Fisetin to Clear Senescent Cells

Fairy8i8 What do you think the fisetin is doing that is only lasting a few weeks? It cant be senescent cells building back up that quickly especially at your age of 38.

Fred Cloud Of course senescent cells can build up that quickly if you review the studies. Also, you need to assume that not all senescent cells were removed, and senescent cells still in the body promote more cells to become senescent. That, and I am basing it off of skin cells and visual queues. I live at a high elevation and have only started to use sunscreen this past week. Being above 3000 feet, I am exposed to more UVA than people at lower elevations, and UVA has been shown to be a major cause of skin wrinkling. So while I have cleared senescent skin cells, I haven't cleared 100%, and the UVA continues its damage, with repair capabilities decreasing as you age. I also live in a dry climate, which exacerbates the wrinkling. Apparently women living in Florida appear 10 years younger than women in my state because of the humidity. I have seen an increase in aging in the last year. Bodies age through multiple means, not just senescence. 

Fairy8i8 I am starting to realize you are right, after reading others reporting that the effects last a few weeks and then they have a reversion into the sasp mode. I have been reading alot and have seen the experts just assume you would only need to kill off senescent cells maybe once or twice a year and that seemed plausible but I don't think it is true. You need to listen to your body and see how long the results last and adjust your timing based on reversion of symptoms.

Fairy8i8 Looking at some studies technically it is a rate of clearing senescent cells that decreases with aging and slows down 5x. So, our immune system leaves senescent cell around for much longer as we age. As I see it there could be three approaches to solve it 1) Intervention leading to fewer senescent cells through inhibition of CD38 and promotion of increase in intracellular NAD+ levels. This leads to boosting immune system to be able to clear more cells. It doesn't appear to be a favorite topic on this forum. But it is an elegant approach and I suspect a part of real solution. I think it is better to clear the senescent cells that need to be cleared continuously and only do being cleaning occasionally.  2) Senolytics (Fisetin and others). Utilizing mega doses of some harsh senolytics just seems to drastic.  Also, human body is not lab mouse body. Even if senolytics work (remove all cells that need to be removed), this doesn't address the rate of immune system slowing down clearing the cells. So basically, you would need to use senolytics at least every 5 days? 3) suppressing senescence. Rapa, my preferred mode (only because it works and it is clearer on what to do and can be used topically too)

How about EltaMD UV Clear Broad-Spectrum SPF 46? It has good UVA protection and is moisturizing too. Retin-A over 6-12 months’ period can eradicate 40% of wrinkles too. Both are scientifically proven and supported by substantial amount of research to achieve what they claim to achieve.

Fred Cloud Many of the experts are starting companies to clear senescence, so they are looking at making drugs that would clear a lot more cells than just fisetin alone. Also, they are anticipating an expensive treatment (possibly using drugs like dasatinib), so of course they know most people would not take it monthly, nor might it be advised. That's what I like about fisetin - it has a history of human use, we have not yet found a toxic limit, though that may be studied more in the future as people take higher doses, and it is quite effective and cheap.

In the mouse studies, fisetin did not clear 100% of the senescent cells, so I do not expect it to clear all of them, which means more are being produced in the body regularly around the existing senescent cells. (Also, it does not clear all types of senescent cells, but does clear fat and skin senescent cells.) When they pulsed the dose every 2 weeks, by the last dose, the number of senescent cells increased from one cycle to the next, but at a small rate, so especially as you age, you should still expect some accumulation. The last trial in the study gave a higher dose, I think over 5 days, if I remember correctly, and then the animals were sacrificed and examined. This group had the greatest decrease in senescent cell number, but we do not know the lifetime effects because they were sacrificed soon after the dose.

I began with 2 days monthly because that was what the human study was doing at the time, so I figured that if researchers could get approval to give it to healthy 70+ year old women, then it would probably be okay for me too. As I said, the skin, particularly on my face, showed improvements, but the improvements would go away after a month. Skin has a pretty short turnover rate, and at my age, it is probably around 30 days, so seeing results diminish over this period is understandable, especially with regular UVA exposure. I decided that I didn't want to stay "steady state," but wanted continual improvement and clearing, so I began a 2 week cycle, and I am happy with it.

There are other ways to play with dosing - increasing the dose and doing it for 5 consecutive days, for example, but I am relatively young, so I do not feel the need to rush into something like that before there is a clinical trial, or we at least see the results of the human trials at the 2 days/month for 2 months level.

Joe smith You bring up some interesting points.

1) I am not familiar with CD38 inhibition, but I do take Elysium (a nicotinimide riboside supplement) to increase NAD+ production. I am interested in Nuchido Time+ to increase NAD+, but I haven't read of anyone using it or their results.

2) There is a minimum effective dose of Fisetin that makes it effective as a senolytic, and the mouse studies do show that increasing the dose does increase clearance. I wasn't sure myself, but seeing the nickel sized mole on my mom's face go away convinced me that fisetin, even at the about 100mg/pound dose for 2 days (just pills swallowed with water, no fancy mixing with oil or adding peperine) definitely does SOMETHING. She only took it for 2 days and didn't do it the following month, either, and I saw her 5 months later.  I think every 5 days would be too often. My husband, who had severe sepsis last year and was a day away from dying, says that taking it makes his muscles feel sore like a good weight lifting workout. The cells need time to rebuild and recover as well. Taking it too often would interrupt the rebuilding phase. 

It would be interesting to see if fisetin had a positive effect on clearing senescent immune cells and improving the immune response. At the very least, it could make the cells easier to clear. We do not know the mechanism, but it sure helped my mom and her mole, and she was 69.

I think UltaMD products are great, but I have a 4% nicotinamide cream that I use that already has the spf 50 in it, so I am starting there because I'd rather just use 1 cream on my face. I have not tried Retin-A because when I read the study, it reduced the appearance of fine lines and wrinkles in 40% of patients, NOT 40% of wrinkles. That means 60% of study participants saw NO fine line or wrinkle reduction at all. Because of the significant reddening and other side effects, I didn't want to go that route. I know that some inflammation can induce a healing response, but I'd rather do something periodically and have my skin heal completely than have something that creates chronic inflammation and irritation. My uncle had skin cancer, and he goes in to his dermatologist every year to have the area lasered. He has the doctor do his whole face at the same time, and he looks AMAZING. I would rather a treatment like that once a year - no underlying redness  or thin skin like you often get with Retin-A, just thick healthy looking skin and even skin tone.

Fairy8i8 1) Nuchido is quite interesting as the company is built around more modern concept important to the point I’m trying to convey here but clearly failing i.e. the single intervention by itself like taking NMN or NR or (I believe also senolytics) is counterproductive you take one step forward (your mole will shrink or you get more energy) and two steps back. Read her blog to get an idea https://nuchido.com/blogs/articles/ageing-nad-and-biological-complexity I don't know if her formula works, we need more testing but her scientific concept of network is very very interesting.
2) I want to apply the same concepts of networks to reducing senescence. What I believe you and other people on this forum and thread are accomplishing is short term positive gain but long term negative effect. Why? because you have to use two much senolytics and too often. I total agree with that every five days is too often but how with senolytics alone you can mimic what your body is doing when you are young? I don’t know and after reviewing a lot of the research on the subject I believe the researchers got no clue either. Hence, if anything you will need to accomplish it either through some senolytics which don’t yet exist or perhaps through network effect with other supplements and drugs together. Maybe all the ingredients already exist but cookbook is lacking? We need to make sure we don't take 2 steps backs.
3) Retin -A please don't look at one study but rather look at metastudy and drill down to individual studies. Also, what is the study that you are quoting? Please provide the link. Further I must disagree with you vigorously on your conclusions/statement son the subject. Please check out this metastudy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699641/ Tretinoin will reduce wrinkles and melasma in nearly all if not all the subjects that stick to it. The degree of it will of course vary. After a month or so you will look bad due to redness peeling etc. but then with long term use results show up. And no, your skin doesn't get thinner. If anything, it may get a bit thicker overall. The outer layer of course initially will do get thinner but then after 6-12 months it goes back to normal. If you have too much redness peeling go with weaker dose until your skin acclimates. And yes, both fractionated laser and RF micro needling work very well and produce beautiful results. Much more spectacular than Tretinoin. Also, they partially achieve their results by reducing number of senescent cells in the skin? Can you see the potential network effect here if you combine fractioned laser with senolytic or CR?

Joe smith Thanks! I'll look at the metastudy. I was referring to the study information included with the drug, which referenced the 40% of people saw a reduction (no specific amount of reduction given). There is also quality research on niacinamide as a topical. I follow some cosmetic chemists (thebeautybrains), and both Retin-A and 4% niacinamide were given an A rating by them as to quality double blind placebo controlled studies published in peer reviewed journals. I decided to go with the niacinamide first because it is over the counter and didn't cause irritation for me. All in all, I don't need redness and peeling when there are other options at this time and people still think I'm a college student. Topicals may enhance some things, but I prefer an overall health approach that will help not only my facial skin, but vital organs and other such functions. I'm not so into beauty to want to spend a bunch of money on it alone. I might try laser down the road, mostly because of the phenomenal results I saw with my uncle, and because I had a lot of sunburns on my face and shoulders as a child. If the laser his doctor is using prevents his skin cancer from coming back, then I am all about getting that done to prevent any problems of my own in the future. Besides, I already spend plenty on my anti-aging routine LOL!

Fairy8i8 Did I read this right, you wrote senescent cells increased when they pulsed the dose every 2 weeks? How could they end up with more senescent cells after the round of senolytics?

 "When they pulsed the dose every 2 weeks, by the last dose, the number of senescent cells increased from one cycle to the next,"

Joe smith So you feel increased senescent cell populations are mainly a lack of immune system clearance? Lets back up first, senescent cells are thought to occur from reaching hayflick limit and aged cells that dysfunction from age and telomere shortening, so as as a result senescent cells should occur at a higher rate in general but I agree it is certainly aggravated by a declining immune clearance rate.

Fred Cloud I don't feel. (well sometimes I do 🙂.) I'm only interested in the scientific proof, research and reason . Check this out Senescent cell turnover slows with age providing an explanation for the Gompertz law: https://www.nature.com/articles/s41467-019-13192-4

What do you think?

Fred Cloud Yes, you read that right. Fisetin does NOT get rid of 100% of senescent cells. It decreases the number.

Here is the study. Look at Figure 2B & 2C. Even at higher doses, like in Figure 4, it's still not 100%.

https://www.sciencedirect.com/science/article/pii/S2352396418303736

Fairy8i8 NAM is good and as you pointed out it has a solid research support behind it. It is meant to reduce irritation. In your dry climate I'd combine it with triglycerides for good skin barrier. And as you may know, you can buy quite potent retinoic acid OTC - adapalene 0.1%. OTC, It is a gel so it may be too drying for you but a cream version is the mildest of all retinoic acids and was meant to avoid skin irritation. You know people start retinoic acids in early twenties and I saw beautiful maintenance results after 15/20 years of continuous use. Anyway I agree with you that overall health approach is even more important. My issue is that we need to bridge the gap between research studies on senolytics on mice and what we need to do ourselves. In my mind it starts with simple testing on small short lived primates to establish safety and then drill down into dosages and safe amount. No efficacy for now. Just safety. I believe we need to do it ourselves. before some people die. Now!

Fairy8i8 Sorry for the confusion. I did not mean or question the 100% clearance. I was referring to when you said senescent cell amounts increase after taking a round of senolytics.

"senescent cells increased when they pulsed the dose every 2 weeks"

How is that possible that would you have more senescent cells after killing some of them off with a senolytic round?

Joe smith They have done safety studies on fisetin. The standard ones to determine toxicity of a substance. It doesn't seem to be very toxic. It's also been a supplement and taken for over a decade at lower doses by humans. I'm not worried about safety, but I also read various studies where they looked at potential toxicity and didn't find it. I think each person needs to investigate and decide for themselves. It's because of these previous studies that they went right into clinical trials in humans. I don't need to look at a primate when there are human study results coming soon. 

Glad the retin-A has worked well for you. It's good to hear people's positive results. I think I would go with the prescription form rather than an OTC form if I go that route.

Fred Cloud If you look at the Figures 2, it will be clear that it IS possible when you are looking at specific time points. After the first round, the number decreased. Then during the period of no fisetin, the senescent cells increased, but remained lower than the control group (indicating clearance, not suppression). After 4 weeks, when they were given the fisetin again in their diet over a 2 week period, the rate of increasing senescent cells declined, but there was still a net increase, just less. The body is constantly making new senescent cells, so this is no surprise. The researchers were excited that after the first round, the number of senescent cells stayed lower than the control group, which indicates senescent cell clearance, and not just a suppression mechanism where fisetin must be taken constantly. It did continue to increase, but at the second round, the rate flattened a bit, though still a slight increase. Just look at the graph. 

What this tells me is that a higher dose may be needed for effective clearing as you age. 2 months is quite a few years in mouse age. But overall, there was about a 40% reduction in senescent cells compared to the control group, and that is HUGE.

The implications of reducing the number of sick, inflammation producing cells by almost half in the body means a lot. Just ask my uncle with rheumatoid arthritis who started taking 1500mg for 2 days each month last fall, just half a bottle of pills swallowed with water. He can button his shirt without pain. Not having finger joint pain in an arthritis sufferer is a big deal in terms of increased quality of life.

I have sport injury onset arthritis in my big toe joint. Since taking fisetin, it doesn't hurt. I used to not be able to walk a block without serious pain. Today, I just hiked a mountain with my kids with no pain. 

I am taking fisetin because it has helped me. I feel the difference. My orthopedic surgeon told me that my toe flexion would just steadily decline and the pain would increase until I needed a joint replacement when my toe would no longer flex. Between omega-3 and the fisetin, I don't have pain, and I have full flexion 8 years later. 40% reduction of senescent cells feels great.

Fairy8i8 Yes, this thread is titled fisetin to clear senescent cells, but we are really  talking here about  at least 3 key senolytics: Fisetein, Azithromycin, and Dasatinib. And some others too.  Basically a cocktail taken concurrently whose safety is not at all established in humans.  That's what i want to test asap. And if there are studies please share. With respect of fisetin, yes I have seen statements in a research paper saying that it is relatively safe. And yes people are supplementing with the Fisetin as it is readily OTC available. However, it is logical non sequitur to say it is safe when taken 3 days in a row 1.5 gr a day, monthly or even quarterly for the next 5 years. There is no such study in humans and won't be any time soon because it is too dangerous and Dr Josef Mengele is currently not available to conduct such a study. Now you can test marmosets for 9 months which is equivalent of 5 years in humans to establish safety record for fisetin and combo (F+A+D+Q) which I'm much more concerned about. 

Joe smith Are you personally taking any of these senolytics? It would be nice to get a study combing the 3. However, I think cocktails like that are more likely to be studied by one of the many startups because they would be drugs registered with the FDA, and we would not see those results for about 10 years or more.

Fairy8i8 Well I have quercetin and Fisetin in the fridge. But I'm not taking them now. I'm taking prescribed low-dose Rapa for anti-aging and I'm concerned about interactions. I don't have the other ones like D or A. More serious stuff for sure. That said I'd love to test them all on marmosets to establish the safety first. And then if it checks out then why not? I would test them on me and few other willing volunteers but do super extensive monthly blood tests and med supervision and take it from there. And yes, I don't want to wait for some startup 10 years from now to show you and me the results and try to charge us arm and a leg. I want to do it openly now for everybody to benefit.

JGC   I know here in Spain, only 5% of population is estimated to have had Covid-19, and then what are the odds that someone in the general population practicing senolytics.  Not impossible, but probably a much greater chance they were using Azithromycin to treat Covid-19 which is not only can protect from bacterial infection, but blast fibroblast  in the lungs also.  If you go to Dr. Green's Rapa website, it discusses treatment of Covid-19 with senolytics.    https://rapamycintherapy.com/