The Power of Fisetin in Longevity

In the battle against aging, one key player is the removal of senescent cells—those “aging” cells that linger in the body, contributing to inflammation and tissue damage over time. Fisetin, a naturally occurring flavonoid found in various fruits and vegetables, has recently drawn attention as a potent senolytic—a compound that specifically targets and clears out these senescent cells.

This cellular “clean up” is crucial for longevity, as the buildup of senescent cells is closely linked to aging and numerous age-related health challenges. But the benefits of fisetin don’t end there. Beyond its senolytic effects, fisetin provides a strong antioxidant defense, combating oxidative stress that can otherwise lead to cellular damage. It also supports pathways associated with calorie restriction, a dietary approach widely recognized for its potential to extend lifespan.

Curious to learn how fisetin may contribute to a longer, healthier life? Read on as we explore the fascinating science behind fisetin’s potential to boost longevity and enhance overall well-being.

Understanding Fisetin as a Senolytic

Fisetin is a naturally occurring compound found in various fruits and vegetables, including strawberries, apples, persimmons, and onions. 

In fact, the earliest record of isolated fisetin dates back to 1833 taken from the smoke bush (Rhus cotinus). Chemically, fisetin belongs to the flavonol class—a group of polyphenolic compounds known for a range of bioactive effects, from antioxidant to anti-inflammatory properties. Its molecular structure, containing multiple hydroxyl groups, enables it to neutralize free radicals effectively, which is crucial for maintaining cellular health (1).

Thanks to its unique antioxidant capabilities, fisetin has drawn significant interest from researchers over the past two decades. It plays a distinctive role in senolytic research, showing promising results in laboratory and preclinical studies for selectively clearing senescent cells.

Why Do We Need to Clear Up Senescent Cells?

Senescence is a cellular response to stress, where cells lose their ability to divide but remain metabolically active. These senescent cells (also known as ““zombie cells”) secrete a range of harmful inflammatory molecules, collectively known as the senescence-associated secretory phenotype (SASP) (2). 

The SASP refers to the harmful molecules that senescent cells secrete, which can disrupt tissue homeostasis and contribute to aging and age-related diseases (3). These molecules include:

1. Pro-inflammatory Cytokines: These molecules are responsible for triggering inflammation in surrounding tissues. Key examples include:
• Interleukins (IL-1, IL-6, IL-8): These cytokines promote inflammation, immune cell recruitment, and tissue damage.
• Tumor Necrosis Factor-alpha (TNF-α): A potent pro-inflammatory cytokine that can contribute to chronic inflammation and tissue damage.
2. Growth Factors: Some of these molecules, while important for tissue repair, can have negative effects when overexpressed in a senescent context. Examples include:
• Transforming Growth Factor-beta (TGF-β): Can promote fibrosis and scarring in tissues, contributing to tissue stiffness and dysfunction.
• Vascular Endothelial Growth Factor (VEGF): Can promote abnormal blood vessel growth, which is associated with various age-related diseases, including cancer.
3. Matrix Metalloproteinases (MMPs): These enzymes break down extracellular matrix (such as collagen) proteins, leading to tissue degradation. Overexpression of MMPs, like MMP-1 and MMP-3, can contribute to the loss of tissue integrity and function.
4. Exosomes and MicroRNAs: Senescent cells also secrete exosomes and microRNAs, which can affect neighboring cells by altering their gene expression and promoting senescence in healthy cells.
5. Interferons: For example, Interferon-gamma (IFN-γ) can induce a state of senescence in surrounding cells, perpetuating the cycle of cellular aging and dysfunction.

Importantly, senescent cells can push neighboring cells into a state of senescence through paracrine signaling (surrounding cells), further exacerbating tissue dysfunction and accelerating the aging process. This accumulation of senescent cells contributes to the decline of vital tissues, including the skin, muscles, and organs, and is linked to various age-related diseases such as cardiovascular disease, Alzheimer’s, and osteoarthritis (4). 

By targeting and clearing senescent cells, we can reduce systemic inflammation, improve tissue regeneration, and enhance cellular function, helping to slow the aging process and promote healthier longevity.

What Are Senolytics?

Senolytics are compounds that target senile cells, damaged cells that have permanently stopped dividing but do not undergo normal cell death (5). Identifying and removing senescent cells is essential for maintaining healthy tissues and slowing the onset of age-related diseases, which is why senolytics are a key focus of longevity research.

Its ability to target “zombie cells” makes fisetin a particularly valuable agent for promoting longevity, comparable in efficacy to other known senolytics like quercetin and dasatinib.

Fisetin’s senolytic mechanism of action is based on its disruption of signaling pathways that sustain senescent cells. A primary target is the PI3K/AKT pathway—a cell signaling cascade involved in cell survival and inflammation. Fisetin appears to selectively inhibit this pathway in senescent cells, diminishing their survival capacity (6). 

Additionally, fisetin can induce apoptosis in damaged or dysfunctional cells, including senescent cells, by modulating key apoptosis-related proteins such as Bcl-2, Bax, and caspases. This helps to clear damaged cells that contribute to age-related diseases (7).

Thereby, fisetin exerts anti-cancer effects by inhibiting cell proliferation, inducing apoptosis in cancer cells, and preventing angiogenesis (formation of new blood vessels that tumors need to grow). It also modulates signaling pathways involved in tumor growth such as the p53 pathway.

Antioxidant Properties of Fisetin

One of fisetin’s most notable functions is its role as a powerful antioxidant that actively protects cells from oxidative stress. Oxidative stress arises when there’s an imbalance between free radicals and antioxidants in the body, leading to cellular damage that accelerates aging and contributes to various chronic diseases.

By reducing oxidative damage, fisetin supports the health of multiple cellular structures, including DNA, proteins, and cell membranes. Its antioxidant action protects cells from harmful oxidative byproducts, thereby helping to reduce the risk of chronic diseases such as cardiovascular disease, and neurodegenerative disorders (8).

At the molecular level, fisetin’s antioxidant properties further enhance its senolytic action. By reducing oxidative stress, it helps minimize DNA damage, thereby preventing cells from prematurely entering a senescent state. 

Healthy cells are better able to maintain balanced cell cycles, efficient immune responses, and optimal cellular repair processes. Fisetin's antioxidant properties directly contribute to improved cellular function:

• Fisetin modulates key inflammatory signaling pathways, including the NF-κB pathway, to reduce chronic inflammation. It can also decrease the production of pro-inflammatory cytokines and chemokines, which contribute to aging and disease progression (9).
• Fisetin has been found to protect brain cells by reducing oxidative damage, promoting neuronal survival, and enhancing synaptic plasticity. It can also help prevent neurodegenerative diseases like Alzheimer’s and Parkinson’s by modulating pathways involved in neuroinflammation and mitochondrial function (4).

• Fisetin protects mitochondria from oxidative damage and helps promote mitochondrial biogenesis, which is essential for maintaining cellular energy levels and preventing mitochondrial dysfunction, a hallmark of aging and many age-related diseases (10).

Thus, fisetin not only combats oxidative stress but also plays an active role in the prevention of age-related diseases, making it an attractive addition to longevity-focused wellness programs.

Mimicking Calorie Restriction

One of the most exciting aspects of fisetin is its ability to mimic the benefits of calorie restriction (CR), a dietary approach that has consistently been shown to extend lifespan and promote health in various organisms. 

Calorie restriction, which involves reducing calorie intake without malnutrition, activates specific cellular pathways that enhance metabolic efficiency, increase resilience to stress, and reduce inflammation—ultimately contributing to improved longevity. Fisetin appears to simulate some of these same effects, offering similar benefits without requiring dietary restrictions.

Fisetin influences several metabolic and cellular pathways activated by calorie restriction: 

• One of the key pathways is the AMPK pathway, often called the “cellular energy sensor.” When energy levels are low, as in a state of calorie restriction, AMPK is activated, leading to improved energy metabolism, increased fatty acid oxidation, and enhanced mitochondrial function. Fisetin has been shown to stimulate AMPK, thereby supporting energy balance and reducing cellular stress, much like calorie restriction (11).
• Fisetin can inhibit the mechanistic target of rapamycin (mTOR) pathway, which is involved in cellular growth and metabolism. Inhibition of mTOR promotes autophagy, reduces protein synthesis, and supports longevity by mimicking the effects of calorie restriction (12).
• Additionally, fisetin has effects on the SIRT1 pathway, another pathway activated during calorie restriction. SIRT1 is a protein associated with cellular repair and longevity, and its activation is linked to improved DNA stability and reduced inflammation. By activating SIRT1, fisetin helps to maintain cellular health and protect against age-related diseases, similar to the mechanisms seen with calorie restriction (11).
• Fisetin has been shown to activate autophagy, a cellular process that degrades and recycles damaged or dysfunctional cellular components. By stimulating autophagy, fisetin helps to maintain cellular health and function, particularly in aging cells (12).

Through these pathways, fisetin supports metabolic efficiency, reduces cellular inflammation, and enhances resilience to stress, offering benefits aligned with those observed in calorie restriction. For those interested in longevity and cellular health, fisetin’s ability to simulate these beneficial effects without altering diet makes it a valuable addition to wellness routines.

Natural Sources vs. Supplements

Fisetin is a naturally occurring flavonoid found in a range of fruits and vegetables. When discussing natural sources of fisetin, several fruits and vegetables stand out. Notably, strawberries contain the highest concentration, with about 160 µg/g of fisetin, followed by apples (26.9 µg/g), persimmons (10.6 µg/g), lotus root (5.8 µg/g), onions (4.8 µg/g), and grapes (3.9 µg/g). 

While these foods contribute to our overall antioxidant intake, consuming enough fisetin from dietary sources to reach therapeutic levels can be challenging. 

Studies examining fisetin’s potential for longevity and cellular health typically use doses much higher than what can be obtained from diet alone. To give context, therapeutic doses in studies often range from 100 to 500 mg daily—requiring a significantly larger intake than can be achieved through food alone.

Why Supplement with Fisetin?

To attain a fisetin dosage with potential senolytic or therapeutic effects, supplements can offer a concentrated and reliable source of this potent compound. Fisetin supplements provide a purified form of the flavonoid, ensuring a consistent and higher dose compared to dietary sources, which vary in fisetin content based on factors such as ripeness, growing conditions, and storage.

Moreover, supplemental fisetin is often formulated for enhanced bioavailability. In its natural form, fisetin has limited absorption in the body, but modern supplements use various delivery systems, like encapsulation, to improve uptake and efficacy. This makes supplements a practical and effective option for those looking to leverage fisetin’s full benefits for cellular health and longevity.

Modern formulas are designed to enhance the benefits of individual ingredients by combining them with others that complement their effects. Take Jung+ Longevity Foundation, for example—where the synergistic power of one ingredient amplifies the benefits of another, optimizing longevity and health outcomes. This precision formulation targets all 12 known drivers of aging, modulating key longevity mechanisms such as AMPK, mTOR, sirtuin signaling pathways, NAD+ levels, mitochondrial health, and cellular renewal. The result is a comprehensive approach to promoting youthful skin, a sharper mind, and a stronger body.

Integrating Fisetin into Your Longevity Regimen

Incorporating fisetin into a daily health regimen can be a strategic way to support longevity and cellular health. Here are practical tips on how to integrate fisetin supplements effectively and maximize their benefits.

1. Choose the Right Dosage

Studies suggest that daily doses between 50 mg and 150 mg may be effective for promoting longevity and supporting cellular health. However, the optimal dosage can vary depending on individual health goals, age, and existing health conditions.

Even if strawberries offer a much higher concentration of this flavonol than other produce, typical supplement pills contain around 100 mg of fisetin, a dose significantly higher than what would typically be obtained from dietary sources. 

We need to eat more than 600 grams of strawberry to achieve such concentration, daily! This amount is not only expensive, but can cause allergy, digestive issues and blood sugar fluctuations (~7.4 grams of sugars in 100 grams)

2. Timing for Optimal Absorption

Take fisetin with food, ideally alongside a meal containing healthy fats. Fisetin is fat-soluble, and consuming it with fats can help enhance its absorption in the body.

For those interested in mimicking calorie restriction effects, consider taking fisetin in the morning, as some studies suggest that antioxidants may have a more pronounced metabolic impact when taken earlier in the day.

3. Combine with Complementary Antioxidants

Pairing fisetin with other antioxidants, such as quercetin or pterostilbene, can support its effects. These compounds work synergistically, helping to boost antioxidant defenses and mimic calorie restriction even further.

Jung’s Longevity Foundation offers a well-rounded antioxidant blend that can be complemented with a fisetin supplement for those looking to cover multiple longevity-supportive pathways in one regimen.

Potential Side Effects and Safety Considerations

While fisetin is generally regarded as safe and well-tolerated, there are a few considerations to keep in mind when incorporating it into your routine, particularly at higher doses.

1. Known Side Effects

• Mild Digestive Issues: Some individuals may experience mild digestive symptoms, such as nausea or stomach discomfort, especially when taking higher doses of fisetin. Taking it with food can often minimize these effects.
• Headache or Dizziness: Although uncommon, some people report mild headaches or dizziness, typically when starting fisetin for the first time or taking higher doses. Starting with a lower dose can help you gauge tolerance.

2. Interactions with Other Supplements and Medications

• Blood-Thinning Medications: Fisetin has mild blood-thinning properties, so individuals taking anticoagulants or antiplatelet medications, such as warfarin, should use caution. This combination may increase bleeding risk.

3. Who Should Use Fisetin with Caution?

• Pregnant or Nursing Individuals: There is limited research on the safety of fisetin during pregnancy or breastfeeding, so it’s best for these individuals to avoid fisetin or consult a healthcare provider first.
• Individuals with Blood Disorders: Due to its potential mild blood-thinning effects, fisetin may not be suitable for people with clotting disorders or those undergoing surgery soon.
• People with Existing Health Conditions: Those managing chronic conditions, particularly cardiovascular or autoimmune disorders, should consult their healthcare provider to ensure fisetin doesn’t interact with medications or exacerbate their condition.

4. Consult a Healthcare Provider

• To ensure fisetin is safe for you, particularly if you take medications or other supplements, it’s always recommended to speak with a healthcare provider before beginning a fisetin regimen. They can help tailor dosage and timing to your individual health profile and ensure fisetin complements, rather than interferes with, your overall health plan.

The Future of Fisetin in Longevity Research

Current research is focused on fisetin's senolytic capabilities, examining how it can clear senescent cells to prevent tissue aging and reduce the incidence of age-related diseases. Beyond its senolytic action, fisetin is being studied for its potential to enhance metabolic function, support cognitive health, and improve immune response, areas that are pivotal in extending health span.

Scientists are also looking into fisetin’s impact at the genetic and epigenetic levels. With more insights into how fisetin influences gene expression linked to longevity and cellular repair, we may see fisetin formulations optimized to target specific health outcomes.

As clinical trials advance, they could reveal new applications, refine effective dosages, and increase our understanding of fisetin’s interactions within the human body. With this continued exploration, fisetin may soon become a widely recognized tool in the quest for healthy aging and longevity.

References:

1. Fisetin: A Dietary Antioxidant for Health Promotion (2013). Antioxidants & Redox Signaling.
2. A proteomic atlas of senescence-associated secretomes for aging biomarker development (2020). PLOS Biology.
3. The senescence-associated secretome as an indicator of age and medical risk (2020). JCI Insight.
4. The role of cellular senescence in neurodegenerative diseases (2024). Archives of Toxicology.
5. Cellular senescence and senolytics: the path to the clinic (2022). Nature Medicine.
6. Dietary flavonoid fisetin: a novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management (2012). Biochemical Pharmacology.
7. Fisetin Deters Cell Proliferation, Induces Apoptosis, Alleviates Oxidative Stress and Inflammation in Human Cancer Cells, HeLa (2022). International Journal of Molecular Sciences.
8. Antioxidant properties of the flavonoid fisetin: An updated review of in vivo and in vitro studies (2017). Trends in Food Science & Technology.
9. Fisetin derivatives exhibit enhanced anti-inflammatory activity and modulation of endoplasmic reticulum stress (2023). International Immunopharmacology.
10. Fisetin represses oxidative stress and mitochondrial dysfunction in NAFLD through suppressing GRP78-mediated endoplasmic reticulum (ER) stress (2022). Journal of Functional Foods.
11. Fisetin Protects Against Hepatic Steatosis Through Regulation of the Sirt1/AMPK and Fatty Acid β-Oxidation Signaling Pathway in High-Fat Diet-Induced Obese Mice (2018). Cellular Physiology and Biochemistry.
12. Fisetin inhibits inflammation and induces autophagy by mediating PI3K/AKT/mTOR signaling in LPS-induced RAW264.7 cells (2021). Food and Nutrition Research.