Fisetin

What are Flavonoids?

Flavonoids are commonly found in most plants and exhibit a wide range of biological activities, including antioxidant, anticancer, anti-inflammatory, antibacterial, immune-stimulating, and antiviral properties (Duarte et al., 1993; Jang et al., 2005; Rice-Evans et al., 1996). Due to these properties, flavonoids have been extensively studied for their potential contributions to health, disease protection, and longevity.

What is Fisetin, and where is it found?

Fisetin (3,3’,4’,7-tetrahydroxyflavone) is a bioactive flavonol molecule found in fruits and vegetables such as strawberry, apple, persimmon, grape, onion, and cucumber at concentrations in the range of 2–160 μg/g (Arai et al., 2000). Fisetin was measured in freeze-dried vegetables and fruits after acid hydrolysis of the parent glycosides. The highest concentration of fisetin was found in strawberries (160 μg/g), followed by apples (26.9 μg/g) and persimmons (10.5 μg/g). The estimated average dietary intake is approximately 0.4 mg/day, which is far lower than the amounts used in research or supplementation (Kimira et al., 1998). Because natural dietary levels are low, most studies investigating fisetin’s senotherapeutic and neuroprotective effects use concentrated supplemental forms to achieve measurable biological impact. This suggests that diet alone may not provide sufficient fisetin to meaningfully influence cellular pathways associated with healthy longevity.

How Does Fisetin Influence Ageing?

Fisetin has been shown to affect multiple pathways involved in maintaining neuronal function during ageing.

1. Antioxidant Activity + Glutathione (GSH) Support

Glutathione (GSH) is an antioxidant present in almost every cell in the body, playing a role in the detoxification of drugs and xenobiotics (L.F. Chasseaud, 1979). Reactive oxygen species (ROS) are chemically reactive oxygen-derived molecules generated as by-products of cellular metabolism, particularly within mitochondria. At elevated levels, they cause oxidative stress by damaging DNA, proteins, and lipids, accelerating functional decline and contributing to ageing. Depletion of GSH increases mitochondrial dysfunction and ROS (Reactive Oxygen Species) production. Additionally, lipoxygenase activation, lipid peroxidation and calcium influx result in the induction of cell death due to GSH depletion (Tan et al., 2001; Maher, 2019). Glutathione also possesses certain antiaging properties (Furukawa et al., 1987). Fisetin helps counteract these effects by restoring mitochondrial activity and metabolic function, reducing oxidative stress, and scavenging ROS. It exhibits direct antioxidant activity in addition to increasing intracellular antioxidants such as glutathione (Naeimi and Alizadeh, 2017). Additionally, fisetin has been indicated to regulate key neurotrophic factor-induced signalling pathways. It acts as a promising neuroprotective compound and prevents oxytosis/ferroptosis-mediated cell death (Ishige et al., 2001; Maher, 2019; Maher, 2020). Fisetin also prevents lipid peroxidation and increases the antiapoptotic factor Bcl2 (Reddy et al., 2021). Together, these effects highlight fisetin’s role as a promising neuroprotective compound capable of helping maintain cellular homeostasis more effectively than external antioxidant supplementation, which does not enhance intrinsic GSH systems.

1. Mitochondrial Protection

Mitochondria regulate cellular energy production through ATP synthesis. With ageing, mitochondrial efficiency declines, leading to increased ROS generation and reduced energy availability. This excess ROS drives oxidative stress, which contributes to chronic inflammation, cellular damage, and eventual cell death processes closely linked to the ageing phenotype (Zhang et al., 2025).

Fisetin helps preserve mitochondrial function by maintaining mitochondrial membrane potential, supporting ATP production, and reducing mitochondrial ROS generation (Maher P., 2009). Through these actions, fisetin limits mitochondrial-mediated oxidative stress and prevents activation of downstream cell-death pathways, thereby helping sustain cellular energy balance and viability during ageing.

1. Anti-inflammatory Effects (Microglial Modulation) 

Chronic, low-grade inflammation, referred to as inflammaging, contributes to age-related tissue dysfunction and cognitive decline, with microglia acting as key drivers when persistently activated. In ageing and neurodegenerative settings, overactive microglia release cytokines and reactive mediators that damage neurons, disrupt synapses, and impair cognition (Jasim et al., 2025).

Here is how fisetin helps (mechanisms):

• It reduces oxidative signalling in microglia by lowering levels of ROS generated in response to hydrogen peroxide (H₂O₂), a reactive oxygen compound used experimentally to mimic oxidative stress. By reducing ROS and limiting ATP-induced microglial movement toward injury sites (a behaviour associated with inflammatory activation), fisetin helps keep microglia in a less inflammatory state (Chuang et al., 2014)
• It suppresses the iNOS/NO inflammatory pathway by inhibiting the production of inducible nitric oxide synthase (iNOS) and nitric oxide (NO), both of which increase during microglial activation. iNOS is an enzyme that produces NO, a signalling molecule that becomes neurotoxic at high levels and contributes to inflammation-driven neuronal damage. Fisetin reduces iNOS expression and NO production in response to inflammatory triggers such as LPS and IFN-γ, helping protect neurons from harmful inflammatory signalling (Chuang et al., 2014)
• It lowers the production of the pro-inflammatory cytokine IL-1β by decreasing IL-1β gene expression (mRNA) in response to inflammatory stimulation (Chuang et al., 2014). IL-1β (interleukin-1 beta) is a key cytokine released by activated microglia that promotes neuroinflammation, impairs synaptic function, and contributes to cognitive decline.
• It inhibits the JAK–STAT inflammatory signalling pathway by reducing activation of STAT1 and its upstream regulators, JAK1 and JAK2 (Chuang et al., 2014). JAK (Janus kinases) and STAT (Signal Transducer and Activator of Transcription) proteins relay inflammatory signals within microglia and activate genes that promote inflammation. By reducing phosphorylation of STAT1, fisetin helps prevent excessive activation of inflammation-related genes.
  
  
• It increases the activity of heme oxygenase-1 (HO-1), an endogenous antioxidant enzyme that protects neurons by reducing oxidative stress and inflammation (Chuang et al., 2014). This occurs through activation of p38 and PI3K/Akt, two intracellular signalling pathways involved in stress response and cell survival. Increased HO-1 helps suppress downstream inflammatory mediators such as iNOS and NO, offering additional neuroprotection.
  
  

By calming microglial activity, fisetin helps preserve neural integrity and may protect cognitive function during ageing.

1.  Inhibition of 5-Lipoxygenase (5-LOX)

5-Lipoxygenase (5-LOX) is a non-heme iron–containing dioxygenase that catalyses the conversion of arachidonic acid, released from membrane phospholipids by phospholipases, into 5-hydroperoxyeicosatetraenoic acid (5-HPETE). 5-HPETE is subsequently converted into the unstable epoxide leukotriene A4 (LTA4), which is then metabolised into leukotriene B4 (LTB4) or conjugated with glutathione (GSH) to generate cysteinyl leukotrienes, key pro-inflammatory mediators (Phillis et al., 2006).

5-LOX is expressed in the brain, and its expression and enzymatic activity increase with age, particularly in the hippocampus, a region essential for learning and memory (Chinnici et al., 2007). Age-dependent upregulation of 5-LOX contributes to the elevated production of leukotrienes and lipid peroxidation, which promote neuronal membrane damage, synaptic dysfunction, and chronic neuroinflammation. Moreover, genetic disruption of 5-LOX reduces β-amyloid burden in transgenic mouse models, suggesting that 5-LOX activity contributes to amyloidogenic processes associated with ageing and neurodegenerative decline (Firuzi et al., 2008).

Fisetin has been identified as a potent inhibitor of 5-LOX. Early in vitro studies demonstrated that fisetin suppresses 5-LOX activity in stimulated peritoneal leukocytes (Laughton et al., 1991). More recently, fisetin has been shown to inhibit 5-LOX derived from human peripheral blood mononuclear leukocytes with an IC₅₀ of approximately 0.585 μM, comparable to or stronger than several known LOX inhibitors (Maher P., 2009). These findings indicate that inhibition of the 5-LOX metabolic pathway is a direct molecular target of fisetin.

Given the age-related elevation of 5-LOX expression in the hippocampus and its association with neuroinflammation, oxidative membrane damage, and cognitive decline, fisetin-mediated 5-LOX suppression may help preserve neuronal homeostasis during ageing. By reducing leukotriene synthesis and limiting downstream inflammatory lipid signalling, fisetin likely contributes to long-term maintenance of CNS function.

Fisetin as a Senotherapeutic

Senescent cells are cells that have stopped dividing but do not die; instead, they remain in the body, releasing inflammatory chemicals. Senescent cells accumulate with age and contribute to chronic inflammation, tissue dysfunction, and the development of age-related diseases. Research has shown that targeted removal of these cells can extend lifespan and delay the onset of age-associated pathologies (Baker et al., 2011; Demaria et al., 2014). 

In a 2018 study, a panel of 10 flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts driven by oxidative and genotoxic stress, respectively. Fisetin emerged as the most potent senolytic compound tested (Yousefzadeh et al., 2018). 

Key Findings from the study:

• Acute or intermittent fisetin treatment reduced senescence markers in multiple tissues of progeroid and old mice.
• Fisetin reduced senescent cells in murine and human adipose tissue.
• Late-life fisetin administration restored tissue homeostasis.
• Fisetin treatment reduced age-related pathology in mice.
• Fisetin increased both median and maximum lifespan in wild-type mice.
• Fisetin showed senotherapeutic activity in mice and in human tissues.

These findings establish fisetin as one of the most promising natural senolytics, with broad relevance for ageing and age-related disease.