Potential therapies that target ageing and age-related disorders have been the subject of much investigation. Natural materials, such as plant-based chemicals, are among the most commonly studied agents. Fisetin & Quercetin are examples of potential micronutrients (polyphenol) and flavonoids that demonstrate efficacy against ageing and age-related changes.
In 2019, when David wrote Lifespan, he occasionally added resveratrol to his morning yoghurt. In the middle of 2021, he indicated that he was trying out a new formulation that included the antioxidants fisetin and quercetin. Let’s look at both compounds and the clinical trials.
What is Fisetin?
The first isolated fisetin was extracted from the smoke bush (Rhus cotinus) in 1833; therefore, it has been around for a long time. Since then, it has been recognized as a metabolic byproduct of several plants in their green portions, fruits, barks, and hardwoods. It is a flavanol having antioxidant effects similar to a variety of other plant polyphenols and can stimulate the production of the main antioxidant glutathione. This fascination is based on the relatively recent understanding that this chemical is not only an exceptionally potent antioxidant agent but also displays amazing selectivity in modulating several processes critical to maintaining healthy organisms (homeostasis).
Benefits of Fisetin.
Recent research into its beneficial biological effects—including antioxidant, anti-inflammatory, anti-cancer, neuroprotective, and anti-ageing properties—suggests that this high-purity material is appropriate for pharmaceutical development and will be of considerable interest.
- As An Anti-Cancer: Promising antitumor efficacy in various cancers has been observed using this compound. It was studied in 2020 that fisetin inhibits the development of cancer cells, stops their proliferation, and triggers their programmed death (apoptosis). Its role in breast (by lowering the mobility of cells to almost 76%), lung, pancreatic and liver cancer has also been studied and proven beneficial. Another 2019 human study looked at how fisetin affected human glioblastoma cells (invasive & uncontrollable form of brain cancer) treatment with fisetin caused apoptosis of these cells.
- Impeding Angiogenesis: Fisetin has also been found to reduce angiogenesis in cancerous cells; signals tumour cells utilize as a “switch.” In laboratory research, Fisetin was shown to decrease vascular endothelial growth factor (VEGF) development by as much as 92% in human umbilical vein endothelial cells.
- As an anti-ageing: According to scientists, cellular senescence leads to ageing. Senescent cells, sometimes known as “zombie cells,” do not die; instead, they assemble and inflame the cells and tissues around them. Cellular senescence eventually weakens an organism by increasing its vulnerability to age-related diseases. Senolytics, on the other hand, are substances that eliminate senescent cells. Fisetin is a powerful senolytic, especially compared to other flavonoids. According to a study published in the journal Aging, it successfully eradicated senescent cells when supplied to human umbilical vein endothelial cells.
In a 2018 rat study comparing 10 different phytochemicals, fisetin was found to be “the most powerful,” garnering widespread media attention.
https://www.thelancet.com/article/S2352-3964(18)30373-6/fulltext
Professor Paul D. Robbins, an ageing specialist, led a team of researchers that studied the effects of ageing and lifespan in rats. Compared to control mice, treated animals lived 10% longer and showed fewer signs of ageing. In light of these encouraging findings, a clinical trial is under process to investigate the significant effects of fisetin supplements on age-related impairment in humans.
https://www.thelancet.com/action/showPdf?pii=S2352-3964%2818%2930373-6
Even when administered late in a mouse’s life (about equal to a human being in their 50s or 60s), fisetin has increased both the median and maximum longevity.
- As a Brain Health Booster: As far as neurological disorders are, this compound has been studied in Alzheimer’s, Parkinson’s, and Huntington’s, as well as in models of stroke, neurotoxicity, and traumatic brain damage. Its neuroprotective and memory-enhancing effects were demonstrated in recent mouse studies. Mice with Huntington’s Disease (HD), a hereditary disorder that causes neuron death and damage, were used in one study. The motor deficits and death rate of HD mice administered fisetin was slowed by 30%. Has shown positive results in a clinical experiment with stroke patients and potential in various settings.
- As a Calorie Restrictor: The scientific community agrees that 10-40% calorie restriction improves health and longevity, and here this compound also finds its role. There is evidence that fisetin produces a comparable effect to calorie restriction by setting the same three pathways (activating sirtuins, boosting autophagy, and raising AMPK). Also, these pathways’ activity decreases with age, but studies in mice reveal that fisetin can increase it, so preserve cellular youth.
- As Antioxidants: Oxidative stress comes from an imbalance of free radicals and antioxidants. Fisetin’s antioxidant properties have been studied to prevent cellular damage caused by free radicals. It has anti-inflammatory capabilities by blocking inflammatory pathways and reducing inflammatory chemical synthesis. According to the research findings, fisetin may aid in maintaining glutathione levels in the body. Its reduced levels have been associated with a higher risk of developing cancer, diabetes, and cardiovascular disease.
In older postmenopausal women, fisetin’s effects on modifying biological markers of inflammation, insulin resistance, bone resorption, and frailty have been thoroughly evaluated in recent clinical studies.
- For Diabetic Complications: Fisetin’s effectiveness in lowering blood sugar levels in diabetics is also being investigated. The ability to suppress inflammation and protect blood vessels and other tissues was demonstrated in a 2014 study on mice. Similar findings were seen while testing human cell lines in the same investigation.
- For Bone Health: Fisetin’s potential benefits stem from the fact that it inhibits bone-degrading osteoclast activity.
Food Sources:
Most fisetin can be found in the foods listed below, as reported by research published in 2013 in the scientific journal Antioxidants and Redox Signaling.
| Fruit/Vegetable | Amount in µg/g |
| Strawberry | 160 |
| Apple | 26.9 |
| Persimmon | 10.6 |
| Lotus Root | 5.8 |
| Onion | 4.8 |
| Grape | 3.9 |
| Kiwi | 2.0 |
| Peach | 0.6 |
| Cucumber | 0.1 |
The flavonoid consumption from the food sources was determined to be 0.4 mg daily.
Dosage:
In clinical studies, participants consume dosages of fisetin ranging from 100 mg per day to 2,000 mg per day. ClinicalTrials.gov reports that the average dose in human studies is 20mg per kilogram of body weight. Individuals between 100 and 250 pounds have the following dosing range options:
- A daily dose of 900mg for every 100 pounds (45 kilograms)
- 1,360mg x 7 days / 150lb (68kg)
- To maintain a healthy weight of 200 lbs (91 kg), a daily dose of 1,820mg is required.
To sum up, the most effective strategy to reap the therapeutic benefits of fisetin is to take a supplement with around 20mg/kg of body weight, preferably with some fat, to improve absorption as it has poor bioavailability.
Dr Sinclair himself takes 500 milligrams of fisetin in the morning with some yoghurt.
Effective Timeline:
7 Days: In a trial of 7 days, 100mg of fisetin was given to Stroke Rehabilitators which improved the reperfusion time dramatically and improved the treatment outcome of this widely used stroke therapy.
7 weeks: In a clinical trial including patients with colon cancer, daily dosing at 100 mg for a total of 7 weeks was beneficial in decreasing inflammation.
Most ongoing and proposed human trials will use a dosage of 20 milligrams per kilogram of body weight to determine the effects of fisetin. There are currently 17 fisetin clinical trials registered with ClinicalTrials.gov as of publication (August 2022). While others are already up and running, others are still in the planning stages.
Side effects:
Although fisetin comes from plants, the possible dangers and side effects of using it are yet unclear. That is why no information on fisetin’s potential health hazards or long-term negative effects has been identified. But thus far, cell or animal tests have shown no harm.
Quercetin.
Quercetin has antioxidant effects and is a flavonoid. Many health benefits, including protection against illnesses, including osteoporosis, lung cancer, and cardiovascular disease, have been attributed to it.
Health Benefits of Quercetin.
The antioxidant properties of quercetin have been linked in studies to a wide range of possible health advantages.
- Anti-Inflammatory: The anti-inflammatory effects of quercetin have been studied and found to be promising. Quercetin inhibited the production of inflammatory molecules such as tumour necrosis factor-alpha (TNF) and interleukin-6 (IL-6) in human cells in vitro. 500 mg of quercetin was found to considerably reduce morning stiffness, morning discomfort, and post-activity pain in a study of people with rheumatoid arthritis.
- Anti-Cancer Properties: Due to its antioxidant qualities, quercetin may be effective against cancer. It has been found in rodent studies that Quercetin suppresses prostate cancer cell growth in test tubes and animals. Liver, lung, breast, bladder, blood, colon, ovarian, lymphoid, and adrenal cancer cells responded similarly to the chemical in test tubes and animal experiments. (1) (2) (3). In human trials, High intakes of quercetin in the diet have been linked to a decreased risk of pancreatic cancer, particularly in male smokers.
- Helps with Blood Pressure: Several studies have shown promising results in demonstrating quercetin’s potential to lower blood pressure. In culture, the chemical appeared to have a vasodilatory action. In 9 human investigations ingesting more than 500 mg of quercetin daily lowered systolic and diastolic blood pressure by 5.8 mm Hg and 2.6 mm Hg, respectively.
- Cardiovascular Health: Some research suggests that eating foods rich in quercetin, such as tea, onions and apples, can reduce the risk of heart disease-related death in elderly men. By reducing blood pressure and cholesterol and by relaxing blood vessels, quercetin has been found to benefit the cardiovascular system. It can also boost a man’s erections because they increase blood flow, a common cause of erectile dysfunction in males.
- As Anti-Aging Agent: The anti-ageing effects of quercetin have been studied in vitro and in vivo with promising results. (1) (2) (3) More research is ongoing to prove its efficacy.
- As Neuroprotective: The antioxidant properties of quercetin have been studied for their potential to stave against neurodegenerative diseases, including Alzheimer’s and dementia. In a study, mice were given quercetin after every day, and the infusions corrected multiple Alzheimer’s symptoms, and the mice performed better on learning tests.
- Increases Exercise Performance: Taking its supplement may marginally increase endurance exercise performance, according to a meta-analysis of 11 human trials.
- Against inflammation: Potential anti-inflammatory effects of quercetin may help alleviate allergy symptoms. Evidence from in vitro and animal research suggests it may inhibit inflammatory enzymes and reduce inflammatory compounds like histamine levels. Further studies from Pharmacognosy Review reveal that quercetin may be an efficient antihistamine because it inhibits the release of histamine from cells.
- May Slow Skin Aging: Treatment of skin conditions, including dermatitis with quercetin, has also been demonstrated to be effective. (1) Wrinkles can be reduced by topical therapy boosting the skin’s moisture and flexibility.
- Lowers Blood Sugar: The chemical has shown promise in lowering fasting blood sugar levels and protecting against diabetic complications in human and animal studies.
Food Sources
The human body lacks the ability to produce quercetin, yet it is found in a wide variety of food and drink. More than twenty plant sources contain the bioflavonoid quercetin, including red wine, onions, green tea, apples, and berries are just a few of the foods and plants that contain this compound. Consuming quercetin-rich onion for 24 weeks was shown in research published in 2021 to be associated with a reduction in cognitive decline. It is abundant in cranberry too. In the United States, its consumption ranges between 6 and 18 milligrams (mg) daily.
| Food | Quercetin (mg per 100 g) |
| Raw capers | 233.84 |
| Raw hot/yellow peppers | 50.73 |
| Raw red onions | 39.21 |
| Cooked asparagus | 15.16 |
| Raw cranberries | 14.84 |
| Raw hot/green peppers | 14.7 |
| Raw lingonberries | 13.3 |
| Raw blueberries | 7.67 |
| Raw red leaf lettuce | 7.61 |
| Raw white onions | 6.17 |
| Tinned tomatoes | 4.12 |
| Red apples | 3.86 |
| Gala apples | 3.8 |
| Golden delicious apples | 3.69 |
| Raw broccoli | 3.26 |
| Raw sweet cherries | 2.29 |
| Black grapes | 2.08 |
| White grapes | 1.12 |
Keep in mind that the growing circumstances may affect the quercetin content of foods. Organic tomatoes have 79% more antioxidant quercetin than ordinary tomatoes, according to one study.
On its own, quercetin has a low bioavailability, meaning the body poorly absorbs it. Therefore, dietary supplements may contain vitamin C or digestive enzymes such as bromelain, which may enhance absorption. Some study suggests quercetin has a synergistic impact with resveratrol, genistein, and catechins.
Dosage: Typical doses vary from 500–1,000 mg per day. When used in moderation, this compound may be safe for most people when taken orally. Supplemental quercetin can be purchased in the form of tablets or capsules. It has been shown that taking 500 mg of quercetin twice daily for 12 weeks is safe. Long-term or excessive usage has not been studied yet for safety.
Dr David Sinclair takes 500 milligrams of quercetin in the morning with some yoghurt.
Side Effects & Precautions:
This flavonoid has been linked to headaches and numbness in the extremities. Although generally harmless, it may interfere with some drugs, such as antibiotics and blood thinners. There is also a concern that doses above 1 gram might harm the kidneys as it may impair the function of proteins.
Intravenous (IV) use of quercetin in doses less than 722 mg is considered safe. However, IV administration of higher doses may be dangerous. Damage to the kidneys has reportedly been seen at greater dosages.
Effective Timeline:
The meta-analysis found that quercetin supplementation significantly lowered blood pressure, with the greatest benefit shown at or above 500 milligrams per day.
7 Days: It was found in a 2022 study that 7-day oral questioning supplementation of 1000mg increases high-intensity cycling time.
A meta-analysis of 11 clinical studies until July 2010 revealed quercetin supplementation enhanced endurance by 3%. 11 days of quercetin 1,000 mg per day was the median treatment duration.
4 Weeks: 35 prehypertensive adults consumed pure epicatechin 100 mg/day and quercetin-3-glucoside 160 mg/day for 4 weeks, reducing inflammation markers.
8 Weeks: In an 8-week trial of 50 women with rheumatoid arthritis, 500 mg of quercetin decreased morning stiffness, morning discomfort, and after-activity pain.
Another study based on durations of 8 weeks and doses of 500 mg/day of quercetin significantly decreased fasting plasma glucose levels.
10 Weeks: In a 10-week trial, 72 women were given a 500mg daily dose of quercetin and the total cholesterol, LDL, and triglycerides were reduced among the population.
3 Months: In 3-month research, 500 mg of quercetin, 500 mg of vitamin C, and 50 mg of bromelain greatly protected healthcare workers from Covid-19.
6 months: A short experiment in children with Autism demonstrated substantial improvement in adaptive functioning and general behaviour after 26 weeks of luteolin from chamomile (100 mg), quercetin (70 mg), and quercetin glycoside rutin (30 mg).
To combat ageing and age-related diseases, polyphenols, and flavonoids, in particular, provide a promising new avenue to explore. As a powerful antioxidant, anti-inflammatory, and senolytic molecule, fisetin shows extraordinary potential.
