848 replies to this topic

[trying2survive]

Well, I looked up the symptoms of tumor lysis and one is cramps; and I have had more muscle cramps while trying FOXO4-dri -- I didn't mention on foxo4dri.com because I thought it was a coincidence (and a very minor problem)... but could be more.

[Daniel Cooper]

Well, I looked up the symptoms of tumor lysis and one is cramps; and I have had more muscle cramps while trying FOXO4-dri -- I didn't mention on foxo4dri.com because I thought it was a coincidence (and a very minor problem)... but could be more.

 

 

Presumably you've had a longer course of treatment with this stuff than any other human on the planet.   Any obvious benefits to report?

 

I'm starting to get a little concerned that we haven't had anyone report anything semi-dramatic.  Aren't you 50ish?  I'd think that would be old enough to notice some definite improvement from killing off senescent cells.

 

It looked like you might have seen some hairloss recovery?  Has that panned out?

[trying2survive]

Yes, Foxo4-dri definitely has given me benefits. See foxo4dri.com for specifics in Bio-age, blood-work, and exercise endurance. I'm 52 now. I think my hair is about the same as after my first round which appeared to give a small improvement.

[Vantika]

This brings up a point I had made a ways back.
It seems that if FOXO4-dri pans out for people, as it did for rodents, one should at least be aware of tumor lysis syndrome.
Along the same logic, I'm a little concerned about the lack of reported side effects, albeit on the start of a very limited human trial here on Longecity. I'd think that effectiveness of this compound as well as proper dosage, might be positively correlated with certain side effects related to a cellular die off.
Mice seem far far less susceptible to tumor lysis syndrome than humans, which would argue against using the rodent studies as an argument against this concern.

 

Heh. Funny you should mention that. I was just getting ready to write a post along those lines.

 

The bottom line is that Meatsauce (to my knowledge the only one so far to have taken it) has -- I think -- developed a mild case of gout, presumably from hyperuricemia caused by tumor lysis syndrome.

 

I've been chatting with Meatsauce since jdlancaster519 mentioned running blood tests for negative side-effects a couple days ago.  It turns out he (Meatsauce) developed some joint pain (in his back, neck and ankle) shortly after his last injection, which he says is mostly only noticeable at night.

 

He initially didn't think it was related to the peptide, since apparently his bed sucks, which could explain the neck and back, and he lifts weights, so an ankle injury could have been from that. But after hashing this out with him in some detail, he's related the following facts: 1) this feels like the pain is coming from his joints themselves, not the surrounding muscle/tendons; 2) it's persisted a couple weeks, though is now subsiding; and 3) it's basically only present at night when he moves the affected joints around.

 

From what I've read, joint pain at night is textbook gout. Body temperature lowers enough to somewhat reduce solubility to allow sodium urate crystals to precipitate, thereby causing the joint pain.

 

Gout is purely my diagnosis/conjecture and hasn't been confirmed by any empirical tests.  Also, Wikipedia claims, "Two common conditions related to excess uric acid, gout and uric acid nephrolithiasis, are not features of tumor lysis syndrome."  Yet the symptoms fit, with no other obvious explanation that I can see.  Do your own  homework on this.  I've done only a preliminary analysis, and haven't really had time to dig into this thoroughly.

 

Anyway, we just figured this out two days ago.  In light of this information/speculation, I offered to write up a post warning about this possibility along with a prophylaxis protocol for tumor lysis syndrome (specifically the hyperuricemia aspect), which obviously I haven't gotten around to doing/posting yet.

 

In any event, it looks like the peptide works.

[Daniel Cooper]

Makes you wonder if people shouldn't be starting with a lower dose and ramping up, to avoid massive apoptosis in one hit.

 

I would think this would be particularly desirable in older patients that have a much higher senescent cell load.  I would think they are the ones that might get into potentially problematic lysis events.

 

 

 

 

 

 

[The Capybara]

As strange as it sounds, it is encouraging to hear about Meatsauce's side effects.

I think it's best to wait for more reports, but meanwhile those trialing this compound may want to (perhaps) read up on allopurinol used as a prophylaxis in chemo.

[Nate-2004]

Yes, Foxo4-dri definitely has given me benefits. See foxo4dri.com for specifics in Bio-age, blood-work, and exercise endurance. I'm 52 now. I think my hair is about the same as after my first round which appeared to give a small improvement.

 

What was your diet like? Did you eat or take a lot of things that curb inflammation or did you try to increase inflammation? If you read earlier in the thread there were some cited studies showing better results with more inflammation.

[trying2survive]

I didn't think about the inflammation aspect, so my eating habits were basically healthy (with junk food a only couple times / week).

[Vantika]

As strange as it sounds, it is encouraging to hear about Meatsauce's side effects.

I think it's best to wait for more reports, but meanwhile those trialing this compound may want to (perhaps) read up on allopurinol used as a prophylaxis in chemo.

 

I actually already hastily ordered some a few months ago, in anticipation of this contingency, thinking at the time, given my relatively young age, there was only a slight chance I would need it (hence the haste).

 

Now that I've started (just barely) looking into it further, it seems that febuxostat might be superior for this purpose.

[Benko]

Probably obvious, but if some sort of tumor lysis syndrome is what is happening, then people taking it should drink a lot of water and stay well hydrated.

[recon]

Redacted. I was wrong in theory.

Edited by recon, 08 February 2018 - 01:29 AM.

[stefan_001]

@Vantika you wrote:

"2) it's persisted a couple weeks,"

 

Does that make sense this persists for weeks? I would imagine the cells that died off to be removed from the body fast, levels of hyperuricemia to normalize and the condition to be over?

Edited by stefan_001, 08 February 2018 - 07:55 AM.

[Vantika]

@Vantika you wrote:

"2) it's persisted a couple weeks,"

 

Does that make sense this persists for weeks? I would imagine the cells that died off to be removed from the body fast, levels of hyperuricemia to normalize and the condition to be over?

 

Just to be clear, we're talking about the presence/persistence of uric acid / sodium urate crystals in the synovial fluid inside of the affected joints that would be causing these symptoms (joint pain at night).

 

When cells die, they release nucleic acids (from their DNA, mRNA, etc.), of which adenine and guanine are purines and metabolized into uric acid, which can build up in the blood.  If uric acid then concentrates inside of the joints, it causes gout.

 

I don't sufficiently understand the physiology of whether dissolved uric acid in (synovial fluid) solution and/or precipitated solid-form sodium urate crystals in and around the internal periphery of the joint can persist at higher concentrations in the synovial fluid of the joint than in systemic blood plasma, or whether uric acid must reach equilibrium concentration with plasma.  Or -- looking at this a bit differently -- I don't know over what time frame equilibrium must (or is likely to) be achieved.

 

If a two week state of disequilibrium is not uncommon (e.g. due to sequestration of solid-form crystals in some pocket(s)/compartment(s) of the joint, some resistance these crystals possess to dissolution, and/or limited passage/diffusion of uric acid through some membrane present therein) then his two-week duration of symptoms is nothing unusual.

 

On the other hand, if rapid dissolution and subsequent equilibrium is almost always achieved, then that suggests one or more of the following: 1) his systemic uric acid levels (which were never measured) are still high for whatever reason; 2) he suffered some minor joint damage from friction/trauma by said crystals that is not fully healed; or 3) it's not gout.

 

I've read that acute gout attacks typically last 3-10 days, but they can often last longer.

 

As to whether they can persist without concurrently high plasma uric acid levels, WP says, "Hyperuricemia is a classic feature of gout, but nearly half of the time gout occurs without hyperuricemia and most people with raised uric acid levels never develop gout. Thus, the diagnostic utility of measuring uric acid levels is limited."  This suggests to me that persistent states of uric acid disequilibrium (in plasma vs joint fluid) are indeed possible.

 

But, OTOH, maybe this subset of gout cases (those without concurrent hyperuricemia or at least without hyperuricemia persisting long enough to be measured) typically happen to be of shorter duration than the rest, which would reduce the probability of the gout diagnosis being correct.

 

Then again, maybe Meatsauce had past injuries at or near (and thus a high senescent cell concentration in proximity to) his affected, potentially-gouty joints, which caused an abnormally high build up of uric acid within them.

 

So I don't know. You tell me. I know little more about gout than you do. That would be a good topic for you to look into.

 

(And, for that matter, I know even less about gout ultimately derived from an etiology of senescent cell lysis. I suspect this sort of information presently might be hard to come by. )

 

As I mentioned in my post, "Do your own homework on this." I'd be interested in hearing whatever you (or anyone else) learn(s).

[Rocket]

I think it just goes to show you gotta be prepared for unexpected things happening when people here experiment on themselves. Everything we take with the exception of vitamins all have side effects.

In my own case, when I megadosed dasatanib I became very ill for a day. It seems like meatsauce got what could be gout. You have to expect side effects from taking cancer medication! Hopefully its a sign that some senescent cells were killed off and their remains are being removed from his body. But honestly, meatsauce is something like 31 years old..... He probably has no need to clear out whatever minuscule amount of senescent cells he has that haven't been removed by his body. I can understand a 40yo doing this, but 30 or 31 there is no way I would be injecting cancer medicine. It could do more harm to his heslthy cells to outweigh removing a handful of senescent cells.

Also senescent cells play important roles in the body like wound healing. When you lift weights like I do, you're causing trauma to your muscles that heals and adapts and remodels into bigger muscle. Remove senescent cells from the body and perhaps your body doesn't heal and adapt from weight training or long distance running.

In my case I am 4 weeks into healing a broken 2nd metatarsal. Would I inject myself with something to clear out senescent cells and potentially damage the healing process should senescent cells ne playing a role in material bridging the two halves of bone until it full calcifies? No way.

I have more questions than answers. The body is continually remodeling itself... Do senescent cells play a role in that process? Idk. If so then wiping them from your body is going to cause more problems than it fixes. All we have is a pic of a before and after mouse, but mice are not humans.... So, you're rolling the dice. Its too bad they didn't trial it on something more like humans such as primates.

BBuyer beware and good luck.

[Vantika]

Also senescent cells play important roles in the body like wound healing. When you lift weights like I do, you're causing trauma to your muscles that heals and adapts and remodels into bigger muscle. Remove senescent cells from the body and perhaps your body doesn't heal and adapt from weight training or long distance running.

...

I have more questions than answers. The body is continually remodeling itself... Do senescent cells play a role in that process? Idk. If so then wiping them from your body is going to cause more problems than it fixes. All we have is a pic of a before and after mouse, but mice are not humans.... So, you're rolling the dice. Its too bad they didn't trial it on something more like humans such as primates.

 

If I understand you correctly, this is a common misconception.

 

Senescent cells are needed only transiently and locally in the healing process.  They are created by the injury itself, at the site of the injury, and used only temporarily to heal that injury (by secreting growth factors for new cell growth and MMPs to degrade the ECM of damaged tissue).  Once the particular injury that they were surrounding has fully healed, from everything I've read, most of them either enter apoptosis or are cleared out by macrophages. Those that survive beyond that only serve to create pathology over the long term.

 

All of Jan van Deursen's experiments indicate a complete lack of any pathology -- on the contrary, only benefits and healthspan and lifespan extension -- from periodically clearing them out.  Specifically there is no impaired wound healing ability as long as senescent cells are not cleared at the time of wounding.  Everything I've seen said/written by other experts (e.g. Judy Campisi) emphatically agrees on this point.

 

The notion that maintaining a persistent, long-standing reserve of senescent cells is somehow useful for wound healing is simply a misunderstanding of the oft-mentioned (but incompletely explained) fact that newly created senescent cells are locally and temporarily used in wound healing.  On the contrary, once too many of them have accrued, they impair wound healing by locking stem cells needed for tissue repair/regeneration into a state of permanent stemness, preventing them from differentiating into the specialized types needed to replace dead/damaged cells (so-called "senescence stem-lock").

 

Unfortunately when this wound healing role is mentioned in passing in a review paper or a popular press article or something, it's usually just as a bullet point or a brief mention in a list of their functions that rarely includes the full explanation given above, and people often jump to the wrong conclusions.

 

As for your strenuous exercising/lifting, obviously you don't use a senolytic when you currently have unhealed wounds.  Take a break while you use them.

 

If you already understood all of this, I apologize for unintentionally being pedantic or patronizing.  But the way your phrased things made it seem to me as if you didn't.

 

 

But honestly, meatsauce is something like 31 years old..... He probably has no need to clear out whatever minuscule amount of senescent cells he has that haven't been removed by his body. I can understand a 40yo doing this, but 30 or 31 there is no way I would be injecting cancer medicine.

 

When you take into account that:

1. they accumulate at an exponential rate by converting their neighbors to senescence,
2. you're not going to be able to kill all of them, because we have no universally effective senolytic, nor is the development of one (or even a set of them jointly functioning as a universal one) at all guaranteed, due to the heterogenous nature of senescent cells, and
3. then do the math on #1 and #2 (and I mean "do the math" literally, as in figuring out what strategy will minimize their accumulation, given the mathematical model above);

then, if your goal is to maximize life expectancy, I think his decision is rational and justifiable.

[Andey]

 

...

 

 Looks like you are overstretching a bit with: "they accumulate at an exponential rate by converting their neighbors to senescence" -   and  - "When cells die, they release nucleic acids (from their DNA, mRNA, etc.), of which adenine and guanine are purines and metabolized into uric acid, which can build up in the blood.  If uric acid then concentrates inside of the joints, it causes gout."

 

  I haven't seen any data supporting the first statement, as for the second one - I dont think you get more purines than from a can of sardines, its negligible.

Edited by Andey, 09 February 2018 - 11:34 AM.

[meatsauce]

At 31 I don't have many senescent cells but I think it's much easier to prevent aging rather than having to reverse it once it has occurred. I might not see an effect from it or other drugs/therapies I try but when I'm 40 or 50 hopefully the efforts will show that I have maintained a youthful body. 

Edited by meatsauce, 09 February 2018 - 05:59 PM.

[The Capybara]

As far as I can tell, there are two lots of the FOXO4-dri out there being tested. I think it would be wise to run a tandem mass spec on both samples to at least verify that they are the same peptide. I could probably have samples run here in Arizona.
If this is a preliminary scientific evaluation, we should at the very least have some sort of third party evaluation.
I'm not being a wet blanket, but after reading the foxo4dri.com blog, I'm not seeing anything there that couldn't simply be placebo effect. There is nothing that dramatic that shouts of any remarkable activity at this point, as far as I can tell.
I would expect that they'll be a lot more optimistic and subjective reporting from the latest group buy.
Shouldn't we verify that everyone is using the real thing? Shouldn't that be the foundation that reports are built on?

[Daniel Cooper]

I agree Capybara.  I'm a little concerned with the level of effect being seen.

 

It would be nice to know the distribution of ages of people experimenting with this stuff. It could be that that group just skews young and we really just don't expect to see a great effect because they aren't carrying a significant senescent cell load.  But, if we see a number of people 50+ with nothing very dramatic to report then I think you have to question if the compound is what we think it is, or if there is some underlying flaw in going from a mouse model to a human.

 

If you're 50+, unless you're in really excellent shape and an exceptional genetic specimen, you've got some age related issues you've noticed.  Osteoarthritis, degenerative disc disease, neurological deficits, declining endurance, etc.  I'd think you'd see some noticeable improvement in those issues if you really made a significant dent in your senescent cell load.  In particular, I'd think osteoarthritis would be significantly affected by killing off large numbers of senescent cells. 

 

Have people registered their ages and age related complaints somewhere in this thread?  If not that might be helpful.

 

 

 

 

 

 

[The Capybara]

I absolutely agree.
Once you've hit your 50's you're past your 3dB rolloff point on the Bode plot of life.
You're on a much faster path to illness and disability, and this process only accelerates with time. One would think, based on papers published, that an effective and targeted senolytic would cause an increase in "health capacitance" and thus objectively measurable health markers, and if there was a senescent cellular die off, some sort of fairly noticeable acute side effects.
As much as I hate to admit it, 50 is not young in humans no matter how well you eat or how much you exercise. There should be a substantial senescent cell burden if the published papers are correct.
In my opinion.
I think the first step is to third party test all batches of samples bring used. If they come back legit, then we can speculate about dose issues, routes of administration etc
This is truly a potential breakthrough compound. Anecdotal reports have some value, but objective data rules in the end.

[extendcel]

The issue with 3rd party testing is that it's cost prohibitive. Perhaps for group buys, everyone participating can split the fee. Other than that, we can only trust the HPLC and MS results from the manufacturer and they are sending the real thing. I think people should get blood work before using this compound at the very least.

Personally I'm waiting for more results before hopping on board.

[smithx]

I can do and have previously offered to do GC/MS testing of samples, but we need a standard to compare them to. That's why I proposed going with Pepscan, which produced the peptide used in the study, or at least getting a sample from them which we can then compare to everything else.

[Vantika]

 

...

 

Looks like you are overstretching a bit with: "they accumulate at an exponential rate by converting their neighbors to senescence" -   and  - "When cells die, they release nucleic acids (from their DNA, mRNA, etc.), of which adenine and guanine are purines and metabolized into uric acid, which can build up in the blood.  If uric acid then concentrates inside of the joints, it causes gout."

 

 I haven't seen any data supporting the first statement, as for the second one - I dont think you get more purines than from a can of sardines, its negligible.

 

Well, if you haven't seen any evidence that senescent cells accumulate exponentially, then I guess none must exist, and you should stop reading right here to spare yourself some utterly mind-blowing cognitive dissonance. 

 

On a more serious note, if I may ask, how much time did you spend searching the literature before posting that?  (Non-rhetorical question; I'm genuinely interested in the answer.)

 

                                                                                                                                        

 

So, if you haven't seen any data in that regard, perhaps you should take a look at this:

 

"Cellular Senescence in Aging Primates"

pubmed: https://www.ncbi.nlm...pubmed/16456035

publisher: http://www.sciencema...g&pmid=16456035

sci-hub: http://sci-hub.la/10...science.1122446

 

Quoting ibid.:

 

"Thenumber of dermal fibroblast nuclei containing foci of 53BP1, a marker of DNA double-strand breakage (DSB) [senescence marker], increased exponentially with age and reached a value of 30 to 35% in very old (25 to 30 years old) animals (Fig. 1A and fig. S1A).
...
The frequency of TIF-positive nuclei [senescence marker] increased exponentially with age, reaching a value of 15 to 20% in very old animals (Fig. 1B).
...
Thirty individuals in six age groups (five animals per group) were analyzed. Each point represents one animal; there is considerable overlap between the data points, especially at younger ages. 200 to 600 fibroblasts were scored for each animal (error bars show SD). Exponential regressions gave the best fit when applied to the data points [exponential: (A) R^2=0.9136; (B) R^2=0.8849; linear: (A) R^2=0.7856; (B) R^2=0.7884]. The insets (upper left in each panel) show the same data points plotted on a semi-log scale to further illustrate the exponential accumulation of 53BP1 foci and TIFs with age."

 

[emphasis added]

→ source (external link)

 

                                                                                                                                        

Or this:

 

"Chemotherapy and Stem Cell Transplantation Increase p16INK4a Expression, a Biomarker of T-cell Aging."

pubmed: https://www.ncbi.nlm...pubmed/27591832

publisher: http://www.ebiomedic...0378-4/fulltext

sci-hub: http://sci-hub.tw/10...iom.2016.08.029

 

Quoting ibid.:

 

"The expression of markers of cellular senescence increases exponentially in multiple tissues with aging.

...

Expression of p16INK4a in peripheral blood T lymphocytes increases exponentially with chronological age, doubling about every decade (Zindy et al., 1997, Krishnamurthy et al., 2004, Liu et al., 2009)."

 

[emphasis added]

→ source (external link)

 

                                                                                                                                        

Or this:

 

"The Fountain of Youth by Targeting Senescent Cells?"

pubmed: https://www.ncbi.nlm...pubmed/28041565

publisher: http://www.cell.com/...4914(16)30172-1

sci-hub: http://sci-hub.tw/10...med.2016.11.006

 

Quoting ibid.:

 

It is later in life, when the levels of senescence have exponentially increased [30], that actual health problems arise (Box 2).

 

[emphasis added]

→ source (external link)

 

                                                                                                                                        

Or this:

 

"Ink4a/Arf expression is a biomarker of aging."

pubmed: https://www.ncbi.nlm...pubmed/15520862

publisher (full-text): https://www.jci.org/...cles/view/22475

 

Specifically this chart:

https://www.ncbi.nlm...4230/figure/F1/

 

Quoting the caption for Figure 1A, ibid.:

 

"Expression of the Ink4a/Arf locus increases with aging. (A) Relative expression. The ratios (log2 scale) of the expression of cell cycle inhibitors – old (26 months)/young (2.5 months) – from 15 tissues is graphed ± SEM. Each estimate represents the mean of 8–32 quantitative RT-PCR reactions on independent RNA samples derived from 4–6 mice. *Minimum estimate of old/young ratio."

 

[emphasis added]

→ source (external link)

 

When they specifically design this graph (Figure 1A) with logarithmic scale on the y-axis, and choose 2 (not 10, not Euler's number) as the exponential base, what are they telling you?  Might this suggest some kind of doubling phenomenon is occurring?  (Note: I'm not suggesting division of senescent cells.)

 

                                                                                                                                        

I could keep going.

 

When you said you hadn't seen any evidence, how hard did you look?

How much time did you spend looking?

 

jdlancaster519 just posted a study (nice find, BTW!) that at least very strongly hints at their exponential growth (if not expressly spelling it out) just a few days ago in this very thread.

 

All this has been known for quite some time now.  I don't really have time to dig up more references.  I'm sure you can find more if you search the literature yourself:

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

https://scholar.google.com/

 

So now let's do some eighth-grade math.

 

Let's say we start out with one senescent cell within the vicinity of a certain location.  Let's say that, for every year it remains alive, it converts (on average) one other nearby cell to senescence through paracrine signalling.  Purely as an example, let's say it ends up converting a total of two (on average) nearby cells to senescence.  (These numbers are all arbitrary and chosen only for pedagogical purposes.)  And then each of those cells also convert two nearby cells to senescence.  And then each of those convert two.  And so on, ad infinitum.  What type of growth does this describe?

 

Exponential growth, a priori, is the expected outcome.  It's really pretty obvious that this is what would happen as soon as you know about the (expressly mentioned in my post) paracrine-signalling conversion mechanism (and you can find your own references for that; see above search engines), even without all of the corroborating empirical evidence showing exponential accumulation to be true.

 

I mean, did you think I was making this up?  How much time did you spend thinking about this before posting?

 

I don't mean to be rude, but by thoughtlessly and lazily posting stuff like this without doing any thinking or searching you end up subjecting others to the negative externalities of the Bullshit Asymmetry Principle, which states,  "The amount of energy needed to refute bullshit is an order of magnitude bigger than to produce it."

 

As you can probably tell, it took me quite a bit longer to write my post than you spent on yours.

 

This is a serious problem on this site, which is largely why knowledgeable people seldom post.  Posts like that and the resulting BAP tarpit discourage those even semi-knowledgeable from participating and consequently massively reduce the quality of discussion here.  I myself (and I'm hardly an authority in this area) didn't even bother registering an account on this site until I absolutely needed to in order to participate in the Dasatinib group buy, despite the fact that I had been lurking here for about a decade, precisely for this very reason.  I'm sure there are many knowledgeable lurkers sitting on the sidelines because of this.

 

I don't mind being told I'm wrong or even having my arguments ruthlessly attacked and torn to shreds, as long as people apparently spend more than about five seconds' worth of thought in doing so.  Not only would I merely not mind it, I would actually be delighted if I could learn something from you.

 

 

... as for the second one - I dont think you get more purines than from a can of sardines, its negligible.

 

In accordance with the Bullshit Asymmetry Principle, I'm not going to take the time to address your second point regarding the quantity of uric acid that can potentially result from tumor lysis syndrome.  Do your own searching.  It won't take long.  It's well documented elsewhere.

 

Regarding the "sardines" part of your comment, I'll say only this: Are you injecting that can of sardines directly into your bloodstream?  Do you think first-pass metabolism and oral bioavailability each might play a role?  Did you think about that before posting?

 

Quoting: "Purine-Rich Foods, Dairy and Protein Intake, and the Risk of Gout in Men" (http://www.nejm.org/...56/NEJMoa035700)

 

"First, little is known about the precise identity and quantity of individual purines in most foods, especially when they are cooked or processed.5 In addition, the bioavailability of various purines contained in different foods varies substantially. For example, dietary experiments have shown that the bioavailability is greater for RNA than for an equivalent amount of DNA,20 greater for ribonucleotides than for nucleic acid,21 and greater for adenine than for guanine.17 Finally, the outcome examined in these metabolic studies was hyperuricemia, rather than gout,17-21 and a substantial proportion of patients with hyperuricemia will not have gouty arthritis.22,23 Thus, it has been difficult to predict whether a certain “purine-rich” food or food group that is commonly consumed actually affects the risk of gout and, if it does, to what extent."

→ source (external link)

 

                                                                                                                                        

 

For future reference, when I'm unsure about something, I try to state so explicitly and prominently, usually qualifying my remarks and adorning my prose with lots of probabilistic modifiers.  When I don't do that, it typically means I'm pretty sure I'm right, and you should probably think twice before presuming otherwise.

 

Out of politeness, I wouldn't have bothered calling you out on this were it not for the fact that this topic is pretty important -- potentially having life-changing consequences for people -- and thus any spreading of misinformation, whether out of ignorance or laziness or whatever the cause, could potentially be pretty harmful.

[jdlancaster519]

That was a tough response, but i understand the frustration and amount of time it takes to pull references and format good responses. Not to mention the confusion that can be caused. However, I am going to use the Bullshit Asymmetry Principle (Brandolini's Law) reference at work. I had to google it. It perfectly explains how I feel when I have to prove/disprove some excuse or rule someone made up at work (Army).

 

I'm pretty young (34), but I'm hoping some of our older friends with joint problems find removing senescent cells improves their symptoms. My joints hurt from trauma (ex pro fighter, and I'm in the Army) and the following paper suggests that it might help, but who knows. https://www.ncbi.nlm...les/PMC5785239/

[The Capybara]

Where's the feedback icon for "Damn!" ?

[Vantika]

That was a tough response, but i understand the frustration and amount of time it takes to pull references and format good responses. Not to mention the confusion that can be caused. However, I am going to use the Bullshit Asymmetry Principle (Brandolini's Law) reference at work. I had to google it. It perfectly explains how I feel when I have to prove/disprove some excuse or rule someone made up at work (Army).

 

The frustration had been building up in me, man!  This shit was starting to get time consuming.  Nobody ever wants to do any work.  Half of them won't even read more than three paragraphs.  They just want to be spoon-fed the answers.  It's almost as if they're baiting people to do all their homework for them by intentionally being outrageously lazy and ignorant.

 

It's an ADD pandemic.  And it's spreading.  It's the beginning of the TL;DR apocalypse.  Which will be worse than the zombie apocalypse.  My curse will be to ultimately achieve immortality by the skin of my teeth, only to find myself living in the wasteland of its aftermath, longing for the death I was so unjustly denied by my senolytics.

 

I'm pretty young (34), but I'm hoping some of our older friends with joint problems find removing senescent cells improves their symptoms. My joints hurt from trauma (ex pro fighter, and I'm in the Army) and the following paper suggests that it might help, but who knows. https://www.ncbi.nlm...les/PMC5785239/

 

Yeah, that probably will work.  I didn't catch it on my first reading of that paper back when it was first published, so it probably bears mention now: "UBX0101" is just Navitoclax (aka ABT-263).  Unity Bio has apparently rebranded it for IP/marketing/bureaucratic reasons for their clinical trials.  I initially thought they had developed some new compound, but nope, just good Navitoclax, AFAICT.  (IIRC, the footnotes seem to indicate that once you follow them through.)

 

There was some substantial discussion of Navitoclax somewhere back in the Dasatinib group buy thread.  Forum search is your friend.  I trust nobody's gonna ask me for references on this, right? 

[TaiChiKid]

 

@Vantika you wrote:

"2) it's persisted a couple weeks,"

 

Does that make sense this persists for weeks? I would imagine the cells that died off to be removed from the body fast, levels of hyperuricemia to normalize and the condition to be over?

 

Just to be clear, we're talking about the presence/persistence of uric acid / sodium urate crystals in the synovial fluid inside of the affected joints that would be causing these symptoms (joint pain at night).

 

When cells die, they release nucleic acids (from their DNA, mRNA, etc.), of which adenine and guanine are purines and metabolized into uric acid, which can build up in the blood.  If uric acid then concentrates inside of the joints, it causes gout.

 

I don't sufficiently understand the physiology of whether dissolved uric acid in (synovial fluid) solution and/or precipitated solid-form sodium urate crystals in and around the internal periphery of the joint can persist at higher concentrations in the synovial fluid of the joint than in systemic blood plasma, or whether uric acid must reach equilibrium concentration with plasma.  Or -- looking at this a bit differently -- I don't know over what time frame equilibrium must (or is likely to) be achieved.

 

If a two week state of disequilibrium is not uncommon (e.g. due to sequestration of solid-form crystals in some pocket(s)/compartment(s) of the joint, some resistance these crystals possess to dissolution, and/or limited passage/diffusion of uric acid through some membrane present therein) then his two-week duration of symptoms is nothing unusual.

 

On the other hand, if rapid dissolution and subsequent equilibrium is almost always achieved, then that suggests one or more of the following: 1) his systemic uric acid levels (which were never measured) are still high for whatever reason; 2) he suffered some minor joint damage from friction/trauma by said crystals that is not fully healed; or 3) it's not gout.

 

I've read that acute gout attacks typically last 3-10 days, but they can often last longer.

 

As to whether they can persist without concurrently high plasma uric acid levels, WP says, "Hyperuricemia is a classic feature of gout, but nearly half of the time gout occurs without hyperuricemia and most people with raised uric acid levels never develop gout. Thus, the diagnostic utility of measuring uric acid levels is limited."  This suggests to me that persistent states of uric acid disequilibrium (in plasma vs joint fluid) are indeed possible.

 

But, OTOH, maybe this subset of gout cases (those without concurrent hyperuricemia or at least without hyperuricemia persisting long enough to be measured) typically happen to be of shorter duration than the rest, which would reduce the probability of the gout diagnosis being correct.

 

Then again, maybe Meatsauce had past injuries at or near (and thus a high senescent cell concentration in proximity to) his affected, potentially-gouty joints, which caused an abnormally high build up of uric acid within them.

 

So I don't know. You tell me. I know little more about gout than you do. That would be a good topic for you to look into.

 

(And, for that matter, I know even less about gout ultimately derived from an etiology of senescent cell lysis. I suspect this sort of information presently might be hard to come by. )

 

As I mentioned in my post, "Do your own homework on this." I'd be interested in hearing whatever you (or anyone else) learn(s).

 

 

Here are some notes I took from 23andMe about my SNPs. I suffer from gout and would suggest avoiding alcohol esp beer/cider and hard liquor as well as fructose drinks (like soda pop) while trialing FOXO4 due to the following reearch reports on 23andMe.

 

GOUT
    In my 23andMe results: AC at rs2231142 gives odds ratio 1.74x higher risk (ABCG2 gene).
    In my results TT at rs606458, each T is a risk allele for gout (URAT1 gene).
CC at rs1333049 gives odds ratio by 1.43x higher risk in a 900 Han chinese cohort.  I am chinese.  Coronary Artery Disease is also associated with high uric acid levels.

     The gene SLC2A9 (aka GLUT9 or glucose transporter 9) encodes a protein that helps to transport uric acid in the kidney. Several SNP's of this gene are known to have a significant correlation with blood uric acid:  A ketogenic diet impairs the ability of the kidney to excrete uric acid, due to competition for transport between uric acid and ketones.

Alcohol:  High intake of alcohol (ethanol), a significant cause of hyperuricemia, has a dual action that is compounded by multiple mechanisms. Ethanol increases production of uric acid by increasing production of lactic acid, hence lactic acidosis. Ethanol also increases the plasma concentrations of hypoxanthine and xanthine via the acceleration of adenine nucleotide degradation, and is a possible weak inhibitor of xanthine dehydrogenase. As a byproduct of its fermentation process, beer additionally contributes purines. Ethanol decreases excretion of uric acid by promoting dehydration and (rarely) clinical ketoacidosis.  Interestingly, beer & hard liquor are bad, but not red wine!

Fructose:  High dietary intake of fructose contributes significantly to hyperuricemia. In a large study in the United States, consumption of four or more sugar-sweetened soft drinks per day gave an odds ratio of 1.82 for hyperuricemia. Increased production of uric acid is the result of interference, by a product of fructose metabolism, in purine metabolism. This interference has a dual action, both increasing the conversion of ATP to inosine and hence uric acid and increasing the synthesis of purine.  Fructose also inhibits the excretion of uric acid, apparently by competing with uric acid for access to the transport protein SLC2A9. The effect of fructose in reducing excretion of uric acid is increased in people with a hereditary (genetic) predisposition toward hyperuricemia and/or gout.

 

    Note well:  pop such as Pepsi, Coke, etc was converted from glucose to fructose back in 1980 or so which saved the manufacturers a ton of money vs. sucrose since fructose tastes a lot sweeter dollar for dollar.  Avoid like the plague to allow uric acid clearance from lysed senolytic cells amino acids.

Serum Concentration:  Following Le Chatelier's principle, lowering the blood concentration of uric acid may permit any existing crystals of uric acid to be gradually dissolved into the blood, from whence the dissolved uric acid can be excreted. Maintaining a lower blood concentration of uric acid similarly should reduce the formation of new crystals. If the person has chronic gout or known tophi, then large quantities of uric acid crystals may have accumulated in joints and other tissues, and aggressive and/or long duration use of medications may be needed.

 

pH:  Therapies that alter pH principally alter the pH of urine, to discourage a possible complication of uricosuric therapy: formation of uric acid kidney stones due to increased uric acid in the urine (see Nephrolithiasis). Dietary supplements that can be used to make the urine more alkaline include sodium bicarbonate, potassium citrate, magnesium citrate, and Shohl's Solution (now replaced by Bicitra). Medications that have a similar effect include acetazolamide.

[Michael]

I didn't catch it on my first reading of that paper back when it was first published, so it probably bears mention now: "UBX0101" is just Navitoclax (aka ABT-263).  Unity Bio has apparently rebranded it for IP/marketing/bureaucratic reasons for their clinical trials.  I initially thought they had developed some new compound, but nope, just good Navitoclax, AFAICT.  (IIRC, the footnotes seem to indicate that once you follow them through.)

 
This is incorrect (tho' I agree with you that the way the footnotes are cited makes it look that way). Long-time senescence researcher and blogger Dr. Dominick Burton:

http://www.aston.ac....ominick-burton/
https://scholar.goog...S_SgAAAAJ&hl=en

(Burton's revamped senescence blog:
https://cellsen.wixs.../senescentcell/
 
... confirmed to me that he was told by UNITY CEO Ned David of Unity that it is not ABT-263/Navitoclax, but a novel molecule from their stable. They will not be publishing the structure or revealing the identity; however, in an interview months previously, David said:
 
“We have molecules that are 300 times more poisonous to these cells than to non-senescent ones.”
 
This compares to Navitoclax/ABT263which had EC50 values for senescent vs normal cells ranging in different in vitro models from 8.69 to 21 (PMID 26657143, Supplemental Fig. 1(e)).

Edited by Michael, 11 February 2018 - 03:28 PM.
Fixing broken link — H/T @Vantika

[Vantika]

This is incorrect (tho' I agree with you that the way the footnotes are cited makes it look that way). Long-time senescence researcher and blogger Dr. Dominick Burton ...  confirmed to me that he was told by UNITY CEO Ned David of Unity that it is not ABT-263/Navitoclax, but a novel molecule from their stable.

 

Excellent find!  Thank you for the correction! 

[meatsauce]

 They will not be publishing the structure or revealing the identity; however, In an interview months previously, David said:

 

“We have molecules that are 300 times more poisonous to these cells than to non-senescent ones.”

 

This compares to Navitoclax/ABT263which had EC50 values for senescent vs normal cells ranging in different in vitro models from 8.69 to 21 (PMID 26657143, Supplemental Fig. 1(e)).

 

 

Seems like we need to send in a spy.