Fisetin: The Strongest Known Natural Senolytic – ALIVE BY SCIENCE – Bioavailable NAD+ Boosters

Fisetin: The Strongest Known Natural Senolytic

Fisetin Relieves Senescent Cell Burden

Fisetin, a naturally occurring plant flavonoid protects the body from accumulating harmful waste and activates Sirtuins, proteins responsible for regulating cellular health and aging.  (Source)

Functioning as a “senolytic,” clearing away dysfunctional senescent cells and allowing healthy cells to thrive, fisetin has shown potent senotherapeutic activity in mice and in human tissues.  (Source)


Fisetin Increases Lifespan by 10%

New research found that receiving fisetin regularly increases lifespan by about 10% and improves quality of life in aging mice.

Mice given fisetin lived an average of about 2.5 months longer, an almost 10% extension of lifespan—even when treatment was started at the human equivalent of 75 years of age. (Source)


Anti-Proliferative Effect of Fisetin in Vivo

Fisetin is known to have anti-aging, anti-cancer, and anti-viral effects and is being evaluated for its potential inhibitory role against cancer in several in vitro and in vivo studies. (Source)

“Emerging data indicate that fisetin possesses potent anti-proliferative activity against various cancer cells.”


More Senotherapeutic Activity than 24 Other Flavonoids

“Twenty-four flavonoids were compared for their cytotoxicity on cancer cells and their effect on the morphology of endothelial cells so as to predict the antiangiogenic activity of these compounds.

Fisetin, the most active agent, presented cell morphology that was distinct.” (Source)


Poor Bioavailability When Taken Orally

Fisetin administration is complicated by its low water solubility. Taken orally, fisetin is converted to an inactive form in the body.  But scientists have discovered that protecting fisetin in a liposome enhances permeation into cells.  (Source)

“Because of fisetin’s limited water solubility, we designed a liposomal formulation and evaluated its biological properties in vitro and in Lewis lung carcinoma (LLC) bearing mice.” (Source)

The challenge up until now was that fisetin is converted to an inactive form in the digestive tract. This means very little is absorbed into the bloodstream.


Liposomal Fisetin Increased Absorption 47-Fold

 

Fisetin-loaded liposomes have been shown to improve the solubility of fisetin and increase its blood residence time.

New studies show liposomal fisetin is up to 47x more bioavailable, which allows smaller dosages that put less strain on the liver.  (Source)

 

 

“In vivo, liposomal fisetin allowed a 47-fold increase in relative bioavailability compared to free fisetin.

The effect of liposomal fisetin on LLC tumor growth in mice at low dose (21 mg/kg) allowed a higher tumor growth delay.

In conclusion, fisetin liposomes markedly improved fisetin bioavailability and anticancer efficacy in mice and this formulation could facilitate the administration of this flavonoid in the clinical setting.”  (Source)


What are Liposomes?

Liposomes are vesicles composed of lipids, typically natural phospholipids, which organize themselves
in water to form an aqueous core surrounded by a lipidic bilayer.

This structure allows liposomes to transport both hydrophilic and lipophilic compounds, and this pharmaceutical preparation is now used in the clinical setting.

Liposomal formulations are increasingly being employed to reduce toxicity, improve absorption viability, and maintain biological activity.  (Source)


Liposomes Enhance Fisetin Bioavailability

These liposomal spheres are able to mask nutrients, that would otherwise expose fisetin to the harsh environment of the digestive tract.

Without liposomes, fisetin is degraded by the acids of the stomach and has limited entry into our intestinal cells due to a lack of transporters to bring the nutrients inside.

In fact, over 75% of traditional dietary supplements are not fully absorbed and thus have poor bioavailability.  (Source)


High Doses Removed 25-35% Aged, Dysfunctional Senescent Cells

In a 2018 study, fisetin was found to be effective in reducing senescent markers. The study proved that high fisetin doses administered over a couple of days were able to rid tissues and organs of approximately 25-35% of the zombie cells accumulated in different organs. (Source)


Fisetin Destroys Zombie Cells

 

Liposomal Fisetin has been shown to be capable of selectively destroying senescent cells in old tissues and is a natural alternative to some of the harsher senolytic therapies.

Its activation during embryonic development and normal adult life is linked with beneficial properties, however persistent (chronic) senescence exerts detrimental effects that foster aging and age-related disorders.  (Source)

 


What are Zombie Cells?

One of the main hallmarks of aging is increased cellular senescence.  Some scientists refer to these dysfunctional, senescent cells as “zombie cells.” Zombie cells are cells that have reached the end of their lifespan but don’t die.

When cells become old or no longer divide, they’re supposed to die off to make room for new cells.  But as we age, many cells become senescent instead.

Senescent (or aging) cells have been the main focus for Fisetin.  Most senescent cells are found in skeletal, fat, and kidney tissue, as well as being found in the skin of all vertebrate forms.

Zombie cell accumulation with age results in higher levels of certain senescence-associated proteins, which drive aging-related processes and promote age-related disease.  (Source)


What Causes Cellular Senescence?

 

 

Senescent cells don’t just linger around.  They pump out toxic compounds that degrade nearby cells and incite chronic inflammation that causes systemic damage.  (Source)

Several factors are thought to cause cellular senescence:

  • DNA damage
  • Chronic inflammation
  • Decreased sirtuin levels
  • Oxidative stress
  • Nutrient signaling dysfunction
  • Mitochondrial damage
  • Telomere erosion

Chronic Administration Extends Median and Maximal Lifespan

“Chronic administration of fisetin to wild-type mice late in life improved tissue homeostasis suppressed age-related pathology, and extended median and maximum lifespan.  (Source)

This result is the first to document extension of both health span and lifespan by a senolytic with few side effects, even though administration was started late in life.”


Fisetin Reduced Deficits Following a Stroke

Fisetin is one of the most common and bioactive flavonoids which possesses potential neuroprotective effects. Fisetin also enhances learning and memory, decreases neuronal cell death, and suppresses oxidative stress.  (Source)

Researchers investigating safe and effective neuroprotective treatments for stroke discovered fisetin to be a potent therapeutic approach.

“Based upon the results of these screens, we tested the best flavonoid, fisetin, in the small clot embolism model of cerebral ischemia in rabbits. Fisetin significantly reduced the behavioral deficits following a stroke, providing proof of principle for this novel approach to identifying new compounds for the treatment of stroke.” (Source)


No Adverse Side Effects, Even at High Doses

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

Thus, our results suggest that supplementation or even intermittent treatment with this safe, natural product could improve healthy aging, even in elderly individuals.”  (Source)


References

Fisetin is a Senotherapeutic that Extends Health and Lifespan

Liposomal Encapsulation of the Natural Flavonoid Fisetin Improves Bioavailability and Antitumor Efficacy

The Flavonoid Fisetin as an Anticancer Agent Targeting the Growth Signaling Pathways

How Fisetin Reduces the Impact of Age and Disease on CNS function.

Nanoemulsion Formulation of Fisetin Improves Bioavailability and Antitumour Activity in Mice

Fisetin Reduces the Impact of Aging on Behavior and Physiology in the Rapidly Aging SAMP8 Mouse

Cellular Senescence in Aging and Age-Related Disease: from Mechanisms to Therapy

Inhibition of Akt/mTOR Signaling by the Dietary Flavonoid Fisetin

Fisetin Induces Sirt1 Expression while Inhibiting Early Adipogenesis in 3T3-L1 Cells

A Novel Approach to Screening for New Neuroprotective Compounds for the Treatment of Stroke

Neuroprotective Effects of Fisetin in Alzheimer’s and Parkinson’s Diseases: From Chemistry to Medicine