40 replies to this topic

[Kentavr]

So I dont think there are specific symptoms of cell senescence, it is different for everyone.

 

There is an assumption. Senescent cell complaints can be similar to those caused by defective mitochondria. In fact, these are complaints about the consequences that SASP causes.

 

Makes sense but it in practice it turns out not to be true. I have been scouring the internet for experiences on senolytics and some as young as late 30s to early 40s have noticed they have reversion of symptoms at 3 weeks and they have been doing these rounds for a couple of years with the same effect. I argued initially because it just didnt make sense but their symptoms that are relieved and then revert are undeniable. It doesnt make sense why this would be but its turning out to be the case.

 

 

People in their 30s and 40s usually do not have many senescent cells. However, there can be many defective mitochondria.

 

Senolytics will not help such people.

 

Defective mitochondria ignite the SASP

 

https://www.nature.c...1580-020-0228-x

 

A cell that has defective mitochondria is not necessarily a senescent cell.

 

Such cells may well persist after senolytic therapy.

 

Senescent cells take weeks to over a month to form and acquire a SASP. This fact is mentioned in the text of the study:

 

https://www.ncbi.nlm...les/PMC7248649/

 

This fits very well within the interval you reported.

 

Perhaps they will be helped by the mitochondrial fusion and division protocol that Turnbuckle is developing to reduce the number of defective mitochondria.

 

 

Edited by Kentavr, 12 August 2021 - 03:22 PM.

[ortcloud]

Interesting.

 

You could also probably use urolithin-a to kill off the defective mitochondria

[FlorianReicht]

100$ per month for mitopure (urolithin-a), that's what I paid for all sups needed below

 

Currently I've done 2 cycles of Turnbuckle's updated Mito Fission/Fusion Protocol

 

https://www.longecit...-58#entry903440

 

love it so far I've noticed decreased resting HR, better sleep, faster regeneration

[ortcloud]

It's hard to imagine that anyone would build up a significant number of senolytic cells in 3 weeks. Cellular senescence doesn't work that way.  I'd have to suspect that the placebo effect is in play here.

 

After contemplating that things didnt add up here on this phenomenon because senescent cells should build that quickly and the placebo theory didnt make sense because too many people on different forums all had the same timespan 3-4 weeks and it was a sharp reversion, it wasnt gradual like it should be if it was senescent cells building at a natural rate. So I continued to do more research and finally figured it out.

 

The answer to this riddle is that fisetin is not just a senolytic but also senomorphic, which means it just puts the cells to sleep for a while and then they revert and wake back up and start emitting sasp again, which explains everything like the timespan and the sharp reversion.

[Kentavr]

After contemplating that things didnt add up here on this phenomenon because senescent cells should build that quickly and the placebo theory didnt make sense because too many people on different forums all had the same timespan 3-4 weeks and it was a sharp reversion, it wasnt gradual like it should be if it was senescent cells building at a natural rate. So I continued to do more research and finally figured it out.

 

The answer to this riddle is that fisetin is not just a senolytic but also senomorphic, which means it just puts the cells to sleep for a while and then they revert and wake back up and start emitting sasp again, which explains everything like the timespan and the sharp reversion.

 

You can try IP6 as a senolytic as it induces apoptosis through the P53 modulation pathway:

https://pubmed.ncbi....h.gov/18652568/

Perhaps it will be a good alternative to the FOXO4-DRI peptide, as it is available as a supplement and is quite cheap.

 

P53 is the more root cause of the accumulation of senescent cells (see fig.4):

https://www.ncbi.nlm...les/PMC8344376/

 

About half of all cancers are P53-dependent.

 

Also, if you are in doubt about the senolytic power of fisetin, you can try combining it with IP6 and see how well the combination of these supplements works.

Edited by Kentavr, 11 October 2021 - 12:32 PM.

[timedilation]

Do we know the elimination half-life of FOXO4-DRI?  Is it destroyed in the process of causing apoptosis, or does it have to be excreted or broken down some other way?

[DJSwarm]

Be careful about synergy, the body doesn't always distinguish between effects and side effects.

 

I have so far tried D 60 mg + Q 1000mg + F 1200mg (reported minimum dose of F for senolytic effect), While on it I felt washed out but not too bad. Less than the covid shot.

 

Have been following the Mayo women's fisetin study (2000mg x 2 days once a week). Also I have found it reported that berberine is a potent mTOR1 inhibitor (that synergizes with rapamycin so caution there), so I did a two day 3000mg fisetin (fisetin seems to be dose dependent so adjusted for my size) + 1000 mg berberine x 2 days. no noticeable side effects.

 

Per the mouse studies, my fur and energy have improved. 

[ambivalent]

Have been following the Mayo women's fisetin study (2000mg x 2 days once a week).

 

 

This referenced the uncompleted P2 measuring gait I assumed? I have been comsidering this for my 75-year old mother, the trial completion date was originially 2020 iirc. How long have you been taking the protocol and what have been the side effects?

 

I have taken larges doses of F intermittently, up to 6gm. The tell tell effect I notice is increased weakness in an arthrtitic knee, followed by an above baseline strengthening several days later as I assume, the hoarding senescent cells are cleared with new ones eventually replacing them.

 

Refuced histamine (a study validates this effect) and improved clarity. 

 

Thanks.

Have been following the Mayo women's fisetin study (2000mg x 2 days once a week).

 

 

This referenced the uncompleted P2 measuring gait I assumed? I have been comsidering this for my 75-year old mother, the trial completion date was originially 2020 iirc. How long have you been taking the protocol and what have been the side effects?

 

I have taken larges doses of F intermittently, up to 6gm. The tell tell effect I notice is increased weakness in an arthrtitic knee, followed by an above baseline strengthening several days later as I assume, the hoarding senescent cells are cleared with new ones eventually replacing them.

 

Refuced histamine (a study validates this effect) and improved clarity. 

 

Thanks.

Have been following the Mayo women's fisetin study (2000mg x 2 days once a week).

 

 

This referenced the uncompleted P2 measuring gait I assumed? I have been comsidering this for my 75-year old mother, the trial completion date was originially 2020 iirc. How long have you been taking the protocol and what have been the side effects?

 

I have taken larges doses of F intermittently, up to 6gm. The tell tell effect I notice is increased weakness in an arthrtitic knee, followed by an above baseline strengthening several days later as I assume, the hoarding senescent cells are cleared with new ones eventually replacing them.

 

Refuced histamine (a study validates this effect) and improved clarity. 

 

Thanks.

[DJSwarm]

After contemplating that things didnt add up here on this phenomenon because senescent cells should build that quickly and the placebo theory didnt make sense because too many people on different forums all had the same timespan 3-4 weeks and it was a sharp reversion, it wasnt gradual like it should be if it was senescent cells building at a natural rate. So I continued to do more research and finally figured it out.

 

The answer to this riddle is that fisetin is not just a senolytic but also senomorphic, which means it just puts the cells to sleep for a while and then they revert and wake back up and start emitting sasp again, which explains everything like the timespan and the sharp reversion.

 

Do you have the link to your senomorphic study?

 

I can only find things like:

 

Fisetin is a senotherapeutic that extends health and lifespan

 

At a dose of 5 μM, fisetin was most effective in reducing the fraction of SA-ß-gal positive MEFs (Fig. 1A). Luteolin and curcumin also showed weak activity at a dose where quercetin was ineffective. In addition, fisetin reduced senescence in MEFs and IMR90 cells in a dose-dependent manner (Fig. 1B and C). These results are consistent with our previous finding that fisetin selectively reduces the viability of senescent HUVECs without affecting proliferating cells [32]. In HUVECs, fisetin induces apoptosis as measured by caspase3/7 activity, whereas in MEFs, fisetin suppressed markers of senescence without evidence of cell killing [32].

 

There dose seem to be some senomorphic mention here (excellent read BTW) Senescent Cells  In  a  cell  culture  study  comparing  ten  flavonoids,  fisetin  was  determined  to  be  the  most  potent  senolytic,  even proving  to  be  superior  to  quercetin.  Acute  or  intermittent  fisetin  treatment  studies  in  both  old  and  progeroid  mice significantly  reduced  senescence  markers  in  multiple  tissues.  The  agent also  reduced  senescence  in  a  subset of  cells in  murine  and  human  adipose  tissue.  (36) It  is  important  to  note  that  fisetin  can  be  bipolar;  it  can  be  senolytic  to  some  cells,  while  only  being  senomorphic  to others. (Called out Preadipocytes  ([It was] senomorphic  in  some  studies))

 

Main take away, fisetin's senolytic activity seems dose dependent: "I  think  the  clinical  answer  hinges  on  if fisetin  is  taken  alone  or in  combination  with  other senotheraputics. If taken alone,  it  should  be  used  as  a  high  dose,  intermittent  therapy.  If  used  in  combination,  it  can  be  used  at  a  lower,  but more  continuous  therapy.  The  third  option  is  to  combine  strategies  and  use  a  daily  small  dose  consistently,  with intermittent large  dose  boluses."

 

It should be noted there is no universal senolytic yet which targets every tissue.  

[ortcloud]

Do you have the link to your senomorphic study?

 

I can only find things like:

 

Fisetin is a senotherapeutic that extends health and lifespan

 

Main take away, fisetin's senolytic activity seems dose dependent: "I  think  the  clinical  answer  hinges  on  if fisetin  is  taken  alone  or in  combination  with  other senotheraputics. If taken alone,  it  should  be  used  as  a  high  dose,  intermittent  therapy.  If  used  in  combination,  it  can  be  used  at  a  lower,  but more  continuous  therapy.  The  third  option  is  to  combine  strategies  and  use  a  daily  small  dose  consistently,  with intermittent large  dose  boluses."

 

Its been too long to recall where I found it but that may be the study.

 

Here is what I also found that was very interesting that I didnt mention before. I found that the detection method they use apparently can't discriminate if the cell is just asleep in a senomorphic state versus if it is dead(senolytic).

 

Because the staining detects SASP, and cells that have been silenced from senolysis and senomorphisis both stops secreting SASP so you cant tell the difference.

 

So this study that showed fisetin is the most powerful senolytic may actually not be the case it might just be a very powerful senomorphic or a combination of both. But clues from the real world indicate that alot of the effects of fisetin dont persist long term and wear off at the 3-4 week mark. So it points to it having strong senomorphic versus senolytic effects.

 

I always thought it was strange that people needed to re-dose fisetin monthly to keep their various symptoms clear versus other senolytics like dasatinib and foxo4 were much longer such as 6-12 months.

 

Most people didnt seem to have an issue with that discrepancy and just chalked it up to new senescent cells forming but to me there was a big red flag that the difference between the two was pretty big and something else was going on here and this explains it.

[DJSwarm]

Its been too long to recall where I found it but that may be the study.

 

Here is what I also found that was very interesting that I didnt mention before. I found that the detection method they use apparently can't discriminate if the cell is just asleep in a senomorphic state versus if it is dead(senolytic).

 

Because the staining detects SASP, and cells that have been silenced from senolysis and senomorphisis both stops secreting SASP so you cant tell the difference.

 

So this study that showed fisetin is the most powerful senolytic may actually not be the case it might just be a very powerful senomorphic or a combination of both. But clues from the real world indicate that alot of the effects of fisetin dont persist long term and wear off at the 3-4 week mark. So it points to it having strong senomorphic versus senolytic effects.

 

I always thought it was strange that people needed to re-dose fisetin monthly to keep their various symptoms clear versus other senolytics like dasatinib and foxo4 were much longer such as 6-12 months.

 

Most people didnt seem to have an issue with that discrepancy and just chalked it up to new senescent cells forming but to me there was a big red flag that the difference between the two was pretty big and something else was going on here and this explains it.

 

I've personally had very durable results from intermittent, acute dosing (avoiding any chronic dosing to avoid side effects). I took a six month break just to check this. But I don't usually do just fisetin and I'm not treating a disorder. If one had a senescent cell disorder; there is a possibility that there is a heightened rate of senescence or sensitivity to the same which is driving it. :( I also rotate through various combinations in the stack, mainly because each senolytic has specific cell lines it effects and rotating through various senolytics seems like it would give the best over all coverage. At the moment I've run various combinations of (one of Dasatinib (60mg), Theaflavin (1000mg-ish but just a guess here), Long Pepper (who knows but 4x4:1 capsules) + (both of Fisetin (20mg/kg and 40mg/kg, Quercetin (1000mg)) and Berberine (mTOR1 inhibitor 1000mg). I also try to get liposomal preparations when possible and use 10mg bioperine, 400mg bromalin, and emulsified lecithin/oil (aka chocolate) to improve absorption and bioavailability. I may also add skullcap for same reason. I'm considering a single dose of Rapamycin, though I'm also concern about its level of side effects.

 

Just briefly reading through a couple papers, not all the tests are just the SASP stain assays. Also, there are a number of one and done studies where effects were durable, though those were mainly D+Q or R. So far, I've used either D, LP or T as an "enabler" in each trial except one, which may be helping to push me towards senolytic activity.

 

All nicely speculative of course, but improvements to my fur and vigor seem to be tracking brother mouse even though I've had a minimum two week break between runs.