Dasatinib and Quercetin: Impact on Cellular Senescence

Cellular senescence is a state in which cells lose their ability to divide, contributing to aging and age-related diseases. While senescent cells play a role in wound healing and tumor suppression, their accumulation over time drives chronic inflammation and tissue dysfunction. Targeting these cells has become a focus in longevity research.

Dasatinib, a tyrosine kinase inhibitor, and quercetin, a plant-derived flavonoid, have been studied for their ability to selectively eliminate senescent cells. Their combined effects may offer therapeutic benefits in mitigating age-related decline.

Mechanisms Of Dasatinib

Dasatinib targets multiple tyrosine kinases, affecting pathways that regulate cell survival and proliferation. Originally developed for chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL), its inhibition of BCR-ABL, SRC family kinases, and other signaling molecules has been repurposed for senolytic applications. Senescent cells rely on pro-survival networks to resist apoptosis, and dasatinib disrupts these pathways.

A key mechanism involves inhibiting ephrin type-B receptor 2 (EPHB2), a kinase essential for cell adhesion and survival. Senescent human preadipocytes and endothelial cells are particularly sensitive to dasatinib due to their dependence on EPHB2 signaling. Blocking this pathway weakens their structural integrity, making them more prone to programmed cell death.

Dasatinib also interferes with SRC family kinases, which contribute to adhesion, migration, and survival. Senescent cells often show increased SRC activity, reinforcing their resistance to apoptosis. By suppressing SRC signaling, dasatinib disrupts cytoskeletal organization, impairing their ability to maintain homeostasis. Preclinical models have shown a significant reduction in senescent cell burden in aged tissues, particularly in adipose and vascular systems.

Mechanisms Of Quercetin

Quercetin, a naturally occurring flavonoid, influences cellular senescence by modulating oxidative stress, kinase activity, and proteostasis. Found in apples, onions, and berries, it disrupts pathways that sustain senescent cell viability. Unlike dasatinib, which primarily targets tyrosine kinases, quercetin interferes with inflammation, metabolic stability, and stress responses.

A primary mechanism involves inhibiting PI3K/AKT and mTOR signaling, which are crucial for cell growth and survival. Persistent activation of these pathways in senescent cells promotes resistance to apoptosis. By suppressing PI3K/AKT activity, quercetin reduces phosphorylation events necessary for survival, sensitizing senescent cells to death. Studies have shown significant reductions in senescent fibroblasts and endothelial cells following treatment.

Quercetin also disrupts proteostasis by inhibiting heat shock proteins (HSPs), particularly HSP70 and HSP90, which support protein stability under stress. Senescent cells exploit these chaperones to prolong survival. Downregulating HSPs increases proteotoxic stress, leading to protein misfolding and cell death. Research has demonstrated that quercetin-treated senescent cells exhibit heightened proteasomal dysfunction, accelerating their clearance.

Additionally, quercetin influences the intracellular redox environment by acting as both an antioxidant and a pro-oxidant under specific conditions. While it neutralizes reactive oxygen species (ROS), it can also induce oxidative stress in senescent cells by disrupting glutathione homeostasis. Excessive ROS accumulation triggers mitochondrial dysfunction and apoptosis. Preclinical models show quercetin treatment leads to mitochondrial depolarization in senescent cells, reinforcing its role in promoting their clearance.

Combined Influence On Cellular Senescence

Dasatinib and quercetin enhance senescent cell clearance by targeting multiple survival pathways. Dasatinib disrupts tyrosine kinase signaling, while quercetin interferes with proteostasis and oxidative stress regulation. Together, they improve the efficiency of eliminating dysfunctional cells.

Cell Cycle Regulation

Senescent cells are characterized by irreversible cell cycle arrest, primarily mediated by the p16^INK4a^ and p21^CIP1^ pathways. Dasatinib and quercetin influence these regulatory mechanisms by reducing cyclin-dependent kinase inhibitors (CDKIs), weakening the stability of the senescent state. Dasatinib disrupts upstream tyrosine kinase signaling that reinforces CDKI expression, while quercetin interferes with PI3K/AKT signaling, indirectly modulating cell cycle regulators.

Studies show that co-administration of these compounds lowers p16^INK4a^ and p21^CIP1^ levels in senescent fibroblasts and endothelial cells, promoting apoptosis. This dual approach is particularly effective in aged tissues where senescent cells accumulate due to chronic stressors like oxidative damage and metabolic dysfunction. By weakening the molecular barriers maintaining cell cycle arrest, dasatinib and quercetin facilitate senescent cell clearance, reducing their detrimental impact on tissue homeostasis.

Apoptotic Pathways

Senescent cells evade apoptosis through pro-survival networks, including the BCL-2 family of proteins and the PI3K/AKT/mTOR axis. Dasatinib and quercetin enhance apoptotic susceptibility by targeting these pathways from different angles.

Dasatinib inhibits SRC family kinases, which help maintain mitochondrial integrity, leading to mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release. Quercetin downregulates anti-apoptotic proteins such as BCL-2 and BCL-xL while promoting oxidative stress, further sensitizing senescent cells to apoptosis.

Preclinical studies demonstrate that combining these compounds significantly increases caspase-3 and caspase-7 activation, key markers of apoptosis. This synergy ensures the efficient removal of senescent cells, improving cellular turnover and reducing age-related pathologies.

Inflammatory Signaling

Senescent cells secrete a pro-inflammatory cocktail known as the senescence-associated secretory phenotype (SASP), which includes cytokines like IL-6, IL-8, and TNF-α. This chronic inflammation contributes to tissue degeneration and systemic aging.

Dasatinib and quercetin mitigate SASP activity by interfering with NF-κB and STAT3 signaling, key regulators of inflammatory gene expression. Dasatinib suppresses NF-κB activation by inhibiting upstream kinases such as SRC and JAK, while quercetin directly inhibits STAT3 phosphorylation, reducing pro-inflammatory cytokine transcription.

Experimental models show that treatment with both compounds significantly decreases SASP-related factors, lowering systemic inflammation and improving tissue function. Reducing inflammatory signaling alleviates the harmful effects of senescent cell accumulation and supports tissue regeneration and repair.

Pharmacological Interactions

The concurrent use of dasatinib and quercetin presents a complex pharmacological landscape, as both influence multiple biochemical pathways. Their combined administration requires careful consideration of bioavailability, metabolism, and potential synergistic or antagonistic effects.

Dasatinib is primarily metabolized by the cytochrome P450 (CYP3A4) enzyme system, and quercetin modulates CYP enzymes, potentially altering dasatinib metabolism and affecting drug clearance rates. Understanding these interactions is crucial for optimizing therapeutic efficacy while minimizing unintended consequences.

Additionally, overlapping effects on kinase signaling and oxidative stress pathways raise concerns about dose-dependent interactions. Quercetin’s inhibition of PI3K/AKT could amplify dasatinib’s suppression of tyrosine kinase activity, intensifying cellular stress responses. While this may enhance senolytic efficacy, excessive kinase inhibition risks unintended cytotoxicity in non-senescent cells. Clinical research has yet to establish precise dosing strategies that balance these effects, underscoring the need for controlled administration protocols.

Observations In Preclinical Research

Preclinical studies support the senolytic potential of dasatinib and quercetin, particularly in age-related conditions characterized by excessive senescent cell accumulation. In vitro models show that this combination effectively reduces senescent cell burden across various tissues, including adipose, endothelial, and musculoskeletal systems.

In human preadipocyte studies, dasatinib selectively eliminated senescent cells within 48 hours, while quercetin enhanced the process by destabilizing survival pathways. These findings have been validated in ex vivo tissue samples from aged donors, where combined treatment significantly decreased senescence-associated β-galactosidase (SA-β-gal) activity, a common biomarker for cellular senescence.

Animal models provide additional insights into the physiological benefits of senescent cell clearance. In murine studies, dasatinib and quercetin administration improved physical function, including endurance and muscle strength in aged mice. Longitudinal studies indicate that intermittent treatment extends healthspan by mitigating age-related tissue deterioration.

Experiments using progeroid mouse models, which exhibit accelerated aging, show that senescent cell clearance reduces systemic inflammation and preserves organ function. These findings suggest that targeting senescence may delay the onset of age-associated diseases, paving the way for future clinical applications.