Out With The Old…

Fisetin is a flavonoid (specifically, a flavonol), but it’s a little different than most. While it has the usual antioxidant, anti-inflammatory, and anti-cancer properties you might reasonably expect from flavonoids, it has an extra anti-aging trick up its sleeve that most don’t.

❝Fisetin is a flavonol that shares distinct antioxidant properties with a plethora of other plant polyphenols. Additionally, it exhibits a specific biological activity of considerable interest as regards the protection of functional macromolecules against stress which results in the sustenance of normal cells cytoprotection. Moreover, it shows potential as an anti-inflammatory, chemopreventive, chemotherapeutic and recently also senotherapeutic agent❞

~ Dr. Grynkiewicz & Dr. Demchuk

Let’s briefly do some due diligence on its expected properties, and then we’ll take a look at its bonus anti-aging effects.

The flavonol that does-it-ol

Because of the similar mechanisms involved, there are three things that often come together, which are:

• Antioxidant
• Anti-inflammatory
• Anticancer

This list often gets expanded to also include:

• Anti-aging

…although that is usually the last thing to get tested out of that list.

In today’s case, let’s kick it off with…

❝Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a dietary flavonoid found in various fruits (strawberries, apples, mangoes, persimmons, kiwis, and grapes), vegetables (tomatoes, onions, and cucumbers), nuts, and wine that has shown strong anti-inflammatory, anti-oxidant, anti-tumorigenic, anti-invasive, anti-angiogenic, anti-diabetic, neuroprotective, and cardioprotective effects❞

~ Dr. Harish Pal et al.

Read more: Fisetin and Its Role in Chronic Diseases

Understanding its anticancer mechanisms

The way that fisetin fights cancer is basically “all the ways”, and this will be important when we get to its special abilities shortly:

❝Being a potent anticancer agent, fisetin has been used to inhibit stages in the cancer cells (proliferation, invasion),prevent cell cycle progression, inhibit cell growth, induce apoptosis, cause polymerase (PARP) cleavage, and modulate the expressions of Bcl‐2 family proteins in different cancer cell lines (HT‐29, U266, MDA‐MB‐231, BT549, and PC‐3M‐luc‐6), respectively. Further, fisetin also suppresses the activation of the PKCα/ROS/ERK1/2 and p38 MAPK signaling pathways, reduces the NF‐κB activation, and down‐regulates the level of the oncoprotein securin. Fisetin also inhibited cell division and proliferation and invasion as well as lowered the TET1 expression levels. ❞

~ Dr. Muhammad Imran et al.

Read more: Fisetin: An anticancer perspective

There’s also more about it than we even have room to quote, here:

Fisetin, a Potent Anticancer Flavonol Exhibiting Cytotoxic Activity against Neoplastic Malignant Cells and Cancerous Conditions: A Scoping, Comprehensive Review

Now For What’s New And Exciting: Senolysis

All that selectivity that fisetin exhibits when it comes to “this cell gets to live, and this one doesn’t” actions?

It makes a difference when it comes to aging, too. Because aging and cancer happen by quite similar mechanisms; they’re both DNA-copying errors that get copied forward, to our detriment.

• In the case of cancer, it’s a cell line that accidentally became immortal and so we end up with too many of them multiplying in one place (a tumor)
• In the case of aging, it’s the cellular equivalent of “a photocopy of a photocopy of a photocopy” gradually losing information as it goes

In both cases…

The cell must die if we want to live

Critically, and which quality differentiates it from a lot of other flavonoids, fisetin has the ability to selectively kill senescent cells.

To labor the photocopying metaphor, this means there’s an office worker whose job it is to say “this photocopy is barely legible, I’m going to toss this, and then copy directly from the clearest copy we have instead”, thus keeping the documents (your DNA) in pristine condition.

In fisetin’s case, this was first tested in mouse (in vivo) studies, and in human tissue (in vitro) studies, before moving to human clinical studies:

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

The natural product fisetin has senotherapeutic activity in mice and in human tissues. Late life intervention was sufficient to yield a potent health benefit.❞

~ Dr. Matthew Yousefzadeh et al.

Read in full: Fisetin is a senotherapeutic that extends health and lifespan

There’s lots more science that’s been done to it since that first groundbreaking study though; here’s a more recent example:

Fisetin as a Senotherapeutic Agent: Biopharmaceutical Properties and Crosstalk between Cell Senescence and Neuroprotection

Want some?

We don’t sell it, but here for your convenience is an example product on Amazon

Enjoy!

Kava, sometimes also called “kava kava” but we’re just going to call it kava once for the sake of brevity, is a heart-shaped herb that bestows the powers of the Black Panther is popularly enjoyed for its anxiolytic (anxiety-reducing) effects. Despite the similarity of the name in many languages, it is unrelated to coffee (except insofar as they are both plants), and its botanical name is Piper methysticum.

Does it work?

Yes! At least in the short-term; more on that later.

Firstly, you may be wondering how it works; it works by its potentiation of GABA receptors in the brain. GABA (or gamma-aminobutyric acid, to give it its full name), as you may recall, is a neurotransmitter that is associated with feelings of calm; we wrote about it here:

GABA Against Stress/Anxiety

So, what does “potentiation of GABA receptors” mean? It means… Scientists don’t for 100% sure know how it works yet, but it does make GABA receptors fire more. It’s possible that to some degree GABA fits the “molecular lock” of the receptors and causes them to say “GABA is here”; it’s also possible that they just make them more sensitive to the real GABA that is there, or there could be another explanation as yet undiscovered. Either way, it means that taking kava has a similar effect to having increased GABA levels in the brain:

Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABA_A Receptors: Functional Characteristics and Molecular Mechanism

As for how much to use, 20–300mg appears to be an effective dose, and most sources recommend 80–250mg:

Kava as a Clinical Nutrient: Promises and Challenges

This review of clinical trials found that it was more effective than placebo in only 3 of 7 trials; specifically, it was beneficial in the short-term and not in the long-term. For these reasons, the researchers concluded:

❝Kava Kava appears to be a short-term treatment for anxiety, but not a replacement for prolonged anti-anxiety use. Although not witnessed in this review, liver toxicity is especially possible if taken longer than 8 weeks.❞

Source: The effectiveness and safety of Kava Kava for treating anxiety symptoms: A systematic review and analysis of randomized clinical trials

Another review of clinical trials found better results over the course of 11 clinical trials, though again, short-term treatment only was considered to be where the “safe and effective” claim can be placed:

❝Compared with placebo, kava extract appears to be an effective symptomatic treatment option for anxiety. The data available from the reviewed studies suggest that kava is relatively safe for short-term treatment (1 to 24 weeks), although more information is required. Further rigorous investigations, particularly into the long-term safety profile of kava are warrant❞

Source: Kava extract for treating anxiety

Is it safe?

Nope! It has been associated with liver damage:

FDA | Consumer Advisory: Kava-Containing Dietary Supplements May be Associated With Severe Liver Injury

The likely main mechanism of toxicity is that it simply monopolizes the liver’s metabolic abilities, meaning that while it’s metabolizing the kava, it’s not metabolizing other things (such as alcohol or other medications), which will then build up, and potentially overwhelm the liver:

Constituents in kava extracts potentially involved in hepatotoxicity: a review

However, traditionally-prepared kava has not had the same effect as modern extracts; at first it seemed the difference was the traditional aqueous extracts vs modern acetonic/ethanolic extracts, but eventually that was found not to be the case, as toxicity occurred with industrial aqueous extracts too. The conclusion so far is that it is about the quality of the source ingredients, and the problems inherent to mass-production:

Kava hepatotoxicity in traditional and modern use: the presumed Pacific kava paradox hypothesis revisited

Meanwhile, short-term use doesn’t seem to have this problem, if you’re not drinking alcohol or taking medications that affect the liver:

Mechanisms/risk factors – kava-associated hepatotoxicity ← you’ll need to scroll down to 4.2.4 to read about this

Want to try it?

If the potential for hepatotoxicity doesn’t put you off, here’s an example product on Amazon ← we do not recommend it, but we are not the boss of you, and maybe you’re confident about your liver and want to use it only very short-term?

Take care!