1079 replies to this topic

[sthira]

I think people are right about "noticing" things, I'm not sure what people are trying to notice without lab work and testing like pre/post BP and HRV and other factors. Also it may only be a significant impact over the long run. Like, if senescent cells are something that builds up over time then killing what few there are in one's 40's may stave off a buildup for a decade.

I'm one of those who questions "noticing" things, and I'm not sure what to notice by trying various experiments combining fasting with D+Q. I did these self-experiments last year (D+Q+ PF), and what did I expect to feel? I don't know. But I had blood tests taken before and after, and the numbers didn't change from healthy baseline.

Regarding (unreliable) subjective experiences, however, I now notice both higher energy levels and lower energy levels.

For higher energy, I mean once my body gets revved up and into action, I have so much energy it's ... sick. Like, I feel as if my body can go on and on into increasingly extreme physical exertion. I like it. My increased stamina is remarkable, I'm even called "Energizer Bunny" by colleagues, and feel as if I have to work sometimes to contain high energy. I wish I could bottle up that extra energy, and hold it in reserve for when I need it.

For lower energy, I notice that once my body calms down and I sleep, or I have extended rest days from my vigorous profession, I feel like I could just hibernate the winter away. I'd be happy for months just being asleep. Put me to sleep, I'd sleep the months away in happy self-renewal.

Once I'm up, I'm way up. Once I'm down, leave me alone, world, I'm happy in recovery. I can't think of a way to measure these two energy states, though, without expensive brain imaging. Maybe treadmill testing lol.... And I'm not sure these effects are even real.

Prolonged fasting alone, with rest, is claimed to send the body into deeper regenerative cycles; breaking these prolonged fasts is then claimed rebuild parts of the body that were damaged, and then providing the body with more energy. That's the claim, anyway.

I'm giving credit to the fasting, though, and my 10% daily CR practice because (for me) I think the D+Q was useless in "clearing senescent cells." I'm not sold on these items clearing zombie cells in already healthy human bodies.

This writing has nothing to do with fisetin, however; but I also noticed nothing from high doses of fisetin combined with prolonged fasts (5-10/d).

[Nate-2004]

It may be you have no more death resistant senescent cells to kill haha.  I'll probably stop trying after this and just fast for weight maintenance instead. There are other hallmarks of aging to work on besides senescent cells. This current fast is one of the harder ones for me, not sure why, but I'm just constantly thinking of food. It'll be 96 hours around 18:00 today and I'll be done in the morning.

Edited by Nate-2004, 20 December 2018 - 04:06 PM.

[brasscupcakes]

op2040 thank you very belatedly for your thoughtful response to my questions. I will probably follow your lead and try occasional fisetin megadoses to clear out senescent cells. re rectal administation of supplements: it is regrettable that there isnt more interest here. injections and iv administation are too costly for most of us. homemade lipsomal concoctions even when successfully formulated take much time to prepare and taste dreadful. if suppositories showed high bioavailabilty the benefits might make the squick factor irrelevant but there is scant data on the subject. Thanks again for your great posts and happy holidays!

[RichardAlan]

For those who are already taking Fiseting, what dose and frequency are you taking.  Also where are you sourcing the supplement from?

[Ovidus]

...

Regarding (unreliable) subjective experiences, however, I now notice both higher energy levels and lower energy levels.

For higher energy, I mean once my body gets revved up and into action, I have so much energy it's ... sick. Like, I feel as if my body can go on and on into increasingly extreme physical exertion. I like it. My increased stamina is remarkable, I'm even called "Energizer Bunny" by colleagues, and feel as if I have to work sometimes to contain high energy. I wish I could bottle up that extra energy, and hold it in reserve for when I need it.

For lower energy, I notice that once my body calms down and I sleep, or I have extended rest days from my vigorous profession, I feel like I could just hibernate the winter away. I'd be happy for months just being asleep. Put me to sleep, I'd sleep the months away in happy self-renewal.
....

 

This is very remarkable. 
And you were not such an "either on or fully off" type of person previously? To me this sounds like a very dramatic effect -as difficult as it may be to quantify.

 

After how many rounds of (D+Q+ PF) have you started feeling this? Is this something that materialized suddenly or was there a shift towards this sort of state little by little?

 

Thanks

[sthira]

This is very remarkable.
And you were not such an "either on or fully off" type of person previously? To me this sounds like a very dramatic effect -as difficult as it may be to quantify.

After how many rounds of (D+Q+ PF) have you started feeling this? Is this something that materialized suddenly or was there a shift towards this sort of state little by little?

Thanks

First, tbh I am sort of an "either on or off type person" so take my self-observations with rolled eyes. I do feel as if these on-offs have deepened, however, but that could be placebo. Or it may be a combination of placebo and the real effects that fasting alone, minus the compounds. I'm not giving much cred to these compounds for several reasons.

Here are my skeleton notes of last year's experiment :

"Adventures in D+Q+ Fasting:

"Round 1: Tues 4/11/17
144.4 lbs (am)
Fast: Day 5 (120hrs)
Green smoothie 1130am
Green smoothie 730pm
****Dasatinib: 50 mg 8pm (1)
****EMIQ: 300 mg 8pm (1)
145.4(pm)
BP: 95/50
Felt nothing unusual

###

Round 2: Weds 4/12/17
Started eating @8am (post-136.5 hrs fast)
Stopped eating @ 2pm
*****Dasatinib: 70 mg (3pm)
*****EMIQ: 400 mg (3pm)
*****Dasatinib: 70 mg (830pm)
*****EMIQ: 400 mg (830pm)
148.0 lbs(pm)
BP: 100/65

Thurs 4/13/17
Very weak, refed, felt no difference between fasting alone and D+Q

###

Round 3: Mon 9/11/17
Fast: Day 2 (48hrs)
YTD: 68

*****100mg dasatinib (noon)
*****400mg EMIQ (noon)
*****80mg dasatinib (730pm)
*****500mg EMIQ (730pm)
Felt nothing unusual

###

Round 4: Fri 12/29/17
Fast Day 4 (96hrs)
YTD: 102
*****100mg dasatinib (430pm)
*****400mg EMIQ (430pm)
Felt nothing unusual

####

Round 4.1: Mon 4/7/18
Fast Day 3 (72hrs)
151.4 lbs
BP: 88/58
*****550mg EMIQ (230pm)
No dasatinib
Felt nothing unusual"

If blood tests had changed, I'd include them. They didn't. Standard ole' boring and barely relevant blood values stayed within ranges before and after the heroics of self-experimentation, so there's no use listing them here.

I wanted to report something objective, so I measured my vertical leap (which is important to me) but sadly it has gone downward a few inches as the years drag me toward eventual oblivion.

I feel that when senescent cells become measurable to average consumers like me that this measurability will be an enormous advance. I wonder measurement tests will will be developed anytime soon and then shared with the general public?

For those who are already taking Fiseting, what dose and frequency are you taking. Also where are you sourcing the supplement from?

For my experiment this year with fisetin, I took Doctor's Best in combo with fasting. On days 4, 5, and 6 earlier this year I took a gram each day. I felt nothing, didn't test blood values, have nothing objective to report, and I probably won't try this experiment again until we hear more about the clinical trial currently underway (that's still recruiting) in humans (elderly females).

[Oakman]

Interesting read in this study on senescent therapy with valuable insights and some cautions. Probably posted before, nevertheless...

 

The role of senescent cells in ageing

 

A couple of paragraphs caught my eye because so many are saying "I felt nothing."  These results seem very pertinent to what many seem to experience. This 1st comment was related to cells in Vitro, so it could be logical to say that cells in vivo take even longer to show result after exposure to senescent compounds.

 

Cultured cells usually reach senescence within several weeks after exposure to senescence-inducing stressors, but remain viable for months thereafter42. Senescent cells continue to evolve even after extended periods of culture, thereby progressing to a stage that has been termed ‘deep’ or ‘late’ senescence 

 

....during ageing-related senescence, the switch from temporal to persistent cell-cycle arrest appears unscheduled and stochastic in nature, probably involving the combined effects of distinct senescence-inducing stressors acting simultaneously on a cell. The kinetics and efficiency of senescent-cell clearance may constitute another key difference between acute and chronic senescence. During repair and embryogenesis, disposal of senescent cells seems very efficient and under strict temporal control11–14. Conversely, ageing-related senescent cells, may be more persistent due to deterioration of the immune system with ageing70,71, but further experiments are needed to refine our understanding of the relationship between senescence and the (ageing) immune system.

 

...chronic senescent cells which develop after a prolonged period of gradually increasing cellular stresses are expected to exhibit high SASP heterogeneity due to a more complex and diverse spectrum of effector pathways involved in establishing this type of longer lasting senescent state. SASP heterogeneity may therefore be a mechanism to create subsets of senescent cells that are highly resistant to immune clearance and drive tissue degeneration.

[Ovidus]

Thank you so much sthira

I really appreciate the detailed response

[Rocket]

If people feel nothing from taking senolytics, then assuming they are odd enough to have S cells, then it isn't working.

Senescent cells "leak" chemicals into the body that make the body less healthy. If you take something to wipe out those cells, then all those "bad" chemicals will be released in a very short time and make the host feel ill as all those millions of S cells are killed. If you feel nothing, either the drug dose not work or the dose is too low.

[eigenber]

Or, if the leaky chemicals hypothesis is true, then it might be that there wasn't enough senescent cells in the body to generate ill feeling in the host.

[QuestforLife]

Interesting read in this study on senescent therapy with valuable insights and some cautions. Probably posted before, nevertheless...

The role of senescent cells in ageing

A couple of paragraphs caught my eye because so many are saying "I felt nothing." These results seem very pertinent to what many seem to experience. This 1st comment was related to cells in Vitro, so it could be logical to say that cells in vivo take even longer to show result after exposure to senescent compounds.

Cultured cells usually reach senescence within several weeks after exposure to senescence-inducing stressors, but remain viable for months thereafter42. Senescent cells continue to evolve even after extended periods of culture, thereby progressing to a stage that has been termed ‘deep’ or ‘late’ senescence

....during ageing-related senescence, the switch from temporal to persistent cell-cycle arrest appears unscheduled and stochastic in nature, probably involving the combined effects of distinct senescence-inducing stressors acting simultaneously on a cell. The kinetics and efficiency of senescent-cell clearance may constitute another key difference between acute and chronic senescence. During repair and embryogenesis, disposal of senescent cells seems very efficient and under strict temporal control11–14. Conversely, ageing-related senescent cells, may be more persistent due to deterioration of the immune system with ageing70,71, but further experiments are needed to refine our understanding of the relationship between senescence and the (ageing) immune system.

...chronic senescent cells which develop after a prolonged period of gradually increasing cellular stresses are expected to exhibit high SASP heterogeneity due to a more complex and diverse spectrum of effector pathways involved in establishing this type of longer lasting senescent state. SASP heterogeneity may therefore be a mechanism to create subsets of senescent cells that are highly resistant to immune clearance and drive tissue degeneration.

It's a very good point Oakman. Not only do various in vitro studies use different cell types but also use different methods to induce senescence - passaging, radiation, chemicals, etc. It is likely age related cellular senescence is induced by a wide range of factors and so any one method found in an in vitro study may only affect some of them.

The fisetin study atleast also looked at mice, so we can have more hope it will be efficacious.

I for one however, think most of aging in humans occurs pre-senescence, i.e. pre full arrest and we will likely not experience the same benefits mice do. But it is only my opinion, and it would be nice to be proven wrong.

[Mind]

If people feel nothing from taking senolytics, then assuming they are odd enough to have S cells, then it isn't working.

Senescent cells "leak" chemicals into the body that make the body less healthy. If you take something to wipe out those cells, then all those "bad" chemicals will be released in a very short time and make the host feel ill as all those millions of S cells are killed. If you feel nothing, either the drug dose not work or the dose is too low.

 

I would tend to think older people would be more likely to subjectively "feel" something from senolytic therapy, since most of them have a lot more senescent cells and SASP signalling.

 

I am not sure if the "bad chemical"-release-thought is appropriate here, because senescent cells produce "bad signalling", they don't store large volumes of deleterious signalling chemicals (as far as I am aware).

 

On the whole "feeling" something when engaging in various therapies, I don't think this is a very valuable metric nor should we expect it to be. Most of the current supplements we take for slowing or reversing aging (including new experimental senolytics), are only marginally effective, as far as we know, and only address one of the incredible multitude of the ways we age. We shouldn't expect "one silver bullet to kill a thousand different werewolves". Objective testing is the key. i am particularly interested in functional testing, like reaction time, memory recall, etc...

[OP2040]

op2040 thank you very belatedly for your thoughtful response to my questions. I will probably follow your lead and try occasional fisetin megadoses to clear out senescent cells. re rectal administation of supplements: it is regrettable that there isnt more interest here. injections and iv administation are too costly for most of us. homemade lipsomal concoctions even when successfully formulated take much time to prepare and taste dreadful. if suppositories showed high bioavailabilty the benefits might make the squick factor irrelevant but there is scant data on the subject. Thanks again for your great posts and happy holidays!

 

Thanks brasscupcakes!  Wishing you all the best for whatever path you decide to take.

[QuestforLife]

I am not sure if the "bad chemical"-release-thought is appropriate here, because senescent cells produce "bad signalling", they don't store large volumes of deleterious signalling chemicals (as far as I am aware).

Well we do know dying cells release apoptosis products and some of those can be quite harmful, like mitochondrial DNA that causes sterile inflammation. But those apoptosis products also include the signalling molecules that spur regeneration. So it's hard to say whether removing senescent cells is helpful because they are no longer present, or because of the regeneration that their removal spurs, assuming it does so (in aged humans with limited regenerative potential).

In my view the more 'silver bullets' you require, the less you understand aging. Once it's completely understood a single silver bullet will probably suffice.

[Harkijn]

Getting back to Mind's main point: the trouble with SCs is not so much their toxicity but the fact that they are stuck in a loop producing an inordinate amount of bad signals compared to their size.

It seems to me too that most relatively healthy people will not notice anything in particular from senolytics. However, perhaps wishful thinking, what about people with rather mysterious chronic diseases such as polyneuropathy? This condition is so crippling that many sufferers are willing to spend  money on vitamins that might give some relief. It would be feasible as well as ethical to experiment with plantbased senolytics. And an effect if any could be measureable.....

[Turnbuckle]

On the whole "feeling" something when engaging in various therapies, I don't think this is a very valuable metric nor should we expect it to be. Most of the current supplements we take for slowing or reversing aging (including new experimental senolytics), are only marginally effective, as far as we know, and only address one of the incredible multitude of the ways we age. We shouldn't expect "one silver bullet to kill a thousand different werewolves". Objective testing is the key. i am particularly interested in functional testing, like reaction time, memory recall, etc...

 

If you are old enough and the senolytic strong enough, you will certainly feel something. But that response will decline with the level of senescent cells, and that makes it difficult for a self-experimenter to compare different regimes. I agree that any one senolytic is unlikely do the job as there are two hundred cell types and likely a spectrum of senescent cell sensitivities within each cell type. Thus in vitro experiments with a single cell type made senescent by a single chemical shouldn't get anyone too excited. 

Edited by Turnbuckle, 24 December 2018 - 11:47 AM.

[johnross47]

Bearing in mind all of the issues above, I am about to try this for a second time. The first time I took 600mg for five days. This time I'm taking 1g for three days, because of the discussion of doses further back. Watch this space.

 

[male_1978]

I have a question: A friend of mine who had a metastatic cancer and suffered from chemotherapy wants to try out 3g of fisetin. He makes a full blood analysis every three weeks.

 

Are there any values in the blood analysis where we could expect to see a difference? What changes could you imagine?

 

 

[stefan_001]

I have a question: A friend of mine who had a metastatic cancer and suffered from chemotherapy wants to try out 3g of fisetin. He makes a full blood analysis every three weeks.

 

Are there any values in the blood analysis where we could expect to see a difference? What changes could you imagine?

 

I would also use polyphenols in case of cancer. Some of them have been also shown to have synergetic effects in combination with chemotherapy or other treatment. My recommendation would be to first go to pubmed or google scholar and search for the name of the polyphenol and cancer type to find out if fisetin is the best option. Other compounds:

- honokiol

- luteolin

- curcumin

- and some more

[stefan_001]

Bearing in mind all of the issues above, I am about to try this for a second time. The first time I took 600mg for five days. This time I'm taking 1g for three days, because of the discussion of doses further back. Watch this space.

 

I have used fisetin at 200-300mg level for very long time, several stretches of months long. SImlarly I have done some high doses. Personally I don't quite believe in the couple large shots. I dont think you will wipe out a lot of cell overnight.
 

[Oakman]

I have used fisetin at 200-300mg level for very long time, several stretches of months long. SImlarly I have done some high doses. Personally I don't quite believe in the couple large shots. I dont think you will wipe out a lot of cell overnight.
 

 

That is a very good question that certainly has not been adequately answered. On one side you have the mouse studies that show, yes, you can remove senescent cells quickly with a one shot, high dose regimen. On the other hand, I don't believe anyone has done any studies of a lower, longer dose regimen for senescence,

 

It's hopefully possible to remove senescent cells more gradually with a continuous lower dose, in fact, I've done that @100mg/day for months. The bigger question is, how to tell if it did anything? And really, how to tell anything conclusive in humans, regardless of dose? There are so many different tissues that could benefit, and different molecules are required, depending. There is a current study with humans, whereby Fisetin 20/mg/kg/day, is given orally for 2 consecutive days, for 2 consecutive months.. Will be interesting to see what comes of that.

 

https://clinicaltria...how/NCT03430037

[Zisos]

I have noticed that 'Unity Biotechnology' has osteoarthritis as the first target. As I understand, they inject their senolytic substance in the joint, and presumably new cartilage will grow after senescent cells die. .

 

If  Unity's senolytic substance is effective, I would expect that fisetin might also be effective.

 

It would be interesting to know:

a) If this makes sense as a possibility

b) If so, what would be an appropriate solvent?

c) What would be the dose? (For knee / for finger)

d) Would 'iontophoresis' be a more appropriate delivery method (to avoid injection)?

 

Has anyone tried it, or does anyone have any suggestions?

 

Thank You

 

 

[able]

That is a very good question that certainly has not been adequately answered. On one side you have the mouse studies that show, yes, you can remove senescent cells quickly with a one shot, high dose regimen. On the other hand, I don't believe anyone has done any studies of a lower, longer dose regimen for senescence,

 

It's hopefully possible to remove senescent cells more gradually with a continuous lower dose, in fact, I've done that @100mg/day for months. The bigger question is, how to tell if it did anything? And really, how to tell anything conclusive in humans, regardless of dose? There are so many different tissues that could benefit, and different molecules are required, depending. There is a current study with humans, whereby Fisetin 20/mg/kg/day, is given orally for 2 consecutive days, for 2 consecutive months.. Will be interesting to see what comes of that.

 

https://clinicaltria...how/NCT03430037

 

 

Yes, it is a good question. If it actually has potential to make a huge improvement from 2 doses, that will be very exciting.

 

I love that this clinical trial is testing for improved mobility (Improved 6 minute walk - gait speed) as the primary endpoint.  

 

Kinda seems like they expect it to make a noticeable difference.  

 

On another tack, I don't understand why some people here seem to view senolytics as competition for NAD+ boosters.  I see  them as having great potential as complementary therapies.  

 

Removing senescent cells to decrease systemic inflammation should conserve NAD+, making it easier for NAD+ boosters to restore youthful levels.  

[xEva]

I have noticed that 'Unity Biotechnology' has osteoarthritis as the first target. As I understand, they inject their senolytic substance in the joint, and presumably new cartilage will grow after senescent cells die. .

 

If  Unity's senolytic substance is effective, I would expect that fisetin might also be effective.

 

It would be interesting to know:

a) If this makes sense as a possibility

b) If so, what would be an appropriate solvent?

c) What would be the dose? (For knee / for finger)

d) Would 'iontophoresis' be a more appropriate delivery method (to avoid injection)?

 

Has anyone tried it, or does anyone have any suggestions?

 

Thank You

 

I don't think that injecting something, especially into a knee joint, which requires  knowledge of anatomy +hands-on experience, not to mention a good chance of introducing an infection or inducing an allergic reaction by preparing a solution yourself from the ingredients whose sterility is not even mentioned by vendors, is something a person without a specialized education should even consider. Which leaves only (d) on your list. I would be very interested to learn what a iontophoresis expert would say.

Edited by xEva, 04 January 2019 - 03:48 AM.

[RichardAlan]

 

The Mayo Clinic is doing a study of Fisetin 

Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Adults (AFFIRM-LITE)

Fisetin 20/mg/kg/day, orally for 2 consecutive days, for 2 consecutive months.

https://clinicaltria...cntry=US&rank=2

 

 

Can someone clarify this for me.  Does this mean for example just four treatments on January 1 & January 2 and then February 1 and February 2?

[RichardAlan]

ok, I think I've settled on this routine.  The study VP posted would equate to 1700 mg for someone my size

 

I am going to go for 1000 mg for 5 days, throw the remainder in the last day.  I was thinking of taking a nac before each just in case my liver needs the extra protection, though I sincerely doubt it's necessary, I have it so I'm going to use it.  Then not sure if repeat at year 1/5/10?  Seems weird to not take a supplement daily, but it doesnt seem necessary to do so.

 

What's a nac? 

[male_1978]

I have used fisetin at 200-300mg level for very long time, several stretches of months long. SImlarly I have done some high doses. Personally I don't quite believe in the couple large shots. I dont think you will wipe out a lot of cell overnight.
 

 

Ok, lets discuss this.

 

200-300 mg equals about 1,5 kg of strawberries a day. Thats probably more than people usually eat regularily. From this standpoint one could expect an outcome which is beyond experiences from healthy food.

 

However, by this study (https://www.ncbi.nlm...2/figure/f0005/ ) i would asssume that another substance, curcumin is about half as effective as fisetin. If i take the double dose to get a similar effect this would be about 500 mg of curcumin. Anyone could get this from eating 5 gram of tumeric daily, which is only one teaspoon. I assume that many people in india eat this amount without thinking about it for decades.

 

The question to me is: Do people in india age differently?

[Harkijn]

Can someone clarify this for me.  Does this mean for example just four treatments on January 1 & January 2 and then February 1 and February 2?

Yes, that is how I interpret it. And I assume that the dosage is per kg bodyweight. So a lady weighing 50kgs will get 1000mgs on day 1, 1000mgs on day two, then waits for a month and repeats the procedure. Then the researchers remeasure their gait.

It would be really spectacular if there was a measurable improvement.  Some studies seem designed to discredit certain substances...

[Harkijn]

Ok, lets discuss this.

 

200-300 mg equals about 1,5 kg of strawberries a day. Thats probably more than people usually eat regularily. From this standpoint one could expect an outcome which is beyond experiences from healthy food.

 

However, by this study (https://www.ncbi.nlm...2/figure/f0005/ ) i would asssume that another substance, curcumin is about half as effective as fisetin. If i take the double dose to get a similar effect this would be about 500 mg of curcumin. Anyone could get this from eating 5 gram of tumeric daily, which is only one teaspoon. I assume that many people in india eat this amount without thinking about it for decades.

 

The question to me is: Do people in india age differently?

Well, in the literature the relatively low incidence of Alzheimers in India (as compared to US and EU) is often hypothesized to be related to curry use...

[Zisos]

I don't think that injecting something, especially into a knee joint, which requires  knowledge of anatomy +hands-on experience, not to mention a good chance of introducing an infection or inducing an allergic reaction by preparing a solution yourself from the ingredients whose sterility is not even mentioned by vendors, is something a person without a specialized education should even consider. Which leaves only (d) on your list. I would be very interested to learn what a iontophoresis expert would say.

 

Thank you for your comment xEva.

 

I fully agree with you. I would never think of injecting into a joint at home. In fact, I would even hesitate to have a professional do it. This is exactly the reason that I am asking about 'iontophoresis'.

Your comment about the 'sterility of fisetin is not mentioned by the manufacturer' is also very valid. I did not think about it.

 

Maybe I did not phrase my question correctly:

What I really meant to ask is this:

-Would it be prudent to 'deliver' fisetin directly to the joint? (not considering the method of delivery)

-If so, what would be the most appropriate solvent?

 

And assuming it is prudent to do so:

-Would 'iontophoresis' work?