12 replies to this topic

[osris]

I just came across the study below that says fisetin can mess up the way cells divide and organize their genetic material, which can lead to cells having the wrong number of chromosomes. This is called "aneuploidy." It can also break parts of the chromosomes, which can cause sections of the genetic material to be lost, added, or rearranged. This is called "clastogenic."

 

Given this should we stop taking fisetin?

 

 

'Fisetin: A Dietary Antioxidant for Health Promotion'

 

"It was thereby concluded that fisetin acted both as an aneugen (affecting cell division and mitotic spindle apparatus resulting in the loss or gain of whole chromosomes, thereby inducing aneuploidy) and a clastogen (causing breaks in chromosomes, leading to sections of the chromosome being deleted, added, or rearranged). At low doses, fisetin was capable of interfering with proper chromosomal segregation and acted as an aneugen, whereas at higher concentrations, fisetin through effective inhibition of topoisomerase II inhibitor exerted clastogenic effects causing double-stranded DNA breaks in the cells (52). Treatment with fisetin suppressed activation of HMC-1 mast cells by interfering with cell-to-cell interaction and inhibiting the activity of nuclear factor-kappa B (NF-κB) and MAPK, demonstrating its potential as an anti-inflammatory agent"

 

https://www.ncbi.nlm...les/PMC3689181/

[Mind]

I read through this white paper summarizing the studies of fisetin to date. Except for theorizing that aneuploidy caused by fisetin might be problematic, the paper is a ringing endorsement for the use of fisetin in combatting cancer and age related diseases. The paper makes fisetin look like a super supplement - the best flavonoid you could possibly take.

[osris]

Yes, I was thinking that too. 

 

Maybe fisetin's senolytic activity necessarily causes limited aneuploidy as part of the cell-destroying mechanism that any senolytic needs to work properly.

[osris]

Here is what ChatGPT says:
 

"Research has shown that fisetin is a substance that can affect the way our cells divide and replicate DNA. It does this by interfering with a crucial enzyme called human topoisomerase II-α, which is necessary for DNA replication. Fisetin also messes with the way our chromosomes separate during certain stages of the cell cycle.

 

So, fisetin has two main effects:

 

It can disrupt the division of cells and the structure that helps in that process, potentially causing cells to have the wrong number of chromosomes, which is called aneuploidy.

 

It can also cause damage to chromosomes by breaking them or rearranging parts of them, a condition known as clastogenic effects.

Interestingly, fisetin's impact depends on the dose. At low doses, it mainly messes with chromosome separation, while at higher doses, it can cause serious DNA damage by breaking the strands of DNA in our cells.

 

Additionally, fisetin has been found to have anti-inflammatory properties. It can prevent certain immune cells, called HMC-1 mast cells, from becoming overly active. It does this by interfering with the way these cells communicate with each other and by blocking certain molecules (NF-κB and MAPK) that are involved in inflammation. So, fisetin might be useful as an anti-inflammatory treatment."

[osris]

Here's another article:

 

'Fisetin induces DNA double-strand break and interferes with the repair of radiation-induced damage to radiosensitize triple negative breast cancer cells':

 

"Similar to ionizing radiation (IR), fisetin induces DSB. Additionally, fisetin impairs repair of IR-induced DSB through suppressing the classical non-homologous end-joining and homologous recombination repair pathways, leading to chromosomal aberration as tested by metaphase analysis."

 

https://pubmed.ncbi.....gov/35989353/#

 

Here is the above quote in simple terms, thanks to ChatGPT:

 

"Fisetin, like ionizing radiation, causes something called "double-strand breaks" (DSB) in DNA. What's more, fisetin makes it harder for the cell to fix these breaks that are caused by ionizing radiation. It does this by blocking two repair methods, known as "classical non-homologous end-joining" and "homologous recombination." This interference results in problems with the structure of chromosomes, which was confirmed by studying cells during a specific phase of cell division called metaphase."

 

All this new information about the risks of fisetin are making me think twice about it's long-term safety.

Edited by osris, 25 September 2023 - 09:50 AM.

[Mind]

 

Here's another article:

 

'Fisetin induces DNA double-strand break and interferes with the repair of radiation-induced damage to radiosensitize triple negative breast cancer cells':

 

"Similar to ionizing radiation (IR), fisetin induces DSB. Additionally, fisetin impairs repair of IR-induced DSB through suppressing the classical non-homologous end-joining and homologous recombination repair pathways, leading to chromosomal aberration as tested by metaphase analysis."

 

https://pubmed.ncbi.....gov/35989353/#

 

Here is the above quote in simple terms, thanks to ChatGPT:

 

"Fisetin, like ionizing radiation, causes something called "double-strand breaks" (DSB) in DNA. What's more, fisetin makes it harder for the cell to fix these breaks that are caused by ionizing radiation. It does this by blocking two repair methods, known as "classical non-homologous end-joining" and "homologous recombination." This interference results in problems with the structure of chromosomes, which was confirmed by studying cells during a specific phase of cell division called metaphase."

 

All this new information about the risks of fisetin are making me think twice about it's long-term safety.

 

 

Your key phrase here is "long term safety".

 

1. In natural concentrations found in food, fisetin has no known negative side effects, short or long term. Since fisetin is a minor flavonoid in food, I suspect it would be hard to tease out any negative long-term effects in observational studies

2. Short-term animal studies are overwhelmingly positive. I am unsure if there is a negative short-term study. Fisetin has even been found to have anti-cancer activity, according to the white paper you provided.

3. Long-term high-dose fisetin might be problematic due the the effects on DNA. Pure speculation, but perhaps some of the seemingly super positive effects from fisetin (and other similar flavonoids), are from hormesis. If this is the case, then these compounds would not be a good choice for concentrated high-dose long-term supplementation.

[osris]

Yes, it is high-dose fisetin that concerns me. I take the Life Extension Senolytic Activator, which is 25 times more bio-active than regular fisetin. 

[Neurocryo]

Yes, it is high-dose fisetin that concerns me. I take the Life Extension Senolytic Activator, which is 25 times more bio-active than regular fisetin. 

I’ve taken that with one of my stacks in the early afternoon for about a year and a half almost 2 years.

 

The other supplements with it are grape seed extract, pterostilbene, Niagen, zinc picolinate, curcumin, and a shot of green tea.

 

Hopefully I’m not the walking dead.

[smithx]

I've been every 2 or 4 weeks taking:

 

fisetin - 20mg -25mg /Kg

quercetin - 20m5-25mg/Kg

grapeseed extract - 15mg/Kg

curcumin - 20mg/Kg

ginger root extract - 15mg/Kg

 

as a senolytic. I wonder if I've caused any damage. Food for thought.

 

Edited by smithx, 07 January 2024 - 07:32 AM.

[johnhemming]

I think these mainly operate as HDAC inhibitors.

[osris]

I think these mainly operate as HDAC inhibitors.

 

It seems you are correct. This is what ChatGPT says:
 

 

Fisetin: Fisetin is a flavonoid found in various fruits and vegetables. Studies have suggested that fisetin may have HDAC inhibitory properties.

 

Quercetin: Quercetin is another flavonoid present in many fruits, vegetables, and grains. It has been investigated for its anti-inflammatory, antioxidant, and potential anticancer properties. Some studies suggest that quercetin may act as an HDAC inhibitor.

 

Grapeseed Extract: Grapeseed extract contains a variety of polyphenols, including proanthocyanidins. Some studies suggest potential HDAC inhibitory effects.

 

Curcumin: Curcumin is the active compound in turmeric and has been extensively studied for its anti-inflammatory and antioxidant properties. Some research suggests that curcumin may modulate HDAC activity.

 

Ginger Root Extract: Ginger contains various bioactive compounds, including gingerols and shogaols. While ginger has been studied for its anti-inflammatory and antioxidant effects, its role as an HDAC inhibitor may vary.

[zorba990]

From Targeted Antioxidants in Exercise-Induced Mitochondrial Oxidative Stress: Emphasis on DNA Damage
https://www.ncbi.nlm...les/PMC7698504/

"sporadic and strenuous bouts of exercise incite oxidative stress due to an augmented production of reactive oxygen and nitrogen species (RONS) [8]. An accumulation of RONS impairs cell function by oxidatively modifying nucleic acids, where DNA damage and insufficient repair may potentially lead to mutagenic, clastogenic, and carcinogenic effects [9]. Currently, the majority of exercise redox research has focused on nuclear DNA damage [10,11], with a scant understanding on the relationship between exercise and mitochondrial redox dynamics in vivo. Further, evidence postulates a clear connection between mitochondrial dysfunction and disease progression [12], primarily driven by an increase in mitochondria ROS production and mtDNA damage [13,14]. This mtDNA damage can function as a redox signal thereby inducing a physiological and/or simultaneous pathological outcome as depicted in Figure 1 and briefly differentiated in Box 1."


Which I read as HIT can cause the same issues. So avoid HIT? OR

Take fisetin pre-workout and ramp the damage up then wait for the adaptation?

[osris]

I fed the information in this thread into ChatGTP and asked it to write a balanced article and here it is:

 

DEBUNKING FEARS THAT FISETIN IS DANGEROUS

 

 

In recent years, the natural compound fisetin has garnered attention for its potential as a senolytic agent, promising to target and eliminate senescent cells implicated in aging and age-related diseases. However, concerns have been raised regarding fisetin's safety and its purported genotoxic effects. It's crucial to address these concerns and provide reassurance to individuals considering fisetin supplementation for senolytic purposes.

 

Understanding Fisetin's Mechanism of Action

 

Before delving into the safety profile of fisetin, it's essential to understand how this natural compound functions as a senolytic agent. Fisetin belongs to a class of molecules called flavonoids, which are abundant in various fruits and vegetables. Research has demonstrated that fisetin exhibits potent antioxidant, anti-inflammatory, and senolytic properties.

 

Senescent cells are cells that have ceased to divide and undergo functional changes, secreting pro-inflammatory molecules and contributing to tissue dysfunction. Fisetin has been shown to selectively induce apoptosis, or programmed cell death, in senescent cells while sparing healthy cells. This targeted approach holds immense promise for mitigating age-related pathologies and promoting healthy aging.

 

Addressing Concerns About Genotoxicity

 

One of the primary concerns raised about fisetin is its potential genotoxicity, as highlighted in certain studies. Claims suggesting that fisetin induces DNA double-strand breaks and interferes with chromosomal integrity have sparked apprehension among individuals considering fisetin supplementation.

 

However, it's crucial to contextualize these findings. While fisetin may exhibit genotoxic effects at higher concentrations in vitro, the doses typically used in senolytic studies are substantially lower and have not been associated with adverse effects in vivo. Moreover, the genotoxic effects observed in experimental settings may not translate to similar outcomes in human studies, especially when considering the body's robust mechanisms for DNA repair and detoxification.

 

Examining the Safety Profile of Fisetin

 

Numerous preclinical studies and clinical trials have evaluated the safety of fisetin supplementation, and the findings overwhelmingly support its favorable safety profile. Fisetin has been administered to animals and humans at varying doses for extended periods without significant toxicity or adverse effects reported.

 

Furthermore, fisetin's status as a naturally occurring compound found in fruits and vegetables underscores its safety and tolerability. Unlike synthetic pharmaceuticals, fisetin is derived from plant sources and has been consumed as part of the human diet for centuries.

 

Embracing the Benefits of Fisetin as a Senolytic

 

Despite the misconceptions and concerns surrounding fisetin, the accumulating evidence supports its potential as a safe and effective senolytic agent. By selectively targeting senescent cells, fisetin holds promise for addressing age-related diseases, enhancing longevity, and promoting overall well-being.

 

It's essential for individuals considering fisetin supplementation to consult with healthcare professionals and adhere to recommended dosages. Additionally, ongoing research efforts are needed to further elucidate fisetin's mechanisms of action, optimize treatment regimens, and explore its potential synergies with other interventions for healthy aging.

 

In conclusion, while questions may arise regarding fisetin's safety profile, the evidence overwhelmingly supports its safety and efficacy as a senolytic agent. By dispelling misconceptions and embracing its transformative potential, we can harness the power of fisetin to unlock new frontiers in the pursuit of healthy aging and longevity.

I fed the information in this thread into ChatGTP and asked it to write a balanced article and here it is:

 

DEBUNKING FEARS THAT FISETIN IS DANGEROUS

 

 

In recent years, the natural compound fisetin has garnered attention for its potential as a senolytic agent, promising to target and eliminate senescent cells implicated in aging and age-related diseases. However, concerns have been raised regarding fisetin's safety and its purported genotoxic effects. It's crucial to address these concerns and provide reassurance to individuals considering fisetin supplementation for senolytic purposes.

 

Understanding Fisetin's Mechanism of Action

 

Before delving into the safety profile of fisetin, it's essential to understand how this natural compound functions as a senolytic agent. Fisetin belongs to a class of molecules called flavonoids, which are abundant in various fruits and vegetables. Research has demonstrated that fisetin exhibits potent antioxidant, anti-inflammatory, and senolytic properties.

 

Senescent cells are cells that have ceased to divide and undergo functional changes, secreting pro-inflammatory molecules and contributing to tissue dysfunction. Fisetin has been shown to selectively induce apoptosis, or programmed cell death, in senescent cells while sparing healthy cells. This targeted approach holds immense promise for mitigating age-related pathologies and promoting healthy aging.

 

Addressing Concerns About Genotoxicity

 

One of the primary concerns raised about fisetin is its potential genotoxicity, as highlighted in certain studies. Claims suggesting that fisetin induces DNA double-strand breaks and interferes with chromosomal integrity have sparked apprehension among individuals considering fisetin supplementation.

 

However, it's crucial to contextualize these findings. While fisetin may exhibit genotoxic effects at higher concentrations in vitro, the doses typically used in senolytic studies are substantially lower and have not been associated with adverse effects in vivo. Moreover, the genotoxic effects observed in experimental settings may not translate to similar outcomes in human studies, especially when considering the body's robust mechanisms for DNA repair and detoxification.

 

Examining the Safety Profile of Fisetin

 

Numerous preclinical studies and clinical trials have evaluated the safety of fisetin supplementation, and the findings overwhelmingly support its favorable safety profile. Fisetin has been administered to animals and humans at varying doses for extended periods without significant toxicity or adverse effects reported.

 

Furthermore, fisetin's status as a naturally occurring compound found in fruits and vegetables underscores its safety and tolerability. Unlike synthetic pharmaceuticals, fisetin is derived from plant sources and has been consumed as part of the human diet for centuries.

 

Embracing the Benefits of Fisetin as a Senolytic

 

Despite the misconceptions and concerns surrounding fisetin, the accumulating evidence supports its potential as a safe and effective senolytic agent. By selectively targeting senescent cells, fisetin holds promise for addressing age-related diseases, enhancing longevity, and promoting overall well-being.

 

It's essential for individuals considering fisetin supplementation to consult with healthcare professionals and adhere to recommended dosages. Additionally, ongoing research efforts are needed to further elucidate fisetin's mechanisms of action, optimize treatment regimens, and explore its potential synergies with other interventions for healthy aging.

 

In conclusion, while questions may arise regarding fisetin's safety profile, the evidence overwhelmingly supports its safety and efficacy as a senolytic agent. By dispelling misconceptions and embracing its transformative potential, we can harness the power of fisetin to unlock new frontiers in the pursuit of healthy aging and longevity.