Life Extension Magazine®
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Issue: Winter Edition 2020

Fisetin: A Longevity Senolytic

The plant extract fisetin increased lifespan by 10% even when fed to rodents the equivalent of 75 human years. Fisetin counteracts aging via several mechanisms including functioning as a potent senolytic. A new patented green technology increases the bioavailability of fisetin 25 times higher.

Scientifically reviewed by:  Dr. Gary Gonzalez, MD, on November 2020. Written By Zach White.

For decades, scientists have searched for compounds that can slow degenerative aging processes.

A recent focus is a plant extract called fisetin.

Found in strawberries, apples, and other plants, fisetin has a range of benefits that may increase longevity.1,2

Fisetin has been shown to:

  • Function as a senolytic, clearing away dysfunctional senescent cells and allowing healthy cells to thrive,3
  • Protect the brain in various models of neurodegenerative disorders,2,4-9
  • Improve outcomes in people who have suffered strokes,10
  • Help prevent malignant changes in cells,11-14 and
  • Help fight obesity and type II diabetes.15-17

Several human trials are currently underway.

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 blood stream.

For the first time, scientists have developed a low-cost method to increase absorption up to 25 times higher,18 thus enabling fisetin to be distributed throughout the body.

What Is Fisetin?

Fisetin , a flavonoid, is found in various fruits and vegetables including strawberries, apples, persimmons, grapes, and onions.

Its benefits overlap with some other flavonoids, including green tea catechins and quercetin. But it has its own unique set of biological properties.

Most notably, a recent study found fisetin to be the most potent senolytic compound among a group of flavonoids that were tested.3 Senolytics are at the center of today’s anti-aging research.

Fisetin Extends Lifespan

Graph showing longer lifespan in old mice with fisetin supplementation

When cells become old or dysfunctional, they’re supposed to die off to make room for new cells. But as we age, many cells become senescent instead.

What this means is that these cells lose their ability to divide or perform basic functions and refuse to die. Some scientists refer to senescent cells as “zombie cells.”

Senescent cells don’t just linger around. They pump out toxic compounds that degrade nearby cells and incite chronic inflammation that causes systemic damage.19

Cellular senescence has become a major target for anti-aging research. Preclinical studies indicate that compounds called senolytics remove senescent cells and can slow or even reverse aging processes.3,20-22

Recent research has found that fisetin is an exceptionally powerful senolytic. When compared to other plant compounds, including quercetin, fisetin was the most effective at removing senescent cells, both in cell culture and in mice.3

The effects are dramatic. 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.3

The Mayo Clinic has begun clinical trials to study the ability of fisetin to reduce senescent cell burden in aging humans.23

Anti-Aging Properties

Sirtuin proteins are another anti-aging target.24,25 These cellular protectors are found in all cells in the body, and are vital for keeping cells performing at peak level.

Sirtuin function tends to diminish with age. But fisetin activates sirtuin function in cells, countering this decline.26-30 In various animal models, sirtuin activation has been shown to extend lifespan significantly.24,25,31,32

Fisetin may protect against aging in other ways:

  • It reduces inflammation, a driver of many chronic illnesses and even of aging itself.2
  • It mimics some of the effects of a calorie-restricted diet, which has been shown to boost resistance to disease and increase lifespan.1,2,29,34
  • It helps prevent oxidative damage that leads to accelerated aging and degenerative disease.33

What you need to know

Fisetin Promotes Healthy Longevity

  • Fisetin is a compound found in several fruits and vegetables, including strawberries, apples, grapes, and onions.
  • Fisetin is the most potent senolytic compound found among a panel of flavonoids, selectively removing senescent cells and extending longevity in animal studies.
  • This flavonoid has also been shown in preclinical studies to help protect against cancer, type II diabetes, and obesity, and in a human study to improve outcomes in stroke victims.
  • Taken orally, pure fisetin is converted to an inactive form in the body. But scientists have discovered that combining it with galactomannans from fenugreek prevents that from happening.
  • A new formulation boosts the bioavailability of fisetin by 25 times, allowing more of it to circulate throughout the body, promoting health and supporting longevity.

Preventing Obesity and Diabetes

Woman in pink shirt preparing a salad

Obesity leads to a skyrocketing risk of metabolic disorders such as type II diabetes. It also increases the risk for cardiovascular disease, cancer, dementia, and many other disorders.

Preclinical studies show that fisetin appears to act as a kind of “metabolism control switch,” reducing fat cell accumulation and suppressing activation of the protein mTOR, which is linked to weight gain. In mice fed a high-fat diet, fisetin prevented increase in body weight and accumulation of harmful white fat tissue.15

Fisetin also helped fight fat accumulation in the livers of animals fed a high-fat diet, a common occurrence with metabolic disease that can compromise liver function and lead to fatty liver disease.35-38

Fisetin may provide benefits for those already suffering from type II diabetes.

In rodent models of diabetes, fisetin lowers body weight and leads to improved glucose control with lower hemoglobin A1c levels, a marker of blood sugar regulation over time.16,17

Poorly controlled diabetes often causes disabling or life-threatening complications throughout the body. In mice, fisetin significantly reduces the severity of diabetic complications, including slowing the progression of cataracts, preventing kidney damage, and improving kidney function.16,39

A human trial of fisetin’s ability to protect kidney function, particularly in diabetes patients, is currently underway.40

Brain Benefits

People who suffer from a stroke are often treated with medication to dissolve the clot blocking blood flow to the brain. This can save a patient’s life, prevent damage to the brain, and even reverse the symptoms of stroke in some patients.

But ER doctors are working against the clock when treating acute (ischemic) stroke. The best chances of success occur when treatment begins within three hours of the onset of symptoms.41 Many people suffering a stroke are treated too late and suffer permanent neurological injury (and paralysis).

A recent study shows that combining clot-dissolving medication with fisetin significantly extends the treatment window.10

Patients receiving fisetin in addition to usual treatment up to five hours after a stroke had neurological outcomes as good as those treated within three hours. This extension of the therapeutic window means that many stroke victims who would otherwise suffer permanent loss of brain function have a better chance of recovery.

Fisetin has also shown neuroprotective benefits in animal models of Alzheimer’s disease, Parkinson’s disease, ALS (amyotrophic lateral sclerosis), and other brain pathologies, reducing the severity of disease and improving cognitive function.2,4-9

Fighting Cancer

Scientist using a microscope

Fisetin has shown potential in preventing cancer and limiting the growth and spread of existing tumors in preclinical studies. Among its anti-cancer properties:

  • Fisetin induces apoptosis, or programmed cell death, in cancer, which can facilitate removal of tumor cells.47-50
  • As an anti-inflammatory, fisetin reduces compounds that contribute to chronic inflammation and cancer progression.42-45 In a study of patients with colorectal cancer, fisetin reduced levels of pro-inflammatory mediators.46
  • Fisetin enhances autophagy,51 cellular housekeeping that keeps cells functioning normally. Enhanced autophagy can inhibit cancer cell survival.
  • Fisetin helps prevent angiogenesis, the formation of new blood vessels, in cancer, starving tumor cells of oxygen and glucose.52,53
  • Fisetin helps prevent oxidative damage which can contribute to DNA mutations and cancer development.42,43
  • Fisetin may inhibit cancer cell migration and metastasis, the spread of cancer to a different part of the body.54

Improved Bioavailability

In its pure form taken orally, there’s a problem with fisetin: Once it reaches the gut, enzymes in the body rapidly modify it into a form which is inactive and all but useless.

Scientists have discovered a way around this problem. By combining it with natural compounds called galactomannans isolated from the herb fenugreek, fisetin is protected from being modified in the intestinal tract. It remains active and can be readily absorbed into the bloodstream.

In a recently conducted study, researchers found that the newly formulated fisetin-galactomannan combination, using a patented green technology, increases bioavailability (how much is absorbed and circulates) in people by 25 times.18

This opens a brand-new door in enabling aging people to derive meaningful benefits by supplementing with a low-cost nutrient.

OPTIONS TO REMOVE SENESCENT CELLS

Most of you are reducing your senescent cell burden by:

  • Two-day-a-week fasting (not eating 2 days each week) or time-restricted eating (fasting 16-18 hours most days) and/or some other form of dietary restriction,
  • Several times a year dosing using dasatinib + quercetin and/or,
  • Weekly dosing using black tea theaflavins + quercetin + apigenin.

Fisetin is arguably one of the most focused, targeted senolytic agents, based upon current science. For the first time, people can obtain it in bioavailable form as opposed to taking over 1,400 mg a day of fisetin by itself and hoping enough is absorbed into your bloodstream.

For those who want to continue with a weekly senolytic program, taking seven capsules once-a-week of bioavailable fisetin along with a black tea theaflavins + quercetin + apigenin formula is an option.

Alternatively, you may also take the bioavailable fisetin dose daily for its other benefits and continue with weekly black tea theaflavins + quercetin + apigenin.

There is potential benefit to daily senolytic as this is how it happens in younger people with strong immune systems that constantly remove senescent cells.55

Studies are planned for using bioavailable fisetin on differing dosing schedules to ascertain the ideal protocol to removing senescent cells and reducing the “senescent associated secretory phenotype” (SASPs).

While the longevity data on dasatinib are compelling, some people experience mild flu symptoms or GI upsets, whereas fisetin does not cause these unpleasant side effects.

We look forward to results from human trials to identify the optimal senolytic protocol for aging persons to follow. This may involve several senolytic compounds based on individual response rates as measured by the “senescent associated secretory phenotype,” skin punch measures of senescent fibroblast cells, or other senolytic measuring methods being explored.

Highlights from Recent Study

  • Senescent cell production rate increases with age due to accumulation of mutations, telomere damage, other factors triggering cell senescence.
  • Senescent cells catalyze their own production by paracrine and bystander effects.
  • Senescent cell removal decreases with age due to decline in immune surveillance functions.
  • Senescent cells reduce their own removal rate.

Karin O, Agrawal A, Porat Z, et al. Senescent cell turnover slows with age providing an explanation for the Gompertz law. Nat Commun. 2019 Dec 2;10(1):5495.

Senescent Cell Removal Declines with Aging

Senescent cells turn over in five days in 3-month-old mice but take 25 days in 22-month-old mice. This model predicts a vicious cycle where senescent cells accumulate faster and are degraded slower.

At the point of 30% senescent cell load animals often appear to reach tipping point resulting in death.

“Our results suggest that treatments that remove senescent cells can therefore have a double benefit: an immediate benefit from a reduced senescent cell load, and a longer term benefit from increased senescent cells removal.”

https://www.nature.com/articles/s41467-019-13192-4.

Summary

Man doing situps in a boardwalk area

Fisetin is a compound found in many plants, including strawberries and apples.

It is the most effective senolytic compared to a panel of flavonoids, removing aged, dysfunctional senescent cells in preclinical studies. This may help improve function in older age, shield against chronic disease, and increase healthy longevity.

In mice, fisetin alone extended lifespan by approximately 10%.

Extensive research also demonstrates the potential of fisetin to help protect against cancer, stroke, obesity, type II diabetes, and other metabolic disorders.

A new fisetin formula compounds it with fenugreek, which protects it from inactivation in the gut. This allows more fisetin to be absorbed and distributed throughout the body for systemic benefits.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

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