February 18, 2025

Molecular Secrets of Killing “Zombie Cells” through Dietary Senolytics: The Role of Quercetin, Fisetin, and Curcumin in Fighting Aging

As we age, our bodies accumulate “zombie cells,” or “senescent cells”, which no longer divide but remain metabolically active. These cells secrete harmful inflammatory molecules called the senescence-associated secretory phenotype (SASP), damaging surrounding tissues and contributing to the aging process and age-related diseases. Dietary senolytic compounds found in natural foods offer a promising approach to selectively eliminating so-called zombie cells/senescent cells, thereby rejuvenating tissues and combating aging.  

“Zombie Cells” and “Dietary Senolytics”: A Brief Overview

“Zombie cells,” initially serve a protective role by halting the proliferation of damaged or stressed cells. However, their persistent presence becomes harmful over time, leading to chronic inflammation, tissue degeneration, and impaired regeneration. Senolytics are compounds specifically designed to target these vulnerable cells, inducing programmed cell death (i.e.,   cellular apoptosis) and restoring tissue health. In this article, we will explore the molecular mechanisms through which dietary senolytics—such as quercetin, fisetin, and curcumin—interact with specific signaling pathways to induce apoptosis in zombie cells while suppressing their harmful effects.

1. Quercetin: The Flavonoid Warrior Against Zombie Cells  

I. Sources: Quercetin is a naturally occurring flavonoid found in various fruits and vegetables, including apples, berries, onions, and citrus fruits. It has gained significant attention for its senolytic properties, which target and eliminate zombie cells (senescent cells) that contribute to aging and age-related diseases. (Azeem et al, 2023)

II. Molecular Mechanisms of Quercetin

Quercetin exerts its senolytic effects by targeting specific cellular pathways involved in the survival and inflammation of senescent cells (Azeem et al, 2023; Islam et al, 2025). Below is a detailed description of its molecular mechanisms:

Pathway 1. PI3K/AKT/mTOR Pathway Inhibition

Role in Senescence: The PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway is hyperactive in senescent cells, contributing to their resistance to apoptosis and promoting their survival. This pathway supports the production of anti-apoptotic proteins like Bcl-2 and Bcl-xL, which stabilize the mitochondrial membrane and prevent cell death.

Quercetin’s Action: Quercetin inhibits the activation of PI3K, effectively shutting down the downstream AKT and mTOR signaling cascade. This inhibition reduces the expression of anti-apoptotic proteins, destabilizing the mitochondrial outer membrane. Destabilization triggers the release of cytochrome c from the mitochondria into the cytoplasm. Cytochrome c activates caspases, specifically caspase-9, followed by caspase-3. This activation drives apoptosis in zombie cells. This selective targeting of senescent cells ensures that healthy cells remain unaffected.

Pathway 2. AMPK Activation

Role in Cellular Metabolism: AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis. It is activated under low-energy conditions, promoting catabolic processes like autophagy (cellular recycling) and inhibiting anabolic processes like protein synthesis via mTOR suppression.

Quercetin’s Action: Quercetin directly activates AMPK, restoring energy balance and promoting mitochondrial biogenesis and turnover. By enhancing autophagy, AMPK activation reduces the accumulation of damaged organelles and proteins in senescent cells, a hallmark of cellular aging. This increased turnover and reduced oxidative stress further sensitizes zombie cells to apoptotic triggers. AMPK activation also indirectly inhibits mTOR, reinforcing Quercetin’s ability to suppress survival pathways in senescent cells.

Pathway 3. SASP Suppression

Role of SASP: Senescent cells release SASP (senescence-associated secretory phenotype) factors, including inflammatory cytokines (IL-6, IL-8, TNF-α), chemokines, and proteases. SASP drives chronic inflammation, disrupts tissue architecture, and promotes the spread of senescence to neighboring cells.

Quercetin’s Action: Quercetin inhibits the activation of NF-κB (nuclear factor kappa B), a transcription factor that controls the expression of SASP components in the cells. NF-κB is activated by upstream signals like IKK (IκB kinase), which phosphorylates and degrades IκBα, an NF-κB inhibitor. Quercetin stabilizes IκBα, preventing NF-κB activation and nuclear translocation. This suppression of NF-κB reduces SASP factors such as IL-6, IL-8, and TNF-α, alleviating chronic  inflammation and tissue damage caused by senescent cells.

III. Anti-Aging Potential of Quercetin

Quercetin’s senolytic properties make it a valuable compound for combating age-related dysfunction (Deepika & Maurya, 2022). Its anti-aging effects have been demonstrated in various preclinical and clinical models:

Vascular Health: Quercetin enhances vascular elasticity by reducing the burden of senescent endothelial cells, improving blood flow, and lowering arterial stiffness. These benefits are amplified when Quercetin is combined with Dasatinib, a kinase inhibitor that targets senescent fat progenitor cells.

Inflammation Reduction: By suppressing SASP, Quercetin alleviates systemic inflammation, which is a major driver of chronic diseases like arthritis, diabetes, and neurodegeneration.

Tissue Regeneration: Quercetin promotes the repair of aged tissues by eliminating zombie cells that impede regeneration. This has been observed in skin, muscle, and bone models, highlighting its potential to restore tissue functionality in aging individuals.

The above schematic diagram illustrates the key signaling pathways modulated by Quercetin in senescent cells.

Quercetin stands out as a potent senolytic flavonoid with the ability to target and eliminate senescent cells through mechanisms that inhibit PI3K/AKT/mTOR signaling, activate AMPK, and suppress SASP. Its anti-aging effects, including enhanced vascular health, reduced inflammation, and improved tissue regeneration, make it a promising candidate for therapeutic interventions aimed at extending healthspan. To date, the senolytic combination of Quercetin combined with Dasatinib has been tested in several human clinical trials for the treatment of idiopathic pulmonary fibrosis (NCT02874989), chronic kidney disease (NCT02848131), skeletal health (NCT04313634), hematopoietic stem cell transplant survivors (NCT02652052) and Alzheimer’s disease (NCT04063124). However, with ongoing research into its mechanisms, Quercetin represents a natural and accessible approach to tackling the burden of zombie cells and promoting longevity.

2. Fisetin: The Potent Senolytic Flavonoid

I. Sources: Fisetin, a flavonoid abundant in strawberries, apples, cucumbers, and persimmons, is recognized as a potent senolytic compound capable of selectively inducing apoptosis in senescent cells (i.e., zombie cells). These cells accumulate during aging and contribute to tissue dysfunction through their secretion of pro-inflammatory factors known as the senescence-associated secretory phenotype (SASP). Below is a detailed explanation of the molecular mechanisms by which Fisetin exerts its senolytic effects, supported by existing scientific evidence (Zhou et al., 2023).

II. Molecular Mechanisms of Fisetin

Pathway 1. Caspase Activation via Mitochondrial Dysfunction

Senescent cells resist apoptosis by upregulating anti-apoptotic proteins and suppressing pro-apoptotic proteins, thereby stabilizing the mitochondrial membrane and maintaining cell survival.

i) Role in pro-apoptotic and anti-apoptotic Protein Balance: In senescent cells, pro-apoptotic proteins like Bax (Bcl-2-associated X protein) and Bak (Bcl-2 homologous antagonist/killer) promote mitochondrial outer membrane permeabilization (MOMP). On the other hand, anti-apoptotic proteins such as Bcl-2 (B-cell lymphoma 2) and Bcl-xL (Bcl-2-like 1) protect mitochondrial integrity and prevent apoptosis by inhibiting Bax and Bak.

Fisetin’s Action: Fisetin increases the expression and activation of Bax and Bak, destabilizing the mitochondrial membrane. In addition, Fisetin reduces the expression of Bcl-2 and Bcl-xL, thereby removing the inhibitory effect on pro-apoptotic proteins. This disruption shifts the balance in favor of apoptosis, sensitizing senescent cells to cell death mechanisms.

ii) Role in Cytochrome c Release: Mitochondrial outer membrane permeabilization (MOMP) triggers the release of Cytochrome c from the mitochondria into the cytosol by Bax and Bak oligomerize on the mitochondrial outer membrane. In the cytosol, Cytochrome c forms a complex with apoptotic protease-activating factor 1 (Apaf-1) in the presence of ATP, creating the apoptosome. This leads to the activation of caspase-9, an initiator caspase.  

Fisetin’s Action: Fisetin enhances the oligomerization process by activating Bax and suppressing Bcl-2, ensuring effective cytochrome c release.

iii) Activation of Executioner Caspases: Caspase-9 activates downstream executioner caspases, such as caspase-3 and caspase-7. These caspases cleave structural and regulatory proteins, ultimately dismantling the senescent cell.

Pathway 2. Suppression of NF-κB and SASP Inhibition

Fisetin targets the NF-κB signaling pathway, a major regulator of the inflammatory SASP, to reduce the pro-inflammatory environment created by senescent cells.

i)NF-κB in SASP Regulation: NF-κB drives the transcription of SASP components, including interleukins (IL-6, IL-8), tumor necrosis factor-alpha (TNF-α), and matrix metalloproteinases (MMPs). These factors perpetuate tissue damage and inflammation.

Fisetin’s Action: Fisetin inhibits IκB kinase (IKK), which prevents the phosphorylation and degradation of IκBα (an inhibitor of NF-κB). By stabilizing IκBα, Fisetin blocks the translocation of NF-κB subunits (p65 and p50) into the nucleus, preventing SASP gene transcription. This reduction in SASP factors alleviates inflammation and prevents senescence spread to neighboring cells (Beltzig et al., 2022).

Pathway 3. Downregulation of p53 and p21 Expression

Senescent cells rely on high levels of cell cycle inhibitors, such as p53 and p21, to maintain their cell cycle arrest and resist apoptosis.

i) p53 and p21 in Senescence: p53, a tumor suppressor protein, becomes hyperactive in senescent cells, driving the expression of p21, a CDK (cyclin-dependent kinase) inhibitor. Together, p53 and p21 reinforce cell cycle arrest and block the apoptotic machinery.

Fisetin’s Action: Fisetin reduces the expression of p53 and p21, weakening the senescent cell’s survival mechanisms. This reduction sensitizes zombie cells to mitochondrial dysfunction and caspase activation, facilitating their clearance.

Pathway 4. Antioxidant Activity and Mitigation of Oxidative Stress

Fisetin possesses strong antioxidant properties that protect non-senescent cells from damage caused by reactive oxygen species (ROS).

i) ROS in Senescence: Senescent cells accumulate high levels of ROS due to mitochondrial dysfunction, which drives oxidative damage to DNA, proteins, and lipids. ROS also activates NF-κB, amplifying SASP production and creating a feedback loop of inflammation.

Fisetin’s Action: Fisetin scavenges ROS directly, reducing oxidative stress in tissues. It also modulates the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase, which further counteract ROS accumulation. This dual action protects healthy cells while sensitizing senescent cells to apoptosis by reducing their reliance on ROS-driven survival pathways (Khan et al., 2013).

III. Anti-Aging Potential of Fisetin

Fisetin’s ability to clear senescent cells and suppress inflammation translates into significant anti-aging effects:

Extension of Health span: Studies show that intermittent administration of Fisetin reduces systemic inflammation and improves markers of age-related dysfunction, effectively extending health span.

Improvement of Age-Related Conditions: Cardiovascular Health: Fisetin improves vascular elasticity and reduces arterial stiffness by targeting senescent endothelial cells (Mahoney et al., 2024).

Bone Health: Fisetin alleviates bone loss by clearing senescent osteocytes that impair bone remodeling (Hambright et al, 2023).

Suppression of Chronic Inflammation: By reducing SASP factors, Fisetin alleviates inflammation associated with conditions like arthritis, diabetes, and neurodegeneration.

Fisetin is a versatile flavonoid that exerts potent senolytic effects by inducing apoptosis in senescent cells through mitochondrial dysfunction, caspase activation, NF-κB suppression, and p53/p21 downregulation. Its additional antioxidant properties protect non-senescent cells, making it a unique compound for combating aging and age-related diseases. With its natural abundance and minimal side effects, Fisetin holds immense promise as a dietary senolytic and anti-aging intervention. Currently, Fisetin has entered several clinical trials for chronic kidney disease (NCT03325322), skeletal health (NCT04313634), osteoarthritis (NCT04210986), COVID-19 (NCT04476953, NCT04537299, NCT04771611), survivors of childhood cancers (NCT04733534) and frailty (NCT03675724). Further clinical studies are needed to explore its full therapeutic potential in humans.

The above schematic diagram illustrates the key signaling pathways modulated by Fisetin in senescent cells.

3. Curcumin: The Multifunctional Modulator

I. Source: Turmeric

II. Molecular mechanism of Curcumin

Curcumin, the active compound in turmeric, is widely known for its anti-inflammatory and antioxidant properties. In the context of senescence, curcumin exhibits powerful senomorphic effects, meaning it modulates the harmful activity of senescent cells without necessarily eliminating them. By targeting key molecular pathways—such as NF-κB inhibition and Nrf2 activation—curcumin suppresses the pro-inflammatory senescence-associated secretory phenotype (SASP) and protects against oxidative stress, reducing the negative impact of senescent cells on tissues (Bielak-Zmijewska et al., 2019; Zia et al., 2021).

Pathway 1: NF-κB Inhibition

The NF-κB pathway is a central driver of inflammation and a key regulator of SASP components such as pro-inflammatory cytokines (IL-6, IL-8), chemokines, and proteases.

Curcumin’s Role in NF-κB Inhibition

Blocking IKK Activation: The activation of NF-κB begins with the phosphorylation of IκBα (Inhibitor of NF-κB) by the IκB kinase (IKK) complex. Phosphorylation tags IκBα for proteasomal degradation, freeing NF-κB subunits (p50 and p65) to translocate into the nucleus. Curcumin prevents this step by inhibiting the IKK complex, stabilizing IκBα and preventing its degradation.

Inhibition of NF-κB Nuclear Translocation: By stabilizing IκBα, curcumin blocks NF-κB subunits from entering the nucleus, where they would otherwise bind to promoter regions of SASP-related genes. This inhibition significantly reduces the transcription and release of SASP components, including IL-1β, IL-6, TNF-α, and matrix metalloproteinases (MMPs), which are responsible for chronic inflammation and tissue damage associated with senescence.

Reduction in Inflammatory Feedback Loops: The suppression of SASP factors by curcumin also interrupts autocrine and paracrine signaling that reinforces the senescent phenotype in cells and spreads senescence to neighboring cells.

Outcome of NF-κB Inhibition: By targeting NF-κB, curcumin reduces chronic inflammation driven by senescent cells, alleviating tissue damage and mitigating age-related conditions such as arthritis, cardiovascular diseases, and neurodegeneration (Lushchak et al., 2023).

Pathway 2: Nrf2 Antioxidant Pathway Activation

Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that plays a critical role in cellular defense against oxidative stress. Senescent cells accumulate reactive oxygen species (ROS) due to mitochondrial dysfunction, which exacerbates SASP activity and DNA damage.

Nrf2’s Role:

Nrf2 regulates the expression of genes encoding antioxidant and detoxification enzymes, such as:

Superoxide dismutase (SOD): Neutralizes superoxide radicals.

Catalase: Breaks down hydrogen peroxide into water and oxygen.

Glutathione-S-transferase (GST): Detoxifies harmful products of oxidative stress.

Curcumin’s Action on Nrf2 Activation:

Disrupting Nrf2-Keap1 Binding: Under normal conditions, Nrf2 is bound to Keap1 (Kelch-like ECH-associated protein 1) in the cytoplasm, which targets Nrf2 for proteasomal degradation. Curcumin disrupts this interaction, freeing Nrf2 from Keap1 and allowing it to translocate to the nucleus.

Nuclear Translocation and Gene Activation: Once in the nucleus, Nrf2 binds to antioxidant response elements (AREs) in the promoter regions of target genes. This activates the transcription of antioxidant and detoxifying enzymes, enhancing the cell's ability to combat oxidative stress and repair damage.

Reducing Oxidative Stress in Senescent Cells: Elevated ROS levels in senescent cells contribute to DNA damage, SASP activation, and mitochondrial dysfunction. By activating Nrf2, curcumin reduces ROS levels, impairing the survival of senescent cells. Additionally, reduced oxidative stress prevents the initiation of senescence in healthy cells exposed to stress.

III. Epigenetic Modulation by Curcumin

Beyond NF-κB inhibition and Nrf2 activation, curcumin also influences gene expression through epigenetic modifications:

Histone Acetylation: Curcumin acts as a histone deacetylase (HDAC) inhibitor, promoting histone acetylation at specific genomic loci. This process enhances the transcription of genes involved in antioxidant defense and apoptosis while repressing pro-inflammatory genes.

DNA Methylation: Curcumin modulates DNA methyltransferase (DNMT) activity, reducing hypermethylation at promoters of tumor suppressor genes and apoptosis-inducing genes. This restores the expression of genes necessary for regulating cell death and suppressing inflammation.

Outcome of Epigenetic Modulation: Curcumin’s epigenetic effects complement its signaling pathway modulation, enabling long-term suppression of SASP-related genes and enhanced expression of pro-apoptotic and antioxidant genes.

IV. Overall Impact of Curcumin on Senescent Cells

Reduction of SASP: By inhibiting NF-κB, curcumin suppresses the inflammatory secretions of senescent cells, mitigating their harmful effects on surrounding tissues.

Lower Oxidative Stress: Through Nrf2 activation, curcumin enhances cellular antioxidant defenses, reducing ROS and preventing oxidative damage in both senescent and healthy cells.

Improved Cellular Environment: Curcumin's dual action not only diminishes the inflammatory and oxidative stress burden of senescent cells but also prevents the spread of senescence to neighboring cells.

Curcumin’s dual targeting of the NF-κB and Nrf2 pathways makes it a powerful senomorphic agent. By suppressing SASP via NF-κB inhibition and reducing oxidative stress through Nrf2 activation, curcumin improves the tissue environment, reduces inflammation, and mitigates the harmful effects of senescent cells. Additionally, its epigenetic modulation further enhances its efficacy, making it a promising candidate for anti-aging therapies and interventions against age-related diseases.

The above schematic diagram illustrates the key signaling pathways modulated by Curcumin in senescent cells.

Synergistic Benefits and Combination Therapy

Combining dietary senolytics such as quercetin, fisetin, and curcumin enhances their individual effects on “Zombie cells”/ “Senescent cells” by simultaneously targeting multiple molecular pathways. Quercetin and fisetin work together to disrupt anti-apoptotic signaling pathways, including the balance between Bcl-2 and Bax, as well as the PI3K/AKT/mTOR pathways. This sensitizes senescent cells to apoptosis and reduces pro-inflammatory components of the senescence-associated secretory phenotype (SASP) through inhibition of NF-κB. Curcumin complements these effects by activating the Nrf2 antioxidant pathway, which reduces oxidative stress and prevents the spread of senescence to nearby cells. This combined therapy maximizes the effectiveness of senolytics while minimizing inflammation and oxidative damage. Preclinical studies have shown that combining senolytics like quercetin and fisetin can effectively clear senescent cells and improve health span, with curcumin's anti-inflammatory properties and epigenetic modulation providing additional benefits. These multi-targeted approaches represent a promising strategy for addressing the complexities of cellular senescence and age-related dysfunction. As research progresses, dietary senolytics may offer more affordable and accessible anti-aging interventions, providing hope for a healthier and longer lifespan.

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ABOUT THE AUTHOR

Dr. Subrata Sabui, PhD in Life Science and Biotechnology

 

 

 

 

 

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