Fisetin for Aging, Cancer, Inflammation, and more - A Complete Review

Fisetin for Aging, Cancer, Inflammation, and more - A Complete Review

fisetin for health longevity mood cancer and  more


   
Anti-aging used to be a sure-fire path to snake oil.

 

Almost every version of skin care product promises younger looking and feeling skin.

 

We've been through the Resveratrol fad.  We're now in the NAD/NMN phase.

 

These are interesting and maybe they have effects on pathways tied to aging (like Sirtuin, etc) but something changed recently.

 

First, there was the groundbreaking study on metformin and reversing epigenetic aging.

 

We have a full review of metformin and maybe better yet, berberine, it's non-prescription alternative here.

 

That's the powerful AMPK pathway.  Really check it out.

 

It was shown to reverse epigenetic aging by 2.5 years after 1 year of use.

 

Then there's the other key pathway which is directly implicated in aging, cancer, and general health.

 

Autophagy.  Senescent cells.  

 

Before your eyes glaze over, don't worry...we'll explain all of it.

 

Fisetin is turning out to potentially be the most powerful player in this pathway with a strong safety profile.

 

We're going to look at all of it since this may be the 1-2 punch with our AMPK stimulator berberine.

 

These are the areas we'll get into: 

  • What is Fisetin
  • How does fisetin work
  • How fisetin helps with senescent cells
  • Fisetin and aging
  • Fisetin and cancer
  • Fisetin and inflammation
  • Fisetin and neuroprotection for mental health
  • Fisetin for Dementia and Alzheimer's
  • Fisetin and quercetin
  • Fisetin and curcumin
  • Fisetin safety and side effects
  • How much fisetin to take
  • What's the best fisetin to buy 

 

Let's get started before we age another minute!

What is Fisetin 

An apple a day…

 

Turns out that maybe our mother's statement had some validity to it.

 

In that very apple is a substance called fisetin which you can purchase here.

 

It's a member of the family of chemicals called flavonoids.

 

Flavonoids give different fruits and vegetables their color essentially.

 

Fisetin is found in strawberries, apples, grapes, cucumbers, onions, and more.

 

Flavonoids are an interesting new bundle to explore for researchers as they can have powerful effects in our body.

 

Fisetin may be one of the most promising.

 

We're attracted to substances that affect very base-level systems in the body.

 

AMPK (see berberine review here) is a perfect example with knock-on effects on almost every other pathway as it's a system aged at over 2 billions years old.

 

Evolution likes this pathways and converved it across every living thing with a cell and nucleus.

 

Fisetin affects another key system with implications across a range of different pathways.

 

It's most powerful role may be that of being a senolytic...and a strong one at that.

 

Let's dive into that now.

How fisetin helps with senescent cells as a senolytic 

Stay with us...we'll explain all.

 

Basically, as cells continue to live and divide, they can accumulate errors.

 

This can be from random mutation, chemicals, stress, oxidation, or a random sun ray with enough power to cut right through our DNA.

 

The cells can continue to function more or less till it reaches a point where it's better to get rid of it.

 

Why?

 

These so-called zombie or "senescent" cells start to leak inflammatory and caustic chemicals into their surroundings which just ruins the cellular neighborhood.

 

As researchers put it: 

Senescent cells are characterized by their inability to proliferate, resistance to apoptosis, and secretion of factors that promote inflammation and tissue deterioration. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115505/

 


This is the current thought behind why our bodies start to show a general level of low grade inflammation as we get older.

 

Researchers stumbled on this with mice and followed by removing these cells for powerful effects: 

This year alone, clearing the cells in mice has been shown to restore fitness, fur density and kidney function. It has also improved lung disease and even mended damaged cartilage. 

https://www.scientificamerican.com/article/to-stay-young-kill-zombie-cells/

 

Now...don't fret.

 

We have an entire system which scans for suspects cells and then destroys them.

 

It's called autophagy or apoptosis.

 

You don't have to memorize those...just know its our bodies police on the beat looking for faulty cells and then triggering their death and removal.

 

This is exactly what should happen with pre-cancerous cells!

 

In fact, senescence is a protective measure against cancer...STOP dividing, faulty cell!

 

Senescent cells, however, just sit there, unable to divide any longer but they're still chemically active which is the issue.

 

Here's the most exciting piece for us (us being living, multicellular life).

 

Any substance that boosts the system to remove these zombie cells  is called a senolytic and it's one of the two most exciting and new areas of research on aging and all aging-related illness (which is almost all of them).

 

This gets complicated really fast but we can focus on a major pathway specifically.

 

mTOR.  

 

You don't hear that everyday.  Yet!

 

It's short for mammalian target of rapamycin.

 

That last word may be more familiar.

 

It's the main target for resveratrol...the old captain of anti-aging.

 

mTOR is a very powerful cellular housekeeping pathway.

 

It appears to act as a switch in response to good and bad times: 

This pathway, which responds to diverse environmental cues, controls many processes that generate or use large amounts of energy and nutrients. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3331679/

 

During good times, it leads to a growth bent.

 

During bad times (famine, etc), it drops which results in housekeeping at the cellular level.

 

This aligns it with the AMPK pathways which metformin and berberine impact - you can read about here.

 

What's the repercussion of this pathway on health and aging? 

The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue,[29] and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers. 

https://en.wikipedia.org/wiki/MTOR

 

As we'll see below...aging and age related diseases!

 

Simply put...mTOR governs the life and death cycle of cells.

 

Why go into all of this?

 

As we get older, excessive mTOR activity can lead to a host of issues.

 

Research is showing that substance which block or inhibit its activity can have powerful effects in the body and brain.

 

What about fisetin?

 

Using prostate and lung adenocarcinoma cells, we observed that fisetin acts as a dual inhibitor of the PI3K/Akt and the mTOR pathways. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813433/

 

Needless to say, lots of the research stems from cancer.

 

But that's only a small part of the story for fisetin and senolytics.

 

We'll look at all the facets below.

 

Why Fisetin? 

The researchers also compared fisetin against other compounds, including resveratrol, luteolin, rutin, epigallocatechin gallate, curcumin, pirfenidone, myricetin, apigenin, and catechin. This study showed that fisetin was the most effective of these compounds. 

https://www.leafscience.org/fisetin-may-be-a-low-hanging-fruit-for-aging/

 

Those are some heavy hitters.  

 

Curcurmin (turmeric)  purchase here.  Resveratrol purchase here.  EGG (green tea) purchase here.

 

Their primary pathway is this mTOR one and it's to remove the defective senescent cells we described above.

 

Another study:Curcumin (turmeric).  Resveratrol.  EGG (green tea).

Of the 10 flavonoids tested, fisetin was the most potent senolytic.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652/

 

See why we're excited?

 

Another study found the following: 

Per the data in the open access paper below, dosing with fisetin destroys 25-50% of senescent cells depending on organ and method of measurement.  

https://www.fightaging.org/archives/2018/10/animal-data-shows-fisetin-to-be-a-surprisingly-effective-senolytic/

 

Let's really dive down further into the effects of all of this below.

 

We'll start with the big one since it partially derives from all the others.

 

Aging.

Fisetin and aging 

As we get older, our immune system's ability to govern senescent cells diminishes.

 

It's literally a biomarker of aging!

There is increasing evidence suggesting that senescent cells accumulate in aging tissues and organs, thereby impairing physiological processes, including regeneration, and contributing to organismal aging. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115505/

 

To show just how powerful these senescent or zombie-cells are, look what happens when they're injected into younger mice: 

Conversely, injection of senescent cells is sufficient to drive age-related conditions such as osteoarthritis, frailty, and decreased survival. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652/

 

Goodness...they're dead weight (quite literally).

 

The first real insight was around quercetin (another flavonoid and dasatinib (a cancer drug).

 

The treatment of mice reduced a host of age-related issues including osteoporosis and frailty. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078/

 

Dasatinib has side effects but quercetin is safe and effective.

 

Turns out, Fisetin is more effective as a senolytic.

 

Researchers were looking to improve on quercetin's effect and fisetin showed a superior effect: 

Fisetin treatment extended the health and lifespan in WT mice even when treatment was initiated in aged animals. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652/

 

That last part is important...even when started at an older age (because you're probably not reading this at age 18).

 

Check out the chart here: 

https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=6197652_gr1.jpg

 

Two key points.

 

Fisetin reduced senescent cells the most while not affecting health cells!

 

Curcumin had the next best effect on both accounts

 

This is great and all but we would expect to see an effect on aging or this is all just window-dressing.

 

Glad you asked.

 

This resulted in an extension of median as well as maximal lifespan. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652/figure/f0025/

 

Plus, all the age-related markers 

  • Lesions in organs
  • Glutathione (see CBD and glutathione) for oxidation
  • A reduced level of all the inflammatory cytokines

 

This research was very sophisticated and well-thought out.

 

They're drilling down into chemical pathways in different cell types.  Great work!

 

Most importantly, they applied the same tests to human cells to measure translation from mice to men.

 

Their synopsis: 

Here, we demonstrate that when tested against a panel of other flavonoids, fisetin had the most potent senotherapeutic effects in several cell types in vitro and showed strong anti-geronic effects in vivo. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652/

 

Geronic??  Getting older.

 

The new term to focus on is "healthspan", not lifespan.

 

Meaning, we don't just want more years but more GOOD years!

 

Check out this study on the original quercetin study: 

Taken together, these data demonstrate that periodic treatment with senolytics is sufficient to reduce the burden of senescence markers, reduce frailty, and extend healthspan significantly. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078/

 

There are literally charts where the control group (no senolytics) of mice are unable to support themselves under their back legs.  Frailty.

 

That's why there's currently a clinical trial to test its effect on frailty by Mayo Clinic. 

https://clinicaltrials.gov/ct2/show/NCT03430037?cond=fisetin&cntry=US&rank=2

 

People...everyone over age 40 should be on these!

 

They also have a chart comparing all the age-related health issues in the link above.

 

Of course, there was impact across a range of issues tied to aging.  

 

First and center is cancer.

Fisetin and cancer 

A great deal of the research stems from fisetin's effect on cancer.

 

Across a range of cancers including triple-negative cancers that don't respond to hormones or other pathways.

 

This makes complete sense considering its effect on cell birth and death cycles.

 

In fact the current thought is that this process of removing fault genes was a stopgap to protect against cancer in terms of evolution.

 

Different events in cancer initiation and progression such as apoptosis, extracellular matrix remodeling, epithelial to mesenchymal transition, cancer-associated inflammation, and oxidative stress can be controlled by fisetin and quercetin.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572624/

 

Fisetin shares this ability with both quercetin and curcumin but as we saw above, fisetin was the more powerful senolytic.

 

There are so many pathways affected with fisetin and cancer fighting that we can quickly get lost in the woods.

 

Let's zero down on some key ones.

 

Fisetin and Cancer Apoptosis

 

That's a big word.

 

It simply means cell death.

 

Essentially, Fisetin causes cancer cells (but not healthy cells) to initiate the cell death pathway.

 

You want to see how complicated this gets with our cell death machinery? 

Further, Li et al. also documented the apoptotic capacity of fisetin in T24 and EJ human bladder cancer cells, acting through overexpression of Bax, Bcl2 associated agonist of cell death (Bad), and Bcl-2 antagonist/Killer 1 (Bak) and inhibition of Bcl-2 and B-cell lymphoma-extra large (Bcl-xL). 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572624/

 

That review go through multiple pathways (all equally complicated) across multiple types of cancer.

 

That's the part of the machine that kills a cell when it's faulty (basically, the extreme version of senolytic action above).

 

Fisetin also blocked cancer's ability to continually split and grow: 

For instance, fisetin is identified as a regulator of cell cycle checkpoints, leading to cell arrest through CDK inhibition in HL60 cells and astrocyte cells over the G0/G1, S, and G2/M phases.

 

Fisetin also blocks the pathways by which cancer spreads throughout the body (metastasized) via the so-called extracellular matrix.

 

Remember the triple-negative breast cancers that don't respond well to traditional means?

The in vitro findings from another study by Li et al. concluded that fisetin could significantly overpower growth and metastasis in MDA-MB-231 and BT549 triple-negative breast cancer cell lines. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572624/

 

The summation: 

Dietary flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) found in many fruits and vegetables has been shown in preclinical studies to inhibit cancer growth through alteration of cell cycle, inducing apoptosis, angiogenesis, invasion, and metastasis without causing any toxicity to normal cells. 

https://www.ncbi.nlm.nih.gov/pubmed/27059089

 

We need clinical trials but that's probably not going to happen since Big Pharma is unable to patent and profit off of fisetin.

 

Universities will have to take up the mantle on this one.

 

This review goes through fisetin's effects in research by cancer type: 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689181/

 

A key component of both aging and cancer intersect at our next topic.

 

Inflammation.

Fisetin and inflammation 

It's well documented that as we get older, low-grade and chronic inflammation creeps into the system.

 

The effects of this are widespread and ultimately, ruinous.

 

Let's introduce an important new term...SASP.

 

senescence-associated secretory phenotype

 

It's basically what senescent cells are leaking out into their environment before removal.

 

Why is SASP important? 

SASP contributes to fuel a state of chronic, systemic, low-grade inflammation, called “inflammaging,” which is one of the main risk factors for the development of the major ARDs. 

https://www.hindawi.com/journals/mi/2018/9076485/

 

Why?

 

Remember that the whole reason we even have this senescence process to keep damaged cells from replicating.

 

It's an anti-cancer insurance policy.

 

The problem is that these cells continue to operate albeit without spreading.

 

A faulty cell makes faulty outputs.

 

Let's look at one key component (of many).

 

IL6

 

The most prominent cytokine of the SASP is interleukin (IL)-6, a pleiotropic pro-inflammatory cytokine. 

https://link.springer.com/article/10.1007/s10555-010-9220-9

 

We've seen IL6 in our CBD and neuroinflammation or CBD and inflammation reviews.

 

It's a powerful, inflammatory agent in the body.

 

Downstream, IL6 increased markedly with senescent cells.

 

IL6 is a keystone responder in our immune system with knock-on effects far and wide.

 

When released chronically, we have major issues.

 

Autoimmune is a perfect example: 

All these clinical data and animal models suggest that IL-6 plays critical roles in the pathogenesis of autoimmune diseases.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176007/

 

In fact, a major push is to find a substance that inhibits (slows down) IL6 processing without nasty side effects.

 

How about this one, research community: 

Fisetin significantly inhibited COX-2 expression and reduced prostaglandin E2 production, and it suppressed the levels of IL-8, CCL5, monocyte chemotactic protein 1, tumor necrosis factor α, and IL-6. 

https://www.ncbi.nlm.nih.gov/pubmed/29758489

 

Oh...that COX2 there...that's just the entire pain pathway that Tylenol and COX inhibitors (Celebrex) use for pain.

 

Check out CBD versus Tylenol to understand more.

 

The IL8 and IL6 though are what we're after.

 

Huge implications on health if left unchecked.

 

Why would senescent cells release these toxic (in excess) substances?

 

What could possibly be the point?

 

IL-6 also issues a warning signal in the event of tissue damage.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176007/

 

It's like the car alarm that won't turn off.

 

Faulty cell here.  ALERT ALERT

 

The cell won't divide any longer (senescence) but it won't die either.

 

These cells accumulate as we age in tissue tied to illness.

 

Then, there's ROS. 

 

Reactive Oxygen Species because no fair just calling it oxidation.

 

Either way, too much of it just causes more damage to clean up.

 

Cumulatively, oxidative stress leads to pathological changes, and ROS are associated with the early onset of more than 200 clinical diseases [3], especially chronic diseases, such as Parkinson’s disease, Alzheimer’s disease, cancer, cardiovascular disease, diabetes, etc. [4,5,6,7,8]. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413105/

 

Check out CBD and oxidative stress or CBD and glutathione (our primary antioxidant).

 

CBD is actually a more powerful antioxidant than Vitamin C or E!

 

Speaking of ROS and glutathione: 

It has been reported that fisetin protects against H2O2-induced cell damage by inhibiting ROS generation, thereby maintaining the protective role of the cellular glutathione (GSH) system. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413105/

 

Beautiful.

 

This also makes sense with senescent cells.

 

Guess how the body breaks up cellular machinery whether faulty cells or cancer.

 

ROS!

 

It jacks up levels of oxidative stress to actually cut apart the cell.

 

Oxygen is biology's scissors!

 

Low-grade inflammation, however, is like bringing a bag of scissors to a balloon party (terrible analogy but really couldn't come with anything).

 

Inflammation is tied to just about every health issue out there.

 

Just check out CBD and inflammation for anxiety or CBD and neuroinflammation for anxiety as an example.

 

Fisetin may be our ace in the hand: 

Fisetin not only has direct antioxidant activity but it can also increase the intracellular levels of glutathione, the major intracellular antioxidant. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527824/

 

In fact, it's showing powerful effects comparable to medications: 

Fisetin along with quercetin and myricetin had the lowest oxidation potential, more active than trolox. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689181/ 

 

Next up...the hidden star and secret culprit of most of our health pathways.

Fisetin for  the immune system and autoimmune  

First, understand that the inflammatory response IS the immune system.

 

The IL6's and IL8's we mentioned above tied to all sorts of gene pathology?

 

Immune agents.  

 

Microglia?  Immune agent.

 

TL4 and LPS response?  Immune pathways.

 

To put it simply: 

Chronic inflammation is a prolonged and dysregulated immune response leading to a wide variety of physiological and pathological conditions such as neurological abnormalities, cardiovascular diseases, diabetes, obesity, pulmonary diseases, immunological diseases, cancers, and other life-threatening conditions. 

https://link.springer.com/chapter/10.1007%2F978-3-319-41334-1_10

 

Chronic inflammation from senescent cells will eventually mess up the immune system.

 

The knock on effects of this are profound. 

  • Mental health issues
  • Cancer
  • Autoimmune

 

Almost everything!

 

What does fisetin do within this framework? 

Findings of this study showed that Fisetin significantly inhibited Th1 and Th2 cytokine production, cell cycle and the ratio of T CD4+/CD8+ cells in vitro. 

https://www.frontiersin.org/articles/10.3389/fimmu.2019.00051/full

 

IL6 and IL8 are cytokines (of many).

 

Then there's are favorite subject...allergy and histamine response.

 


That was a huge issue as estradiol (our main estrogen) pulled away during perimenopause.

 

Fisetin's effect on mast cells (where histamine is released)?:

One study on the effects of Fisetin on human mast cells (HMC-1) showed that Fisetin could down-regulate mast cell activation

 

In fact, fisetin showed the biggest response on allergic and histamine pathways: 

Among the flavonoids examined, kaempferol and quercetin showed substantial inhibitory activities in cytokine expression but less so than those of fisetin. 

https://www.jacionline.org/article/S0091-6749(03)01078-9/fulltext

 

Why would evolution favor this effect in strawberries and apples?

 

Simple...if your carrier doesn't cause an allergic or immune response, that food source is more likely to thrive long term and pass down genes!

 

It's a little Trojan Horse we can take advantage of with our immune system under assault (pesticides, chemicals, antibiotics, etc).

 

The biggest impact may be on autoimmune.

 

We're starting to see more research on this pathway such as with lupus: 

Fisetin inhibits pristine-induced systemic lupus erythematosus in a murine model through CXCLs regulation.

https://www.spandidos-publications.com/10.3892/ijmm.2018.3903

 

Similar effects are found across different autoimmune diseases.

 

Take arthritis, one of the most common.

 

In vivo, fisetin-treated mice exhibited less cartilage destruction and lower OARSI scores. 

https://www.sciencedirect.com/science/article/pii/S1567576917300644

 

This was a result of reductions in multiple inflammatory agents as expected.

 

We look forward to more information across the autoimmune field.

 

Let's go north...to the brain.

Fisetin and neuroprotection for mental health 

This is actually exciting times for a range of mental health conditions.

 

Anxiety and depression are starting to show their cards (see CBD and anxiety or CBD and depression for perimenopause here).

 

Serotonin was just a work around for BDNF (see CBD and BDNF).  GABA interactions with estrogen and CBD are also interesting (see CBD and GABA or Estradiol review).

 

A great deal of the new research is on inflammation of our nervous system.

 

That's the immune system's role.  The microglia are front and center.

 

We've seen above how fisetin is a powerful antioxidant and immune modulator.

 

Let's see how this impacts inflammation in the nervous system.

 

We'll start with the microglia since they are the primary governors of our brain's immune response.

 

So...what does fisetin do there?

In the present study, treatment with fisetin inhibited microglial cell migration and ROS (reactive oxygen species) production. 

https://www.mdpi.com/1420-3049/19/7/8820/htm

 

ROS...the little scissors in our brain!

 

Another group of researchers induced neuroinflammation by injecting lead into mice.

 

The effects of fisetin were impressive and widespread across the resulting inflammation and cellular destruction.

Fisetin suppressed activations of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), NF-κB and subsequently inactivate pro-inflammatory factor including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α).  

https://www.ncbi.nlm.nih.gov/pubmed/31539617

 

That TLR4 is very fascinating.  It's the main sentry in our immune system on the lookout for bacteria and elevated levels are tied to all sorts of mental health issues.

 

Check out our review of low dose naltrexone to understand why it's so important.

 

We've been looking for an alternative for LDN (due to the need for prescription) for a while now and fisetin may hit some of those pathways.

 

We see the other nasty cytokines included there.

 

Let's look at some individual mental health conditions understanding that inflammation is now showing up across the board.

Fisetin and Anxiety

New research is showing fisetin may calm anxiety that results from inflammation (such as from diabetes, etc): 

"Most mice put in a large area become exploratory," says Maher. "But anxious mice tend not to move around. Akita mice showed enhanced anxiety behavior, but fisetin feeding restored their locomotion to more normal levels." 

https://www.sciencedaily.com/releases/2011/06/110627183932.htm

 

Remember that inflammation is growing as we get older due to the senescent cell chemical leakage.

 

There's a huge tie between obesity (major epidemic now), senescent cells, and anxiety.

 

Read this next part slowly (maybe twice...it's really important!): 

Importantly, we show that clearance of senescent cells alleviates the obesity-related impairment in adult neurogenesis and decreases obesity-induced anxiety-like behavior. 

https://www.sciencedirect.com/science/article/pii/S1550413118307459

 

Neurogenesis is literally brain repair.  We lose it as we get older.

 

Learn all about why it's so important for anxiety at our CBD and neurogenesis for anxiety article.

 

BDNF does all the heavy lifting by the way.

 

We saw above how fisetin is a powerful senolytic (removes these cells), more powerful than the quercetin they used in the study.

 

It's not just anxiety though.

Fisetin and Depression

This gets even more interesting than just the anti-inflammatory angle (from overactive immune, obesity, age, senescent cells, etc) we just looked at.

 

Fisetin was able to directly influence the powerful serotonin and noradrenaline system tied to depression: 

Moreover, neurochemical assays showed that fisetin produced an increase in serotonin and noradrenaline levels in the frontal cortex and hippocampus. 

https://www.sciencedirect.com/science/article/pii/S016643281100876X

 

Serotonin is the key pathways that SSRI's use albeit with nasty side effects.

 

Rather than just boosting serotonin levels, fisetin inhibits the backend destruction of these neurotransmitters.

 

It slows down MAO which breaks them down.

Monoamine oxidase (MAO) activity in the mouse brain was inhibited by 14.7% after treatment with fisetin, while MAO-B activity was not affected.

 

MAO inhibitors without nasty side effects is one Holy Grail of medical community.

 

Ummm….Fisetin?

 

Depression is appearing to reflect one or two (maybe both) facets: 

  • Excessive damage as the result of stress, inflammation, immune reaction, etc
  • Lowered ability to repair and grow connections (BDNF, serotonin, etc).

 

Fisetin appears to hit it from both angles.

 

We could look at any mental health issue and find similar pathways.

 

Let's pick one of the most difficult and heart breaking as an example.

Fisetin and schizophrenia.

First, schizophrenia is a very complicated and potentially, multifaceted (as in terms of causes) disease.

 

There is a subsection (not sure what percentage) tied to inflammation and overactive immune response.

 

 

Along this path is the connection between infection in utero or during critical times of brain development.

 

It has been suggested that immune activation with a shift to a pro-inflammatory state of the cytokine network in response to still undefined environmental agents, herpesviruses infections, or microbiome. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210638/#sec5-brainsci-08-00188title

 

Elevated inflammatory markers (the very cytokines we saw above) are a well-documented hitchhiker with schizophrenia.

 

Basically, the immune system's response to early infection (plus genetics of course) causes microglia to overly prune brain synapses.

 

Studies are starting to really dive into this:  

Activated microglia are present in schizophrenia patients within the first 5 years of disease onset. 

 

Research here.

 

This article goes through fisetin's effect on neuroinflammation in more detail but the net effect that matters for our discussion: 

Notably, fisetin also significantly attenuated inflammation-related microglial activation and coordination deficit in mice in vivo. 

https://www.ncbi.nlm.nih.gov/pubmed/24972270

 

Remember how we said that TLR4 was important (which fisetin calms down)??: 

We found evidence of alterations in the expression of the initial elements of the TLR4 signalling pathway (TLR4, Myeloid differentiation primary response gene 88 [MyD88] and nuclear factor-κ B [NF-κB]) in the PFC of patients with schizophrenia.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853215/

 

A gene tied to TLR4 activity has a major association with schizophrenia risk.

 

The plot thickens!

 

We're going to do a full, deep dive on schizophrenia in light of the effects that CBD has there (truly remarkable).

 

There's a synopsis of the antipsychotic effects here.

 

Between powerful immune calming effects in the nervous system and neurotransmitter support (the MAO angle), fisetin could be a powerful support mechanism.

 

We could look at almost every mental health issue but let's focus down on one tied to loss of brain function.

Fisetin and dementia or Alzheimer's 

This is very interesting.

 

Let's start with the animal studies.

 

There's a learning test for mice (involving learning the pathway through a maze submerged in water).

 

The mouse has to learn and remember where the underwater path is to get across.

 

Researchers bred mice to have the signature amyloid buildup with Dementia (and resulting cognitive deficits).

 

Here's the result for Dementia bred mice and wild type mice after fisetin: 

In contrast, the AD mice showed very little learning over the 5 days of the acquisition task while the fisetin-fed AD mice behaved almost indistinguishably from the wild type mice in this task. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527824/

 

Let's translate that because it's too cool.

 

  • Wild type mice had no problem learning and remembering the path.
  • The dementia-bred mice were unable to learn and remember the path at all.
  • Dementia bred mice WITH fisetin learned the same as the wild type mice!

 

Yes, it's an animal study but still very cool and those mice are the workhorse studies in Dementia and Alzheimer's studies.

 

As for the social retrenchment and anxiety that accompanies dementia and Alzheimer's?

 

As shown in Figure 2D, the AD mice spent significantly more time in the open arms than the wild type mice. This behavior was reversed in the AD mice fed fisetin.

 

Next up...choline.  Purchase here

 

It may be THE key for dementia (you can supplement or eat eggs).

 

In fact, one of the major medications for dementia called Aricept operates by blocking the breakdown of acetylcholine (the usable form of choline in our brain).

 

Researchers use a chemical called scopolamine to block acetylcholine and then test what works to prevent the resulting cognitive issues.

 

That's how Aricept gained respectability (and FDA approval).

 

What about fisetin?

 

A single oral dose of 40 mg/kg bw of fisetin was as effective as donepezil at rescuing the memory deficit induced by scopolamine as determined using the passive avoidance test.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527824/

 

Holy $%$

 

Donepezil is Aricept.  

 

Aricept is over $500/month.  The list of side effects is nasty.

 

The typical Pharma ad horror show talking points as the lady is playing lawn darts with her smiling son.

 

Check them out here.

 

This is very exciting.

 

Remember how dementia and Alzheimer's are both characterized by build up in amyloid plaques and other misshapen proteins and molecules?

 

Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors.

https://www.nature.com/articles/srep24933

 

Let's back up and really understand that.

 

The whole point of fisetin was its powerful effect to get rid of senescent cells.

 

That's autophagy.

 

Here, fisetin is boosting this system to get rid of the plaques tied to dementia!

 

That Nrf2 is a very fascinating pathway.

 

It's a powerful initiator of our anti-oxidant army in the brain.


Our brain is a massive user of energy and therefore creates lots of waste material (oxidants).

 

But watch this: 

But as we get older, Nrf2 declines in activity—and that’s the main risk factor for Parkinson’s disease and other forms of dementia.  

https://www.worldwide.com/blog/2016/11/dementia-research-can-nrf2-aging-brains/

 

This may be the key to fisetin's anti inflammatory power: 

Taken together, fisetin translocated Nrf2 into the nucleus and upregulated the expression of downstream HO-1 gene by inhibiting the degradation of Nrf2 at the post-transcriptional level.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413105/

 

It stops nrf2 from being broken down!

 

We could write all day on this but we'll have to break it out separately.  Check out CBD and Dementia for its role.

 

Some questions that come up regularly.

Fisetin and quercetin 

Can, or better yet, should we take fisetin and quercetin (purchase here) together.

 

We know that fisetin is a more powerful senolytic and they both operate in very similar pathways.

 

But not exact!

 

We'll leave all the "synergistic" sales pitch to other sites.

 

If it's not based on research (see our work on CBD and anxiety here), then we'll pass.

 

That being said, there are slightly different pathways that quercetin and fisetin can act on as you drill down into the research.

 

For this reason, we take both to cover bases.  

 

Curcumin is a similar situation.

Fisetin and curcumin 

Curcumin is a very popular supplement with established anti-inflammatory and anti-oxidative qualities.

 

This is inline with some of the effects of Fisetin.

 

There may be different pathways though that Curcumin affects which are advantageous. Purchase here

 

We've been looking for a natural alternative to low dose naltrexone (see full review here) for a while.

 

Curcumin may downregulate the opioid system in a similar fashion so that it can function better.

 

The net net is this….

 

Our systems are so incredibly complicated.  There are bound to be small differences in effects between fisetin, quercetin, and especially curcumin.

 

All have powerful anti-inflammatory and neuroprotective effects albeit in subtly different ways.

 

The safety of all three is very high as well.

 

Until we see a reason not to take them together, we will.

 

Speaking of safety…

Fisetin safety and side effects 

We talked about the terrible side effects for Aricept (dementia), SSRI's, and MAO inhibitors which mirror what fisetin supports in the body.

 

What about fisetin?

 

This is going to be a real short section.

 

You literally can't find side effects: 

Importantly, no adverse effects of fisetin have been reported, even when given at high doses.  

https://www.leafscience.org/fisetin-may-be-a-low-hanging-fruit-for-aging/

 

This appears for both short term and and long term use: 

However, in the case of fisetin, there is no evidence for either short- or long-term toxicity. In a short-term study done by an outside laboratory, mice were orally administered 2000 mg/kg bw of fisetin, examined for 48 hr and sacrificed. No indications of toxicity were observed.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527824/

 

That's a very high dose! 

 

Much higher than what most people take as a supplement.

 

They looked for signs of toxicity from such high doses: 

Following sacrifice, multiple tissues (lungs, spleen, liver, kidneys, heart, stomach, intestine, testes and ovary) were examined using standard toxicological pathology criteria and no toxicity was associated with fisetin treatment. 

 

Interestingly, it doesn't appear to "use up" the coveted P450 liver pathway which is used to process most of our medications: 

It also showed no inhibitory effects on the activities of cytochrome P450s 3A4, 2C9 and 2D6 at concentrations up to 10 μM (unpublished results). 

 

At this time, there's no signs of side effects or toxicity.

 

Some practical question then.

How much fisetin to take 

What does research say about fisetin dosing.

 

A study on colon cancer and fisetin showed anti-inflammatory effects at 100 mg/day.

 

Other studies showed that you need at least 50 mg to make it through the so-called "first pass" which is the liver and our digestive gauntlet.

 

Our real goal here is that of a senolytic...removing the zombie-like cells.

 

100 mg doses were found to do this in mice.

 

The estimation for humans is 500 mg and we can even use a "hit and run" approach.

 

Studies showed that fisetin would clear out the senolytic cells and then you could use it periodically to have this effect.

 

We haven't found studies (or a reason) to avoid taking it continuously.

 

One protocol used in trials advocate about 1500 mg (for a 170 pound person) for 2 days and then doing this again one month later.

 

It's called the Mayo Protocol (Mayo clinic is doing the clinical trial now).

 

That's a very high dose and until we get results back, the 100-500 range is where we'll stay.

 

The bulk of the supplements on the market with legitimate brands (very important) are at 100 mg.

 

That's where we are till we get better research (the trials should help).

What's the best fisetin to buy 

As we've found with many (many) other supplements, the brand is critical here.

 

First, we're not comfortable buying anything that goes in our body from Amazon.

 

It's just too easy for China to throw an exact label on a bottle and feed you God knows what.

 

Unfortunately, that's the world we live in.

 

As for brands, we take our cue from Consumer Labs where they actually test for impurities and contaminants (not to mention levels).

 

We're using fisetin in a suite of options: 

 

For now, this is the best approach we have for aging and age-related illnesses.

 

Of course, CBD is a powerful adjunct to this entire suite with its effects on mitochondria health.

 

Mitochondria may be the first domino to fall in aging!  More on CBD and longevity here.

 

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