Results from a Trial of the Senolytic Fisetin in a Single Individual with Autoimmunity
Today's materials from the Intraclear Biologics team may be of interest to those following the development of senolytic therapies. Since the Mayo Clinic has yet to publish results from their clinical trials of fisetin as a senolytic therapy, and may not do so for a few years yet, it is good to see even preliminary data from other sources. Senolytic therapies selectively destroy senescent cells, though only one approach (the combination of dasatinib and quercetin) has been definitely shown to destroy significant numbers of senescent cells in humans. Data has yet to be published on whether fisetin performs as well in humans as it does in mice.
The Intraclear Biologics data is an example of the Mayo Clinic's senolytic dose of fisetin applied to a single younger patient with autoimmunity - in effect a well-conducted self-experiment. The age of the patient, mid-thirties, is far too young to have any meaningful age-related accumulation of senescent cells. But various lines of work from recent years suggest that many autoimmune conditions are at least in part driven by the presence of senescent cells, a bidirectional dysfunctional relationship between the immune system and senescent cells in the tissue under attack. Type 1 diabetes, for example, and perhaps rheumatoid arthritis. Unfortunately, no assessment of senescent cell burden was carried out in this study, so it is possible that other mechanisms are involved in the lowered inflammation and other benefits experienced by the patient. Still, the results point the way to larger studies that include more comprehensive assessments.
Preliminary results of trials of Fisetin in a person with autoimmune thyroiditis
Since senescent cells also arise in the immune system, being one of the causes of autoimmune diseases, there is a hypothesis that the destruction of senescent cells will help in the prevention and treatment of many autoimmune diseases. It is important that the mechanisms of cell senescence and the effects of their destruction by senolytics are similar in mice and humans. For example, it has been shown that the combination of dasatinib (a relatively aggressive chemotherapeutic) and quercetin (a flavonoid) works in humans as well as in mice when it comes to destruction of senescent cells.
Some drugs that have established senolytic effects are available for purchase just now. However, they are usually used in much lower dosages than is required for the senolytic effect. Such substances include the readily available and cheap bioactive flavonoid fisetin. Mice experiments show that fisetin is about as effective against senescent cells as the dasatinib + quercetin combination. The advantage of fisetin, which is a plant substance, is its safety compared to many other drugs that have shown a senolytic effect.
There are currently three trials of fisetin as a senolytic in humans. They are conducted in Mayo Clinic (USA), where a special treatment protocol was developed. Mayo Protocol consists of taking 20 mg/kg of fisetin orally for two days in a row, after which a person takes the second course after a month or two months. Because of the availability and safety of fisetin, we decided to conduct our own trial of this drug in a person with autoimmune thyroiditis. It is noteworthy that, unlike most tests, we focus not on chronic inflammation, but on immune function.
In accordance with animal experiments, the inflammatory factors C reactive protein and rheumatoid factor decreased. Antibodies to thyroglobulin did not change, which means the autoimmune response does not decrease. TSH returned to normal value, which allowed the patient to reduce the dose of hormone therapy.
Fisetin diminishes the expression and secretion of inflammatory cytokines and facilitates autophagosome-lysosome fusion and degradation via inhibition of the PI3K/AKT/mTOR signaling pathway.
I guess the autoimmune patient's relsults aren't much based on the assumed senolytic action of fisetin.
... also ... when you look at fisetin 'studies'
https://scholar.google.com/scholar?start=0&q=fisetin+inflammation
it seems it cures like literally everything... via various mechanisms: cancer, liver damage, depression, brain damage, asthma, metabolic dysfunction, UVB-induced skin damage, sepsis-induced multiple organ dysfunction, acute pancreatitis, systemic lupus erythematosus,retinal degradation, osteoporosis, cardiotoxicity, PD, AD, cardiac hypertrophy, neurological disorders, allergies,... take your pick.
It's a bit like metformin or rapamycin in that regard. ;p
I wonder why so many people still suffer from those diseases. But then again if it seems to be too good to be true...
no improvement with fisetin in psoriasis, no improvement in felt psoriatic arthritis, taken both daily 100mg-500mg and intermittent 3000-5000 mg. CaAKG helped a bit.
Also, don't forget that fisetin has very poor water, alcohol and fat solubility. The results might vary widely due to differences in personal absorption rates. This is one of the reasons it is safe. It basically passes trough the digestive system and has very little activity. It might turn out that mice require much loser concentration to have an effective senolytic action. So something as simple different bio-availability can negate all the efforts.
Fisetin is fairly fat soluble. Not so in water.
@JLH
Do you have some numbers ?
I couldn't find anything useful.
As suggested by researchers at Salk Institute I started taking fisetin for COPD phlegm problem. Taking 100mg before meals helps control the phlegm. My problem is not from what I breathe, but from eating or drinking almost anything. Some people say stay away from dairy foods, but that is not the problem. It is for anything I eat. Phlegm may occur almost instantly or within an hour. I take it 3 times a day, not intermittently like Mayo protocol.
What I would like to know is what effect this constant low dosage, as compared to Mayo protocol, has on senescent cells. What I am looking for is stopping the deterioration of my lungs as I get older. I have not smoked in 30 years.
For this trial, or the Mayo trial, Is the 20 mg/kg given as a bolus (all at once), or spread out over the day? And did they do anything to aid in absorption, such as give with fat or a meal
This is an update on using Fisetin for COPD phlegm problem. I have changed to taking 100mg Fisetin (novusetin) immediately AFTER meals. (usually 300mg/day) It greatly helps my phlegm problem. It seems there is action at the top of the stomach that may be affecting the vagus nerve or the bio actions taking place immediately as food enters the stomach. Intermittent heavy dosage like Mayo Clinic is using on their trials would not be effective for this condition.
Also, I am convinced it helped eliminate a small cancer nodule in my lung as other researchers have reported as possible.
I take a combination of liposomal fisetin and quercetin (1000/200mg per 2 capsules).
I have taken as much as 4000mg/800mg per day. The only side effects are very vivid weird dreams and extremely thin blood.
I should probably take it regularly or at least on some sort of defined regimen, but i haven't.
I have MS and it definitely reduces fatigue and weakness.
I have been taking low dose Fisetin for 3 weeks now along with quercetin. I have a rare blood disorder called mastocytosis and also have the cutaneous form on my skin called uticaria pigmentosa. This causes severe inflammation. I am 48 and also full of arthritis in my spine that is very painful. After one week on Fisetin I noticed that I was walking better with less pain. Week 2 and I can exercise longer. Week 3 and the uticaria itching and inflammation pain is gone. I tested by drinking a glass of red wine which would normally cause a flare up and nothing happened. I have not had to fill my body with mast cell stabilizers and anti inflammatory drugs for weeks now and I have more energy. I can't wait to explore more with Fisetin.
I have ulcerative active co,itis and am on biologics. Will be starting entyvio soon. I was hoping to take fisetin 2x per month to clear senescence. Not sure how much I should take.
I started taking Fisetin about 4 years ago based on Dr. James Kirkland's research on senescent cells and their effects on aging. At the time, I was 75 y.o. and beginning to notice multiple symptoms of advancing age. Mild arthritic pain in multiple joints, brain fog, slowing cognitive functions and loss of ability to focus on complex subjects. Initially I started taking Fisetin doses at 20 mg/kg body weight, three times per day for three consecutive days, repeating at 3 month intervals. At first there were only minor, seemingly insignificant effects including a mild increase in my color vision. Colors appeared brighter, more intense or saturated for a few hours after the first day of each three day dose. My sense of smell also seemed to increase for a few days. Both sensations gradually faded back to normal within a day or two. After the third course of three day doses at about 9 months from the beginning I increased by doses to 25 mg/kg body weight and added Echinacea with each dose on the assumption that stimulation of macroglial activity might make senescent cell removal more effective. By the end of the first year and having taken four, three day courses of Fisetin I noted that most of my arthritic aches and pains had gradually faded away. Some improvement in cognitive processing speed and reduction in brain fog seemed apparent although self evaluation is inherently inaccurate and no accurate metrics were available. Horvath's biological clock was unknown to me at that time. By the following year, Liposomal Fisetin (Sharoaid) became available. Claimed to greatly increase absorption but still lacking any practical means of measuring absorbed levels, I switched to the lipisomal version and gradually increased to doses of 5 capsules, 3 times per day for three consecutive days at approximately 3 month intervals. Overall I can only detect general changes which may or may not be a result of Fisetin doses. Arthritic pain has faded away. Some cognitive functions seem slightly improved and "brain fog" is less annoying than 4 years ago. Some minor cosmetic details including reduction or complete disappearance of body moles is apparent. Some restoration of scalp hair seems to have reversed the male pattern baldness.
Overall, I feel better than I did before starting the Fisetin doses but still have no satisfactory means of measuring either the effectiveness of the treatments or the level of senescent cell accumulation within my body. I'm hopeful that development of "lab-on-a-chip" testing techniques will become available which can measure some of the blood born markers of senolytic cell activity or decomposition.