1079 replies to this topic

[ceridwen]

While you are waiting eat lots of strawberries

[ambivalent]

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

 

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

 

I note the mention in the article of the drug Navitoclax being withdrawn as a consequence of some patients bleeding to death as the drug targets cell-survival pathways clotting cells dependent upon. It is worth re-stating my experience a few days after taking 3g of fisetin mixed in olive oil (post #208) where a small shaving nick around a wart took 5.5 hours to clot. Blood clotting appeared back to normal in the following week or so but it was a disturbing incident, so a note of caution.  

[tolerant]

While you are waiting eat lots of strawberries

 

Yes, there is even this product available, called 37 Strawberries. But because it was from some unknown brand, I didn't consider it. Although then I thought it I would rather get this than nothing at all.

[tolerant]

I note the mention in the article of the drug Navitoclax being withdrawn as a consequence of some patients bleeding to death as the drug targets cell-survival pathways clotting cells dependent upon. It is worth re-stating my experience a few days after taking 3g of fisetin mixed in olive oil (post #208) where a small shaving nick around a wart took 5.5 hours to clot. Blood clotting appeared back to normal in the following week or so but it was a disturbing incident, so a note of caution.  

 

Is Navitoclax in any way related to fisetin?

[tolerant]

While you are waiting eat lots of strawberries

 

Yes, there is this product available, called 37 Strawberries but because it is from a brand I've never heard it, I only considered it as a back-up plan.

[Michael]

With no objections and 6 endorsements, I've merged all the stuff on azithromycin into a this thread.

Edited by Michael, 02 December 2018 - 06:16 PM.

[male_1978]

To me - and i am not a doctor, just making up my own mind - there is one crucial argument to try finestin: 
 
This is that senescent cells is unlike cancerous cells do not replicate and hence there is no evolution via profileration and selection going on if you use someting against them which is not effective enough. 
 
This means that basically you can try anything against them, as long as you dont harm healthy cells. Why not start with a small dose and increase it over time?

One other thing which draw my attention was the following:

 

 

 

 

Previously healthy young adult mice transplanted with [one million] senescent cells had significantly lower maximal walking speed, hanging endurance, and grip strength by 1 month after transplantation compared to mice transplanted with control cells. […] Reduced walking speed began as early as 2 weeks following a single implantation of senescent cells and persisted for up to 6 months, yet the transplanted cells survived in vivo for only approximately 40 days, consistent with the possibility that senescent cells might induce senescence in normal host cells.” 

https://medium.com/l...lls-cc720d88240
https://www.nature.c...1591-018-0092-9

Could this mean, that even if you remove senescent cells successfully, you might see effects delayed by many months?
 

[to age or not to age]

I'm just finishing my new documentary "To Age Or Not To Age   Transforming The Human Condition" (85 min- tracing my interviews with researchers from 2006 to the present).  A number of number of scientists commented on senescent cells,

including Sinclair, Campisi, Aubrey and the blogger "Reason." I have been thinking that the lag time between ingesting an acute dose of, say, fisetin -along the lines of what the Mayo clinic is conducting, such that a person of say 120 pounds, would take (11) 100mg pills two days in a row - and noticing any effects may take much longer than we think.  If a mouse had changes in a month or a couple weeks, effects on humans could range from a multiple of 12 to 30.  

 

So we might be talking a gradual thing over years. Also, as to the duration of an acute dose (2 days? 5 days?). I'm not sure of the answers to these questions?  Any ideas here?

Edited by to age or not to age, 03 December 2018 - 05:58 PM.

[OP2040]

I am starting to see why people were complaining about high price.  I was so focused on intermittent high doses that the price didn't bother me.  But now that I'm considering adding this to my supplement regime, it seems way to expensive.  It's just behind the super-expensive class of new novel supplements like NMN and mItoQ.  I don't understand why a strawberry extract would be so expensive.  Was it like this before the study? Anybody have any ideas on how to get it cheaper, or maybe a group buy?  Anybody actually taking this as a daily supplement @ $20/mo?

[OP2040]

So we might be talking a gradual thing over years. Also, as to the duration of an acute dose (2 days? 5 days?). I'm not sure of the answers to these questions?  Any ideas here?

 

Congrats on the documentary, it sounds like it will be very informative,

 

I agree completely with this last statement.  We all make note of translation when it comes to dose, but almost never when it comes to time.  A lot of interventions will take much longer for humans than for mice.  It makes sense in terms of life history theory.  Humans don't just live longer, every single part of their life is substantially longer, for example longer fetal development, longer infancy, longer adulthood and longer old age.  It makes no sense to think that a mouse intervention of 6 months to a year would be the equivalent time-span in humans. This is a huge practical issue since we will likely solve aging a long time before we actually know that we solved aging.  And people need to be very patient when they do an intervention, not just giving up on it after a few months because there wasn't an immediate dramatic effect.   The other solution to this is cheap and pervasive diagnostics.  If you could see the actual effect on senescent cells in real time, at monthly intervals, you could at least know that it is a human senolytic, when to stop, and determine if the senescent cells are a big deal or not for humans.

[xEva]

noticing any effects may take much longer than we think.  If a mouse had changes in a month or a couple weeks, effects on humans could range from a multiple of 12 to 30.

 

looking forward to your documentary. When do you think we get to see it?

 

 

re when we could notice the effects of senolytics, I disagree with you. The results should be seen/felt within days.

 

This is not the same comparison as with metabolic rate. Rather, timewise, this should be similar to a wound repair. And I think those parameters are similar in mice and humans (though I'm not 100% sure, but think that if mice could heal their deep scratches within hours, we'd hear about it by now). 

[sphere]

Swanson's periodically has 25% off--like today and they have F. in stock, probably as good as one can do unless bulk powder from China etc. Some excips. silca, mag st. but all the capsules have a bit--30 caps 

 

what are folks adding for bioavailability? one of tweens [polysorbate 80 etc] with propelyne glyco?

In the mouse studies i think one of tweens was used. Bioav. is am important factor so improvements in will make a significant difference [excuse sp errors]

[sphere]

this is good: https://www.ncbi.nlm...les/PMC4708959/

 

if anyone has thoughts please post

looks like using equal amounts olive oil, tween 80, and twice as much propylene glyco as either one of oo and tween 80. works for reserv.

but for 1000 mg a day of Fisetin while fasting for 5 days for example, amounts of those 3 to mix the 1000 mg of F. in??

 

Thoughts?

 

 

[MikeDC]

I took 500mg fisetin for two days and didn’t feel any difference.

[mikeinnaples]

I took 500mg fisetin for two days and didn’t feel any difference.

 

 

Nobody would expect 500mg of Fisetin for two days to have any dramatic affect that someone would 'feel'.

[OP2040]

Nobody would expect 500mg of Fisetin for two days to have any dramatic affect that someone would 'feel'.

 

Exactly.  This kind of nonsense if all too common here.  It's one thing if someone says that and then elaborates a bit.   But so many of them are immediately dismissive one-liners.  Maybe that's how they should conduct clinical trials, based on people's subjective feelings. MikeDC is a special case though, as he downs anything and everything that is not NR as he has all his money invested in them or something. 

 

On another note, I may have just screwed up trying to save some money.  I almost always buy from Amazon.  But in an attempt to save some money I bought 6 bottles from a company called herbspro.  Then I read all the terrible reviews after lol.  Most of the reviews are concerned with customer service or long wait times, so I'm hoping it's just that and they will eventually send me the correct product at least. 

Edited by OP2040, 04 December 2018 - 03:37 PM.

[Oakman]

this is good: https://www.ncbi.nlm...les/PMC4708959/

 

if anyone has thoughts please post

looks like using equal amounts olive oil, tween 80, and twice as much propylene glyco as either one of oo and tween 80. works for reserv.

but for 1000 mg a day of Fisetin while fasting for 5 days for example, amounts of those 3 to mix the 1000 mg of F. in??

 

Thoughts?

 

The question is, does Fisetin have the same dissolution characteristics in these chemicals as Resveratrol does? I guess it would have to be tested, as they did in the study.

 

Also from briefly looking over the study, although the chemical characteristics were better in the enhanced formula, the in vivo results for the bio-markers they tested for were remarkably similar. Further, to save the cost and hassle of purchasing/making this solution, it appears you could simply use more straight Resveratrol.  And this is the case for many "enhanced" formulations, "Does the added cost, complexity, and results of an enhanced delivery methods outweigh the cost of simply using more unadulterated material to get effectively the same result?"

[MikeDC]

Simple oral Resveratrol lowered blood glucose while more fancy methods raised blood glucose. Does it mean that Resveratrol raises blood glucose. But some broken down pieces lowers blood glucose?

[ambivalent]

I took 500mg fisetin for two days and didn’t feel any difference.

 

This could easily be down to known poor bioavailability, I'm confident there were effects when taking 3g of Fisetin mixed in olive oil (post 208), but very possibly with some risk of loss of blood clotting function.

 

Incidentally, it would seem to a sensible idea to create a senolytics forum. 
 

Edited by ambivalent, 04 December 2018 - 04:32 PM.

[Nate-2004]

This could easily be down to known poor bioavailability, I'm confident there were effects when taking 3g of Fisetin mixed in olive oil (post 208), but very possibly with some risk of loss of blood clotting function.

 

Incidentally, it would seem to a sensible idea to create a senolytics forum. 
 

 

This is always a big problem with everything, especially flavinols. They're highly fat soluble but even then rarely make it in. When I tried it during my last extended fast I actually put a tsp of MCT oil into it, just enough to not break the fast. Doubt it was enough but  ¯\_(ツ)_/¯

[ambivalent]

 

Over the next couple of days I noticed my likely arthritic knee worsened noticeably, my other largely problem free-knee also become painful, albeit considerably less. This flare of injuries can be quite common during fasting as healing occurs. The last few days has seen a stubborn post sleep neck-kink. Its not that common for me to get them these days, and they rarely hang around this length of time. Again, though, a fairly weak Fisetin-effect.

 

 

{extract from post 208}

 

 

My knee now is I would say stronger than pre-Fisetin. The process feels similar to that experienced during longer fasts where old injuries flare up but subsequently heal better. The knee has improved considerably this year which I attribute to NMN as well as possibly stem cell therapy. My sense is there is more pain free movement under pressure now than before the senolytic and as mentioned if definitely worsened after taking fisetin (3g mixed with olive oil) . If so it would at least be consistent with this study:

 

www.medicalnewstoday.com/articles/317185.php

 

Not so good for the older mice, though, on regrowth.

 

(my arthritic knee is likely due to a youthfully sustained cruciate knee injury)

[stefan_001]

https://link.springe...0522-018-9785-1

In addition, EGCG treatment also suppressed the accumulation of anti-apoptotic protein Bcl-2 in senescent cells thereby promoting apoptosis mediated cell death. Our results collectively show that EGCG acts as an mTOR inhibitor, SASP modulator as well as a potential senolytic agent thereby indicating its multi-faceted attributes that could be useful for developing anti-aging or age-delaying therapies.

[male_1978]

I have some very practical questions.

 

Assuming that you wanted to try the effects of fisetin with a relatively safe dosage.

 

- Which amount of fisetin would you use and which dosage?

- How long would you take it

- Which Biomarkers would you test before and after the intervention?

- Would you still take NAD+-boosting supplements during that time or no? Why?

 

Thanks!

[PAMPAGUY]

I would encourage people to read this article on Fisetin from joshmittledorf science blog.  Benefits and dangers.

 

https://joshmitteldo...-new-senolytic/

[sthira]

- Which amount of fisetin would you use and which dosage?
- How long would you take it
- Which Biomarkers would you test before and after the intervention?
- Would you still take NAD+-boosting supplements during that time or no? Why

These are good questions. In the Phase 2 Mayo pilot study "Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Women" Kirkland et al are trying fisetin on recruited "70 to 90 year old women 20/mg/kg/day, orally for 2 consecutive days, for 2 consecutive months." https://www.clinical...outcomemeasures

What frailty biomarkers are they testing beyond gait?

For self-testing your own home effects of senescent cell clearing, you might try skin, bone, or organ biopsies -- haha just kidding, don't do that (with booze, kitchen utensils and Amazon microscope)

Meanwhile, you could try standard measures like blood pressure, heart rate variability, common blood tests including inflammation markers, who knows, maybe : https://www.wellnessfx.com/baseline

Regarding NAD+, I swallowed Dartmouth-patented products at (recommended) dosages (such as they are) for about a year of anticipatory hope before.... um ... aww.. I ... gave up. https://www.npr.org/...ke-oil-salesmen

Niagen might work brilliantly for you, though! But in my ignorance, I don't even know if "raising NAD+ levels" in "normally healthy, aging humans" is a health benefit. Is it? Why did the human body -- evolving as it did for eons -- naturally select to lower NAD+ as it ages? It didn't do that for no reason. Or maybe it did do that for no reason. Maybe Mother Nature said to human bodies, ok, you're done breeding now, you're done raising sniveling off-spring, go now, I'm done with you, die. Next.

Futz with raising or lowering or pulsing NAD+ levels all we want, but we can do it for free, right? Stop eating? Fast? Limit calories?

Meanwhile, we have no longer term guidance in this for humans. But I'm not despairing because five years ago I didn't even know what "senescent cells" were yet, or why removing them might be healthy. We have nice preliminary science.

Also, fisetin is one of thousands of compounds found in humble strawberries, maybe not enough fisetin is within strawberries to get "therapeutic benefits" but strawberries taste fine.

[Daniel Cooper]

I have some very practical questions.

 

Assuming that you wanted to try the effects of fisetin with a relatively safe dosage.

 

- Which amount of fisetin would you use and which dosage?

- How long would you take it

- Which Biomarkers would you test before and after the intervention?

- Would you still take NAD+-boosting supplements during that time or no? Why?

 

Thanks!

 

 

On the last question, I would halt all supplements during the relatively brief time that I was dosing with a senolytic.  I just don't want to have any potentially confounding untested factors mucking things up.  The only exception to that is I might try it with some other known senolytics like curcumin with the thought that I might get some synergistic activity.  But, I'd still probably run some fisten only rounds, just in case I got some "dis-synergy".

[Oakman]

These are good questions. In the Phase 2 Mayo pilot study "Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Women" Kirkland et al are trying fisetin on recruited "70 to 90 year old women 20/mg/kg/day, orally for 2 consecutive days, for 2 consecutive months." https://www.clinical...outcomemeasures

What frailty biomarkers are they testing beyond gait?

For self-testing your own home effects of senescent cell clearing, you might try skin, bone, or organ biopsies -- haha just kidding, don't do that (with booze, kitchen utensils and Amazon microscope)

Meanwhile, you could try standard measures like blood pressure, heart rate variability, common blood tests including inflammation markers, who knows, maybe : https://www.wellnessfx.com/baseline

Regarding NAD+, I swallowed Dartmouth-patented products at (recommended) dosages (such as they are) for about a year of anticipatory hope before.... um ... aww.. I ... gave up. https://www.npr.org/...ke-oil-salesmen

Niagen might work brilliantly for you, though! But in my ignorance, I don't even know if "raising NAD+ levels" in "normally healthy, aging humans" is a health benefit. Is it? Why did the human body -- evolving as it did for eons -- naturally select to lower NAD+ as it ages? It didn't do that for no reason. Or maybe it did do that for no reason. Maybe Mother Nature said to human bodies, ok, you're done breeding now, you're done raising sniveling off-spring, go now, I'm done with you, die. Next.

Futz with raising or lowering or pulsing NAD+ levels all we want, but we can do it for free, right? Stop eating? Fast? Limit calories?

Meanwhile, we have no longer term guidance in this for humans. But I'm not despairing because five years ago I didn't even know what "senescent cells" were yet, or why removing them might be healthy. We have nice preliminary science.

Also, fisetin is one of thousands of compounds found in humble strawberries, maybe not enough fisetin is within strawberries to get "therapeutic benefits" but strawberries taste fine.

 

A good summation. Esp. the comments about what Nature has intended for us. It's blatantly obvious that EVERYTHING ages and dies into its constituent molecules in this universe...everything...from stars to the whole universe (well, we think) to plants and people. It only makes sense, we are a physical presence, and so we break down in every way possible. Nature is telling us that it is simply too difficult, nay impossible, to keep anything from experiencing entropy over time.

 

Anything and everything we do is only delaying the eventual decay to ashes. Not to say we shouldn't try to delay the inevitable with the good fight, but in the end...

[stefan_001]

I think nature decided to give us a brain so we have a chance to fix its mistakes like the fact we die too soon, get sick etc.

Edited by stefan_001, 07 December 2018 - 09:32 PM.

[sthira]

"Just Say No To Entropy" -- I'll clear space on the back of my Subaru for another sticker.

I think we should fight! But I was just saying I don't think we know how much fisetin to take in order to clear senescent cells, or even if we should take fisetin, and if we should take it, then for how long, and if we did know for how long, then we'd still have these other metabolic challenges, which led to this NAD+ reckoning.

Assuming Mother Nature gradually reduces humanity's NAD+ because Mother Nature doesn't care about us after we're done reproducing -- boo hoo -- then we should seek to repair the cause of the depletion organ by organ. I think that's where the science is going -- or should be -- repair rather than just replenish with precursors.

[sthira]

@sthira what if it is not about repair? Perhaps the human body internal state is simply instable and processes go pear shaped. Organ damage follows. There is no intelligence inside a cell or the wider organism, its just a balance of processes and some will start to run away. Replenish helps us steering the "process" back to "safe" terretory.

I don't think rpair and replenish are mutually exclusive; we do both (and more) until we're dead. But evolution had no incentives to keep at it for as long as, say, Turritopsis dohrnii, the immortal jellyfish.

Now we have incentives and a growing stash of tools. The merging of the life sciences with the computer sciences we hope shall extend human lifespan. If we merge our carbon-based biology with the non-carbon, we'll create a new species. Humanity 2.0.

On one hand, we evolved brains to fix mistakes, you wrote, like we die too soon, and then on the other hand we have no intelligence inside our cells or within the wider organism, you also wrote. I agree we have insufficient intelligence on our own to extend human lifespan for as long as an ocean quahog. But we're busy creating new tools to help us do it.

Edited by sthira, 08 December 2018 - 02:41 AM.