459 replies to this topic

[pone11]

Inflammation Markers as a Proxy for Measuring Senescent Cell Clearance

The following is speculation on my part.  Levels of inflammatory markers might serve as a rough proxy for accumulated senescent cells in the body.  Two possible markers are sedimentation rate and C-reactive protein level (hs-CRP) .  Comparing levels of these markers before and after an attempt to clear senescent cells might indicate if the attempt was in part successful.  My results are shown below.  My doctor commented that he had not seen such a low sed rate in individuals my age (61).

 

Inflammation Markers, Before and After Attempts to Clear Senescent Cells                                                  

Test                                 Reference              Pre-Clearance 7/2004      Pre-Clearance10/2006     Post-Clearance 5/2016

Sedimentation Rate        0 - 20 mm/hr                      --                                       5                                    1

 

C-Reactive Protein                                                  1.75                                  0.87                                0.8

 

 

Distinguish acute inflammation, like a muscle or joint that hurts, from chronic low-level inflammation that is associated with activation of the innate immune system.

 

In my own case, my CRP is - and always has been - microscopic, around 0.3 or lower.  But I do have some chronic inflammatory process at the level of my innate immune system, and one marker of that is C4a.

 

If you want to believe Irina Conboy's recent work, the kind of chronic inflammation associated with aging of tissue would involve activation of the TGF-Alpha system:

https://www.ncbi.nlm...PMC4637204/#R40

 

She actually has had luck upregulating muscle and neurogenesis in aged animals by using ALK5 inhibitors to block parts of the TGF-Alpha system.

 

My point is that the presence of the kind of acute inflammation that generates a high CRP reading is like a five-alarm fire.  Putting out that fire isn't evidence that aging is slowing, because aging - according to Conboy - is due to the over-expression of certain growth factors that then become the source of a chronic low level of inflammation that is not measured by gross indicators like CRP.

 

If you want to explore the kind of inflammation that might be a marker for aging, you might be better off tracking your cytokines over time.

[corb]

Judith Campisi had a talk for senescent cell removal on the Rejuvenation Biotechnology Conference that is going on at the moment.

https://www.youtube....h?v=56YExhTuKgw - around the hour and a half mark.

 

Some interesting lifespan studies, I'm not sure if I've not seen them before, I suspect I have.

The maximum lifespan expectancy of the mice was not affected significantly. The healthspan on the other hand was.
It's good to point it out from time to time that no therapy on it's own is a silver bullet.

That being said, it's very hard to decide if in this case senolysis can be evaluated well enough in mice, mainly because they don't seem to suffer from the diseases driven by senescent cells with the same intensity as we do, so possibly the effects might be better than expected when translated to a larger mammal. It's an open question at this point.

Edited by corb, 17 August 2016 - 05:48 AM.

[albedo]

Good find Corb. Actually I was viewing the video when I saw you post. At ~1:35 she gets to the possible (causative vs. just associative) driving impact of senescent cells on age different pathologies of age related diseases and she gets to inflammation as common cause. It looks sometime to me aging research is becoming a matter of connecting dots as "inflammaging" is what many others are working on in this area, see e.g. the work of Claudio Franceschi in Bologna etc...

[Oakman]

 

 

Why bother with plain quercetin when we can buy both liposomalquercetin and micelizedquercetin, which each are taken into circulation many times better than plain quercetin?

 

I haven't had time to read this entire thread, but I don't think that I've seen anyone mention these more efficient delivery methods.

 

 

I believe I did mention them earlier in this thread Mikey and also believe them to be way better choices.
IIRC one wants the aglycone metabolite of Q, so something that produces more of it would be a nice find.

Its been a while since I've read this thread too.

 

 

I've been reading the thread with an interest in Q. Dosage size seems to be an issue. From the links I didn't see exactly how bioactive these alternatives above are, but then I found EMIQ®.

 

EMIQ®, an Enzymatically Modified Isoquercitrin, gives x17 plasma concentration of quercetin metabolites without high doses, i.e., typical EMIQ doses sold are 50mg and 100mg. It was introduced in 2007 as a food additive (https://am-fe.ift.or...ySanmelin.pdf), but is somehow in pill form for us (?) as a supplement.

 

Reading the GRAS is informative, esp. the latter half

 

http://www.fda.gov/F...y/ucm153867.htm

 

Seems to be made by: 

 

http://theravalues.c...015/10/21/emiq/

 

One product, EnduraQ brand EMIQ contains 100mg, others seem to be 50mg (so either 1.7g or 850mg of quercetin equivalent). I've ordered some.

 

EMIQ® https://www.enduraq.com/pages/formula

 

I read most clinical studies have used a dosage of 200mg.

 

Other useful links:

https://www.enduraq.com/pages/formula

https://www.enduraq....ces-and-studies

https://www.enduraq.com/pages/faqs

 

http://www.ncbi.nlm....pubmed/17484383

http://www.ncbi.nlm....pubmed/19454839

 

Anyone had any experience with it?

[Logic]

I have some pricing on Dasitinib at 500, 100 and 50 gram amounts for a group buy if anyone is interested:

http://www.longecity...ndpost&p=788836

[MidwestGreg]

Interesting thread. I don't know if this has been discussed, but I found the below Dasatinib side effects/benefits. My interest in the Dasatinib/quercetin combination is to try and repair some chronic lung inflammation. It appears that Dasatinib has been shown to have some serious side effects when taken on a continual basis.

 

Anyone care to comment about the relative safety of using Dasatinib/quercetin on an intermittent basis?

 

http://www.atsjourna...m.200705-715CR 

 

"We investigated pleural and pulmonary complications in patients treated with dasatinib, a novel multitargeted tyrosine kinase inhibitor, as part of clinical trial protocols. Of 40 patients who received dasatinib (70 mg twice daily) for imatinib resistance or intolerance, 9 (22.5%) developed dyspnea, cough, and chest pain. Of these nine patients, six had pleural effusions (all were exudates) and seven had lung parenchyma changes with either ground-glass or alveolar opacities and septal thickening (four patients had both pleural effusions and lung parenchyma changes). Lymphocytic accumulations were detected in pleural and bronchoalveolar lavage fluids in all patients except for one who presented with neutrophilic alveolitis. Pleural biopsies revealed lymphocytic infiltration in one patient and myeloid infiltration in another. After dasatinib interruption, lung manifestations resolved in all cases and did not recur in three of four patients when dasatinib was reintroduced at a lower dose (40 mg twice daily). Thus, lung physicians should be aware that lung manifestations, presumably related to an immune-mediated mechanism rather than fluid retention, may occur with dasatinib treatment."

 

versus:

 

https://www.ncbi.nlm...pubmed/26789403

 

"On day 28, lung morphofunction, inflammation, and remodeling were investigated. RAW 264.7 cells (a macrophage cell line) were incubated with silica particles, followed by treatment or not with dasatinib, and evaluated for macrophage polarization. On day 28, dasatinib improved lung mechanics, increased M2 macrophage counts in lung parenchyma and granuloma, and was associated with reduction of fraction area of granuloma, fraction area of collapsed alveoli, protein levels of tumor necrosis factor-α, interleukin-1β, transforming growth factor-β, and reduced neutrophils, M1 macrophages, and collagen fiber content in lung tissue and granuloma in silicotic animals. Additionally, dasatinib reduced expression of iNOS and increased expression of arginase and metalloproteinase-9 in silicotic macrophages. Dasatinib was effective at inducing macrophage polarization toward the M2 phenotype and reducing lung inflammation and fibrosis, thus improving lung mechanics in a murine model of acute silicosis"

 

and,

https://www.jci.org/...cles/view/86249

 

"Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development."

 

http://www.impactjou...iew&path[]=6376

 

"Improved therapies are greatly needed for non-small cell lung cancer (NSCLC) that does not harbor targetable kinase mutations or translocations. We previously demonstrated that NSCLC cells that harbor kinase-inactivating BRAF mutations (^KIBRAF) undergo senescence when treated with the multitargeted kinase inhibitor dasatinib. Similarly, treatment with dasatinib resulted in a profound and durable response in a patient with ^KIBRAF NSCLC. However, no canonical pathways explain dasatinib-induced senescence in ^KIBRAF NSCLC. To investigate the underlying mechanism, we used 2 approaches: gene expression and reverse phase protein arrays. Both approaches showed that DNA repair pathways were differentially modulated between ^KIBRAF NSCLC cells and those with wild-type (WT) BRAF. Consistent with these findings, dasatinib induced DNA damage and activated DNA repair pathways leading to senescence only in the ^KIBRAF cells. Moreover, dasatinib-induced senescence was dependent on Chk1 and p21, proteins known to mediate DNA damage-induced senescence. Dasatinib also led to a marked decrease in TAZ but not YAP protein levels. Overexpression of TAZ inhibited dasatinib-induced senescence. To investigate other vulnerabilities in ^KIBRAF NSCLC cells, we compared the sensitivity of these cells with that of ^WTBRAF NSCLC cells to 79 drugs and identified a pattern of sensitivity to EGFR and MEK inhibitors in the ^KIBRAF cells. Clinically approved EGFR and MEK inhibitors, which are better tolerated than dasatinib, could be used to treat ^KIBRAF NSCLC. Our novel finding that dasatinib induced DNA damage and subsequently activated DNA repair pathways leading to senescence in ^KIBRAF NSCLC cells represents a unique vulnerability with potential clinical applications."

[temperance brennan]

Hears a lot about it, last year my fast essay typer gave me his paper on the subject and before passing it I read it. I was shocked. All the researches were indication that there are such drugs but as far as I know they're very expensive so I din't think an average person would be able to use it that ofter

[MidwestGreg]

"The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases"

 

https://www.ncbi.nlm...es/PMC4286194/ 

 

"We have discovered that bosutinib and dasatinib, which are protein tyrosine kinase inhibitors used in the clinic to treat human cancer, induce anti-inflammatory but block pro-inflammatory cytokine production by inhibiting the serine/threonine kinases known as the salt-inducible kinases."

 

 

Abstract -

 

Macrophages switch to an anti-inflammatory, ‘regulatory’-like phenotype characterized by the production of high levels of interleukin (IL)-10 and low levels of pro-inflammatory cytokines to promote the resolution of inflammation. A potential therapeutic strategy for the treatment of chronic inflammatory diseases would be to administer drugs that could induce the formation of ‘regulatory’-like macrophages at sites of inflammation.

 

In the present study, we demonstrate that the clinically approved cancer drugs bosutinib and dasatinib induce several hallmark features of ‘regulatory’-like macrophages. Treatment of macrophages with bosutinib or dasatinib elevates the production of IL-10 while suppressing the production of IL-6, IL-12p40 and tumour necrosis factor α (TNFα) in response to Toll-like receptor (TLR) stimulation. Moreover, macrophages treated with bosutinib or dasatinib express higher levels of markers of ‘regulatory’-like macrophages including LIGHT, SPHK1 and arginase 1. Bosutinib and dasatinib were originally developed as inhibitors of the protein tyrosine kinases Bcr-Abl and Src but we show that, surprisingly, the effects of bosutinib and dasatinib on macrophage polarization are the result of the inhibition of the salt-inducible kinases.

 

Consistent with the present finding, bosutinib and dasatinib induce the dephosphorylation of CREB-regulated transcription co-activator 3 (CRTC3) and its nuclear translocation where it induces a cAMP-response-element-binding protein (CREB)-dependent gene transcription programme including that of IL-10. Importantly, these effects of bosutinib and dasatinib on IL-10 gene expression are lost in macrophages expressing a drug-resistant mutant of salt-inducible kinase 2 (SIK2).

 

In conclusion, our study identifies the salt-inducible kinases as major targets of bosutinib and dasatinib that mediate the effects of these drugs on the innate immune system and provides novel mechanistic insights into the anti-inflammatory properties of these drugs.

[Bryan_S]

Are old cells breaking our hearts?

http://www.sciencema...king-our-hearts

 

http://science.scien...nt/354/6311/472

 

 

[Iporuru]

A word of warning from another thread: http://www.longecity...se/#entry794452

[mikey]

I'm flooded busy and have't had time to read.

 

Is there a consensus on optimum dosing/application for dasatinib with quercitin?

 

Thank you!

[Logic]

We have reached 250+ grams for the Dasatinib group buy, so it looks like its going to happen.

http://www.longecity...ndpost&p=796956
Please use this thread if you would like to join the group.

[stefan_001]

https://www.ncbi.nlm...senescent cells

 

Our findings do not shake this exciting conclusion but rather suggest reconsidering the nature of such cells and, therefore, modifying the focus of anti-aging drug discovery: from SC-targeting senolytic compounds to agents capable of targeting other p16(Ink4a)/γ-galpH6-positive cells, such as the subpopulation of macrophages, SAMs, described in our work. In fact, the indications of anti-aging activity recently reported for senolytic compounds [52,55,56,74] were different and less pronounced than those described by Baker et al. in mice following eradication of p16(Ink4a)-positive cells [21,23] and may reflect an exaggerated view on SCs as the sole source of inflammaging.

[albedo]

I wonder to which extent some of the substances discussed in this thread should be inputted into Geroprotectors.org "...a manually curated online database that provides instant access to all of the above. An up-to-date, rapidly explorable system that catalogues and summarizes over 200 geroprotective compounds and links them to over 250 studies that support (or refute) their effects in model organisms, Geroprotectors is for the entrant or expert in the field alike..." (1).  I could find quercetin entries but not e.g. dasatinib.

 

(1) Moskalev A, Chernyagina E, De magalhães JP, et al. Geroprotectors.org: a new, structured and curated database of current therapeutic interventions in aging and age-related disease. Aging (Albany NY). 2015;7(9):616-28.

[aribadabar]

Experiment #11  

,,,,

 

Fafner,

 

of all the experimental combinations that you have tried which one(s) do you consider the most promising/successful?

 

Thanks!

[Fafner55]

Fafner,

 

of all the experimental combinations that you have tried which one(s) do you consider the most promising/successful?

 

Thanks!

 

 

Reviewing my notes, I have taken 8 one-time treatments of dasatinib plus other supplements.  Of those I experienced

• a mild fever during the first treatment
• diarrhea 5 times
• mild nausea once
• fatigue for a day to a few days after each treatment 
• noticeable skin sloughing on the 6th day after treatment 3 times

My current preferred treatment is

• 120 mg Dasatinib 
• 100 mg Mebendazole
• 500 mg Pterostilbene
• 2000 mg Honokiol
• Either 2100 mg Quercetin Phytosome or 300 mg EMIQ Quercetin.  I am unsure which is best or if it matters.

I weigh 70 kg.

 

Fafner55

[sthira]

My current preferred treatment is

• 120 mg Dasatinib
• 100 mg Mebendazole
• 500 mg Pterostilbene
• 2000 mg Honokiol
• Either 2100 mg Quercetin Phytosome or 300 mg EMIQ Quercetin. I am unsure which is best or if it matters.

I weigh 70 kg.

Fafner55

Have you tried 3- to 5-day water fasts with this approach? Longo's work is compelling.

Meanwhile, how would you know if you had cleared "30%" of your senescent cells? Think you'd feel or see such a thing? Think blood markers would indicate positive movements?

[Kalliste]

 

My current preferred treatment is

• 120 mg Dasatinib
• 100 mg Mebendazole
• 500 mg Pterostilbene
• 2000 mg Honokiol
• Either 2100 mg Quercetin Phytosome or 300 mg EMIQ Quercetin. I am unsure which is best or if it matters.

I weigh 70 kg.

Fafner55

Have you tried 3- to 5-day water fasts with this approach? Longo's work is compelling.

Meanwhile, how would you know if you had cleared "30%" of your senescent cells? Think you'd feel or see such a thing? Think blood markers would indicate positive movements?

 

 

Even longer fastes might be appropirate to target damaged cells. Isn't it fascinating that the fasting gurus were talking in terms of fasting clearing out damaged cells long before this Senolytica thing got started. 14 Days water faste might clear out senescent cells too, has anyone ever looked at that?
 

[Logic]

 p19ARF appears to be another target.

 

Elimination of p19ARF-expressing cells enhances pulmonary function in mice (2016)

Senescent cells accumulate in many tissues as animals age and are considered to underlie several aging-associated pathologies. The tumor suppressors p19ARF and p16INK4a, both of which are encoded in the CDKN2A locus, play critical roles in inducing and maintaining permanent cell cycle arrest during cellular senescence. Although the elimination of p16INK4a-expressing cells extends the life span of the mouse, it is unclear whether tissue function is restored by the elimination of senescent cells in aged animals and whether and how p19ARF contributes to tissue aging. The aging-associated decline in lung function is characterized by an increase in compliance as well as pathogenic susceptibility to pulmonary diseases. We herein demonstrated that pulmonary function in 12-month-old mice was reversibly restored by the elimination of p19ARF-expressing cells. The ablation of p19ARF-expressing cells using a toxin receptor-mediated cell knockout system ameliorated aging-associated lung hypofunction. Furthermore, the aging-associated gene expression profile was reversed after the elimination of p19ARF. Our results indicate that the aging-associated decline in lung function was, at least partly, attributed to p19ARF and was recovered by eliminating p19ARF-expressing cells.

 

Methods for assessing p19-Arf interactions with cMyc:

https://www.google.c...s/US20060183130

[stefan_001]

We found that fisetin and the BCL-XL inhibitors,
A1331852 and A1155463, are senolytic in vitro,
inducing apoptosis in senescent, but not non-senescent
HUVECs. This adds three new agents to the emerging
repertoire of senolytics reported since early 2015, which
currently includes D, Q, N, and piperlongumine [8, 11,
12, 15].
http://paperchase-ag...99rKYDfZoCD.pdf

[stefan_001]

Luteolin was found to bind with highest negative binding energy and thus, claimed highest potency towards BCL-2 inhibition followed by fisetin.
http://www.tandfonli...93.2017.1298129

[stefan_001]

I started my own experiment. A bit different style than others tried as I plan the duration for 2 months with once a week a 36 hour senescent cell clearance cycle:

 

-24 hour: stop NR supplementation to avoid that NRK path can help scenescent cells survive (speculation on my side, the path exists in cancer cells)

0 hour: 150mg Ptero, 1500mg Q + 300mg Luteolin (for its BCL-X inhibition)

8 hour: 1500mg Q + 300mg Fisetin (for its BCL-X inhibition)

16 hour:: 600mg Honokiol + 300mg Luteolin

24 hours:  600mg Honokiol + 300mg Fisetin

36 hours: normal supplementation including NR

 

I switch to honokiol because it has so many anti-cancer properties so it may kill senescent cells as well. While I haven't read anything of H clearing senescent cells that may simply be because nobody tested it. It does increase SIRT3 that in turn increase autophagy.

 

So I rotate the compounds hoping one combination or the different methods of attack will take some senescent cells out. First round went ok, some light muscle weakness but that could be imaginative or related to stopping NR. Skin felt and feels a bit softer but again may be imaginative. So I will do this for some time once a week.

 

 

Edited by stefan_001, 21 March 2017 - 09:38 PM.

[Fafner55]

Honokiol should contribute to apoptosis of senescent cells. It down-modulates the anti-death Bcl-XL while having no effect on the levels of Bcl-2, Bcl-XS, Bag-1, Bax and Bak proteins. By itself, or with Q,L and F, honokiol might not be sufficient, just as Q without dasatinib is not sufficient for preadipose cells.

 

“Down-modulation of Bcl-XL, release of cytochrome c and sequential activation of caspases during honokiol-induced apoptosis in human squamous lung cancer CH27 cells” (2002) https://drive.google...eUw1NHBsQXV5LUU

Here, we found that honokiol-induced apoptotic cell death was accompanied by upregulation of Bad and downregulation of Bcl-XL, while honokiol had no effect on the levels of Bcl-2, Bcl-XS, Bag-1, Bax and Bak proteins. Moreover, honokiol treatment caused the release of mitochondrial cytochrome c to cytosol and sequential activation of caspases.

[Andey]

I ve just done week ago my first run of D+Q+Honokiol (100-3000-800) with preceding 36hours fast.
So far no ill effects, its a shame there is no metric to measure if it worked. (I am more concerned whether my D from Tldr is a real thing)
If everything would be ok in life I plan to do few another runs splitted by 2 weeks periods, presumably with some Q preloading phase.

[zorba990]

How about methyl jasomate (like from Artemisia)
https://www.ncbi.nlm...cles/PMC440575/
"The senescence-promoting substance of wormwood (Artemisia absinthium L.) as detected by the oat (Avena sativa L. cv “Victory”) leaf assay has been identified as (−)-methyl jasmonate, methyl (1S, 2R)-3-oxo-2-(2′-cis-pentenyl)-cyclopentane-1-acetate, by gas-liquid chromatography-mass spectrometry and optical rotatory dispersion. Its senescence-promoting effect was much stronger than that of abscisic acid, and even at such a low concentration as 1 to 2.5 micrograms per milliliter, it could completely eliminate the anti-senescence action of 2 micrograms per milliliter kinetin. Comparing the biological activity of the (−)- with the (±)-forms of methyl jasmonate, it seemed that only the (−)-form was biologically active."

[sthira]

I ve just done week ago my first run of D+Q+Honokiol (100-3000-800) with preceding 36hours fast.
So far no ill effects, its a shame there is no metric to measure if it worked. (I am more concerned whether my D from Tldr is a real thing)
If everything would be ok in life I plan to do few another runs splitted by 2 weeks periods, presumably with some Q preloading phase.

Thanks, Andey. Maybe one metric would be general inflammation blood tests?

I'm wondering if you've considered adding fisetin since there appears some suggestive in vitro evidence it's senolytic, and fisetin seems relatively non-toxic.

[stefan_001]

Honokiol should contribute to apoptosis of senescent cells. It down-modulates the anti-death Bcl-XL while having no effect on the levels of Bcl-2, Bcl-XS, Bag-1, Bax and Bak proteins. By itself, or with Q,L and F, honokiol might not be sufficient, just as Q without dasatinib is not sufficient for preadipose cells.

“Down-modulation of Bcl-XL, release of cytochrome c and sequential activation of caspases during honokiol-induced apoptosis in human squamous lung cancer CH27 cells” (2002) https://drive.google...eUw1NHBsQXV5LUU
Here, we found that honokiol-induced apoptotic cell death was accompanied by upregulation of Bad and downregulation of Bcl-XL, while honokiol had no effect on the levels of Bcl-2, Bcl-XS, Bag-1, Bax and Bak proteins. Moreover, honokiol treatment caused the release of mitochondrial cytochrome c to cytosol and sequential activation of caspases.

Thanks for pointing to that. Dasatinib inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. So one of these kinases is a weak point in senescent cells. I will browse a bit to see whether some phenols inhibit those also.

Edited by stefan_001, 22 March 2017 - 09:50 PM.

[aribadabar]

How about methyl jasomate (like from Artemisia)
https://www.ncbi.nlm...cles/PMC440575/
"The senescence-promoting substance of wormwood (Artemisia absinthium L.) as detected by the oat (Avena sativa L. cv “Victory”) leaf assay has been identified as (−)-methyl jasmonate, methyl (1S, 2R)-3-oxo-2-(2′-cis-pentenyl)-cyclopentane-1-acetate, by gas-liquid chromatography-mass spectrometry and optical rotatory dispersion. Its senescence-promoting effect was much stronger than that of abscisic acid, and even at such a low concentration as 1 to 2.5 micrograms per milliliter, it could completely eliminate the anti-senescence action of 2 micrograms per milliliter kinetin. Comparing the biological activity of the (−)- with the (±)-forms of methyl jasmonate, it seemed that only the (−)-form was biologically active."

 

Why would you want to take a senescent-promoting compound and not the anti-senescent one such as the abovementioned kinetin ??

[zorba990]

How about methyl jasomate (like from Artemisia)
https://www.ncbi.nlm...cles/PMC440575/
"The senescence-promoting substance of wormwood (Artemisia absinthium L.) as detected by the oat (Avena sativa L. cv “Victory”) leaf assay has been identified as (−)-methyl jasmonate, methyl (1S, 2R)-3-oxo-2-(2′-cis-pentenyl)-cyclopentane-1-acetate, by gas-liquid chromatography-mass spectrometry and optical rotatory dispersion. Its senescence-promoting effect was much stronger than that of abscisic acid, and even at such a low concentration as 1 to 2.5 micrograms per milliliter, it could completely eliminate the anti-senescence action of 2 micrograms per milliliter kinetin. Comparing the biological activity of the (−)- with the (±)-forms of methyl jasmonate, it seemed that only the (−)-form was biologically active."

Why would you want to take a senescent-promoting compound and not the anti-senescent one such as the abovementioned kinetin ??

Well it appears that it only pushes cancer cells to premature death and not normal cells. So this lines them up so they can be shot down when senolytics purge them.

D, Shaklai M, Flescher E.. Jasmonates: novel anticancer agents acting directly and selectively on human cancer cell mitochondria.
http://cancerres.aac...ntent/65/5/1984

Canc Res 2005; 65:1981-993; PMID:15753398; http://dx.doi.org/10...472.CAN-04-3091 [PubMed] [Ref list]

" Jasmonates induced swelling in mitochondria isolated from Hep 3B hepatoma cells, but not in mitochondria isolated from 3T3 nontransformed cells or from normal lymphocytes, in a PTPC-mediated manner. Methyl jasmonate induced the release of cytochrome c from mitochondria isolated from cancer cell lines in a PTPC-mediated manner, but not from mitochondria isolated from normal lymphocytes. A correlation was found between cytotoxicity of methyl jasmonate and the percentage of leukemic cells in the blood of patients with chronic lymphocytic leukemia (CLL). Jasmonates induced membrane depolarization in CLL cells, and swelling and release of cytochrome c in mitochondria isolated from these cells. In conclusion, jasmonates act directly on mitochondria derived from cancer cells in a PTPC-mediated manner, and could therefore bypass premitochondrial apoptotic blocks. Jasmonates are promising candidates for the treatment of CLL and other types of cancer."

[Andey]

 

I ve just done week ago my first run of D+Q+Honokiol (100-3000-800) with preceding 36hours fast.
So far no ill effects, its a shame there is no metric to measure if it worked. (I am more concerned whether my D from Tldr is a real thing)
If everything would be ok in life I plan to do few another runs splitted by 2 weeks periods, presumably with some Q preloading phase.

Thanks, Andey. Maybe one metric would be general inflammation blood tests?

I'm wondering if you've considered adding fisetin since there appears some suggestive in vitro evidence it's senolytic, and fisetin seems relatively non-toxic.

 

 

  

  My impressions on this is that hard to understand inflammation levels from simple blood tests. hsCrp and ESR are more about acute phases of inflammation what is rare and noticible even without tests. Interleukins and TNF-a means something only when you have all them done, but this is prohibitively expensive here, and I dont have expertise to fully undersatnd results myself. And if you have a bad night sleep - your tests are messed up, you are in some viral cold incubation period before some cold - messed up, done some extensive streching or excercise -..., and so on.

I have pretty complicated relashionships with inflammation, coz I spent 2015 and half of 2016 fighting with Lyme. Almost a year on abx. Trying to fix my after a battlefield body since )

  My bro-science marker during treatment was cholesterol levels, if there is no metabolic syndrome present than cholesterol most probably a sign and measure of endotoxin transport activation from infection. But its not really an inflammation marker per se. Even extensive and prolonged IV glutathione treatment that Ive done back than havent touch LDL levels that much, but definitely supressed inflammation a lot.

 

  Usefull information from simple blood test is a state hematopoietic stem cells, rate of renewal of blood cells. (Epitalone seriuosly shifted that test for me)

  Fisetin is on the radar thanks to this thread, but I am not about trying everything firsthand.  Next thing I planned is to try 4-5 day fast (with some MCT Oil 2 times a day to induce bile flow) and D+Q+H at the end. And a run of an Epitalon on top of that to force stem cells to work.