459 replies to this topic

[sthira]

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.

Is your epitalon experience posted here, sorry to be off topic, but I couldn't find it while searching. How much epitalon did you inject, where did you buy it, and how do you plan to time your epitalon injections with your 4-5 day fasting with D+Q+H? Epitalon after the fasting?

[Fafner55]

 

  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)

 

 

Andey,

Could you identify and describe the blood test for hematopoietic stem cells, and provide support for the shift caused by epitalon?

[Andey]

 

 

  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)

 

 

Andey,

Could you identify and describe the blood test for hematopoietic stem cells, and provide support for the shift caused by epitalon?

 

 

  Its just a simplest blood test with RBC count and so on.I cant have tests results near me but if I recall corrrectly my MPV and PDW dipped and PLT count goes up for some time meaning that there was some increase in platelet production that happened in a short period of time (lower PDW means that they all are similar age). My neutrophils count is usually low and it goes up around 20%.

  To be 100% correct I dont sure it all could be attributed to Epitalone alone because I have taken Erbisol same time. Erbisol is a local drug made from chicken embryos. Manufacturer claims that it have some peptide complexes in it but what exactly is a mystery(usual thing for exUSSR drugs but that one is definitely not a snake oil). Doctors here use it to speedup wound healing, treat stomach ulcers and decrease autoimmunity. Anyway I have taken Erbisol before and there was no effect on platelets, but some increase on neutrophils too.

 

P.S. Sorry for derailing this thread. I am not a healthcare professional and all my data is kinda anecdotal and based on n=1. Looking back I should not made such broad claims that Epitalon done something.

Edited by Andey, 23 March 2017 - 02:59 PM.

[Andey]

 

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.

Is your epitalon experience posted here, sorry to be off topic, but I couldn't find it while searching. How much epitalon did you inject, where did you buy it, and how do you plan to time your epitalon injections with your 4-5 day fasting with D+Q+H? Epitalon after the fasting?

 

 

Nope, I just have taken common approach that I ve seen on reddit an here on Epitalon thread. I bought 100mg plain Epitalon from Ceretropic and divided it into 20 days subq injections morning/evening.

My inspiration was this post on reddit (not in dosages but I was kinda impressed on test results)

https://www.reddit.c..._with_epitalon/

Not that often guys do telomere length testing before and after, and not that often it shows results like this.

Trigger point was story about 115 you old woman that have almost all her wbc cells derived just from 2 (two) stem cells. It shows that its rather easy to hit division limit for stem cells and maintaining its proper length is a good idea.

 

For next batch I bought two tester packs from Ceretropic. I want to do 3 runs of different Epitalon types (40mg each for 20 day 2 time a day Subq) with 2 month intervals. This is more a economy driven decison, but I think high dosages Subq are not necessary, people have results with similar volumes even orally.

[simon007]

Nice article about foxo-dri, a protein based senolytic

 

http://www.bbc.com/n...health-39354628

[Harkijn]

Nice article about foxo-dri, a protein based senolytic

 

http://www.bbc.com/n...health-39354628

Yes, a FOXO4 peptide....

[pieter cloete]

Drug 'reverses' ageing in animal tests (BBC News website)

The link:  http://www.bbc.com/n...health-39354628

I just read this a hour ago. The team at Erasmus University Medical Center, in the Netherlands, are planning human trials for what they hope is a treatment for old age.

If this is true I want to be the first on the human trails.

 

[mikey]

Drug 'reverses' ageing in animal tests (BBC News website)

The link:  http://www.bbc.com/n...health-39354628

I just read this a hour ago. The team at Erasmus University Medical Center, in the Netherlands, are planning human trials for what they hope is a treatment for old age.

If this is true I want to be the first on the human trails.

 

 

 

Rather than weight for a trial, we should consider finding a source of the p53, when it becomes available.

 

Group buy???

[pieter cloete]

What is p53. Maybe Turnbuckle or one of the informed people can tell us.

[Andey]

Its about Foxo4 dri peptide
https://www.google.c...6118014A2?cl=en
For my unexperienced sight it have quite a large formula LTLRKEPASEIAQSILEAYSQNGWANRRSGGKRP. It should be very expensive to made from scratch. For example Epitalon is just AGAG and costs 100$ for 100mg

[William Sterog]

I remember reading that Ashwagandha works somehow through P53.
Here it is:
 

There is a related protein called mortalin (a heat shock protein in the Hsp70 family regulating proliferation and stress responses[59] and is enriched in cancer cells[60][61]) which complexes with p53 to sequester it in the nucleus[62] which can increase lifespan in normal cells[63] but also cause cancerous cells to become more robust against chemotherapy.[61] Withanone also seems to bind to mortalin like it does to survivin,[64] binding to the segments of mortalin that MKT-077 (known ligand of mortalin[65]) binds to, at the Phe 272 and Asn 139 (ring lactone group of withanone), with some other bonds at Asp 277 and Arg 284 with binding energies in the range of -5.99 to -6.60kcal/mol.[64]
Withanone is able to downregulate P21WAF1 in normal fibroblast cells (TIG-1, MRC5, and WI38 cells) due to downregulating P53[97] despite the apparent upregulation of p53 in cancerous cells;[98] due to P21WAF1 positively influencing the rate of cellular senesence in normal cells,[99] 2.5ug/mL withanone induced downregulation of P21WAF1 caused 10-12 more population doublings which correlated to a 20% increase in cellular lifespan[97] and not only was there a relative decrease in accumulated molecular damage associated with withanone the increase of P21WAF1 seen with Withaferin-A was abolished with withanone.[97]

[Harkijn]

see also this useful comment:

https://www.fightagi...stalk/#comments

[dnouche]

What is the difference between the peptide used in the study, and a peptide sold online like this one https://www.novusbio...e_nbp1-77175pep ? (I'm not associated with the site in any way or advocating people should try it).

 

 

[Andey]

I ve asked on reddit is it feasible to produce it, got the answer yes

 

https://www.reddit.c..._production_of/

"That's not that big, I'm working with a 350 amino acid protein at work. Your little peptide is tiny. You could use an e coli expression system easily enough, but you are going to run into immunogenicity concerns, and have some difficulty​ purifying it without adding a tag or something. If you fused it to human IgG, and purified it by Protein A/G chromatography, it wouldn't be too hard.

I think few people would use it though since it would have a short shelf life, and have to be injected. Basically you would treat it like insulin."

Sounds like a rocket science though for me ))

Edited by Andey, 24 March 2017 - 02:26 PM.

[pieter cloete]

I am just a retired artisan and have no clue about all these advanced words and formulas. I just hope the trails is in the near future and some company can supply it to us within the next 5 to 8 years.

[Fafner55]

FOX04 is shown to prevent apoptosis in senescent cells, resisting pro-death BAX and anti-death BCL family expression.“Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging” (2017) http://www.cell.com/cell/fulltext/S0092-8674(17)30246-5

 

The combination dasatinib + quercetin overcomes this resistance to apoptosis by further inhibiting BCL family members and promoting BAX. In a sense, this treatment works by pushing harder on the BAX/BCL ratio. “The Achilles' heel of senescent cells: from transcriptome to senolytic drugs” (2015) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078/

 

These publications taken together, with measurements of the fold change in BCL expression show in the resistance to apoptosis in IMR90 lung fibroblasts, the effect of dasatinib (a potent BCL-2 inhibitor) on preadipose cells and Q (an inhibitor or BCL-xL) on HUVEC cells.

 

These insights beg the question of whether the efficacy of D+Q can be improved with other supplements acting on BCl-2, BCL-xL and BAX, as has been suggested in this forum. To lend structure to this question I organized the following table relating supplements to their mechanisms of action and can infer

1. Mebendazole might be synergistic with D in inhibiting BCL-2, possibly improving its efficacy on preadipose cells
2. Honokiol, by potently inhibiting BCL-xL, should be synergistic with Q in targeting HUVEC and similar cells.
3. Pterostilbene is synergistic with Q and astragalus in inhibiting the BCL family and inducing BAX
4. Curcumin and green tea extract inhibit BCL-2 and potently induce BAX (if issues with their bioavailability are addressed with either a phytosome formulation or with piperine).

Could anyone offer other thoughts or suggestions?

 

 BCL,BAX and apoptotic inducers_1.jpg   68.56KB   4 downloads

 

[1] “Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging” (2017) http://www.cell.com/cell/fulltext/S0092-8674(17)30246-5

[2] “Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors" (2016) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854923/

[3] “The Achilles' heel of senescent cells: from transcriptome to senolytic drugs” (2015) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078/

[4] "Philadelphia chromosome"), Src, c-Kit, ephrin receptors, and several other tyrosine kinases.  “Targeting BCL-2 and ABL/LYN in Philadelphia chromosome–positive acute lymphoblastic leukemia” (2016) http://stm.sciencemag.org/content/8/354/354ra114.full   

[5] “Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells” (2008) http://mcr.aacrjournals.org/content/6/8/1308.long  

[6] “Direct binding of Bcl-2 family proteins by quercetin triggers its pro-apoptotic activity” (2014) https://www.ncbi.nlm.nih.gov/pubmed/25211642, https://www.researchgate.net/publication/265559397_Direct_Binding_of_Bcl-2_Family_Proteins_by_Quercetin_Triggers_Its_Pro-Apoptotic_Activity

[7] “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.com/open?id=0B_pfWfFEQDILeUw1NHBsQXV5LUU

https://www.ncbi.nlm.nih.gov/pubmed/12007567

[8] “Bcl-xl and Mcl-1 are the major determinants of the apoptotic response to dual PI3K and MEK blockage” (2015) https://www.spandidos-publications.com/ijo/47/3/1103

[9]  “In vivo preventive effects of insect tea on buccal mucosa cancer in ICR mice” (2014) http://medind.nic.in/jat/t14/i3/jatt14i3p651.htm, https://www.ncbi.nlm.nih.gov/labs/articles/25313755/

[10] “Association between Pterostilbene and Quercetin Inhibits Metastatic Activity of B16 Melanoma” (2005) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1490314/

[11] “Effect of curcumin on Bcl-2 and Bax expression in nude mice prostate cancer” (2015) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583908/

[12] “Polyphenol, an extract of green tea, increases culture recovery rates of isolated islets from nonhuman primate pancreata and marginal grade human pancreata” (2004) https://www.ncbi.nlm.nih.gov/pubmed/15129760

[13] “Epigallocatechin-3 gallate induces growth inhibition and apoptosis in human breast cancer cells through survivin suppression” (2007) https://www.ncbi.nlm.nih.gov/pubmed/17786300

[14] “Effect of quercetin on the expression of Bcl-2/Bax apoptotic proteins in endometrial cells of lipopolysaccharide-induced-abortion mice” (2016) http://www.sciencedirect.com/science/article/pii/S0254627217300080

[15] “Quercetin Induces Tumor-Selective Apoptosis through Downregulation of Mcl-1 and Activation of Bax” (2010) http://clincancerres.aacrjournals.org/content/clincanres/16/23/5679.full.pdf

[16] “Navitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xL” (2011) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3129452/

[17] “The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized” (2006) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953559/

[18] “Enhanced antitumor efficacy with combined administration of astragalus and pterostilbene for melanoma” (2014) http://www.apocpcontrol.org/paper_file/issue_abs/Volume15_No3/1163-1169%2012.7%20Xinyan%20Huang.pdf

 

[Andey]

What a contribution, Fafner55 ! Thank you

I would add also ruxolitinib, https://www.ncbi.nlm...pubmed/26687007, not sure how it works. It should be quite easy in regards of side effects and its an approved drug
I found intresting that there is marker of senescent cells quantity in blood - activin A. I cant find it in commercial labs buts its widely used in academic research (at least google search gives this impression). So potentially we could compare interventions by net results.
Its also intriguing how fasting, excercise, cold exposure, hypoxia or other physical and lifestyle interventions could alter this pathways to augment chemicals.

Edited by Andey, 25 March 2017 - 08:18 PM.

[stefan_001]

Fisetin and Luteolin as discussed earlier

Now this is a contra finding:

"The expression of Bcl-2 significantly increased while the expression of Bax was significantly elevated, in the LPS plus quercetin group compared to the LPS only group."
http://www.sciencedi...254627217300080

Edited by stefan_001, 25 March 2017 - 08:19 PM.

[dnouche]

OK, I did some more googling today, this site below looks like it is selling the peptide from the study (http://www.cell.com/...74(17)30246-5)?

 

https://www.novoprol...ide-318716.html

 

If someone with more knowledge than me could graciously comment. 

 

 

 

 

[stefan_001]

Anacardic acid is another one depending on selectivity:

https://www.spandido...m/ijo/42/3/1045

In this study, AA induced the expression of the pro-apoptotic Bcl-2 family proteins, Bim, Bad, Bak, Bax and Noxa and cytochrome c, and reduced the expression of the anti-apoptotic Bcl-2 family protein, Bcl-XL, in A549 cells. The expression of FoxOs increased on AA treated A549 cells. These results showed the possibility that the increase of pro-apoptotic BH3-only protein, Bim and Noxa by FoxOs and decrease of anti-apoptotic protein, Bcl-XL, induce the outer membrane disruption of mitochondria in AA treated A549. The disruption of mitochondria membrane may induce the release of proapoptotic mediators such as AIF and cytochrome c from mitochondria.

But this somewhat contradicts the finding that FOXO4 inhibition triggering apoptosis in senescent cells.... Hmmm

[Fafner55]

Anacardic acid is another one depending on selectivity:

https://www.spandido...m/ijo/42/3/1045

In this study, AA induced the expression of the pro-apoptotic Bcl-2 family proteins, Bim, Bad, Bak, Bax and Noxa and cytochrome c, and reduced the expression of the anti-apoptotic Bcl-2 family protein, Bcl-XL, in A549 cells. The expression of FoxOs increased on AA treated A549 cells. These results showed the possibility that the increase of pro-apoptotic BH3-only protein, Bim and Noxa by FoxOs and decrease of anti-apoptotic protein, Bcl-XL, induce the outer membrane disruption of mitochondria in AA treated A549. The disruption of mitochondria membrane may induce the release of proapoptotic mediators such as AIF and cytochrome c from mitochondria.

But this somewhat contradicts the finding that FOXO4 inhibition triggering apoptosis in senescent cells.... Hmmm

 

Results with anacardic acid do send a confusing message. Increase in FOX04 and BAK and still get apoptosis? An increase in BIM without much change in BAX? Somehow the life/death balance of these cells tipped but it isn't clear how.

 

It is encouraging to see a natural substance affecting FOX04, even if it is promoting it. There might be other natural substances that inhibit it.

[Andey]

Anacardic acid is another one depending on selectivity:

https://www.spandido...m/ijo/42/3/1045

In this study, AA induced the expression of the pro-apoptotic Bcl-2 family proteins, Bim, Bad, Bak, Bax and Noxa and cytochrome c, and reduced the expression of the anti-apoptotic Bcl-2 family protein, Bcl-XL, in A549 cells. The expression of FoxOs increased on AA treated A549 cells. These results showed the possibility that the increase of pro-apoptotic BH3-only protein, Bim and Noxa by FoxOs and decrease of anti-apoptotic protein, Bcl-XL, induce the outer membrane disruption of mitochondria in AA treated A549. The disruption of mitochondria membrane may induce the release of proapoptotic mediators such as AIF and cytochrome c from mitochondria.

But this somewhat contradicts the finding that FOXO4 inhibition triggering apoptosis in senescent cells.... Hmmm

Results with anacardic acid do send a confusing message. Increase in FOX04 and BAK and still get apoptosis? An increase in BIM without much change in BAX? Somehow the life/death balance of these cells tipped but it isn't clear how.

It is encouraging to see a natural substance affecting FOX04, even if it is promoting it. There might be other natural substances that inhibit it.

Its possible that Foxo4 is not an so much of a bad guy in the room.
For example it increases while fasting https://www.ncbi.nlm...pubmed/12683947, what is kinda counterintuitive.
May be its function is to preserve tissue integrity for some cell types while fasting, or to buffer somewhat apoptosis so it would not happen simultaniously in massive number or cells what could put body into shock.

[stefan_001]

Anacardic acid is another one depending on selectivity:

https://www.spandido...m/ijo/42/3/1045

In this study, AA induced the expression of the pro-apoptotic Bcl-2 family proteins, Bim, Bad, Bak, Bax and Noxa and cytochrome c, and reduced the expression of the anti-apoptotic Bcl-2 family protein, Bcl-XL, in A549 cells. The expression of FoxOs increased on AA treated A549 cells. These results showed the possibility that the increase of pro-apoptotic BH3-only protein, Bim and Noxa by FoxOs and decrease of anti-apoptotic protein, Bcl-XL, induce the outer membrane disruption of mitochondria in AA treated A549. The disruption of mitochondria membrane may induce the release of proapoptotic mediators such as AIF and cytochrome c from mitochondria.

But this somewhat contradicts the finding that FOXO4 inhibition triggering apoptosis in senescent cells.... Hmmm

Results with anacardic acid do send a confusing message. Increase in FOX04 and BAK and still get apoptosis? An increase in BIM without much change in BAX? Somehow the life/death balance of these cells tipped but it isn't clear how.

It is encouraging to see a natural substance affecting FOX04, even if it is promoting it. There might be other natural substances that inhibit it.

Its possible that Foxo4 is not an so much of a bad guy in the room.
For example it increases while fasting https://www.ncbi.nlm...pubmed/12683947, what is kinda counterintuitive.
May be its function is to preserve tissue integrity for some cell types while fasting, or to buffer somewhat apoptosis so it would not happen simultaniously in massive number or cells what could put body into shock.

You may be right. AA btw seems to have some tricks up its sleeve. This could be an interesting compound.
http://link.springer...0495-016-1330-6

[Fafner55]

FOX04 serves to preserve tissue integrity under stress.

 

FOX04 is modulated by SIRT1. The activity of FOX04 is suppressed by SIRT1 inhibitors, such as nicotinamide, and enhanced by SIRT1  activators, such as resveratrol.

“SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress” (2005) https://www.ncbi.nlm.nih.gov/pubmed/16012755?dopt=Abstract

 

From this view, improvements to senolytic treatments could follow from

• Not fasting
• Not taking NR, resveratrol or pterostilbene
• Not engaging in vigorous exercise
• Inhibiting SIRT1 by large doses of nicotinamide, such as 2 to 3 gm.

 

Nicotinamide is a potent inhibitor of SIRT1. I would expect it to decrease FOX04 but don't have support.

1. https://www.researchgate.net/post/How_long_does_it_take_for_Niacinamide_to_inhibit_SIRT1_and_how_long_until_it_stops
2. “Nicotinamide-mediated inhibition of SIRT1 deacetylase is associated with the viability of cancer cells exposed to antitumor agents and apoptosis” (2013) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789038/

 

Are there suggestions for other sirtuin and FOX04 inhibitors? I haven't yet found a good, direct FOX04 inhibitor.

[stefan_001]

I am not sure about the FOXO role:
Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer
https://jmolecularsi.../1750-2187-5-10

But then again the FOXO4 link in the cell publication was quite convincing.


Oridonin looks like another good candidate:

oridonin-induced apoptosis was associated with an increase in the expression of the apoptosis inducer Bax, and a significant reduction in expression of the apoptosis suppressor Bcl-2 in mitochondria.
http://europepmc.org...ct/med/15132839

Edited by stefan_001, 26 March 2017 - 09:16 PM.

[albedo]

In case you missed, I just wish to record here a short discussion on the market place and Unity and Oisin in particular I have seen on the FightAging blog:

https://www.fightagi...-biotechnology/

[stefan_001]

Leptomycin B blocks FOXO4 completely...........

[Kalliste]

 Inositol/IP6 is an inhibitor of Pl3K/AKT? Would it make any sense to involve that in this senescent cell circus?

[Fafner55]

Leptomycin B blocks FOXO4 completely...........

 

This is relevant.

 

“Identification of nuclear export inhibitors with potent anticancer activity in vivo” (2009) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635062/

[Visor]

Tocotrienol-rich fraction of palm oil activates p53, modulates Bax/Bcl2 ratio and induces apoptosis independent of cell cycle association.

Agarwal MK1, Agarwal ML, Athar M, Gupta S.
Author information
Abstract
Anti-cancer properties of palm oil have been attributed to the presence of tocotrienols and carotenoids. Studies from various laboratories have shown that tocotrienol-rich fraction (TRF) of palm oil inhibits cell growth and induces apoptosis in both preneoplastic and neoplastic cells. However, the mechanism by which TRF induces apoptosis remains largely unknown. Since several chemopreventive agents have been shown to utilize p53 pathway in negative regulation of cell growth, using human colon carcinoma RKO cells which express wild type p53, we investigated the effect of TRF on components of p53 signaling network. Treatment of cells with TRF resulted in a dose- and time- dependent inhibition of growth and colony formation. Further, TRF treatment of RKO cells resulted in the induction of WAF1/p21 which appears to be independent of cell cycle regulation and is transcriptionally upregulated in p53 dependent fashion. These results were further confirmed by using cells that express luciferase from a p53 responsive promoter where TRF treatment leads to activation of p53 reporter activity. TRF treatment also resulted in alteration in Bax/Bcl2 ratio in favor of apoptosis, which was associated with the release of cytochrome c and induction of apoptotic protease-activating factor-1. This altered expression of Bcl2 family members triggered the activation of initiator caspase-9 followed by activation of effector caspase-3. These signaling cascades lead to condensed chromatin, DNA fragmentation and shrinkage of cell membrane resulting into apoptosis. Our data suggest that TRF-induced apoptosis in colon carcinoma cells is mediated by p53 signaling network which appears to be independent of cell cycle association.