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Dasatinib group buy from Nyles

dasatinib senolytic senescent scenescent cells sasp senolytics group buy

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#601 Iuvenale

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Posted 05 May 2017 - 08:04 PM

 

I got shingles from this protocol. I've never gotten it before.

Waiting patiently for it to pass and hoping I don't get post-herpetic neuralgia. Taking lemon balm, beta glucans, and lactoferrin.

I guess we need those white blood cells after all.


That's interesting. Were you diagnosed with shingles?

 

No, I waited too long to benefit from medications. I also didn't want it on my medical record, given the current political state. However, it matched the pictures and symptoms on the web perfectly. So, not certain, but pretty certain.



#602 The Capybara

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Posted 05 May 2017 - 08:07 PM

I really have to chime in on this topic....

 

I've used topical dasatinib and quercetin mixed with a detergent to facilitate diffusion into the deeper layers of the skin. I'm certain a small, probably insignificant, amount was absorbed systemically. This was a very strong solution and each time I applied it, I did so for up to 2 hours. This was done on just one arm,and I used the other arm as a control. This solution wasn't just applied in a superficial manner. I put this solution in a long veterinary exam glove that went up as far as my armpit. These gloves are used in large animal medicine.

I believe that I fully documented this experiment somewhere on Longecity.

 

As much as I hate to acknowledge it, I am middle aged and should have a decent load of senescent cells.

 

Here are my results: Nothing at all happened. My skin didn't feel smoother, look any different, lose some objective or subjective aspects of aging, and no flakes of skin fell off at all. Nothing even subtly happened. Months later, my arms are in the same condition as each other.

I don't think that this is the mix we are looking for. Big advances were made with the Foxo4-dri peptide and there is little doubt that very soon more targeted senolytics will arrive.

 

In conclusion I would tell you that we must all be pragmatic about what's out there and available.

There is no reason to harm yourself in the pursuit of health and longevity. That is the opposite of everything we are about.

I give you credit for having the courage to use yourselves as guinea pigs, but I would hold off for a bit.

 

I also want to chime in quickly about some of the advice that's been posted. We have no clue what the best conditions are for taking this mixture. Some advice postings seem to have a aura of authority, but are based on speculation (even if there is some potential logic there). More often than not, those most knowledgeable are wrong, and unanticipated outcomes are more the rule than the exception for any novel compound.

 

Carry on.

 

 


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#603 sthira

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Posted 05 May 2017 - 08:33 PM

I got shingles from this protocol. I've never gotten it before.

Waiting patiently for it to pass and hoping I don't get post-herpetic neuralgia. Taking lemon balm, beta glucans, and lactoferrin.

I guess we need those white blood cells after all.

That's interesting. Were you diagnosed with shingles?
No, I waited too long to benefit from medications. I also didn't want it on my medical record, given the current political state. However, it matched the pictures and symptoms on the web perfectly. So, not certain, but pretty certain.

I think I'm on the same boat with you here. Although I've never had shingles, I'd been fasting a lot prior to taking one dose of 140mg D + 400mg EMIQ. So my immunity was down and then I was in a salt marsh and severely bitten by some blood-sucking species of Ceratopogonidae, biting midges. I swelled horribly and biologist colleagues were concerned about anaphylactic shock.

Shortly thereafter I developed a rash on both shoulders and chest, but I'm unsure if it's shingles. I suspect so. I'm watching the tip of my nose.

Do you experience tingling?
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#604 shadowhawk

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Posted 05 May 2017 - 09:07 PM

I got shingles from this protocol. I've never gotten it before.

 

Waiting patiently for it to pass and hoping I don't get post-herpetic neuralgia. Taking lemon balm, beta glucans, and lactoferrin.

 

I guess we need those white blood cells after all. 

I got shingles after a very stressful time.  Once you get them they seldom come back.  You can get a vaccine. 


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#605 Iuvenale

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Posted 05 May 2017 - 09:39 PM

I didn't feel tingling. It feels like the skin sensations when you have a high fever, and now has morphed into a feeling like I have an abrasion.

One of the hallmarks of shingles is that is only on one half of your body, along a band which follows a nerve pathway. So if you feel it on both sides, it's probably not shingles.
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#606 sthira

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Posted 05 May 2017 - 10:53 PM

Taking lemon balm, beta glucans, and lactoferrin.

I guess we need those white blood cells after all.


Are these working? Your thinking is to boost the immune system?

#607 Iuvenale

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Posted 08 May 2017 - 07:16 PM

 

Taking lemon balm, beta glucans, and lactoferrin.

I guess we need those white blood cells after all.


Are these working? Your thinking is to boost the immune system?

 

 

Shingles are gone now. Lemon balm is anti-herpetic and beta glucan and lactoferrin boost the immune system.



#608 Nate-2004

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Posted 14 May 2017 - 02:14 AM

So I tried mixing Quercetin with 99% DMSO with a small amount of water to dilute. I put about 1200 mg in there and mixed it in, used a dropper and put some of it (no where near all of it) under my tongue and held it there for a couple of mins. 

 

I felt nauseous a few mins later for about 45 mins. Not sure what that means. The nausea is gone mostly now though.



#609 Ark

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Posted 14 May 2017 - 09:22 AM

So I tried mixing Quercetin with 99% DMSO with a small amount of water to dilute. I put about 1200 mg in there and mixed it in, used a dropper and put some of it (no where near all of it) under my tongue and held it there for a couple of mins.

I felt nauseous a few mins later for about 45 mins. Not sure what that means. The nausea is gone mostly now though.


Careful!

#610 Valijon

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Posted 14 May 2017 - 11:24 PM

Could be the dmso. Dmso always made me ill. I no longer use it at all.

#611 Rocket

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Posted 23 May 2017 - 01:16 AM

Well, this topic died a sudden death.

#612 Nate-2004

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Posted 24 May 2017 - 01:29 PM

Well? I think because A: If Dasatanib did anything for us it wasn't noticeable and B: Q isn't bioavailable at all in its senescent cell clearing form. 

 

On the other hand I fasted 72 hrs last week and after a week of food since then my skin is starting to look really good. 

 

I might try it again with dasatanib and sublingual Q with DMSO but I don't think there's much use in it till we can get our hands on more targeted drugs like this FOXO4 one. Hoping to see some good results from the study we recently funded but it'll be years before we see any drug options I'm sure. Hopefully I can stave off and slow aging till then.


Edited by Nate-2004, 24 May 2017 - 01:30 PM.


#613 Junk Master

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Posted 24 May 2017 - 02:48 PM

Been following this one from the beginning.  Sure seemed to be right at the frontier, but now the consensus seems to be wait for FOXO4, huh.  

 

For some reason I kept comparing this approach to Lance Armstrong's remarkable rebuilding/reshaping post chemo.  

 

Going forward a combination of fasting, exogenous ketone esters, "micro-doses" of targeted drugs to remove senescent cells;  and, either a regular routine of sauna, or a form of exogenous heat shock protein really seems quite promising for those of us more into "healthspan" then straight longevity.

 

Add responsible HRT, regular blood work, custom peptides to aid healing from injury, spun platelets, and placental stem cells, I believe genes, money, effort, and knowledge are the only barriers to extending healthspan decades longer already.

 

Great thread.



#614 Valijon

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Posted 24 May 2017 - 02:59 PM

JunkMaster, what you say is right on regarding many things. I've poured a serious amount of time into research on various substances our Dasatanib buy was a shot in the dark. Just one of many that we will take in our quest to increase both health and life span. I feel our most promising substances at the moment are rapamycin, metformin, and potentially things that increase NAD+ or increase SIRT 1 inhibition.

New substances and knowledge are always on the horizon.
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#615 Rocket

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Posted 24 May 2017 - 04:02 PM

Well? I think because A: If Dasatanib did anything for us it wasn't noticeable and B: Q isn't bioavailable at all in its senescent cell clearing form. 

 

On the other hand I fasted 72 hrs last week and after a week of food since then my skin is starting to look really good. 

 

I might try it again with dasatanib and sublingual Q with DMSO but I don't think there's much use in it till we can get our hands on more targeted drugs like this FOXO4 one. Hoping to see some good results from the study we recently funded but it'll be years before we see any drug options I'm sure. Hopefully I can stave off and slow aging till then.

 

What do you expect to happen to you at 40 years old? Or even 50 for that matter as many here are? In your 40s and 50s you don't have that many senescent cells and you are not going to "reverse" age since most of your issues at 40 and 50 are from not taking care of yourself by poor diet and little to no exercise including cardio and weight training and other poor lifestyle choices and leading stressful lives.

 

40s and 50s are not "old" if you take care of yourself from the beginning. Clearing senescent cells is like icing on the cake and it's buying you a healthier "old" age if you keep at it.

 

No one should expect to rejuvenate when they are only in the 40-50 age range. If you want that to happen, get a healthy diet, start doing HIT cardio, and start lifting weights. Not only will it help your body, but it will help your brain as well!

 

I know for a fact there are people in their early 30s taking this drug.... what do they honestly expect to happen!?

 

This is one part of the greater whole that will improve lives as they age, and to go "Awe shit, I still feel like I'm 40 years old, what a waste of time!" is an easy trap to fall into when you expect miracles.


Edited by Rocket, 24 May 2017 - 04:10 PM.

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#616 Nate-2004

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Posted 24 May 2017 - 04:54 PM

You're being awfully presumptuous that I've not been taking the best care of myself as possible over the past 20 years. I do look "young" for my age but nobody's genuinely mistaking me for a guy in his 20's, not anymore at least. Something happened around 39 or 40 where that kind of thing just stopped happening. Maybe it was the grey hairs, but perhaps it was more. While, aside from lower back pain (which has diminished with special stretching exercises) I don't *feel* older, but I do look older, not because I haven't been taking good care of myself, but because slowing aging much less reversing it just doesn't stop the bone and subcutaneous fat loss in the face. If I smile, I have deep wrinkles, if I'm not smiling, I don't, but I have dark circles that show up, especially in 4k video. Note that I've been using moisturizers with retinol for years, I've stayed out of the sun for the majority of my life, I have been exercising at least 3 times a week (now 4) consistently for the better part of 15 years. 

 

Taking good care of yourself doesn't stop or reverse grey hairs on my beard or hair.

 

I'll be removing these soon but just temporarily I'll show you what I mean. I'm not complaining, and I'm not trying to be vain here, just trying to prove a point because I keep hearing this from people who think I shouldn't be expecting so much at 40. We're about rejuvenation and curing aging here, not just about slowing age. Do I wish I had all the knowledge I have today from this site 12 years ago? Hell yeah, but we can only do so much with the information we have.

 

Here's a couple of recent pictures of me not smiling, this is a selfie:

 

https://dl.dropboxus.../notsmiling.jpg

 

However, this one is from a sketch comedy video filmed in 4k:

 

https://dl.dropboxus...ages/sketch.jpg

 

Smiling:

 

https://dl.dropboxus...ges/smiling.jpg

 

Here's what I wanna look like again, smiling at 29 years old:

 

https://dl.dropboxus...Images/me_1.jpg

 

https://dl.dropboxus...es/mcelroys.jpg

 

 

 

 

 

 

 


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#617 Heisok

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Posted 24 May 2017 - 06:18 PM

Not about anybody specific, but I tend to agree with some of what Rocket says. Although, would being in the following situation lead to higher numbers of Senescent cells?  "In your 40s and 50s you don't have that many senescent cells and you are not going to "reverse" age since most of your issues at 40 and 50 are from not taking care of yourself by poor diet and little to no exercise including cardio and weight training and other poor lifestyle choices and leading stressful lives." Is it possible that one 40 or 50 year old might have far more Senescent cells than another? Anybody know? If some thought they woul;d reverse age, perhaps expectations are too high. I do not expect any obvious improvement, except perhaps a subtle increase in general subjective feelings of physical fitness, and the feeling of well being.

 

Junk Master, I do not know that there is any consensus related to D & Q. Is there?

 

Nate, great news about your fasting benefits!

 

 


Edited by Heisok, 24 May 2017 - 06:22 PM.


#618 Andey

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Posted 24 May 2017 - 06:45 PM

We're about rejuvenation and curing aging here, not just about slowing age. Do I wish I had all the knowledge I have today from this site 12 years ago? Hell yeah, but we can only do so much with the information we have.

 

Here's a couple of recent pictures of me not smiling, this is a selfie:

 

 

   You look very healthy, but you are right, there is something intangible that does not allow to judge you as 20-25 yo. Realistically, I havent seen anybody who looked like 20-25 in their 40s. 

As for slow aging vs rejuvenation, lets no fool ourselfs. So far nothing in science was proven to rejuvenate mice let alone human. 

Only hints Ive seen is in the dr Longo work on FMD and pancreas.



#619 mikey

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Posted 24 May 2017 - 06:54 PM

D&Q definitely reduced my blood pressure, which has stayed lower. I noticed the lowered BP a couple weeks after using it, twice.

 

However, I won't use it again, as about five weeks after using it there are some new crevices in my face that were not there. The collagen in my face is extremely healthy. I look maybe 15-20 years younger than my two siblings.

 

I watch facial collagen/wrinkles as a good external barometer of my overall metabolism, so I am quite tuned into changes.

 

I didn't get the "gaunt" look that I've heard people talk about here, though.
 

I will wait a few years for a completely safe senescent agent. Maybe when the price of FOXO4-DRI comes down.


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#620 Rocket

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Posted 24 May 2017 - 07:07 PM

You're being awfully presumptuous that I've not been taking the best care of myself as possible over the past 20 years. I do look "young" for my age but nobody's genuinely mistaking me for a guy in his 20's, not anymore at least. Something happened around 39 or 40 where that kind of thing just stopped happening. Maybe it was the grey hairs, but perhaps it was more. While, aside from lower back pain (which has diminished with special stretching exercises) I don't *feel* older, but I do look older, not because I haven't been taking good care of myself, but because slowing aging much less reversing it just doesn't stop the bone and subcutaneous fat loss in the face. If I smile, I have deep wrinkles, if I'm not smiling, I don't, but I have dark circles that show up, especially in 4k video. Note that I've been using moisturizers with retinol for years, I've stayed out of the sun for the majority of my life, I have been exercising at least 3 times a week (now 4) consistently for the better part of 15 years. 

 

Taking good care of yourself doesn't stop or reverse grey hairs on my beard or hair.

 

I'll be removing these soon but just temporarily I'll show you what I mean. I'm not complaining, and I'm not trying to be vain here, just trying to prove a point because I keep hearing this from people who think I shouldn't be expecting so much at 40. We're about rejuvenation and curing aging here, not just about slowing age. Do I wish I had all the knowledge I have today from this site 12 years ago? Hell yeah, but we can only do so much with the information we have.

 

Here's a couple of recent pictures of me not smiling, this is a selfie:

 

https://dl.dropboxus.../notsmiling.jpg

 

However, this one is from a sketch comedy video filmed in 4k:

 

https://dl.dropboxus...ages/sketch.jpg

 

Smiling:

 

https://dl.dropboxus...ges/smiling.jpg

 

Here's what I wanna look like again, smiling at 29 years old:

 

https://dl.dropboxus...Images/me_1.jpg

 

https://dl.dropboxus...es/mcelroys.jpg

 

My best friend was going gray at 22 when we were in college. I don't think gray hair is a good measure of how well or unwell a person is aging. Now that I think about it, my 19yo girlfriend in college had a few gray hairs that she would pluck out. Gray hair means nothing.

 

There is also a difference in exercising versus training. Most people exercise and slowly go backwards or never progress. You have to push yourself like with HIT training that I mentioned specifically for a reason. I'm just saying most people in the 40s and 50s are where they are physically because they never put the time and effort into being better. I'm not judging you Nate, just making my observations about my peers now that I'm a 40-something.

 

 

 


Edited by Rocket, 24 May 2017 - 07:15 PM.

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#621 sthira

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Posted 24 May 2017 - 07:23 PM

I guess we at any age wouldn't really know how many senescent cells we might have, unless we get a skin biopsy or somehow could test directly or, like, maybe join a clinical study (btw, did you read Reason's helpful post on self experimenting with senescent cell clearance, it's a good read: https://www.fightagi...rug-candidates/)

His comments are on target even if we find this entire field discouraging in general, and discouraging in particular. It's difficult to self experiment when we're in the dark mostly (and due to other obvious factors of lack of money, no support, and limited access to potentially dangerous substances).

Also, do we even know with assurance that this white powder that showed up is indeed dasatinib? We wouldn't be the first suckers in the history of the world.

It's hard to be a mindful human, isn't it, facing reality here in these times when we are promised future treatments (by clickbait sites telling us exaggerated lies?) and we have nothing practical to do or try that'll slow inevitable aging. CR? Fasting? Senescent cell clearance? Rapamycin and metformin mixtures? I mean, we who are attentive to this business of slowing or halting aging are vulnerable to mythologies. Our vulnerabilities are why the supplement and cosmetic industries are booming, of course -- nearly everyone wants to no CVD or cancer or aging joints, sagging skin, thinning hair -- we all seek to slow aging and reverse the cruelties of nature.

Eventually it'll happen -- damage repair and aging reversals. But one thing that seems clear is that a healthy, deliberate, intelligent, consistent lifestyle alone, while important, just isn't going to do it. So we're faced with aging to death despite our best efforts, or being edgy and experimental -- at risk to ourselves.

It's also discouraging to keep hearing the mantra of "Fund SENS" when doing so clearly doesn't seem much help either. Am I ignorant? They need billions of dollars, and frankly my little $50 contribution seems a little sad.

I'll stop whining. But hey, at least we have this forum to vent frustrations. We had this place ten, 15 years ago, too, and if you reread older posts, not much appears to have changed between then and now.

Nate, great news about your fasting benefits!


I agree! Celebrate at least this, and keep trying. Maybe fasting once per month like Longo suggests is something we can work on and attempt. Combine fasting with a vegetable filled diet as we try not to harm ourselves here in the dark times.
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#622 Heisok

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Posted 24 May 2017 - 08:04 PM

"However, I won't use it again, as about five weeks after using it there are some new crevices in my face that were not there. The collagen in my face is extremely healthy. I look maybe 15-20 years younger than my two siblings.I watch facial collagen/wrinkles as a good external barometer of my overall metabolism, so I am quite tuned into changes." Mikey, just to clarify, you do not think it is related to collagen?

 

Rocket, thanks for your persistance. For me at this stage, restarting HIIT would likely have a huge benefit. I believe in it.

 

sthria, great points, and especially agree with this: "Our vulnerabilities are why the supplement and cosmetic industries are booming, of course -- nearly everyone wants to no CVD or cancer or aging joints, sagging skin, thinning hair -- we all seek to slow aging and reverse the cruelties of nature."  My only solution for facial structure loss which resulted in RBF (What the ladies at my wifes work refer to as" resting b@##$ face" due to looking pissed off in spite of not being angry), was to grow a mustache.. LOL.

 

Back to scary D & Q side effects some reported. Have more had shingles symptoms?


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#623 Nate-2004

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Posted 24 May 2017 - 08:43 PM

I donate $50 here and there to SENS but I can't ever get anyone I know to donate even $10 much less $50. It's sad, everyone demands science funding from the government but they won't put their own money where their mouth is. It's all about taking from others by force, or funding it with money already taken from you by force to fund outrageous wars or poverty entrapment systems. It's sad for sure. I'd love to find some way to get people to give money.


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#624 Junk Master

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Posted 24 May 2017 - 11:24 PM

Not to get off topic BUT when it comes to exercise we really need to be more specific-- looks or functionality.  Also, I love me some HIT, BUT the longevity model for lifting should be much more akin to elite endurance athlete models 80/20...with 80% of their workload done mainly to speed recovery.  That's not even touching the surface of periodization, cardio...and HRT...

 

Realistically, HIT lifting 3-4 days a week without HRT past 45-50 is playing the Russian Roulette injury game.  The caveat being the gift of great genes.

 

Now AAARRNNOLD and STALLONE are so "enhanced," in so many ways they are inhuman compared to "us."  Plus, if they get injured they think nothing of a series of placental stem cell injections at $10,000 a stick.


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#625 sthira

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Posted 24 May 2017 - 11:47 PM

Also off topic, but what the hell, we're all friends here and so I'll chime into the exercise diversion and recommend dance -- just not professionally haha or it'll fuck you up royally. But casual dance in any form will work your entire body, your brain and your smile and sense of confidence included. It works strength, flexibility, poise, posture, grace, and it's really good for your brain. Watch people when they dance, they smile, they laugh, they giggle, they let go, they initially think they're awkward, no good at it -- but to dance is our birthright. It feels so ancient.

Yoga is awesome, too, it works the same bodywide muscles and tends to elongate fascia, and it calms you down, draws you inside, helps you focus on breathing. And yoga can kick your ass, too, there are some extremely inspiring people of ALL AGES who excell. Also putting your body into strange, awkward positions like inversions -- handstands, headstands, shoulder stands, even just legs up the wall, and backbends OMG they also works the mind.

The great thing about dance and yoga is they're non-competitive, too, and no one is judging you on how far your body can or cannot go. We're all in this damned aging mess together. Yogis also tend to lean toward a plant based diet, not all yogis, of course, but healthy vegetarianism is common amongst some very healthy folks.

But again, I don't think any amount of ultra purity of lifestyle will repair ultimate damages of aging. The cure is an inside job, many inside jobs, and healthy lifestyle is crucial but we're all aging right on schedule unless better methods are developed.
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#626 Valijon

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Posted 25 May 2017 - 12:17 AM

My endocrinologist put me on trt a few years ago. Cleared up some of the worst of my depression and anxiety. 200mg test cyp and 1mg a day of arimadex. Feeling like the king these days.

#627 Rocket

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Posted 25 May 2017 - 01:04 AM

My endocrinologist put me on trt a few years ago. Cleared up some of the worst of my depression and anxiety. 200mg test cyp and 1mg a day of arimadex. Feeling like the king these days.

That's an irresponsible protocol you are on! Totally irresponsible.
200mg of testosterone a week is not replacement, its a minimal dose for anabolic effects and will put your levels so high it will be off the scale. Not to mention what it will do to your red blood cell count so that needs to be monitored... Liver enzymes need to be monitored.

And 1 mg adex on only 200mg of testosterone will drive your estrogen levels to nothing and will impact your lipids negatively.

When I run 750mg of testosterone on a cycle, 0.5mg adex keeps my estrogen at optimal levels. A full milligram of adex on 200mg of test is way overkill. What is your estrogen level, zero? A half a milligram 3x a week is more responsible.

Whoever your doctor is, is a quack. You may feel good but you're harming your body. You feel good because your doctor put you on a crappy, very crappy, permanent steroid cycle. I feel great when I am on a cycle but the point is you have to cycle on and off because you're harming your body.

You're probably not even lifting and eating an anabolic diet to reap the rewards of being on a cycle. lol

Edited by Rocket, 25 May 2017 - 01:12 AM.


#628 Valijon

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Posted 25 May 2017 - 01:29 AM

Total test was around 1000 a few days post injection. I don't remember e2, alt or last but, he said they r good.

#629 Valijon

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Posted 25 May 2017 - 01:33 AM

I take the adex whenever I feel hot and angry. I think it has something to do with too much estrogen and vasodilation. Is this correct?

#630 jmorris

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Posted 25 May 2017 - 05:30 AM

Hello all,
 
There have been few times in my life when I have wanted something so much and been so unable to get it. Let me tell you, I really want navitoclax. I mean, I really want navitoclax. To regular readers of this space, there is no need to elaborate why.
 
But for now at least, I can't have it. Accepting this idea has been difficult.
 
The problem is one of cost. Navitoclax is a mighty big molecule. It's unusually large for a for anything normally considered a "drug". Because of this, per gram it is typically available for $1000 to $1200. While I can theoretically afford this, it's not something that would be comfortable for me, especially if I wanted to experiment with it more that a couple times per year.
 
Logic has already investigated a group buy. (Thank you for that.) This brings the price down a bit, which is good, but not good enough. Unfortunately, the minimum order for such a synthesis purchase seems difficult to accomplish at this price. I am still hopeful that this group buy will happen but I'm not going to hold my breath.
 
So how to solve? What is the next step? I have spent a great deal of time over the last month trying to figure this out. Below, I am going to enumerate the various choices that I've wrestled with and weigh them here for your entertainment and edification. Note that my goal and the purpose of this list is specifically to kill or silence senescent cells. I realize that there are many other options (TOR, etc) and don't wish to disparage them by act of omission. If you are short on time, please skip to the end to item #8 for my conclusions and a possible group buy proposal that I hope you will consider.
 
The Options:
 
1: Wait for the navitoclax group buy to happen (i.e. Do nothing but wait.):
As I mentioned above, I'm still hopeful that Logic can make it happen but it might be quite a while so I am going to say no to this option.
 
2: Wait for navitoclax to be commercialized for our purposes:
A company named Unity Biotech has sprung up to do exactly this. They have renamed it UBX0101.
 
Jeon, O.H., Kim, C., Laberge, R.-M., Demaria, M., Rathod, S., Vasserot, A.P., Chung, J.W., Kim, D.H., Poon, Y., David, N., et al. (2017). Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med.
 
Unfortunately, they still have to go through all the steps of getting it approved just like any company. In the best of cases it will be years before we have a pill to take. I can imagine that they are going to be setting the price point very, very high. 
 
Question: If you started a company selling a drug that would only need to be taken once a year, what would you price it at? What if that drug was not to cure a disease but to sell to rich people who did not want to get old?
 
Answer: I would price what the market would bear. $50,000 per treatment? $80,000? The sky is the limit.
 
For now not an option.
 
3: Get a group buy together for the FOXO4-DRI drug:
Baar, M.P., Brandt, R.M.C., Putavet, D.A., Klein, J.D.D., Derks, K.W.J., Bourgeois, B.R.M., Stryeck, S., Rijksen, Y., Willigenburg, H. van, Feijtel, D.A., et al. (2017). Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell 169, 132–147.e16.
 
I have news for all of you waiting for FOXO4-DRI to become available. If you think navitoclax is expensive just wait for how much this one is going to cost:
 
Here is the sequence:
GSHMLEDPGAVTGPRKGGSRRNAWGNQSYAELISQAIESAPEKRLTLAQIYEWMVRTVPY
 
61 D-amino acids. Going rate is $55/residue for 100mg @98% purity. That's $3355 for 100mg. And that's a good deal.
 
Peptide synthesis is a mature, highly competitive business. This price is not likely to come down unless a major pharmaceutical company decides to make it giant reactors. Unless you know someone at the factory with sticky fingers, it's going to be expensive.
 
Not an option for now.
 
4: Buy a used peptide synthesis machine and make some FOXO4-DRI myself:
I can see some reasonably prices machines for sale right now at less than $3000. But the machine is not the problem. It's two things: the cost of reagents and the purification. Getting the crude peptide purified at large scale is a huge pain. This is why the markup is so high going from crude peptide ($2/amino acid) to 98%+ ($55/amino acid). In a past life used to purify solid phase synthesis nucleic acids, which are similarly synthesized. It's easy at a few milligrams because you can use HPLC (not that I have one of those right now anyway) but as you go up, the equipment gets expensive fast.
 
I'm not going to rule this option out but I don't want to try with limited equipment and money. 
 
4: Wait for the FOXO4-DRI drug to be commercialized:
Again, years of waiting. Plus, the economics of the price are unlikely to change magically. See #2 above.
 
Not an option for me right now.
 
5: Intravenous quercetin:
Starting to feel desperate here... If I can't have anything else, well then fine. Can I make I.V. quercetin work?
 
This first thing is getting it to dissolve. It's pretty much insoluble, which is why these researchers in the phase I trial used DMSO. But I know something now that they didn't: Beta cyclodextrin greatly increases the solubility of quercetin:
 
Jullian, C., Moyano, L., Yañez, C., and Olea-Azar, C. (2007). Complexation of quercetin with three kinds of cyclodextrins: an antioxidant study. Spectrochim Acta A Mol Biomol Spectrosc 67, 230–234.
 
But what about the dosage? Look here for that info:
 
Ferry, D.R., Smith, A., Malkhandi, J., Fyfe, D.W., deTakats, P.G., Anderson, D., Baker, J., and Kerr, D.J. (1996). Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin. Cancer Res. 2, 659–668.
 
From the paper above, it looks like the dose-limiting side-effects are severe nausea and kidney damage. (Yay!)
 
From page 662, it looks like severe vomiting start at about 630 mg/m^2 which for me is 1209mg. Renal toxicity starts at that point too so I would need to stay as far under 1200mg as possible. (Note that even close to this dosage would involve chemotherapy level nausea.) 
 
Okay, now that I know what dosage I want to avoid, how much do I actually need to be effective?
 
On page 667 it says the 50% effective concentration is someplace in the range of 1 to 10 micromolar. Of course no one takes drugs at the EC50. You would need to be higher than that, probably quite a bit higher since drug-receptor binding is not linear.
 
But then here is the bad news: 
"At doses above 630mg/m^2 [1200mg for me], quercetin plasma levels where in excess of 1 micromolar for at least 3 hours."
 
Crap. These numbers don't work. To get to a therapeutic dose, I would have to be in severe vomiting and renal toxicity range for like eight hours. This would meaning involving not just one bolus injection but a drip. Sounds like torture to me and a possible death sentence if I'm not careful.
 
Nope. Forget that terrible idea. No way I'm doing IV quercetin. (And before you click "Dangerous, Irresponsible" re-read the previous sentence. I am not going use I.V. quercetin.
 
6: Synthesize navitoclax myself:
Attached File  Navitoclax.svg.png   43.14KB   4 downloads
 
Yeah, I'm a chemist, among other things. However, there is no way I want to macro-scale synthesize this entire thing in my "spare" time. It's too daunting to think about while still needing to work at my main job and keep all my other projects alive. 
 
But how about something smaller?
 
7: Synthesize part of navitoclax to help reduce the price:
 
Retrosynthetic analysis of navitoclax gives us three main pieces:
 
Attached File  Nav piece 1 redo.png   310.75KB   5 downloadsAttached File  Nav piece 2.png   15.95KB   5 downloadsAttached File  Nav piece 3-2.png   63.92KB   5 downloads
 
Here are my synthetic goals:
    No reactions needing chromatography.
    No air sensitive reagents or schlenk lines.
    As few expensive reagents or solvents as possible.
    Extend synthesis all the way back to cheap raw materials.
 
I started thinking about making just piece III above. I was only half serious about the idea but after a few days reading and sketching ideas, I had something that looked pretty workable. A while later I spent another couple days and made it even better. Astrazeneca has a patent where they do it in eight step at only 6% yield (US2012/0035134 A1). Abbvie does it in 19% overall yield (US2005/272744 A1). I also found a Chinese patent that claims 24%. By combining all these along with some other reactions I changed to meet the goals listed above, I think I can do it in seven steps at someplace around 40-45% yield starting from D-aspartic acid (cheap) if I don't screw up. How can I achieve a better yield than the patent? I can combine reactions from multiple patents and other literature in ways these patent writers legally cannot.
 
Next I moved on to piece I. This one looks bigger but I think it's actually easier. I think I can do this in seven steps starting from para-cresol (fairly cheap). The fun part is that I think I can get derive the benzyl rings almost completely from para-dicholobenzene (very cheap). There would be some amount air-sensitive steps but they are manageable the way I have it planned.
 
I'm not going to bother with piece II. It would involve large scale chromatography to separate out various product isomers and I can't envision doing that at home. Too messy, too expensive.  
 
In any case, I'm guessing it would take at least 6 months each of spare time to do these at large quantity. Some of my loved ones over the years seemed to think that chemistry is like waving a magic wand over something and poof! Nope, actually, it's a lot of work, especially when you don't have all the right equipment and space. But, after putting almost two weeks of effort doing synthesis planning, I have to at least try one of them, maybe just for the fun of it, so I've started to slowly assemble the items I need. 
 
Nonetheless, I am back at playing the waiting game, even if it's waiting for myself.
 
8: Use a senotherapeutic rather than a senolytic:
 
This is the choice that I have struggled over more than any other and the one I most want to start a discussion about. Here is the story: A few years ago before I ever heard of navitoclax, dasatinib or Longecity I was obsessed with the SASP (Senescence-Associated Secretory Phenotype) and "inflammaging". I spent nearly all my free time researching it for what was about a year. As a reminder, here is the basic sequence:
 
After cells are damaged or reach their division limit this triggers two parallel pathways:
A) p19ARF is activated -> p53 is activated -> p21 is activated -> CDK2 is blocked -> the cell cycle is stopped.
B) p16INK4a is activated -> CDK4 and CDK6 are blocked -> the cell cycle is stopped.
 
Along with this change in the cell cycle, the cells start pumping out inflammatory cytokines. What follows is an inflammatory chain reaction with IL-1alpha being the initiator and IL-6 causing the most damage and sustaining a viscous cycle.
 
Campisi, J., Andersen, J., Kapahi, P., and Melov, S. (2011). Cellular senescence: a link between cancer and age-related degenerative disease? Semin Cancer Biol 21, 354–359.
 
At the time I realized that if I could somehow block IL-6 then maybe I could interrupt or slow down aging. Unfortunately, there are still no small molecule inhibitors of IL-6 receptor. However, there are inhibitors of its downstream signal transducer, Janus kinase 1 (JAK1). Most notably Jakafi (Ruxolitinib) and Xeljanz (Tofacitinib). Sadly, these drugs have dose-limiting side effects due to the fact that they are not selective for JAK1, affecting JAK1/JAK3 and JAK1/JAK2 respectively. At this point I started looking really hard for a selective JAK1 inhibitor. The first one that was publicized was from a European pharmaceutical research company called Galapagos. At the time it was called GLPG0634 but is now is goes by Filgotinib . At the time there was no structure available so I just kind of watched and waited.
 
In the meantime, my hypothesis about JAK1 and IL-6 was confirmed. Check out the following articles:
 
Xu, M., Tchkonia, T., Ding, H., Ogrodnik, M., Lubbers, E.R., Pirtskhalava, T., White, T.A., Johnson, K.O., Stout, M.B., Mezera, V., et al. (2015). JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. PNAS 112, E6301–E6310.
 
In the above paper, they show, ruxolitinib reduces frailty even in very old mice.
 
Xu, M. et al. (2016) Perspective: targeting the JAK/STAT pathway to fight age-related dysfunction. Pharmacol. Res. 111, 152–154
 
Doles, J.D., and Olwin, B.B. (2014). The impact of JAK-STAT signaling on muscle regeneration. Nat Med 20, 1094–1095.
 
Soto-Gamez, A., and Demaria, M. (2017). Therapeutic interventions for aging: the case of cellular senescence. Drug Discov. Today.
 
Xu, M., Palmer, A.K., Ding, H., Weivoda, M.M., Pirtskhalava, T., White, T.A., Sepe, A., Johnson, K.O., Stout, M.B., Giorgadze, N., et al. (2015). Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife e12997.
 
After reading one of the papers above, I decided to take a crack at synthesizing filgotinib. Due to life events, I put on the back burner. This was when I discovered Dasatinib and starting looking for a source. I stumbled across Longecity and here I am.
 
What I am proposing is a Group Buy for one of these JAK inhibitors. Since it would have to be taken every day, the following criteria would have to be met:
 
1: Lack of or limited side effects.
2: Safety established in at least Phase II studies.
3: Small enough molecule to be synthesized at reasonable cost.
4: Potent enough so that small amounts could be taken per day.
 
Right off the bat, Ruxolitinib and Tofacitinib are off the consideration because of their non-specificity for JAK1 and therefore high amount of side effects. That leaves us three drugs that are currently in development for JAK1:
 
1: Filgotinib from Galapagos/Gilead:
Dosage: 25-100 BID or 50-200 QD
 
2: Upadacitinib from Abbvie:
Dosage: 6-18mg BID
 
3: PF-04965842 from Pfizer:
Dosage: 200mg BID I think? (Not a lot of info about this drug yet. Can't remember where I saw this.)
 
Off the bat, upadacitinib looks the best. However, I've spent the last three days deciphering the Abbvie patent. In spite of being about as large as filgotinib, it's much more difficult to synthesize. 17 steps for upadacitinib while filgotinib is seven or eight, depending on how far back you go. Plus, upadacitinib is optically active (chiral), which make the synthesis even more difficult. (And as I've said before, cost does not grow linearly with steps, it's exponential.)
 
Here is the Abbvie patent if you are interested:
Voss, J.W., Camp, H.S., and Padley, R.J. (2015). Jak1 selective inhibitor and uses thereof. US20150118229 A1
 
I think upadacitinib is the best one without considering price. It's about 5X more potent than filgotinib but unless it's less than 5x more expensive per gram which I doubt, I would maybe recommend filgotinib.
 
A years supply of filgotinib would be something like 18-36 grams. If it's cheap that seems like a reasonable purchase, considering its about the size and complexity as dasatinib and I bought 20 grams of that stuff for very little.
 
A years supply of upadacitinib (a better drug in terms of potency and lack of side effects) would be 4.4 to 13.1 grams.
 
So that is my humble suggestion for a viable next step. It is backed by peer-reviewed research showing positive effects on aging and clinical trials demonstrating safety in humans.
 
I welcome your comments.

Edited by jmorris, 25 May 2017 - 05:38 AM.

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