FOXO4-DRI

[Devilseye]

Thank you @Researcher6076 for sharing your research. So F410 is FOXO4-DRI? Because homopeptide told me they only have plain foxo4, but that just makes no sense to me; who would use that and for what? I'll heed your warning and pause.

I actually have some Dasatinib otw now, this will probably be much safer to try. Even that could lead to deleterious results, but at least there's a lot more research on it.

On a side note though, there are some who have used foxo4-dri and have shared their experiences, but it's far and few.

Yeah all small molecule senolytics are anticancer agents. Navitoclax/Venetoclax and dasatanib for example. There are dosage studies on these and phase 3 trials that clearly identify side effect and toxicity profiles. I would definitely do those first and they are fairly cheap and easy to procur.

For FOXO4-DRI it seems to be a potent senolytic but there is so little real world, controlled data on it. Like there is no phase2/3 studies showing proper dosing protocols and measuring effectiveness on a variety of SASP biomarkers. However, I dont see how it could activate latent cancers like someone mentioned since it is an inhibitor of p53 inhibition by FOXO4. I mean p53 activation triggers apoptosis in cancer. Also reduction of SASP phenotype means a healthier tissue microenvironment and less proliferation of cancer cells. If im missing something someone please enlighten me. The DRI also seems associated with cell penetrance so that doesnt seem to be an issue.

In any case, Id much rather do dasatanib/venetoclax with Quercetin/Fisetin than FOXO4. There is real world evidence that these work and their combination can be especially potent. But i dont see what the huge risk is for FOXO4-DRI at small dosage that people have reported.

 

[Devilseye]

The reward would have to be awfully high for me to take the risk.

Yeah thats why i wont be doing any progrowth/prohealing peptides, GH secretagogues and melanotan. Not worth it. However, FOXO4-DRI doesnt fit in that group and should be anti-cancer through its mechanism of action. So im not sure why people are mentioning that here.

 

[Researcher6076]

Yeah all small molecule senolytics are anticancer agents. Navitoclax/Venetoclax and dasatanib for example. There are dosage studies on these and phase 3 trials that clearly identify side effect and toxicity profiles. I would definitely do those first and they are fairly cheap and easy to procur.

For FOXO4-DRI it seems to be a potent senolytic but there is so little real world, controlled data on it. Like there is no phase2/3 studies showing proper dosing protocols and measuring effectiveness on a variety of SASP biomarkers. However, I dont see how it could activate latent cancers like someone mentioned since it is an inhibitor of p53 inhibition by FOXO4. I mean p53 activation triggers apoptosis in cancer. Also reduction of SASP phenotype means a healthier tissue microenvironment and less proliferation of cancer cells. If im missing something someone please enlighten me. The DRI also seems associated with cell penetrance so that doesnt seem to be an issue.

In any case, Id much rather do dasatanib/venetoclax with Quercetin/Fisetin than FOXO4. There is real world evidence that these work and their combination can be especially potent. But i dont see what the huge risk is for FOXO4-DRI at small dosage that people have reported.

Here is the detailed biology: Senescent cells can act as a buffer against cancer in two main ways. First, cell‑autonomous arrest: when a potentially malignant cell senses irreparable damage it enters senescence and permanently stops dividing, which directly prevents that cell from clonally expanding into a tumor. Second, immune recruitment: early senescent cells secrete a short‑lived mix of cytokines and chemokines (the SASP) that attracts innate and adaptive immune cells to clear both the senescent cells and nearby damaged or pre‑malignant cells, reinforcing tumor suppression.

Beyond those direct effects, senescent cells also create local microenvironmental barriers. They can enforce paracrine signals that induce neighboring damaged cells to stop dividing (paracrine senescence), occupy niche space that limits stem/progenitor overgrowth, and maintain extracellular matrix features that are less permissive for invasion. Together these actions reduce the chance that a dormant or pre‑malignant clone will resume growth.

The buffering role is time‑ and context‑dependent. When senescence is transient and immune clearance is efficient, the net effect is protective. But if senescent cells accumulate (aging, immune dysfunction), their chronic SASP shifts from immune‑recruiting to pro‑inflammatory and pro‑mitogenic, remodeling matrix and angiogenesis and thereby promoting tumor emergence instead of preventing it.

 

[Devilseye]

Here is the detailed biology: Senescent cells can act as a buffer against cancer in two main ways. First, cell‑autonomous arrest: when a potentially malignant cell senses irreparable damage it enters senescence and permanently stops dividing, which directly prevents that cell from clonally expanding into a tumor. Second, immune recruitment: early senescent cells secrete a short‑lived mix of cytokines and chemokines (the SASP) that attracts innate and adaptive immune cells to clear both the senescent cells and nearby damaged or pre‑malignant cells, reinforcing tumor suppression.

The buffering role is time‑ and context‑dependent. When senescence is transient and immune clearance is efficient, the net effect is protective. But if senescent cells accumulate (aging, immune dysfunction), their chronic SASP shifts from immune‑recruiting to pro‑inflammatory and pro‑mitogenic, remodeling matrix and angiogenesis and thereby promoting tumor emergence instead of preventing it.

I completely understand that senescence cells, especially in early accumulation phase can have a protective role in buffering cancer formation. Its a matter of two competitive effects though.

One the one hand senescence is intrinsically a protective mechanism, on the other senolytics kill that protective effect BUT they are also themselves anticancer agents.

So which effect is strongest? The protective effect of senescence or anticancer effect of senolytics. I think its hard to argue to dasatanib and venetoclax would in any way contribute to cancer formation, especially in combination. I also think that regarding senolyics in general, there is no real evidence that they cause an increase in cancer in any animal models. So the risk due to the protective effect of senescence is purely theoretical and not rooted in any evidence that I know of. If there is such evidence please let me know im always open to being wrong.

There are lots of things that can be theoretically cancer promoting in some way but the evidence just doesnt pan out in animal or human trials. GLP1s for example, NR/NMN, glutathione, etc. So theres no real reason to fear it imo. Until the evidence changes of course which sometimes, though rarely, happens after decades of usage in the population.

 

[trojanpeptide]

why i wont be doing any progrowth/prohealing peptides, GH secretagogues and melanotan

not all healing compounds are carcinogenic. Keeping inflammation down is a good way to protect oneself from cancer, and that can be achieved using several peptides, including KPV and MT-1. I notice you wrote 'melanotan', but I think you mean MT-2. This one kicks up your HR and BP because it affects more than MC1R (melanocortin receptor 1) and instead attaches to MC1, MC3, MC4, and MC5. Strict MC1R activation is associated with good things. Even BPC-157, I'm on the fence about this one. I think what you mean to say is not 'pro-healing' which is good, but angiogenic, ie. promoters of vascular differentiation, creating new blood vessels, which in turn could feed existing tumors.

FOXO4 is involved in a lot more than just binding p53 folks. It's normally bound by XBP1u in the cytoplasm, and is driven by PDGF-BB, TNF-α, angiotensin II, mechanical and oxidative stress, which are pathological signals. It also interacts directly with myocardin and inhibits smooth muscle contractile gene expression, which is not a good thing. My point is that its a lot more complicated than just Foxo4-p53, and if DRI upsets the XBP1u retention of FOXO4, then that would be disastrous to normal cells.

I've also read that senescent cells could theoretically serve a structural placeholders, which without, we would end up with swiss cheese tissues (that's a bad thing, especially in the context of endothelial tissue in the vascular system... think dissection/rupture).

I agree that more research is required. This is why Cleara Biotechis advancing the FOXO4-p53 technology from a 3rd-generation research peptide (FOXO4-DRI) into 4th-generation therapeutic candidates designed for human clinical translation. Their current work centers on two lead compounds, CL04177 and CL04183, which demonstrate significantly enhanced binding to p53 in senescent cells compared to the original FOXO4-DRI.

Just stuff to keep in mind.

 

[Researcher6076]

I just ordered some from a vendor a week ago that now shows Out of Stock.

I've done 2 cycles of Fox (yes, DRI). Couldn't tell any difference with the first round.

I've had a very small tender point on my left temple for probably over 20 years. It would get a little rough spot the size of the tip of a pencil lead that hurt to the touch. I'd apply a mix of Vitamin D and a specific selenium supplement overnight. It would basically 'eat' the spot that would then heal over the next few days, then in a month or 2 would be back. (although the tenderness never went away fully)

About 2/3 of the way through my last round of Fox, that spot disappeared and hasn't been back. I can push on that spot as hard as I want and I feel nothing. That was a couple months ago. The Fox is the only thing I can think of that was different that time.

Yes! Those kinds of skin patchrs are exactly the kinds of issues foxo4-dri should help. How. Many mg each day? How many days? Did you alternate days?

 

[Devilseye]

not all healing compounds are carcinogenic. Keeping inflammation down is a good way to protect oneself from cancer, and that can be achieved using several peptides, including KPV and MT-1. I notice you wrote 'melanotan', but I think you mean MT-2. This one kicks up your HR and BP because it affects more than MC1R (melanocortin receptor 1) and instead attaches to MC1, MC3, MC4, and MC5. Strict MC1R activation is associated with good things . Even BPC-157, I'm on the fence about this one. I think what you mean to say is not 'pro-healing' which is good, but angiogenic, ie. promoters of vascular differentiation, creating new blood vessels, which in turn could feed existing tumors.

FOXO4 is involved in a lot more than just binding p53 folks. It's normally bound by XBP1u in the cytoplasm, and is driven by PDGF-BB, TNF-α, angiotensin II, mechanical and oxidative stress, which are pathological signals. It also interacts directly with myocardin and inhibits smooth muscle contractile gene expression, which is not a good thing. My point is that its a lot more complicated than just Foxo4-p53, and if DRI upsets the XBP1u retention of FOXO4, then that would be disastrous to normal cells.

I've also read that senescent cells could theoretically serve a structural placeholders, which without, we would end up with swiss cheese tissues (that's a bad thing, especially in the context of endothelial tissue in the vascular system... think dissection/rupture).

I agree that more research is required. This is why Cleara Biotech is advancing the FOXO4-p53 technology from a 3rd-generation research peptide (FOXO4-DRI) into 4th-generation therapeutic candidates designed for human clinical translation. Their current work centers on two lead compounds, CL04177 and CL04183, which demonstrate significantly enhanced binding to p53 in senescent cells compared to the original FOXO4-DRI.

Just stuff to keep in mind.

Wow, i appreciate the knowledge here. I certainly wasnt aware of newer generation peptides from Cleara Biotech. And yes, by prohealing i do mean angiogenic which is progrowth. I also think things like IGF1-LR3 also fall into that category.

In any case, you seem very well versed in the biochemistry of it all. Im looking forward to seeing what Cleara does with their pipeline. Hopefully their candidates go to phase I/II trials and well get more data on dosage, toxicity and stuff.

Thanks for your input!

 

[Researcher6076]

not all healing compounds are carcinogenic. Keeping inflammation down is a good way to protect oneself from cancer, and that can be achieved using several peptides, including KPV and MT-1. I notice you wrote 'melanotan', but I think you mean MT-2. This one kicks up your HR and BP because it affects more than MC1R (melanocortin receptor 1) and instead attaches to MC1, MC3, MC4, and MC5. Strict MC1R activation is associated with good things . Even BPC-157, I'm on the fence about this one. I think what you mean to say is not 'pro-healing' which is good, but angiogenic, ie. promoters of vascular differentiation, creating new blood vessels, which in turn could feed existing tumors.

FOXO4 is involved in a lot more than just binding p53 folks. It's normally bound by XBP1u in the cytoplasm, and is driven by PDGF-BB, TNF-α, angiotensin II, mechanical and oxidative stress, which are pathological signals. It also interacts directly with myocardin and inhibits smooth muscle contractile gene expression, which is not a good thing. My point is that its a lot more complicated than just Foxo4-p53, and if DRI upsets the XBP1u retention of FOXO4, then that would be disastrous to normal cells.

I've also read that senescent cells could theoretically serve a structural placeholders, which without, we would end up with swiss cheese tissues (that's a bad thing, especially in the context of endothelial tissue in the vascular system... think dissection/rupture).

I agree that more research is required. This is why Cleara Biotech is advancing the FOXO4-p53 technology from a 3rd-generation research peptide (FOXO4-DRI) into 4th-generation therapeutic candidates designed for human clinical translation. Their current work centers on two lead compounds, CL04177 and CL04183, which demonstrate significantly enhanced binding to p53 in senescent cells compared to the original FOXO4-DRI.

Just stuff to keep in mind.

I am absolutely watching the fascinating biology in the senescence research space. I think there are real potentials for longevity, possibly cancer, and other unexpected areas. I think the key may be to narrow down the targeting so the therapies can just allow the senescent cells we want to die die.

 

[trojanpeptide]

I also think things like IGF1-LR3 also fall into that category.

IGF1 is related to mTOR activation, which is growth signalling. It's hyperactivation is associated with bad outcomes such as cancer, neurological disorders, and metabolic diseases.

mTOR stands for mammalian target of rapamycin ; that's where rapamycin comes in, as a quencher of this growth cascade.

I am absolutely watching the fascinating biology in the senescence research space. I think there are real potentials for longevity, possibly cancer, and other unexpected areas. I think the key may be to narrow down the targeting so the therapies can just allow the senescent cells we want to die die.

did u catch that article i shared a couple days back? You might like those newer mouse studies.

 

[Researcher6076]

TY

not all healing compounds are carcinogenic. Keeping inflammation down is a good way to protect oneself from cancer, and that can be achieved using several peptides, including KPV and MT-1. I notice you wrote 'melanotan', but I think you mean MT-2. This one kicks up your HR and BP because it affects more than MC1R (melanocortin receptor 1) and instead attaches to MC1, MC3, MC4, and MC5. Strict MC1R activation is associated with good things . Even BPC-157, I'm on the fence about this one. I think what you mean to say is not 'pro-healing' which is good, but angiogenic, ie. promoters of vascular differentiation, creating new blood vessels, which in turn could feed existing tumors.

FOXO4 is involved in a lot more than just binding p53 folks. It's normally bound by XBP1u in the cytoplasm, and is driven by PDGF-BB, TNF-α, angiotensin II, mechanical and oxidative stress, which are pathological signals. It also interacts directly with myocardin and inhibits smooth muscle contractile gene expression, which is not a good thing. My point is that its a lot more complicated than just Foxo4-p53, and if DRI upsets the XBP1u retention of FOXO4, then that would be disastrous to normal cells.

I've also read that senescent cells could theoretically serve a structural placeholders, which without, we would end up with swiss cheese tissues (that's a bad thing, especially in the context of endothelial tissue in the vascular system... think dissection/rupture).

I agree that more research is required. This is why Cleara Biotech is advancing the FOXO4-p53 technology from a 3rd-generation research peptide (FOXO4-DRI) into 4th-generation therapeutic candidates designed for human clinical translation. Their current work centers on two lead compounds, CL04177 and CL04183, which demonstrate significantly enhanced binding to p53 in senescent cells compared to the original FOXO4-DRI.

Just stuff to keep in mind.

for this. I will incorporate some additional FOX)$ known unknown risks in my notes!

 

[trojanpeptide]

TY

for this. I will incorporate some additional FOX)$ known unknown risks in my notes!

u know, theres a guy, Steve Combi, who says he uses FOXO4-DRI, I think maybe a lot ? idk for sure, might be worth reading his threads. Here's a link.

 

[AlexSilver]

u know, theres a guy, Steve Combi, who says he uses FOXO4-DRI, I think maybe a lot ? idk for sure, might be worth reading his threads. Here's a link .

Isn't that whole thread really about how maraviroc does a similar thing? I mean that's a lot to read, will take me some time.

 

[AlexSilver]

u know, theres a guy, Steve Combi, who says he uses FOXO4-DRI, I think maybe a lot ? idk for sure, might be worth reading his threads. Here's a link .

Steve Combi is currently dosing himself with Rapamycin. Seems a lot scarier than good ol D-Retro-Inverso.

 

[trojanpeptide]

Isn't that whole thread really about how maraviroc does a similar thing?

similar, not exact, but yea, nice thread.

Steve Combi is currently dosing himself with Rapamycin. Seems a lot scarier than good ol D-Retro-Inverso.

not really, there's a lot more known about rapamycin then foxo4-dri. I've read a few of his messages; I get the impression that he's tried a lot of meds/peptide.

He explains his dosages in this link. (24mg over a 3 day = 8.0mg per day Twice a year).

 

[Researcher6076]

similar, not exact, but yea, nice thread.

not really, there's a lot more known about rapamycin then foxo4-dri. I've read a few of his messages; I get the impression that he's tried a lot of meds/peptide.

He explains his dosages in this link . (24mg over a 3 day = 8.0mg per day Twice a year).

I replied to a post there, trying to get in touch with him. I want to understand how he got to his protocol.

 

[trojanpeptide]

I replied to a post there, trying to get in touch with him. I want to understand how he got to his protocol.

yes I saw that. He should be on this site too !

But honestly, back to the original query, where do we source authentic foxo4-dri from vendors? I get a lot of different answers depending who you ask.

 

[Researcher6076]

Uther has it. Bella at HK has it. Lydia at ZJ has it, which would probably be my go to. I think I would pay to test this one. prices are not terrible considering this is a hard one to make.

 

[Researcher6076]

So if you were thinking of doing this... would you do it when you were still agining well? Or would you wait until you were showing more functional signs of aging?

 

[trojanpeptide]

So if you were thinking of doing this... would you do it when you were still agining well? Or would you wait until you were showing more functional signs of aging?

I would do it now, in my mid 50s, but I have a lot of 'damaged tissue' as is.

 

[trojanpeptide]

It looks like we got those guys started up again in that thread I posted. Good source of information. Now I really want to order some FOXO4-DRI.