumatoid fibroblast-like synoviocytes.

 

Pterostilbene Inhibits Breast Cancer In Vitro Through Mitochondrial Depolarization and Induction of Caspase-Dependent Apoptosis

 

Caspase-3 protease activation during the process of genistein-induced apoptosis in TM4 testicular cells

 

Can anyone contribute to this speculation?

 

 

[Kalliste]

Well curcumin also seems to be capable of inducing cellular senescence, but maybe those cells can be cleared by the proposed D+Q therapy

 

 

Age (Dordr). 2015 Feb;37(1):9744. doi: 10.1007/s11357-014-9744-y. Epub 2015 Feb 4.

Curcumin induces senescence of primary human cells building the vasculature in a DNA damage and ATM-independent manner.

Grabowska W¹, Kucharewicz K, Wnuk M, Lewinska A, Suszek M, Przybylska D, Mosieniak G, Sikora E, Bielak-Zmijewska A.

Author information

Abstract

Curcumin is considered not only as a supplement of the diet but also as a drug in many types of diseases and even as a potential anti-aging compound. It can reduce inflammation that increases with age and accompanies almost all age-related diseases. It has been suggested that curcumin can play a beneficial role in the cardiovascular system. However, there are also data showing that curcumin can induce senescence in cancer cells, which is a beneficial effect in cancer therapy but an undesirable one in the case of normal cells. It is believed that cellular senescence accompanies age-related changes in the cardiovascular system. The aim of this study was to check if curcumin, in a certain range of concentrations, can induce senescence in cells building the vasculature. We have found that human vascular smooth muscle and endothelial cells derived from aorta are very sensitive to curcumin treatment and can senesce upon treatment with cytostatic doses. We observed characteristic senescence markers but the number of DNA damage foci decreased. Surprisingly, in vascular smooth muscle cell (VSMC) activation of DNA damage response pathway downstream of ataxia-telangiectasia mutated (ATM) was observed. ATM silencing and the supplementation of antioxidants, N-acetyl-L-cysteine (NAC) or trolox, did not reduce the number of senescent cells. Thus, we have shown that curcumin can induce senescence of cells building the vasculature, which is DNA damage and ATM independent and is not induced by increased reactive oxygen species (ROS) level. We postulate that an increase in the bioavailability of curcumin should be introduced very carefully considering senescence induction as a side effect.

http://www.ncbi.nlm....pubmed/25649709

 

Edited by Cosmicalstorm, 23 March 2015 - 08:09 AM.

[Sanhar]

When does senescent cells start to cause havoc? I was of the impression that they do no good. Just barf SASP. Why would I as a 30 year want senescent cells?

 

You need a certain percentage vs. total cell count of senescent cells before it has a meaningful effect on you and I doubt anyone is there much before 60 as noted earlier.  This is to say, basically, that sensescent cells are not going to hurt you, never mind kill you, if you're not around there.  As such there is no therapy reasonably imaginable (at the moment) that would be worth the side effects in terms of dealing with whatever few senescent cells you have.

[Fafner55]

 

When does senescent cells start to cause havoc? I was of the impression that they do no good. Just barf SASP. Why would I as a 30 year want senescent cells?

 

You need a certain percentage vs. total cell count of senescent cells before it has a meaningful effect on you and I doubt anyone is there much before 60 as noted earlier.  This is to say, basically, that sensescent cells are not going to hurt you, never mind kill you, if you're not around there.  As such there is no therapy reasonably imaginable (at the moment) that would be worth the side effects in terms of dealing with whatever few senescent cells you have.

 

 

In old age, approximately 15-20% of cells (dermal fibroblasts) in non-human primates (baboons) show markers for cellular senescence due to telomere shortening, such as upregulation of the binding proteins p53, p21 and p16 (“Cellular Senescence in Aging Primates” http://www.biodados.icb.ufmg.br/cromatina/dna07/telomere.pdf).  In human bone marrow stromal cells cultured in vitro, the percentage of senescent cells increases 4% per population doubling in old bone marrow cells vs only 0.4% per population doubling in young bone marrow cells.

 

The authors go on to state, The number of dermal fibroblast nuclei containing foci of 53BP1, a marker of DNA double-strand breakage (DSB), increased exponentially with age and reached a value of 30 to 35% in very old (25 to 30 years old) animals (Fig. 1A ). As was found in cultured fibroblasts, 100% of 53BP1 foci colocalized with foci formed by g-H2AX, another marker of DSB. The majority of 53BP1 foci (62 T 7.7%) colocalized with telomeric DNA, thus classifying them as telomere dysfunction–induced foci (TIFs).  Thus the authors show that telomere shortening is the major cause of age-related cellular senescence, that senescence increases exponentially with age, and with extreme age a high 30% or so of cells show signs of senescence.

 

 

Assuming a 30 year old baboon is equivalent to a 90 year old person, from Figure 1A I estimate this the percentage of senescent cells in people with age is approximately

 

Age (years)   Senescent Cells (%)

30                  3 - 5%

60                  6 - 10%

90                 30 - 35%

 

 

[Fafner55]

The exponential rate of DNA damage, and by inference cellular senescence, is also supported by Figure 2 of Age-Associated Changes In Oxidative Stress and NAD+ Metabolism In Human Tissue.

[pone11]

 

In old age, approximately 15-20% of cells (dermal fibroblasts) in non-human primates (baboons) show markers for cellular senescence due to telomere shortening, such as upregulation of the binding proteins p53, p21 and p16 (“Cellular Senescence in Aging Primates” http://www.biodados.icb.ufmg.br/cromatina/dna07/telomere.pdf).  In human bone marrow stromal cells cultured in vitro, the percentage of senescent cells increases 4% per population doubling in old bone marrow cells vs only 0.4% per population doubling in young bone marrow cells.

 

The authors go on to state, The number of dermal fibroblast nuclei containing foci of 53BP1, a marker of DNA double-strand breakage (DSB), increased exponentially with age and reached a value of 30 to 35% in very old (25 to 30 years old) animals (Fig. 1A ). As was found in cultured fibroblasts, 100% of 53BP1 foci colocalized with foci formed by g-H2AX, another marker of DSB. The majority of 53BP1 foci (62 T 7.7%) colocalized with telomeric DNA, thus classifying them as telomere dysfunction–induced foci (TIFs).  Thus the authors show that telomere shortening is the major cause of age-related cellular senescence, that senescence increases exponentially with age, and with extreme age a high 30% or so of cells show signs of senescence.

 

 

Assuming a 30 year old baboon is equivalent to a 90 year old person, from Figure 1A I estimate this the percentage of senescent cells in people with age is approximately

 

Age (years)   Senescent Cells (%)

30                  3 - 5%

60                  6 - 10%

90                 30 - 35%

 

 

Nice data, but if true it does make you wonder would an effective senolytic be potentially very dangerous, with the potential to create a massive release of dead cell contents?

 

This would be analogous to tumor lysis.   Tumor lysis is when a chemotherapy kills too many cells rapidly, leading to the release of ions and metabolic byproducts from the intracellular environment into general circulation.   Lysis can cause hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and renal failure.

 

It sounds like you would want to be very conservative in your dosing and observe side effects.   

 

But my further insight is doesn't this suggest a way for us to know that the senolytic is working at all?   Specifically, test your serum potassium, phosphate, calcium, and uric acid before and after the senolytic.   If these values are unchanged, would we have the ability to say that the senolytic did not work at all?

[Fafner55]

These high percentages are for dermal fibroblasts.  I don't know the percentages of senescent cells for other tissue types.  Presumably they would be lower because the skin is exposed to uV radiation.  Furthermore, because of bioavailability the percentage of cells that could be killed with a single treatment would likely be less than the 15 to 30% reported in vitro by The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs and  INVESTIGATION OF THE ROLE OF DIETARY FLAVONOIDS ON CELL DEATH: EVIDENCE TO SUPPORT A NON-CLASSICAL APOPTOTIC MECHANISM.

 

If 8% of my dermal fibroblasts are senescent, and if I can only induce apoptosis in 15% of them, then only 1.2% of my dermal fibroblasts would be affected (over 3 days after treatment).  Other tissues should be affected less.  At my age, I would not expect to experience significant problems from a single treatment.

[pone11]

These high percentages are for dermal fibroblasts.  I don't know the percentages of senescent cells for other tissue types.  Presumably they would be lower because the skin is exposed to uV radiation.  Furthermore, because of bioavailability the percentage of cells that could be killed with a single treatment would likely be less than the 15 to 30% reported in vitro by The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs and  INVESTIGATION OF THE ROLE OF DIETARY FLAVONOIDS ON CELL DEATH: EVIDENCE TO SUPPORT A NON-CLASSICAL APOPTOTIC MECHANISM.

 

If 8% of my dermal fibroblasts are senescent, and if I can only induce apoptosis in 15% of them, then only 1.2% of my dermal fibroblasts would be affected (over 3 days after treatment).  Other tissues should be affected less.  At my age, I would not expect to experience significant problems from a single treatment.

 

The main point is can we identify any metabolic markers that would tell us for sure that any number of senescent cells were killed.   Having such markers in turn gives an objective to change dosing, more safely.

[nowayout]

 

Age (years)   Senescent Cells (%)

30                  3 - 5%

60                  6 - 10%

90                 30 - 35%

 

 

Then small increases in senescent percentage make a big difference.  I am thinking of the rather rapid deterioration in appearance (and often health markers) that happens in most people between 40 and 55.  

 

Either that, or these obvious early symptoms of aging are not due to senescent cells.  

Edited by nowayout, 23 March 2015 - 09:59 PM.

[nowayout]

Mathematically the first organ capable of reaching the Hayflick limit in your body is the thymus. At age 125. No one has reached even close to that age...

 

Well, Jeanne Calment reached 122, which is rather close to that age.   So have several others, for some reasonable values of "close."  So the assertion should be testable. 

 

Edited by nowayout, 23 March 2015 - 10:32 PM.

[nowayout]

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

 

 

The impression I got from reading the reports is that they do in fact work in concert on the same cells.

 

There are many therapies that only work when combined in cocktails.  HIV is an obvious example - only cocktails will reliably suppress HIV, not any of the single drugs in isolation.  
 

[nowayout]

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

The impression I got from reading the reports is that they do in fact work in concert on the same cells.

There are many therapies that only work when combined in cocktails. HIV is an obvious example - only cocktails will reliably suppress HIV, not any of the single drugs in isolation.

By the way, in the case of, e.g., HIV, it is actually harmful to take only part of a cocktail. Resistance develops.

I know senescent cells don't divide, but can anyone think of any other mechanism (e.g. changes in gene expression) for resistance developing if one took only, say, quercetin, as opposed to the cocktail? For example, I think it is it is uncontroversial that individual cells can certainly adapt and develop a tolerance to certain drugs. Are we perhaps better off holding off on quercetin "monotherapy" the time being until we can do the "shock therapy" described in the article?

Edited by nowayout, 23 March 2015 - 11:13 PM.

[niner]

In old age, approximately 15-20% of cells (dermal fibroblasts) in non-human primates (baboons) show markers for cellular senescence due to telomere shortening, such as upregulation of the binding proteins p53, p21 and p16 (“Cellular Senescence in Aging Primates” http://www.biodados.icb.ufmg.br/cromatina/dna07/telomere.pdf

).  In human bone marrow stromal cells cultured in vitro, the percentage of senescent cells increases 4% per population doubling in old bone marrow cells vs only 0.4% per population doubling in young bone marrow cells.
 
The authors go on to state, [/size]The number of dermal fibroblast nuclei containing foci of 53BP1, a marker of DNA double-strand breakage (DSB), increased exponentially with age and reached a value of 30 to 35% in very old (25 to 30 years old) animals (Fig. 1A ). As was found in cultured fibroblasts, 100% of 53BP1 foci colocalized with foci formed by g-H2AX, another marker of DSB. The majority of 53BP1 foci (62 T 7.7%) colocalized with telomeric DNA, thus classifying them as telomere dysfunction–induced foci (TIFs).  [/size]Thus the authors show that telomere shortening is the major cause of age-related cellular senescence, that senescence increases exponentially with age, and with extreme age a high 30% or so of cells show signs of senescence.[/size]
 
Assuming a 30 year old baboon is equivalent to a 90 year old person, from Figure 1A I estimate this the percentage of senescent cells in people with age is approximately[/size]
 
Age (years)   Senescent Cells (%)
30                  3 - 5%
60                  6 - 10%
90                 30 - 35%

These numbers seem too high to me.  That might be due to the particular tissue they looked at, or might have something to do with a difference between merely showing signs of senescence and being badly senescent, i.e. displaying the SASP.   I'm looking for some human data, and haven't found anything yet, but I just ran across this, which seems to argue rather strongly against senescent cell clearance in the young:
 
 

EMBO Rep. 2014 Nov;15(11):1139-53. doi: 10.15252/embr.201439245. Epub 2014 Oct 13.
Senescence and apoptosis: dueling or complementary cell fates?
Childs BG, Baker DJ, Kirkland JL, Campisi J, van Deursen JM.

In response to a variety of stresses, mammalian cells undergo a persistent proliferative arrest known as cellular senescence. Many senescence-inducing stressors are potentially oncogenic, strengthening the notion that senescence evolved alongside apoptosis to suppress tumorigenesis. In contrast to apoptosis, senescent cells are stably viable and have the potential to influence neighboring cells through secreted soluble factors, which are collectively known as the senescence-associated secretory phenotype (SASP). However, the SASP has been associated with structural and functional tissue and organ deterioration and may even have tumor-promoting effects, raising the interesting evolutionary question of why apoptosis failed to outcompete senescence as a superior cell fate option. Here, we discuss the advantages that the senescence program may have over apoptosis as a tumor protective mechanism, as well as non-neoplastic functions that may have contributed to its evolution. We also review emerging evidence for the idea that senescent cells are present transiently early in life and are largely beneficial for development, regeneration and homeostasis, and only in advanced age do senescent cells accumulate to an organism's detriment.

PMID: 25312810 PMCID: PMC4253488 [Available on 2015-11-01]

Edited by niner, 24 March 2015 - 02:20 AM.

[Fafner55]

An observation about Figure 6 of The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs is that while the aging scores of treated mice improved, they did not revert back to much younger levels.  This limited improvement might be due to the remaining percentage of senescent cells, or it could be an indication that age-related gene expression is influenced by additional factors.

[Fafner55]

“The Achilles’ Heel ...”, indicates 10 to 20 uM concentrations of quercetin to be an effective range for clearing senescent cells without reducing the viability of healthy cells in vitro.  The question remains of what dose of quercetin dihydrate might give those plasma concentrations in vivo.  I looked at the following studies for guidance.

 

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.   

 

What is inconsistent with the findings of this report is the fact that 800 mg doses of quercetin are commonly taken without clear changes in age spots, wrinkles or other senescent-related phenotypes.  In my view, this study underestimates the required dosage.

 

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.  

 

Published Long Term Daily Dose of Quercetin glucoside

Plasma Concentration

Target Concentration

Target Dose

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

 

http://examine.com/supplements/Quercetin reports a study of supplementation of quercetin dihydrate at different levels, as shown below.  Like other studies, there was high interindividual variability, with the largest dose being associated with a range of 240–1292 nM serum concentrations.

 

Published Long Term Daily Dose of Quercetin dihydrate

Plasma Concentration

Target Concentration

Target Dose

50 mg

92.2 nM

15 uM

8134 mg

100 mg

171.8 nM

15 uM

8731 mg

150 mg

316.2 nM

15 uM

7116 mg

 

Another reference point is from “The Achilles’ Heel …” which reported that a single dose of 50 mg / kg of quercetin is sufficient to cause apoptotic clearance of senescent cells in at least endothelial cells in mice.  By simple math, the equivalent dosage in a 70 kg person is 3500 mg.

 

After the liver, quercetin exists in the blood solely as quercetin glucuronides. The elimination half life is reported to range from 20 t 24 hours .http://examine.com/supplements/Quercetin, http://www.sciencedirect.com/science/article/pii/S0014579397013677, http://www.direct-ms.org/sites/default/files/Scalbert%20polyphenols%20AJCN.pdf

Quercetin has GRAS (Generally Recognized As Safe) status, and no side-effects have yet been noted in doses of a few grams a day in either humans or animals. http://examine.com/supplements/Quercetin

 

In my view, taking a 3.5 to 8 gm dose of quercetin dihydrate per day for two days appears to be a good starting point, particularly since there are no known side effects.  Experimentation is needed to determine an effective dose.  Unfortunately, I do not currently have metabolic markers or observable measures of the effects of quercetin.

 

[Fafner55]

My tables didn't show properly.  Here they are in another format

 

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

 

PublishedDose PlasmaConcentration TargetConcentration TargetDose

50 mg      92.2 nM      15 uM    8134 mg

100 mg    171.8 nM    15 uM    8731 mg

150 mg    316.2 nM    15 uM    7116 mg

 

[nowayout]

In my view, taking a 3.5 to 8 gm dose of quercetin dihydrate per day for two days appears to be a good starting point, particularly since there are no known side effects.

 

...except reports of possible kidney toxicity at high (acute) doses in humans in one study, as well as kidney neoplasms in male rodents fed high (chronic) doses (curiously not in females).  Curiously, another study claims to have found quercetin beneficial in the context of kidney transplants. 

 

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.  

 

Also, those taking any medications should be aware that quercetin is thought to interact with many drugs.  More information at http://www.webmd.com...name=quercetin 

 

Still, I am considering doing something like you suggest. 
 

[nowayout]

Possibly very worrying for males is quercetin's destructive effect on the testicles claimed in this study.  These were intraperitoneal doses for two weeks but they were also smaller than the 50 mg/kg dose someone stated above for senescent cell clearance in mice:

 

http://onlinelibrary...1311.x/abstract

 

 

Quercetin impairs the reproductive potential of male mice

1. P. Ranawat¹,
2. G. Kaushik¹,
3. U. N. Saikia²,
4. C. M. Pathak¹ and
5. K. L. Khanduja^1,*

Oxidative stress is a leading cause of male infertility. To combat this, germ cells and spermatozoa are endowed with various enzymes, vitamins and proteins. Certain other components of food, including bioflavonoids, also provide protection against free radicals. This study analysed the effect of quercetin, a bioflavonoid, on male reproductive function in adult mice, after intraperitoneal treatment with varying concentrations of quercetin (2, 8 and 20 mg kg⁻¹ b.wt.) for 2 weeks. Quercetin increased the generation of reactive oxygen species and lipid peroxidation in the testis with concomitant decrease in sperm count and motility in a dose-dependent manner. Activities of antioxidant enzymes catalase, superoxide dismutase and levels of reduced glutathione were found to be decreased in a dose-dependent manner. Also, the levels of oxidised glutathione were increased leading to a shift in redox ratio. The testicular histomorphology was also altered dose dependently. Germ cell kinetic study revealed significant loss of various germ cell populations with increasing dose of quercetin. Interestingly, there was a reduction in germinal epithelium thickness concomitant with an increase in seminiferous tubule lumen diameter. In conclusion, the deleterious effects of quercetin on germ cells could be attributed to its pro-oxidant ability that might affect the Sertoli cell functions.

 

Edited by nowayout, 26 March 2015 - 12:48 AM.

[pone11]

“The Achilles’ Heel ...”, indicates 10 to 20 uM concentrations of quercetin to be an effective range for clearing senescent cells without reducing the viability of healthy cells in vitro.  The question remains of what dose of quercetin dihydrate might give those plasma concentrations in vivo.  I looked at the following studies for guidance.

 

 

Does any lab measure either quercetin directly, or some known metabolite of quercetin, such that we could ingest a test dose, and then do a measurement N hours after ingestion to try to calibrate oral dose ingested to effective serum levels?

 

Surely these measurements are done outside just research environments?

 

I found some quercetin bioavailability studies such as this one:

http://www.nature.co...l/1601513a.html

 

I will ask the researcher if he knows of any additional research showing bioavailability for different oral forms of quercetin in humans.

Edited by pone11, 26 March 2015 - 01:42 AM.