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Fisetin as an effective senolytic

· Sandra · Science blog

Fisetin als wirksames Senolytikum

Fisetin is a flavonoid/polyphenol/secondary plant compound. It is a yellow natural dye, but above all it is a naturally occurring senolytic:

a molecule that can selectively trigger the death (apoptosis) of senescent, i.e. old, cells.1 This can both delay age-related diseases and increase lifespan.2

Why is it healthy and "rejuvenating" to eliminate senescent cells?

Senescent cells are cells that no longer divide (as protection against the development of cancer) but are resistant to cell death. They release pro-inflammatory signaling molecules (SASP), which can lead to inflammation of the surrounding cells and, in the worst case, to chronic inflammation of the entire body, and can paradoxically promote cancer. High levels of inflammation also damage tissues and organs. Removing senescent cells with senolytics reduces inflammation levels and the associated damage. Below, we take a closer look at the promising senolytic fisetin.

What are the health benefits of taking fisetin?

So far, six ways are known in which senescent cells can become resistant to cell death (SCAP = Senescent Cell Anti-Apoptotic Pathway). Depending on the cell type, different methods are used for this.

Most senolytics probably do not target all six pathways and therefore cannot kill all types of senescent cells. However, several studies have shown that fisetin can act against four of the six known types.3,4,5,6 Fisetin has, however, shown no senolytic effect on fibroblasts or on preadipocytes (fat cell precursors).

Fisetin as a highly effective senolytic

In one study, fisetin was tested alongside other molecules with senolytic activity: resveratrol, luteolin, rutin, epigallocatechin gallate, curcumin, pirfenidone, myricetin, apigenin, catechin and quercetin. In the tests in vivo in mice and in vitro on human adipose tissue, fisetin at a dose of 5 μM turned out to be the most effective senolytic. Fisetin was then also tested at further, higher doses.7

Fisetin against cancer

Process of carcinogenesis: angiogenesis, proliferation, metastasis

Image by Lecturio: https://www.lecturio.de/artikel/medizin/karzinogenese/ License: CC BY-NC-SA 4.0

The development of cancer (oncogenesis) is a multistep process8 that often takes several years.9 The majority of cancer-related deaths are due to metastasis of the tumor. Once a localized cancer metastasizes to other regions of the body, it is difficult to treat.10 That is why it is all the more important to stop the process of cancer development as early as possible so that metastasis does not occur.11

Fisetin suppresses cell proliferation

Fisetin has proven to be an extremely promising candidate. It has been shown to have anti-proliferative properties in human prostate cancer cells:12 fisetin suppresses cell proliferation. So if cancer develops, fisetin ensures that the cancer cells do not divide as quickly.

Fisetin induces cell death

Furthermore, fisetin has been shown to induce apoptosis in some cancer cells.13 This means that fisetin initiates the death of the cancer cell. These so-called pro-apoptotic properties can probably be attributed to several cell signaling pathways that fisetin can inhibit. These include the NF-κB, MAPK, Wnt, Akt and mTOR signaling pathways, which are known to influence the survival and spread of cells.

One study also showed that pretreatment with fisetin increased the sensitivity to radiation in, for example, chemoresistant human colorectal cancer cells, which increased the likelihood of radiation-induced apoptosis.14 So in some cases, fisetin could increase the effectiveness of chemotherapies in combination with them.

Fisetin reduces oxidative stress

Fisetin is not only effective as an antioxidant itself15, but also raises the level of glutathione, the most important intracellular antioxidant.16

Fisetin against inflammation

Since fisetin ensures that senescent cells that release inflammatory substances are removed, fisetin indirectly leads to lower levels of inflammation.17

Fisetin for the brain

It is assumed that fisetin can help with neurodegenerative diseases. The antioxidant properties of fisetin protect nerve cells from inflammation.18

Preclinical models have also shown that fisetin is effective against the onset, development and/or progression of several neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke (ischemic and hemorrhagic) and traumatic brain injury, as well as in reducing age-related changes in the brain.19

Positive effects of fisetin on metabolism

Fisetin has been shown to have a positive effect on metabolism: less oxidative stress in the liver as well as lower ALT and amylase levels.20

ALT is an enzyme found mainly in the liver. High ALT levels in the blood can indicate liver damage or liver disease, such as hepatitis, cirrhosis of the liver or liver cancer. Low ALT levels therefore usually indicate that the liver is healthy and its function is not impaired.

Amylase is an enzyme that is produced in the pancreas and in saliva and helps to break down complex carbohydrates. High amylase levels in the blood can indicate pancreatic diseases such as pancreatitis (inflammation of the pancreas). Low levels can indicate healthy pancreatic function.

What should I consider when taking fisetin?

Although three clinical trials on fisetin are currently underway, no data from them have been published yet. Accordingly, you should think carefully about whether and how you want to take fisetin, especially in view of potential side effects.

Basically, there are two ways to take fisetin:

  1. daily, at a low dose
  2. 2-3 days a month, at a high dose

The Mayo Clinic protocol for fisetin calls for 20mg/kg of body weight for two days a month.

Potential side effects of fisetin

When fisetin was taken…

  • wound healing took longer21
  • the likelihood increased that fibrosis, i.e. the pathological proliferation of connective tissue, develops during wound healing21
  • liver toxicity could occur if the bioavailability of fisetin is not high. It could therefore be important to ensure increased bioavailability.22

One study also showed that senescent cells prevented the development of fibrosis during liver regeneration and that if this is impaired (e.g. by taking senolytics), it leads to increased fibrosis in the liver.23

Concerns have also been raised that problems could arise (similar to the problems with the rapid breakdown of tumors: tumor lysis syndrome24) when so many cells are killed at once. However, since only about 15% of the body consists of senescent cells25 and taking senolytics only kills about 30%-40% of them26, these problems are relatively unlikely to occur, especially if you do not take fisetin continuously but only for a few days a month (Mayo protocol).

Increasing the bioavailability of fisetin

The bioavailability of fisetin is relatively low, which can have harmful consequences for the liver. However, some studies have shown that the solubility, and thus the bioavailability, of fisetin can be increased, for example, by co-crystallization with caffeine or forms of vitamin B3.27 So there is hope that in a few years there will be fisetin molecules that carry lower health risks while having a greater health effect.

Since fisetin is fat-soluble, it could be helpful to take high-fat foods together with fisetin.

Or foods in which fisetin is naturally contained. These foods could potentially contain substances that combine well with fisetin:28

  • Strawberries: 160μg fisetin per gram
  • Apples: 26.9μg fisetin per gram
  • Persimmons: 10.6μg fisetin per gram
  • Onions: 4.8μg fisetin per gram
  • Grapes: 3.9μg fisetin per gram
  • Kiwis: 2.0μg fisetin per gram
  • Peaches: 0.6μg fisetin per gram

Conclusion: Should I take fisetin as a supplement?

Some websites state that fisetin has not shown any side effects so far. We have tried to explain as many of the known or possible side effects as possible, even though we consider fisetin to be a dietary supplement with great potential. Patients with wounds or liver problems in particular should consult their doctor before potentially taking it.

Sources:

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Author: Sandra