Cellular senescence is a state of irreversible cell cycle arrest accompanied by significant changes in cell morphology, function, and secretory activity.

While transient senescence plays a beneficial role in embryonic development and tissue remodeling through cytokine-mediated intercellular communication, the accumulation of senescent cells in aging tissues drives chronic inflammation via the senescence-associated secretory phenotype (SASP).

SASP components, including pro-inflammatory cytokines, chemokines, and proteases, disrupt cellular homeostasis, impair immune surveillance, and increase the risk of age-related health conditions. ¹

Senescent cells are not inherently harmful, in fact, they serve as a protective mechanism to prevent the proliferation of damaged cells that could lead to cancer. However, as we age, the balance shifts and the accumulation of senescent cells can become detrimental.

This imbalance is exacerbated by the declining efficiency of the immune system, which is less able to clear these cells effectively. The result is a chronic inflammatory state that contributes to tissue dysfunction and the progression of multiple health problems.

Senescent cells and immune dysregulation

The relationship between cellular senescence and immune dysfunction is complex and bidirectional. As the body ages, immune cells themselves become senescent, leading to a decline in their ability to recognize and eliminate senescent cells. This creates a vicious cycle:

Immunosenescence

Immune cells such as T cells and B cells gradually undergo senescence with age. Senescent T cells exhibit weakened pathogen recognition and cytotoxic functions, leading to reduced intensity and duration of immune responses. Concurrently, aged B cells demonstrate diminished antibody production capacity, resulting in impaired humoral immune responses against pathogens.

Immune escape

Under normal physiological conditions, the immune system identifies and eliminates senescent cells. However, as cellular senescence progresses, the surveillance capacity of the immune system progressively declines. This functional deterioration prevents timely and efficient clearance of senescent cells, enabling their immune escape.

Consequently, accumulated senescent cells exacerbate tissue dysfunction and inflammatory responses, creating a self-perpetuating vicious cycle that accelerates age-related physiological decline.

These mechanisms highlight the importance of targeting senescent cells to restore immune function and mitigate age-related inflammation. By reducing the burden of senescent cells, it may be possible to break the cycle of chronic inflammation and improve overall healthspan.

Fisetin: A dual-action agent for cellular health

Since 2018, research by leading institutions has identified fisetin as a potent senotherapeutic agent with two complementary mechanisms of action:

1. Senoprevention: Reducing senescent cell formation

Fisetin delays the onset of cellular senescence by targeting key regulatory pathways: ²⁻³

• Fisetin activates the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, thereby enhancing cellular energy metabolism and stress resistance. This mechanism mitigates energy imbalance and reduces oxidative stress-induced cellular senescence.

• Fisetin suppresses the excessive activation of the rapamycin (mTOR) signaling pathway. It prevents cell cycle dysregulation and curtails the upregulation of senescence-associated genes caused by aberrant mTOR signaling.

• Fisetin decreases the accumulation of intracellular reactive oxygen species (ROS) through its superior antioxidant properties. This alleviates oxidative damage to cellular DNA and proteins, thereby lowering the likelihood of senescence initiation.

A study by West China Hospital demonstrated that fisetin significantly reduced senescent cells formation in mouse alveolar epithelium by modulating the AMPK/NF-κB pathway, decreasing pro-inflammatory cytokines, and alleviating pulmonary fibrosis.²

Another study on pulmonary artery endothelial cells showed that fisetin inhibited the expression of the aging protein p21 and reduced oxidative stress, further validating its senopreventive effects. ³

2. Senolysis: Selective clearance of senescent cells

Fisetin selectively induces apoptosis or autophagy in senescent cells by inhibiting the p53/p21 signaling pathway. Additionally, it enhances the immune system’s ability to recognize and eliminate senescent cells by activating natural killer (NK) cells and macrophages.

Comparative studies have shown that fisetin outperforms other senolytic agents like quercetin, resveratrol, and curcumin, achieving over 68% clearance of senescent cells without harming healthy cells. ⁴

Figure 1: The number of senescent cells by treatment with senolytic agents

This selective action is particularly important because it allows fisetin to target harmful senescent cells while sparing healthy ones.

In preclinical models, fisetin has been shown to reduce senescent cell burden in multiple tissues, including the liver, lungs, and brain, leading to improvements in overall health and lifespan.⁵ These findings imply that fisetin holds the potential to modulate the quantity of senescent cells via multiple mechanisms, thereby bolstering the body’s immune capabilities.

A compelling piece of evidence comes from a 2024 study carried out by the Mayo Clinic, involving 536 long-COVID patients.⁶ Among them, 44 patients received fisetin intervention and 64% of these participants reported significant alleviation in symptoms like fatigue, muscle pain, and orthostatic hypotension.⁶

These results suggest that fisetin can facilitate the body’s normal physiological activities, contribute to maintaining the normal functioning of the immune system, and promote recovery.

Multidimensional health benefits of fisetin: Beyond senolysis

Fisetin’s benefits extend beyond senolysis, offering various systemic health improvements, including:

✨ Skin health support

Fisetin selectively removes approximately 66% of senescent dermal fibroblasts, and increases collagen density by 41.2%, effectively rejuvenating the skin and slowing down the skin aging process, in animal research.⁷

Fisetin also shows promise in improving psoriasis and systemic lupus erythematosus by regulating the mTOR/IL-17A pathway.⁸⁻⁹ Its ability to modulate immune responses without suppressing overall immunity is a key advantage.

✨ Promoting hair regeneration

Fisetin increases telomerase reverse transcriptase (TERT) expression and stimulates the transition of hair follicles from the telogen to the anagen phase.¹⁰⁻¹¹ These actions can support the normal function of hair follicles and play a role in the physiological processes related to hair growth.

Fisetin also inhibits 5α-reductase activity, reducing the conversion of testosterone to dihydrotestosterone (DHT), a key factor in hair loss.¹² This dual-action approach effectively promotes hair regeneration.

✨ Mood and brain function support

Fisetin can penetrate the blood-brain barrier, directly neutralize free radicals, and eliminate pro-inflammatory cytokines in the brain. This helps shield the brain from inflammatory damage and helps with mood regulation.

A 2024 study shows fisetin increases dopamine levels by 1.8 to 2.2 times, highlighting its potential in mood health.¹³ This dopaminergic effect could also benefit individuals with depression or other dopamine-related conditions.¹⁴⁻¹⁵

Figure 2: Striatal dopamine levels of Parkinson’s disease rats

✨ Bone health support

Fisetin has garnered significant attention for its potential applications in bone health. It can improve conditions such as osteoporosis and osteoarthritis through multiple mechanisms, including: reducing pro-inflammatory cytokines (for example, TNF-α and IL-6); upregulating the expression of runt-related transcription factor 2 (RUNX2); and clearing senescent bone cells.¹⁶⁻¹⁹

According to the International Clinical Trials Registry Platform Search Portal, one-third of clinical trials involving fisetin focus on bone health, underscoring its promising therapeutic potential in this field.²⁰

Figure 3: Summary of clinical trials related to bone health of fisetin

Pioneering quality standards

BeFisetin® sets a new benchmark for quality and safety in fisetin ingredients.

After three years of rigorous optimization, BeFisetin has established robust quality standards and is on track to complete the Self-Affirmed Generally Recognized As Safe (SA-GRAS) certification by March 2025.

To further explore fisetin’s potential, Bonerge is conducting a 108-subject clinical trial evaluating its dermatological benefits in combination with urolithin A and ergothioneine. This study, expected to conclude in March 2025, will provide valuable insights into fisetin’s role in skin health.

Figure 4: BeFisetin features

Fisetin represents a groundbreaking advancement in the field of healthy aging, offering a multi-target approach to reducing senescent cell burden, enhancing immune function, and addressing tissue-specific pathologies.

With its SA-GRAS certification underway and a growing body of clinical evidence, BeFisetin is providing safe and effective solutions for age-related health challenges.

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