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.

Comments

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.

Posted by: Jones at November 30th, 2021 3:38 PM

... 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...

Posted by: Jones at November 30th, 2021 4:21 PM

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.

Posted by: SilverSeeker at December 1st, 2021 10:36 AM

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.

Posted by: Cuberat at December 1st, 2021 3:32 PM

Fisetin is fairly fat soluble. Not so in water.

Posted by: JLH at December 1st, 2021 5:33 PM

@JLH
Do you have some numbers ?
I couldn't find anything useful.

Posted by: Cuberat at December 2nd, 2021 6:51 AM

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.

Posted by: Richard DJ at April 6th, 2022 5:25 PM
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