1079 replies to this topic

[Nate-2004]

The dasatinib is low. 2 days of 200 to 250mg each.

 

That sounds way high relative to the initial conclusions drawn in the Dasatinib group buy thread a year or so ago. I upped it to 75mg today.

Edited by Nate-2004, 16 November 2018 - 12:18 AM.

[Rocket]

That sounds way high relative to the initial conclusions drawn in the Dasatinib group buy thread a year or so ago. I upped it to 75mg today.

That's my dose. People can't keep believing that the mouse to human conversion is reliable for all chemicals and substances. It leads to inadequate dosages to trigger the positive effects seen in mouse trials.

My first Dasatinib trial made me feel sick, likely from the senescent cells being processed out of my body. After that subsequent trials less and less sick as there are likely fewer and fewer senescent cells to kill. Just my experience. If you are taking Dasatinib and don't feel anything then the dose is wrong or you are too young to have too many senescent cells. You can't kill off cells in your body, senescent or not, and expect to feel nothing.

[sthira]

I felt nothing from the group-buy dasatinib we all bought despite taking 120mg doses several times during prolonged fasting.

My offhand conclusion was that the stuff we bought from Logic just wasn't real. Could be I'm wrong; but did anyone else notice Logic seemed to disappear from (posting at) this site after our dasatinib group buy? Maybe this was coincidental.

[extendcel]

I think a major point to consider when arguing on the function of senescent cells is that senolytics do not kill all senescent kills, as evident from studies. In the fisetin mice study in particular, the fisetin group had lower senescent cell compared to control, but total senescent cell burden during old age in the fisetin group was still higher than the younger control groups. Taken acutely, current senolytics should not deplete senescent cells in a negative manner, if we believe that they have some important functions in the body. At this stage of development, there is a larger risk of non-selectivity resulting in the death of healthy cells.

Edited by extendcel, 16 November 2018 - 02:51 AM.

[OP2040]

I think a major point to consider when arguing on the function of senescent cells is that senolytics do not kill all senescent kills, as evident from studies. In the fisetin mice study in particular, the fisetin group had lower senescent cell compared to control, but total senescent cell burden during old age in the fisetin group was still higher than the younger control groups. Taken acutely, current senolytics should not deplete senescent cells in a negative manner, if we believe that they have some important functions in the body. At this stage of development, there is a larger risk of non-selectivity resulting in the death of healthy cells.

 

While I agree completely with your logic here. I thought the Fisetin mice in the study came very close to young mouse senescent cell levels?  Either way, absolutely we don't want or need to get rid of all senescent cells.

 

What I find interesting about this whole discussion is the following.  We now have many senolytics, some of which like Fisetin are definitively proven to work in mice on most (if not all) tissues.  I know it's a big assumption to make that these will work almost the same way in humans.   But senescent cell ablation is not as complicated a biological process as epigenetics for example.  It is a highly conserved process, so I tend to believe that it does actually work in humans.   Given all of this, we could actually have resolved one of the Hallmarks of aging already.  It may take years of data gathering and trials to actually prove this.  But the interesting thing is that we could actually be there, and not officially know it for many more years.

 

My personal bias is that senescent cell ablation will be good for healthspan, but not longevity.  Another thing is that we tend to take something here, and immediately report with a thumbs up or down as to it's effects.  Well, humans live a very long lifespan.  The effect of an intervention may take a year to even get the beginnings of a result.  For all these reasons, I think Fisetin is a good bet to stick with long term, or until something is proven to be better. 
 

[XRT doc]

I think there is some misunderstanding on the role of senescent cells. The process of senescence is important in fetal development, wound healing, liver regeneration, but once a cell has become senescent the immune system tries to remove it. I havent seen any evidence that once a cell becomes senescent, there is a benefit to it sticking around, or that they have any sort of role other than signaling to the immune system  "come kill me and some of my neighboring cells"  One of the issues with aging is that the immune cells themselves develop senescence and it becomes less effective at removing accumulating senescent cells.

Edited by XRT doc, 16 November 2018 - 04:52 PM.

[Nate-2004]

I felt nothing from the group-buy dasatinib we all bought despite taking 120mg doses several times during prolonged fasting.

My offhand conclusion was that the stuff we bought from Logic just wasn't real. Could be I'm wrong; but did anyone else notice Logic seemed to disappear from (posting at) this site after our dasatinib group buy? Maybe this was coincidental.

 

We got it lab tested before shipping, assuming we can trust those results he posted... Logic has posted quite a bit since then. Most of us dip in and out and a lot of people are gone that posted back then.

Edited by Nate-2004, 16 November 2018 - 05:15 PM.

[johnross47]

We frequently read people here saying "I felt nothing," or something similar. Apart from the obvious problem of very young people, (by my almost 72 year old standards), not having anything to feel anyway, what is it that people expect to feel, and why? What would it feel like to clear some senescent cells? There may be some visible effects if it does actually clear age spots or something like that but what about the internal parts, which are the bulk of the tissues and presumably the bulk of the problem?

 

I have an issue with inflammation on the lungs and asthma, which is reduced quite a bit by Fostair Nexthaler 200 and Montelukast. If this was further reduced by a reduction in senescent cells I might not notice a huge effect.

[sthira]

We frequently read people here saying "I felt nothing," ...what is it that people expect to feel, and why? What would it feel like to clear some senescent cells?

Well of course no one knows what it would feel like to kill and piss out toxin-spewing death rattle cells. Die little fuckers, die, can I feel your deaths? Maybe once dead we would feel some lost lightness of being, like during youth when you felt you can do anything, you can be anyone... Remember? Once upon a time that boundless light of youth circled you round and round -- you could explore the limits of your own motion with joy in your body, you felt it, like magic.

We've heard said that just one aging intervention -- senescent cell clearing, e.g. -- isn't enough -- we need many other interventions because we're so damaged by living life pushed by gravity and metabolism. But senescent cell clearing is the most promising initial aging-reversal target -- so we're searching for magic. We have no biomarkers so we're like in a dark room, flailing, do you feel anything, no, do you, how about you and you, all anecdote?

We seek magic. Magic is different for everyone. In the near term, I want back my vertical leap, that effortless glide through air that compounding injuries have stolen. In the far term, I want magic to live long enough to explore space, travel the weird universe, to get off this beautiful planet and experience beauties beyond. Senescent cell clearing, as humble as it is, is one first step. Will you feel it when you kill zombie cells? Tell us if you do.

I feel a cup of coffee, though.

[Turnbuckle]

Well of course no one knows what it would feel like to kill and piss out toxin-spewing death rattle cells. Die little fuckers, die, can I feel your deaths? 

 

 

Millions of cells die every second, so it's unlikely that anyone would feel anything remarkably different untless that rate were substantially increased. As with cancer treatments, where that rate goes up massively. If you've ever walked down a cancer ward, you'll see how people are wiped out from chemo.

 

We have no biomarkers so we're like in a dark room, flailing, do you feel anything, no, do you, how about you and you, all anecdote?

 

 

 

We do have biomarkers--epigenetic age.

[sthira]

We do have biomarkers--epigenetic age.

Has the field advanced in the few weeks time since we last had this conversation? In another thread, you said yes we have an epigenetic test to determine age, and I said wow that's fantastic, and then we were corrected by Michael (who's close to the scene) who said, well, no, that's a chronological-age test, and not a biological-aging test; the test we want isn't available retail... yet...

So if we have accurate ways (epigenetic or anything else) to test aging-related damages and repairs, are they now available?

[Turnbuckle]

Has the field advanced in the few weeks time since we last had this conversation? In another thread, you said yes we have an epigenetic test to determine age, and I said wow that's fantastic, and then we were corrected by Michael (who's close to the scene) who said, well, no, that's a chronological-age test, and not a biological-aging test; the test we want isn't available retail... yet...

So if we have accurate ways (epigenetic or anything else) to test aging-related damages and repairs, are they now available?

 

 

We were corrected by Michael? Can you link to this correction?

[sthira]

We were corrected by Michael? Can you link to this correction?

Yeah in this thread: https://www.longecit...477&qpid=861212

Try getting your epigenetic age checked by Osiris Green, before and after. Since OG uses buccal cells from the mouth and such cells take some 20 days from generation to shedding, you should wait a month after treatment to take the second sample.

Good idea. Here's a link to the OG test: https://www.osirisgr...com/product.php

Down comes the hammer:

Not so much. This has only been very informally linked to chronological age (see here): we have zero evidence it's of any value whatsoever as a measure of biological age: as in, no one has even attempted to test it for this. I don't see the point of running the original Horvath clock (see my post earlier in this here), but at least it's been clearly demonstrated as closely correlated to chronological age; OG may be no better than a blindfolded dartboard toss for all we know at this point.

Im sad now :-( I wanted to be wrong because we want to know. But it's still in the future, the misty far out future of more and more promises...

[Turnbuckle]

I don't agree with Michael's argument. You should be able to tell how a treatment is working vis-a-vis epigenetic age using Osiris Green or similar companies. You might have to take a number of tests to get rid of noise, but it seems perfectly legitimate from the testing I've had done. So don't be so quick to believe those who make arguments based on opinion.

[sthira]

I don't agree with Michael's argument. You should be able to tell how a treatment is working vis-a-vis epigenetic age using Osiris Green or similar companies. You might have to take a number of tests to get rid of noise, but it seems perfectly legitimate from the testing I've had done. So don't be so quick to believe those who make arguments based on opinion.

There's this exchange with Neil from OG:

Neil, as far as I can see from the FAQ on your website and from the below interview with Reason at FightAging!, you are only running a couple of gene promoters, not the 353 CpG sites included in the Horvath "clock" or the 71 included 71 in that by Hannum and colleagues — correct? And you've only validated it against a small number of "friends and family members,"? And you've only looked at its correlation with chronological age — unlike the Horvath or Hannum epigenetic "clocks," you have no evidence that a discordance between age as estimated by your assay and chronological age predicts any hard outcomes such as risk of age-related disease or death in the future — again, unlike the Horvath or Hannum epigenetic "clocks.

Right?

Neil's response:

Yes, the method we are using is based on the three gene promoters with the tightest correlation to age, as outlined in the 2011 Bocklandt paper (link). The decision to go with these three tightly-correlated gene promoters as opposed to the full 353 set, or any other set, was primarily a decision of cost. Three genes can be examined individually with basic lab techniques. Large sets would require a microarray approach, which would drive the price up dramatically.

The mathematical model that we’re using was originally based on a data set of as many friends and family members as we could get (as I said, we’re a small operation). The data set has expanded since then.

As far as I’m aware, there have been no studies looking at a correlation between disease or mortality risk for these three gene promoters – unlike the Horvath or Hannum sets. Nor are we in a position to make such an investigation ourselves. We’re offering the service based just on what has been reported and what we have seen – as a measurement of a genetic parameter that corresponds with chronological age.

Michael offers no follow-through. You do, however (in another thread):

Results of my 2 epigenetic age tests

Summary: Epigenetic age went down by 11 years after 3 months of stem cell treatments.

According to 2 epigenetic age results from Osiris Green, I experienced an epigenetic age reversal of 11.2 years in 5 months, the latter 3 months which included my evolving stem cell protocol found in this thread. There were 34 SC treatments in this period, and two days of a treatment to remove senescent cells. The 11-year reversal is a calculated result based on three genes. The detailed results are more complicated. One gene went up 2 years, one went up 10 years, and the third (which supposedly has the lowest deviation) went down 27 years (which is in line with the way I feel). More tests will be needed, for sure.

Test 2: (Actual age 66.83)
Estimated age: 55.7 years old, plus or minus 1.8 years (median absolute deviation).
ASPA Gene -- 68.9 plus or minus 8.6 years (median absolute deviation).
EDARADD Gene -- 34.2 plus or minus 2.7 years (median absolute deviation).
ITGA2B Gene -- 86.1 plus or minus 7.2 years (median absolute deviation).

Test 1: (Actual age 66.42)
Estimated age: 66.9 years old, plus or minus 1.8 years (median absolute deviation).
ASPA Gene -- 70.8 plus or minus 8.6 years (median absolute deviation).
EDARADD Gene -- 60.9 plus or minus 2.7 years (median absolute deviation).
ITGA2B Gene -- 76.3 plus or minus 7.2 years (median absolute deviation).

Caveats: The first test collected saliva, the second gum cells. According to Dr. Neil Copes, CEO of Osiris Green, the second test presented some difficulties. Normally 10-15% of their samples fail QC initially and have to be rerun. Mine failed twice before passing. That is, I assume it passed, as I finally got the results. The discussion can be found here, beginning with post #17.

We're all over the place here, sorry. I'm not really arguing, I'm just past-ready to determine if -- say, Candidate Fisetin -- is worth trying (again) for senescent cell removal, or if fisetin is another dud in the long, storied history of vitamin duds.

To me one way to answer is to know where I began -- how many senescent cells do I have, what species, where are they, and do the benefits of removing them outweigh the detriments? If so, then how do I determine if what I did -- swallow fisetin pills -- resulted in the outcome I wanted -- kill punk cells?

[OP2040]

To me one way to answer is to know where I began -- how many senescent cells do I have, what species, where are they, and do the benefits of removing them outweigh the detriments? If so, then how do I determine if what I did -- swallow fisetin pills -- resulted in the outcome I wanted -- kill punk cells?

 

This is where I'm at too.  I'm fairly convinced that Fisetin is "good enough".  The only thing left would be to have a good way to measure senescent cells to be able to keep them in a target range.  Then we would have a protocol and there would really be nothing left to discuss among those who think an excess of senescent cells is a major cause of aging.   I have looked into possible tests but they just aren't all that convenient yet.  Having said that, I'm pretty content with Fisetin, especially since it has been studied so much and seems to have benefits other than senolytic as well.

[sthira]

This is where I'm at too. I'm fairly convinced that Fisetin is "good enough". The only thing left would be to have a good way to measure senescent cells to be able to keep them in a target range. Then we would have a protocol and there would really be nothing left to discuss among those who think an excess of senescent cells is a major cause of aging. I have looked into possible tests but they just aren't all that convenient yet. Having said that, I'm pretty content with Fisetin, especially since it has been studied so much and seems to have benefits other than senolytic as well.

You're convinced based upon...? Rodent studies? The entire situation is obviously horribly complicated -- just like anything in the world of human metabolism tweaking. Mission is to kill stupid toxin-spitting cells without killing normal healthy cells, especially those in the head and the heart.

But (for we self-experimenters) we need to know not just how to measure the worthless clowns, but also how to remove them (since evidently removal is a good thing) and then to know we did what we thought we did.

One way (expensive, distant, promising) is for biotechs to put stuff (maybe they'll try fisetin, quercetin, dasatinib, longpeppers, whatever) into little egg shaped tubes, senescence-associated beta-galactosidase enzymes (biotechs are doing this already with cancer drugs) and then run them up the chain of in vitro, then rodents, then humans, years and years, dollars and dollars.

Meanwhile, I keep fasting and refeeding, cycling between heaven and hell, because fasting may kill bummer cells for free, then recycle the parts to do something good, then refeeding may help restore the organism.

Anyone know if one of the biotechs is experimenting with shoving fisetin molecules into tiny tubes (senescence-associated beta-galactosidase enzymes) for targeted strawberry-delivery into zombie cells?

Anyone?

[Nate-2004]

Anyone?

 

Yes it was posted just the other day on the subreddit.

 

http://www.sens.org/...senescent-cells

[Dstein]

I find it highly improbable that a drug being used by outpatients for decades have had 97% of their SASP producing senescent cells destroyed. We would have already seen a major correlation by now with mortality and longevity outcomes.

 

 

97% of the senescent cells are targeted. Whereas normal cells are not. There is also a minimum serum concentration requirement.

 

 

 

 

 

 

 

[sthira]

Yes it was posted just the other day on the subreddit.

http://www.sens.org/...senescent-cells

Are they trying with fisetin? I didn't see fisetin as a candidate. Which makes me wonder why.

[smithx]

And it appears from Figure 3 that the overall death rate over that period was higher in the azithromycin group.

 

 

Good find. There appears to be something going on, probably, but the authors do state:

 

However, these data should be interpreted with
caution because the number of deaths during the study
period was relatively small, which increases the risk of a
type 1 statistical error.

 

 

So I don't think we can draw any concrete conclusions yet.

[theone]

What’s more, scientists were able to cause young, healthy cells to stop dividing by heightening CD36 activity within those cells. The effect spread to nearby cells, with almost all of the cells in a petri dish showing signs of senescence when only a small fraction of those cells — about 10 to 15 percent — were overexpressing CD36. New cells placed in the growth medium (a soupy substance) that previously housed the senescent cells also stopped replicating.

 

 

Do Immune cells have the ability to travel to anywhere in the body and spread senescent (to none Immune cells)? If so could one conclude that  these senescent immune cells are the most dangerous? 

Edited by theone, 19 November 2018 - 04:17 PM.

[Florian E.]

Regarding Fisetin there are some studies with liposomal formulations to significantly increase therapeutic effects. But there are still no liposomal fisetin products available on the market.
So, i'm considering to diy my own liposomal fisetin with an ultrasonic cleaner.
And regarding Azithromycin i'm interested what dosage to use on humans ?

[Turnbuckle]

Do Immune cells have the ability to travel to anywhere in the body and spread senescent (to none Immune cells)? If so could one conclude that  these senescent immune cells are the most dangerous? 

 

Good question, for this can happen--

 

Senescent T cells were shown to expand in patients with chronic and persistent infections such as cytomegalovirus (CMV), human immunodeficiency virus (HIV) along with an additive effect of chronological aging. CMV itself is asymptomatic in most of the hosts unless they are immune-compromised. However, the constant reactivation of the virus could have driven the accumulation of senescent T cells as the immune system tries to control virus reactivation [66,67]. HIV infection shares some similarities with the hallmarks of immunosenescence described above. It is of note that HIV is one of the situations where exhausted T cells are also present. HIV-infected patients usually exhibit high levels of inflammation molecules (IL-6, TNFα, C-reactive protein (CRP)), reduced vaccine efficacy and the expansion of senescent T cells.

https://www.ncbi.nlm...les/PMC5578132/

 

[QuestforLife]

Good question, for this can happen--

Not sure it's the senescent T cells causing this to occur - it might just be that their population expands because T cells are dividing many times because of CMV and thereby more are becoming senescent. This is basically exhaustion of the immune system through persistant infection.

Nevertheless this probably would still have knock on effects because of the inability of the senescent immune system to clear other (non immune) senescent cells.

[theone]

Crucially, senescent immune cells seem to release pro-inflammatory monocytes that contribute to low levels of chronic inflammation. Chronic inflammation generally leads to tissue degeneration and more cell senescence. 

 

 

[smithx]

Crucially, senescent immune cells seem to release pro-inflammatory monocytes that contribute to low levels of chronic inflammation. Chronic inflammation generally leads to tissue degeneration and more cell senescence. 

 

One very simple way that's been discussed of getting rid of circulating senescent immune cells is to get rid of a volume of blood, which could be via blood donation.

Apparently this stimulates the body to produce new immune cells to replace the ones which were lost in the donated blood.

 

This also may be one reason why the traditional practice of bloodletting actually can work in some restricted circumstances.

[Rocket]

Perhaps this is the mechanism by which young blood reverses aging: you are reducing the volume of bad "old" blood.

[QuestforLife]

One very simple way that's been discussed of getting rid of circulating senescent immune cells is to get rid of a volume of blood, which could be via blood donation.

Apparently this stimulates the body to produce new immune cells to replace the ones which were lost in the donated blood.

 

This also may be one reason why the traditional practice of bloodletting actually can work in some restricted circumstances.

 

Maybe, but then you remaining immune cells or progenitors have to divide more to replace the removed cells, which in the long run leads to more senescence.

[tolerant]

Would anybody be able to sell me some Fisetin? It seems to be sold out everywhere, perhaps as the result of that October study. I ordered some on Amazon, but it may arrive only next year.