Advancing Alzheimer's disease treatment: A literature review on senolytic intervention

Abstract

Alzheimer's disease (AD) is a leading cause of dementia, currently affecting over 50 million people globally. Despite decades of research, therapeutic development has continued to face high failure rates due to an incomplete understanding of the underlying disease mechanisms. Current drugs like rivastigmine focus on managing cognitive symptoms since there is no known cure to halt the disease's progression. However, recent research has suggested that advanced biological age, particularly the accumulation of senescent cells, is the most significant risk factor for AD pathology, and targeting these aging mechanisms may prove more effective in altering the disease progression. Senescent cells accumulate with age, contributing to inflammatory states and neurodegenerative diseases such as AD. Senolytic drugs, such as dasatinib and quercetin (D + Q), have shown promise in animal models by clearing senescent cells, delaying aging-related decline, and improving AD-related outcomes. This literature review aims to provide a comprehensive overview of the therapeutic potential of senolytic interventions for AD by examining the mechanisms of cellular senescence based on evidence of its accumulation in the human brain, critically analyzing the preclinical and clinical trials involving senolytic compounds, and discussing the implications and limitations of this approach. The findings from recent studies indicate that senolytics may pave the way for effective AD treatments, though further clinical validation is needed.

Keywords

Alzheimer's disease cellular senescence dasatinib quercetin senescence-associated secretory phenotypes senescent cells senolytic intervention

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Neuropathologically, it is characterized by the abnormal accumulation of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, resulting in synaptic loss and neuronal death in brain regions such as the hippocampus.^1,2 Currently, there are over 50 million people affected by the disease globally, and it is expected to triple by 2050 due to an increase in the global aging population.^2–4 In 2024, the Alzheimer's Association estimated that approximately 6.9 million Americans aged 65 and older are living with AD, which is about 1 in 9 people above 64 years.⁵ Despite the impact of this disease, there has been little success in developing a treatment that halts its progression, as current drugs like rivastigmine and donepezil focus on temporarily improving the symptoms.^6–8 This lack of disease-modifying treatments raises the need for novel therapeutic approaches that target the underlying mechanisms of aging in AD rather than its late-stage symptoms, and one of the promising directions emerging from recent research is the targeting of senescent cells through senolytic interventions.^9–11 This review explores the therapeutic potential of senolytic interventions for AD by examining the mechanisms of cellular senescence and its accumulation in the human brain. It synthesizes evidence from preclinical and clinical studies, including insights from the first human trial of senolytics in treating AD, to evaluate the efficacy of this approach. Lastly, it addresses the broader implications and limitations of targeting cellular senescence, offering a critical perspective on its potential to transform AD treatment strategies.

Cellular senescence and its role in Alzheimer's disease

Cellular senescence is one of the fundamental hallmarks of aging that has emerged as a key contributor to age-related diseases, including AD.^12–15 While aging remains the major risk factor for AD, the complex relationship between cellular senescence and neurodegeneration has only recently begun to be elucidated. The aging process induces biological changes such as oxidative stress, proteostasis disruption, vascular dysfunction, and chronic inflammation, resulting in a brain environment prone to the accumulation of senescent cells and neurodegeneration.^12,16

At the molecular level, cellular senescence is an adaptive stress response that permanently halts the proliferation of damaged cells, thereby preventing malignant transformation and limiting uncontrolled cell division.^17–19 This process occurs through multiple pathways, with telomere attrition serving as a primary driver.²⁰ Telomeres undergo progressive shortening from their initial length of 10–15 kb to a critical threshold of 4–6 kb with each cell cycle, ultimately leading to irreversible growth arrest.²¹ Beyond telomere-dependent senescence, a senescent state can be triggered by oxidative stress and excessive oncogenic signaling. While oncogenic signaling initially promotes cell proliferation, overactivation induces a DNA damage response (DDR). This DDR then leads to the activation of key tumor suppressor pathways, particularly the p53-p21 and p16-RB.^22–26 These pathways function by inhibiting cyclin-dependent kinases (CDKs) such as CDK2 and CDK4/6 that are necessary for cell cycle progression, leading to cell cycle arrest (Figure 1).^22,24,25 Although senescence initially serves as a protective barrier against cancer early in life, its accumulation over time outpaces immune clearance, thereby contributing to chronic inflammation and neurodegeneration.^27–30

Figure 1.

Cellular senescence and its drivers. Cellular senescence can be triggered by multiple stressors, including telomere shortening, DNA damage, mitochondrial dysfunction, and deregulated oncogene activation. These stressors activate a DNA damage response pathway that co-activates tumor suppressor pathways like p53 and p16, which inhibit cyclin-dependent kinases (CDK2, CDK4/6), causing cell cycle arrest and senescence. Senescent cells develop a senescence-associated secretory phenotype (SASP) that promotes chronic inflammation, which can affect healthy neurons and contribute to synapse loss, ultimately leading to neurodegeneration. Image created in BioRender.

A defining feature of senescent cells is their development of the senescence-associated secretory phenotype (SASP), a complex secretome that alters the tissue microenvironment and is predominantly regulated by the transcription factors nuclear factor kappa B (NF-κB) and CCAAT/enhancer-binding protein beta (C/EBPβ).^{22,23,31–33} The SASP contains a diverse array of bioactive molecules, including pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), chemokines, matrix metalloproteinases, and reactive oxygen species.^25,34–36 These factors promote a chronic inflammatory state that exacerbates neuronal and glial dysfunction and impairs Aβ clearance, ultimately accelerating AD pathology. For instance, microglia responsible for the clearance of Aβ, lose their phagocytic function after entering a senescent state. This impaired clearance leads to the aggregation of Aβ plaques and other damaged cellular components, resulting in increased neurotoxicity, as shown in studies performed on mice with senescent microglia.^10,36,37 Furthermore, the accumulation of senescent cells, including microglia, is exacerbated by aging, as the immune system becomes less efficient at eliminating them. This results in the increased presence of senescent cells, which contributes to oxidative stress and inflammation, thereby linking cellular senescence to AD progression.^38,39

The central role of senescent cells in AD progression, coupled with their diverse mechanisms of tissue dysfunction, has positioned cellular senescence as a promising therapeutic target.^10,11,40 Rather than focusing solely on disease-specific pathologies, targeting cellular senescence represents a fundamental approach to addressing multiple age-related conditions simultaneously.^9,41,42 This strategy aligns with the broader goal of reducing multimorbidity and increasing healthspan, potentially yielding substantial societal and economic benefits. The strategic elimination of senescent cells, combined with modulation of their inflammatory secretome, represents a potentially powerful approach for intervening in AD progression, particularly given the limitations of current therapeutic strategies focused solely on late-stage disease manifestations.

Senolytic drugs as a therapeutic strategy for Alzheimer's disease

Senolytic drugs have emerged as a promising approach to mitigating the effects of aging on AD progression by selectively eliminating senescent cells.^42–44 These compounds, such as dasatinib and quercetin (D + Q), target senescent cells that contribute to AD's pathophysiology in an attempt to alleviate their detrimental effects in its progression (Figure 2).^43,45,46 This approach has shown potential in several mouse models, where senolytics reduced neuron loss, improved memory, and reduced ventricular enlargement, suggesting that pharmacological clearance of senescent cells could modulate key disease mechanisms in AD.^47–49

Figure 2.

Molecular targets of senolytic drugs and induction of apoptosis in senescent cells. Senolytic drugs induce apoptosis in senescent cells by disrupting vital anti-apoptotic pathways. Dasatinib inhibits the receptor tyrosine kinase EphA2, which activates the MAPK pathway, leading to the activation of p38 MAPK/JNK and subsequent promotion of apoptosis. Navitoclax directly inhibits the BCL-2 family proteins (BCL-xL), which promotes the activation of pro-apoptotic proteins like BAX and BAK, leading to mitochondrial outer membrane permeabilization (MOMP) that triggers caspase activation and ultimately results in apoptosis in senescent cells. Quercetin and Fisetin inhibit the PI3K/AKT/mTOR signaling pathway, reducing pro-survival signals. Image created in BioRender.

Mechanisms of senolytic action

Senolytic drugs target senescent cells by disrupting anti-apoptotic pathways that these cells use to evade cell death. In cellular senescence, certain pro-survival pathways, referred to as senescent cell anti-apoptotic pathways (SCAPs), become upregulated, enabling the senescent cells to resist apoptosis despite accumulating molecular damage.^9,23 SCAPs are characterized by the upregulation of B-cell lymphoma 2 (BCL-2) family proteins, p21, p16^Ink4a, and other related signaling molecules that protect against apoptosis (Figure 2).^50,51 Senolytic agents act by selectively inhibiting key components of SCAPs, thereby sensitizing senescent cells to apoptotic triggers while leaving healthy cells unharmed.⁵²

Among the senolytic compounds that have been identified in various studies, the combination of dasatinib (D), a tyrosine kinase inhibitor, and quercetin (Q), a naturally occurring flavonoid, have been the most extensively investigated and are considered the most effective senolytic therapy for AD, resulting in their focus for this review.⁵³ Dasatinib, originally FDA-approved for cancer treatment, targets the ephrin receptor A2 (EphA2), a member of the tyrosine kinase receptor family, which regulates signaling cascades within senescent cells and is crucial for their survival.^54,55 Quercetin complements this action by inhibiting pro-survival pathways, specifically targeting PI3K/AKT, mTOR, BCL-xL, and HIF-1α, that are overactivated in senescent cells (Figure 2). By suppressing these anti-apoptotic mechanisms, quercetin effectively induces apoptosis in senescent cells while sparing healthy cells.^43,44,52 This has been observed in in vitro models and in vivo animal models of AD.⁵⁶ The effectiveness of D + Q comes from their ability to target multiple pro-survival pathways simultaneously, as this approach is necessary since targeting a single SCAP may be insufficient due to pathway redundancy in senescent cells.⁵⁷ This selective mechanism is critical in the context of AD, as non-senescent cells employ distinct, regulated survival signals that render them insensitive to D + Q-induced apoptosis while senescent cells rely on multiple, overlapping pro-survival networks like EphA2 tyrosine kinase, PI3K/AKT, mTOR, BCL-xL, and HIF-1α, for resistance to cell death. By disabling multiple SCAPs at once, D + Q overcomes this redundancy, ensuring broad and efficient senescent cell clearance without harming healthy cells.^22,58

The choice of D + Q as primary senolytic agents for AD research, rather than other compounds such as navitoclax (a BCL-2 inhibitor) or fisetin (a natural flavonoid), is based on several factors, including the extensive research carried out on their pharmacokinetic profiles, safety, and efficacy in clinical settings like cancer therapies.^28,46 D + Q are also known to cross the blood-brain barrier in rodent models, a critical requirement for treating neurodegenerative conditions such as AD, where the therapeutic agents must reach brain tissue to exert their effects.⁵⁹

Additionally, the half-lives of dasatinib (4 h) and quercetin (11 h) are relatively brief, which can lead to efficient clearance from the system, potentially minimizing off-target effects and toxicity.^60,61 While Fisetin shows potential with its senolytic properties, its individual use as a senolytic drug is less prominent due to its poor bioavailability.⁶² When combined with D and Q, it may have a mitigating effect on their epigenetic aging impact, thereby suggesting that it alters the expected outcomes of these treatments.⁴⁶ Furthermore, navitoclax has shown promise in inducing apoptosis in specific types of senescent cells, but it is less effective in targeting the range of senescent cell types relevant to AD.^31,63 It has been shown to induce apoptosis in other non-senescent cells, including neutrophils and platelets, which rely on the BCL-2 family protein, BCL-XL, for survival, resulting in safety issues such as potentially life-threatening neutropenia and thrombocytopenia.^31,64,65 The potential of senolytics to modify the course of AD by targeting upstream aging mechanisms represents a significant shift from traditional therapeutic strategies.

Preclinical evidence of senolytics in Alzheimer's disease

Preclinical studies employing senolytic interventions in animal models, particularly mice, have demonstrated their potential in ameliorating multiple dimensions of AD pathology. These studies provide crucial insights into the efficacy, mechanisms of action, and limitations of senolytics in animal models, laying the foundation for their potential translation to human clinical trials.

In a study conducted by Fang et al. (2024), they investigated the effects of the senolytic combination of D + Q on APP^NL-F/NL-F mice, a model that carries humanized amyloid precursor protein (APP) and exhibits cognitive decline and higher senescent cell accumulation in white adipose tissue before noticeable cognitive impairment.^11,66 The study measured energy metabolism, blood glucose levels, spatial memory using the Morris water maze test, and senescence marker expression. Results indicated that the D + Q treatment enhanced spatial memory performance and reduced blood glucose levels in female mice. Importantly, senescence markers were significantly decreased both in the hippocampus, such as reduced p16^Ink4a, p21^Cip1/CDKN1A, and SA-β-gal activity, and in peripheral white adipose tissue, demonstrating a systemic reduction in senescent cell burden. However, these benefits were not observed in male mice, and fisetin showed insignificant effects in both sexes.¹¹ The potential sex-specific differences in humans may stem from factors such as the dynamic changes in estrogen levels in women, especially during menopause, which can impact drug metabolism through the regulation of the cytochrome P450 (CYP450) enzyme.⁶⁷ This sex-dependent response highlights the importance of personalized AD therapies, as the efficacy of senolytics may vary significantly between males and females, even within the same pathological context.

Expanding on the role of senolytics in tau pathology, Musi et al. (2018) examined the effects of tau accumulation on cognitive decline and neurodegeneration, focusing on neurofibrillary tangles and their relationship with cellular senescence and brain atrophy.⁴⁸ This led to their application of senolytics, particularly the combination of D + Q on tau transgenic mouse models, as they possess well-defined and aggressive tau pathology in forebrain regions where neurodegeneration occurs simultaneously with cognitive deficits. The study found that the senolytic treatment of D + Q resulted in a 35% reduction in the accumulation of neurofibrillary tangles correlated with enhanced cognitive function. However, only female mice were included in this treatment, making it difficult to understand its effect on males. Additionally, the advanced age of the mouse models at the time of treatment raises questions about the generalizability of the results to earlier disease stages.⁴⁸ Despite these limitations, the study highlights the broader applicability of D + Q across distinct AD pathologies associated with both amyloid and tau manifestations.

The impact of senolytics on modifying the disease state of mouse models exhibiting both plaque and tau pathologies was further supported by Ng et al. (2024).⁶⁸ This study focused on investigating the effects of senescent cell clearance in the 3xTg mouse model, which exhibits both amyloid and tau pathologies associated with AD. They evaluated microgliosis, amyloid, and tau pathology, alongside synaptic function and neuroinflammation through RNA sequencing. Senolytic treatments, including Navitoclax and D + Q, significantly reduced microgliosis, attenuated amyloid and tau pathologies, and improved synaptic function and neuroinflammation. There was also a partial improvement in spatial memory assessed through the Barnes maze in mice with mild disease phenotypes. Complementary findings by Musi et al. (2018) demonstrated the efficacy of D + Q senolytic treatment in advanced disease stages, collectively highlighting the potential of senolytics as therapeutics across both the early and late stages of AD.^48,68

In another complementary study to examine the implications of senolytics in mouse models that undergo age-related cognitive decline similar to human AD patients, Currais et al. (2017) utilized senescence-accelerated prone 8 (SAMP8) mice.⁶⁹ The research analyzed the potential therapeutic effects of fisetin on cognitive dysfunction associated with AD. They assessed markers like glial fibrillary acidic protein (GFAP) and SAPK/JNK associated with inflammation, synaptic function, and stress to evaluate the impact of fisetin on cognitive health. Fisetin treatment significantly reduced cognitive deficits in the aged SAMP8 mice and restored several impaired markers. It significantly improved the stress response proteins, such as an increase in heat shock protein 90 (HSP90) and a decrease in HSP60 to levels similar to young mice, and improved inflammation markers by reducing GFAP and P-JNK/JNK levels, suggesting its potential as a therapeutic agent for age-related neurodegenerative diseases.⁶⁹ However, its performance in clinical trials are restricted by its poor bioavailability, rapid metabolism and targeting of fewer senescent cell types, which may not be sufficient for significant clinical benefits.⁷⁰ This study highlights the need for combination therapies that address the multifactorial nature of AD.

The synthesis of these studies demonstrates that senolytics hold significant promise as a therapeutic strategy for AD, with evidence supporting their ability to reduce amyloid and tau pathology, mitigate neuroinflammation, and improve cognitive function in various mouse models (Table 1). However, critical limitations remain, including sex-specific responses, the influence of disease stage on efficacy, and the need for more comprehensive models that better replicate human AD pathology.^48,68,69 As the field moves toward clinical trials, the insights gained from these preclinical studies will be invaluable in designing human studies that account for their limitations.

Table 1.

Summary of preclinical studies involving senolytic drugs.

Study Title	Senolytic Drug	Animal Model	Protocol	Results
Tau protein aggregation is associated with cellular senescence in the brain.⁴⁸	Dasatinib + Quercetin	Tau rTg4510 and rTg21221 transgenic mouse	Biweekly administration for 3 months	35% reduction in cortical neurofibrillary tangle accumulation, reduced cortical brain atrophy, and restored cerebral blood flow in mouse models.
Fisetin reduces the impact of aging on behavior and physiology in the rapidly aging SAMP8 mouse.⁶⁹	Fisetin	Senescence-accelerated prone 8 (SAMP8) mice	Two groups of 3-month-old SAMP8 mice were on a control diet or fisetin diet for 7 months	Reduced cognitive deficits and restored multiple markers associated with impaired synaptic function in old SAMP8 mice.
Quercetin stabilizes apolipoprotein E and reduces brain Aβ levels in amyloid model mice.⁷¹	Quercetin	5XFAD transgenic mice	Oral administration of quercetin for 10 days	Increased brain apoE levels and reduced insoluble Aβ levels in the cortex.
Quercetin decreases inflammation in the CA1 region of the hippocampus in a triple transgenic mouse model for Alzheimer's disease.⁷²	Quercetin	3xTg-AD mice	Intraperitoneal injection every 48 h for three months	Reduced reactivity of microglia and fluorescence intensity of Aβ aggregates.
A head-to-head comparison between senolytic therapies, dasatinib plus quercetin and fisetin, indicates sex-and genotype-specific differences in translationally relevant income.⁴⁹	Dasatinib + Quercetin and Fisetin	Wild-type (WT) and tau transgenic (rTg4510) mice	Intermittent dosing by oral gavage for 3 days on and 11 days off, for 6 cycles.	Improved performance and increased body weight in female rTg4510 mice. DQ also enhanced run speed in both WT females and males.
Senolytic Intervention improves cognition, metabolism, and adiposity in female APP^NL-F/NL-F mice.¹¹	Dasatinib + Quercetin or Fisetin	APP^NL-F/NL-F mice	Monthly oropharyngeal administration of 5 mg/kg dasatinib + 50 mg/kg quercetin, or 100 mg/kg fisetin	D + Q showed decreased SASP markers in visceral white adipose tissue (vWAT), plasma, and hippocampus for female mice. Also, reduced insulin and glucose levels in female mice while having the opposite effect in male mice. Fisetin had negligible effects in both males and females.
Senolytics improve physical function and increase lifespan in old age.⁶¹	Dasatinib + Quercetin	Luciferase-expressing transgenic mice and INK-ATTAC mice	Intermittent dosing either monthly or biweekly depending on the comparison group.	Alleviation of physical dysfunction and increased lifespan through clearance of senescent cells
Senescence targeting methods impact Alzheimer's disease features in 3xTg mice.⁶⁸	Navitoclax, Dasatinib + Quercetin (D + Q)	3xTg mouse model	Oral gavage administration of navitoclax for five consecutive days followed by 16 days of rest. D + Q were administered by oral gavage twice a week with 2–3 days intervals. The entire treatment last for six weeks.	Reduced microgliosis and improved both amyloid and tau pathology in the 3xTg mice. Lessening of synaptic dysfunction and neuroinflammation.

Clinical trial evidence of senolytics

The exploration of senolytic therapies in human clinical trials has begun to elucidate their potential in treating AD and other age-related conditions. These studies primarily focus on the combination of D + Q, evaluating their safety, feasibility, and preliminary efficacy across various diseases.

The first human trial investigating senolytics for AD, known as the Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD), was a Phase I open-label study assessing the safety, tolerability, and central nervous system (CNS) penetrance of D + Q in individuals with early-stage AD.^56,59 Conducted over a 12-week period, the trial involved five participants aged 65 and older with mild cognitive impairment (Montreal Cognitive Assessment scores between 7 and 23). Participants underwent two baseline visits, including cognitive and physical assessments, blood and cerebrospinal fluid (CSF) sampling, and brain MRI, before initiating the drug regimen. The treatment protocol consisted of intermittent dosing: two consecutive days of oral dasatinib (100 mg) and quercetin (1000 mg) followed by a 13–15-day drug break, repeated over six cycles. This dosing approach was chosen as it balances efficacy with safety by allowing senescent cells to accumulate between doses while minimizing potential toxicity.⁵⁰

Pharmacokinetic analyses revealed that dasatinib was detectable in plasma across all participants post-treatment, with concentrations ranging from 12.7 to 73.5 ng/ml. In CSF, dasatinib was detected in four out of five participants at low levels (0.217 to 0.536 ng/ml), suggesting limited CNS penetration. Quercetin, however, was undetectable in the CSF of all participants, indicating poor CNS accessibility. These findings suggest that while D + Q may hold promise for AD, optimizing CNS delivery remains a critical challenge.^56,59 Ongoing phase II trials aim to address this by evaluating the safety, feasibility, and efficacy of senolytic therapies in around 48 older adult participants with mild cognitive impairment or early-stage AD.⁷³

Beyond AD treatment, senolytic therapies have also been explored in other senescence-associated diseases, such as Parkinson's disease, diabetic kidney disease, and idiopathic pulmonary fibrosis.^74,75 A study by Justice et al. (2019) focused on idiopathic pulmonary fibrosis (IPF), a fatal condition characterized by progressive scarring of the lungs.⁷⁶ In this open-label pilot trial, 14 participants with stable IPF received intermittent dosing of D + Q over three weeks. The primary endpoints were feasibility and safety, with secondary measures assessing changes in physical function. Remarkably, the study reported a 100% retention rate, and participants exhibited significant improvements in physical performance metrics, such as the 6-min walk distance. These results provide preliminary evidence that senolytics may alleviate physical dysfunction in IPF, warranting further investigation in larger, randomized controlled trials.⁷⁶

In the context of diabetic kidney disease (DKD), senolytic therapy has also been evaluated for its potential to reduce cellular senescence. A study by Hickson et al. (2019) administered a three-day course of D 100 mg and Q 1000 mg to nine participants aged 55 to 79 years with DKD followed by assessments of senescent cell markers and circulating SASP factors before and 11 days after treatment.⁴⁵ They observed a significant reduction in adipose tissue senescent cells within 11 days. Specifically, there was a 35% decrease in p16^Ink4a+ cells and a 17% reduction in p21^Cip1+ cells, both indicative of senescence. Additionally, a 62% reduction in senescence-associated beta-galactosidase (SAβgal+) cells was noted, along with a decline in inflammatory crown-like structures. These findings suggest that D + Q effectively targets senescent cell burden in human tissues affected by DKD, supporting the broader applicability of senolytic therapies in age-related diseases.⁴⁵

Collectively, these clinical trials demonstrate the potential of senolytic therapies in modulating disease processes associated with cellular senescence. While initial results are encouraging, particularly regarding safety and feasibility, challenges remain in enhancing CNS drug delivery and confirming efficacy through larger, controlled studies. Addressing these challenges is crucial for the successful translation of senolytic therapies from bench to bedside.

Challenges in translating senolytic therapies

While senolytic therapies hold significant promise for treating AD, their translation from preclinical models to clinical applications faces several challenges. These include safety concerns, limited CNS penetrance, variability in dosing regimens, and the need for long-term efficacy and safety data. Addressing these challenges is critical to ensuring the successful development of senolytics as a viable therapeutic option for AD.

Safety profile of senolytic therapy

The safety of senolytic therapies, particularly the combination of dasatinib (D) and quercetin (Q), has been a primary focus of early clinical trials. The first-in-human trial of senolytics for AD, conducted by Gonzales et al. (2021, 2023), provided valuable insights into the safety and tolerability of D + Q in older adults with early-stage AD.^56,59 The study employed rigorous safety monitoring, including regular assessments of vital signs, laboratory values, and physical examinations. Despite the generally favorable safety profile, several adverse events were observed, including mild hypoglycemia and a slight increase in total cholesterol levels, both of which are known side effects of dasatinib. These metabolic changes, though manageable, highlight the need for careful monitoring of glucose and cholesterol levels in future trials, particularly in older adults who may have preexisting metabolic vulnerabilities.⁵⁰

The intermittent dosing regimen used in the Gonzales et al. (2023) trial, administering D + Q for two consecutive days followed by a 13–15-day break, appears to mitigate some of the adverse effects associated with continuous dosing. This approach, also employed in the Hickson et al. (2019) study on DKD, suggests that intermittent dosing may help balance therapeutic efficacy with reduced toxicity.^45,50 However, the long-term safety of senolytic therapy remains uncertain, as most clinical trials to date have been short-term exploratory studies. Larger, long-term trials are needed to fully characterize the safety profile of senolytics, particularly in the context of chronic diseases like AD.

Limited CNS penetrance

One of the most significant challenges in translating senolytic therapies for AD in humans is their limited ability to penetrate the blood-brain barrier (BBB) and reach therapeutic concentrations in the CNS. In the Gonzales et al. (2023) trial, dasatinib was detectable in the CSF of four out of five participants, but at low concentrations (0.217–0.536 ng/ml), with a CSF-to-plasma ratio of less than 1%. Quercetin, on the other hand, was undetectable in the CSF, raising concerns about its ability to target senescent cells in the brain. These findings underscore the need for strategies to enhance CNS delivery.⁵⁰

Recent advancements in technology offer potential solutions to this challenge. Focused ultrasound (FUS) combined with systemically injected microbubbles has been shown to noninvasively open the BBB and facilitate targeted drug delivery to the brain.⁷⁷ This approach has been applied in the context of AD, with evidence suggesting that FUS-mediated BBB opening can enhance the delivery of anti-amyloid antibodies, potentially reducing amyloid plaque burden and improving cognitive function.⁷⁷ This technique could improve the CNS bioavailability of senolytic agents, thereby enhancing their therapeutic potential for AD.

Dosing regimen optimization

The optimal dosing regimen for senolytic therapies remains unclear. While intermittent dosing has shown promise in reducing adverse effects and maintaining therapeutic efficacy, the ideal frequency, duration, and dosage of senolytics have yet to be determined. For example, the Gonzales et al. (2023) trial used a 12-week regimen with two-day dosing cycles, whereas the Hickson et al. (2019) trial employed a three-day course. Variability in dosing schedules across studies complicates the comparison of results and highlights the need for standardized protocols in future trials. Additionally, the relationship between dosing and disease stage must be explored, as preclinical studies suggest that senolytics may be more effective in early-stage AD than in advanced disease.^45,50

Sex-specific and individual variability

Emerging evidence from preclinical and clinical studies indicates that the efficacy of senolytic therapies may vary by sex and individual genetic or metabolic factors. For instance, the Gonzales et al. (2023) trial observed metabolic changes in response to dasatinib that may differ based on age and genetic background. Similarly, preclinical studies have shown sex-specific responses to senolytics, with female mice often exhibiting greater benefits than males. These findings underscore the importance of incorporating sex-stratified analyses and personalized medicine approaches in senolytic research to ensure equitable therapeutic outcomes.^11,49,56

Long-term efficacy and safety

The long-term effects of senolytic therapy on AD progression and overall health remain poorly understood. While short-term trials have demonstrated the feasibility and preliminary efficacy of senolytics in reducing senescent cell burden and improving cognitive function, the durability of these benefits is unknown. Moreover, the potential for off-target effects or unintended consequences of long-term senescent cell clearance—such as impaired tissue repair or immune dysfunction—warrants further investigation. Longitudinal studies are needed to assess the sustained efficacy and safety of senolytic therapies, particularly in older adults with multiple comorbidities.

Conclusion

In summary, the exploration of senolytic therapies targeting cellular senescence presents a promising avenue for AD treatment. Preclinical studies have demonstrated that senolytic agents, such as D + Q, can effectively reduce senescent cell populations, thereby mitigating neuroinflammation and tau pathology in animal models. These findings have paved the way for early-phase clinical trials, including a Phase I study focusing on the safety and feasibility of senolytic therapy in AD patients. While these initial trials have established a favorable safety profile and the potential for modulating disease progression, challenges remain in optimizing drug delivery to achieve sufficient central nervous system penetration and in determining long-term efficacy. Ongoing research aims to address these limitations, with the goal of translating these promising preclinical outcomes into effective clinical interventions for AD.

Footnotes

Acknowledgements

The author would like to express his sincere gratitude to Professor Trisha Stan, his Capstone advisor, for her invaluable comments, revisions, and suggestions that significantly improved the quality of this paper. The author is also thankful to Dr Mitzi Gonzales for her thoughtful guidance and for providing relevant information regarding the first clinical trial of senolytics in Alzheimer's disease. The figures included in this paper were created using BioRender. Additionally, the author acknowledges the use of ChatGPT-4o (released on May 13, 2024, by OpenAI) for assistance in improving the clarity and readability of this paper.

ORCID iD

Victor C Onuh

Author contributions

Victor C Onuh: Conceptualization; Investigation; Visualization; Writing – original draft; Writing – review & editing.

Funding

The author received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Rajmohan

Reddy

. Amyloid beta and phosphorylated tau accumulations cause abnormalities at synapses of Alzheimer’s disease neurons. J Alzheimers Dis 2017; 57: 975–999.

Breijyeh

Karaman

. Comprehensive review on Alzheimer’s disease: causes and treatment. Molecules 2020; 25: 5789.

Love

RWB

. Aniracetam: an evidence-based model for preventing the accumulation of amyloid-β plaques in Alzheimer’s disease. J Alzheimers Dis 2024; 98: 1235–1241.

Riessland

Orr

. Translating the biology of aging into new therapeutics for Alzheimer’s disease: senolytics. J Prev Alzheimers Dis 2023; 10: 633–646.

Alzheimer’s Association . Alzheimer’s Disease Facts and Figures. https://www.alz.org/alzheimers-dementia/facts-figures (accessed 25 February 2025).

Bailey

Ray

Greig

, et al. Rivastigmine lowers Aβ and increases sAPPα levels, which parallel elevated synaptic markers and metabolic activity in degenerating primary rat neurons. PLoS One 2011; 6: e21954.

Birks

Chong

Grimley Evans

. Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev 2015; 9: CD001191.

Singh

Sadiq

. Cholinesterase Inhibitors. In: StatPearls. Treasure Island, FL: StatPearls Publishing, 2025. http://www.ncbi.nlm.nih.gov/books/NBK544336/ (accessed 27 February 2025).

Chaib

Tchkonia

Kirkland

. Cellular senescence and senolytics: the path to the clinic. Nat Med 2022; 28: 1556–1568.

10.

Gonzales

Garbarino

Kautz

, et al. Senolytic therapy to modulate the progression of Alzheimer’s Disease (SToMP-AD) – outcomes from the first clinical trial of senolytic therapy for Alzheimer’s disease. Res Sq 2021; 9: 22–29. DOI: 10.21203/rs.3.rs-2809973/v1. [Preprint]. Posted 2022.

11.

Fang

Peck

Quinn

, et al. Senolytic intervention improves cognition, metabolism, and adiposity in female APPNL−F/NL−F mice. Geroscience 2025; 47: 1123–1138.

12.

Zhang

Pitcher

Yousefzadeh

, et al. Cellular senescence: a key therapeutic target in aging and diseases. J Clin Invest 2022; 132: e158450.

13.

López-Otín

Blasco

Partridge

, et al. Hallmarks of aging: an expanding universe. Cell 2023; 186: 243–278.

14.

Wissler Gerdes

Zhu

Weigand

, et al. Cellular senescence in aging and age-related diseases: implications for neurodegenerative diseases. Int Rev Neurobiol 2020; 155: 203–234.

15.

Liu

. Aging, cellular senescence, and Alzheimer’s disease. Int J Mol Sci 2022; 23: 1989.

16.

Liguori

Russo

Curcio

, et al. Oxidative stress, aging, and diseases. Clin Interv Aging 2018; 13: 757–772.

17.

Campisi

d’Adda di Fagagna

. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007; 8: 729–740.

18.

Roger

Tomas

Gire

. Mechanisms and regulation of cellular senescence. Int J Mol Sci 2021; 22: 13173.

19.

Ishikawa

. Cellular senescence as a stress response. Cornea 2006; 25: S3–S6.

20.

Victorelli

Passos

. Telomeres and cell senescence - size matters not. EBioMedicine 2017; 21: 14–20.

21.

Campisi

. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol 2001; 11: S27–S31.

22.

Prieto

Graves

Baker

. Insights from In Vivo studies of cellular senescence. Cells 2020; 9: 954.

23.

Gonzales

Garbarino

Marques Zilli

, et al. Senolytic Therapy to modulate the progression of Alzheimer’s disease (SToMP-AD): a pilot clinical trial. J Prev Alzheimers Dis 2022; 9: 22–29.

24.

Mijit

Caracciolo

Melillo

, et al. Role of p53 in the regulation of cellular senescence. Biomolecules 2020; 10: 420.

25.

Kumari

Jat

. Mechanisms of cellular senescence: cell cycle arrest and senescence associated secretory phenotype. Front Cell Dev Biol 2021; 9: 645593.

26.

Yamauchi

Takahashi

. Cellular senescence: mechanisms and relevance to cancer and aging. J Biochem 2024; 177: 163–169.

27.

Hoffmann

González-López

, et al. Cellular senescence in cancer: from mechanisms to detection. Mol Oncol 2021; 15: 2634–2671.

28.

Jin

Duan

, et al. Cellular senescence in cancer: molecular mechanisms and therapeutic targets. MedComm (2020) 2024; 5: e542.

29.

Longo

Massa

. Senolytic therapy for Alzheimer’s disease. Nat Med 2023; 29: 2409–2411.

30.

Campisi

. Aging, cellular senescence, and cancer. Annu Rev Physiol 2013; 75: 685–705.

31.

Song

Tchkonia

Jiang

, et al. Targeting senescent cells for a healthier aging: challenges and opportunities. Adv Sci 2020; 7: 2002611.

32.

Cai

Wei

. mTOR signaling from cellular senescence to organismal aging. Aging Dis 2013; 5: 263–273.

33.

Salminen

Kauppinen

Kaarniranta

. Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal 2012; 24: 835–845.

34.

Lopes-Paciencia

Saint-Germain

Rowell

, et al. The senescence-associated secretory phenotype and its regulation. Cytokine 2019; 117: 15–22.

35.

Onyango

Jauregui

Čarná

, et al. Neuroinflammation in Alzheimer’s disease. Biomedicines 2021; 9: 524.

36.

Gaikwad

Senapati

Haque

, et al. Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer’s disease: evidence from clinical and preclinical studies. Alzheimers Dement 2023; 20: 709–727.

37.

Tamatta

Pai

Jaiswal

, et al. Neuroinflammaging and the immune landscape: the role of autophagy and senescence in aging brain. Biogerontology 2025; 26: 52.

38.

Bhat

Crowe

Bitto

, et al. Astrocyte senescence as a component of Alzheimer’s disease. PLoS One 2012; 7: e45069.

39.

Liu

Hong

, et al. Delphinidin attenuates cognitive deficits and pathology of Alzheimer’s disease by preventing microglial senescence via AMPK/SIRT1 pathway. Alzheimers Res Ther 2025; 17: 138.

40.

Lee

Wang

Steinberg

, et al. A guide to senolytic intervention in neurodegenerative disease. Mech Ageing Dev 2021; 200: 111585.

41.

Di Micco

Krizhanovsky

Baker

, et al. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol 2021; 22: 75–95.

42.

Song

Zou

. Immune clearance of senescent cells to combat ageing and chronic diseases. Cells 2020; 9: 671.

43.

Islam

Tuday

Allen

, et al. Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age. Aging Cell 2023; 22: e13767.

44.

Kirkland

Tchkonia

. Senolytic drugs: from discovery to translation. J Intern Med 2020; 288: 518–536.

45.

Hickson

Langhi Prata

LGP

Bobart

, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine 2019; 47: 446–456.

46.

Lee

Carreras-Gallo

Lopez

, et al. Exploring the effects of Dasatinib, Quercetin, and Fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions. Aging 2024; 16: 3088–3106.

47.

Zhang

, et al. Senescence targeting methods impact Alzheimer’s disease features in 3xTg mice. J Alzheimers Dis 2024; 97: 1751–1763.

48.

Musi

Valentine

Sickora

, et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 2018; 17: e12840.

49.

Garbarino

Tran

Glassman

, et al. A head-to-head comparison between senolytic therapies, dasatinib plus quercetin and fisetin, indicates sex- and genotype-specific differences in translationally relevant outcomes. Alzheimers Dement 2020; 16: e047607.

50.

Reyes

Krasilnikov

Allen

, et al. Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung. Science 2022; 378: 192–201.

51.

Kim

. Senotherapeutics: emerging strategy for healthy aging and age-related disease. BMB Rep 2019; 52: 47–55.

52.

Rad

Grillari

. Current senolytics: mode of action, efficacy and limitations, and their future. Mech Ageing Dev 2024; 217: 111888.

53.

Gonzales

Krishnamurthy

Garbarino

, et al. A geroscience motivated approach to treat Alzheimer’s disease: senolytics move to clinical trials. Mech Ageing Dev 2021; 200: 111589.

54.

Chang

Jorgensen

Pawson

, et al. Effects of dasatinib on EphA2 receptor tyrosine kinase activity and downstream signalling in pancreatic cancer. Br J Cancer 2008; 99: 1074–1082.

55.

Westin

Sood

Coleman

. 18 - Targeted therapy and molecular genetics. In: DiSaia

Creasman

Mannel

, et al. (eds) Clinical gynecologic oncology (Ninth Edition). Philadelphia, PA: Elsevier, 2018, pp.470–492.e10.

56.

Gonzales

Garbarino

Kautz

, et al. Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial. Nat Med 2023; 29: 2481–2488.

57.

Lelarge

Capelle

Oger

, et al. Senolytics: from pharmacological inhibitors to immunotherapies, a promising future for patients’ treatment. NPJ Aging 2024; 10: 12.

58.

Singh

Bhatt

. Targeting cellular senescence: a potential therapeutic approach for Alzheimer’s disease. Curr Mol Pharmacol 2024; 17: e010623217543.

59.

Gonzales

Garbarino

Marques Zilli

, et al. Senolytic therapy to modulate the progression of Alzheimer’s disease (SToMP-AD): a pilot clinical trial. J Prev Alzheimers Dis 2022; 9: 22–29.

60.

Prasanna

Citrin

Hildesheim

, et al. Therapy-induced senescence: opportunities to improve anticancer therapy. J Natl Cancer Inst 2021; 113: 1285–1298.

61.

Pirtskhalava

Farr

, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med 2018; 24: 1246–1256.

62.

Nabizadeh

. Neuroprotective role of Fisetin in Alzheimer’s disease: an overview of potential mechanism and clinical findings. Neurol Lett 2024; 3: 14–25.

63.

Robbins

Jurk

Khosla

, et al. Senolytic drugs: reducing senescent cell viability to extend health span. Annu Rev Pharmacol Toxicol 2021; 61: 779–803.

64.

Anuar

Hisam

Liew

, , et al. Clinical review: navitoclax as a pro-apoptotic and anti-fibrotic agent. Front Pharmacol 2020; 11: 564108.

65.

Wang

Lankhorst

Bernards

. Exploiting senescence for the treatment of cancer. Nat Rev Cancer 2022; 22: 340–355.

66.

Sasaguri

Nilsson

Hashimoto

, et al. APP Mouse models for Alzheimer’s disease preclinical studies. EMBO J 2017; 36: 2473–2487.

67.

Tanaka

. Gender-related differences in pharmacokinetics and their clinical significance. J Clin Pharm Ther 2003; 24: 339–346.

68.

Zhang

, et al. Senescence targeting methods impact Alzheimer’s disease features in 3xTg mice. J Alzheimers Dis 2024; 97: 1751–1763.

69.

Currais

Farrokhi

Dargusch

, et al. Fisetin reduces the impact of aging on behavior and physiology in the rapidly aging SAMP8 mouse. J Gerontol A Biol Sci Med Sci 2018; 73: 299–307.

70.

Tavenier

Nehlin

Houlind

, et al. Fisetin as a senotherapeutic agent: evidence and perspectives for age-related diseases. Mech Ageing Dev 2024; 222: 111995.

71.

Zhang

Zhong

, et al. Quercetin stabilizes apolipoprotein E and reduces brain Aβ levels in amyloid model mice. Neuropharmacology 2016; 108: 179–192.

72.

Vargas-Restrepo

Sabogal-Guáqueta

C-G

. Quercetin ameliorates inflammation in CA1 hippocampal region in aged triple transgenic Alzheimeŕs disease mice model. Biomedica 2018; 38: 69–76.

73.

Wake Forest University Health Sciences . Phase II clinical trial to evaluate the safety and feasibility of senolytic therapy in Alzheimer’s disease. Clinical Trial Registration NCT04685590, clinicaltrials.gov, https://clinicaltrials.gov/study/NCT04685590 (18 December 2024, accessed 28 February 2025).

74.

Kakoty

Kalarikkal Chandran

Gulati

, et al. Senolytics: opening avenues in drug discovery to find novel therapeutics for Parkinson’s disease. Drug Discov Today 2023; 28: 103582.

75.

Miller

Campbell

Jimenez-Corea

, et al. Neuroglial senescence, α-synucleinopathy, and the therapeutic potential of senolytics in Parkinson’s disease. Front Neurosci 2022; 16: 824191.

76.

Justice

Nambiar

Tchkonia

, et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 2019; 40: 554–563.

77.

Noel

Batts

, et al. Natural aging and Alzheimer’s disease pathology increase susceptibility to focused ultrasound-induced blood–brain barrier opening. Sci Rep 2023; 13: 6757.