Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial
Open accessAbstract
Preclinical studies indicate an age-associated accumulation of senescent cells across multiple organ systems. Emerging evidence suggests that tau protein accumulation, which closely correlates with cognitive decline in Alzheimer's disease and other tauopathies, drives cellular senescence in the brain. Pharmacologically clearing senescent cells in mouse models of tauopathy reduced brain pathogenesis. Compared to vehicle treated mice, intermittent senolytic administration reduced tau accumulation and neuroinflammation, preserved neuronal and synaptic density, restored aberrant cerebral blood flow, and reduced ventricular enlargement. Intermittent dosing of the senolytics, dasatinib plus quercetin, has shown an acceptable safety profile in clinical studies for other senescence-associated conditions. With these data, we proposed and herein describe the objectives and methods for a clinical vanguard study. This initial open-label clinical trial pilots an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage Alzheimer's disease. The primary objective is to evaluate the central nervous system penetration of dasatinib and quercetin through analysis of cerebrospinal fluid collected at baseline and after 12 weeks of treatment. Further, through a series of secondary outcome measures to assess target engagement of the senolytic compounds and Alzheimer's disease-relevant cognitive, functional, and physical outcomes, we will collect preliminary data on safety, feasibility, and efficacy. The results of this study will be used to inform the development of a randomized, double-blind, placebo-controlled multicenter phase II trial to further explore of the safety, feasibility, and efficacy of senolytics for modulating the progression of Alzheimer's disease. Clinicaltrials.gov registration number and date: NCT04063124 (08/21/2019).
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0 of 99 cited sources checked · 0 supported · 0 flagged
- Premisecitation
Aging is the strongest risk factor for developing Alzheimer's disease.
“aging is the single most robust risk factor of developing AD (6).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Brookmeyer, 2019, Multistate models and lifetime risk estimation: application to Alzheimer's disease, Stat Med source
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- Premisecitation
Senescent cells can develop a senescence-associated secretory phenotype through dysregulation of p38MAPK, NF-κB, NOTCH, and mTOR signaling.
“Through dysregulation of p38 mitogen-activated protein kinases (p38MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NOTCH, and mammalian target of rapamycin (mTOR) signaling, senescent cells can develop a senescence-associated secretory phenotype (SASP) (22, 23).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [22] Kritsilis, 2018, Ageing, cellular senescence and neurodegenerative disease, Int J Mol Sci source
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- cites [23] Sharma, 2011, Possible underlying influence of p38MAPK and NF-κB in the diminished anti-anxiety effect of diazepam in stressed mice, J Pharmacol Sci source
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- Premisecitation
Dasatinib plus quercetin are the best characterized senolytic agents.
“The best characterized senolytic agents are dasatinib (D) plus quercetin (Q) (D+Q) (32).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] Gerdes, 2020, Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases, Int Rev Neurobiol source
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- Premisecitation
Senescence-implicated pathways overlap between tau-transgenic mice and human brain tissue with NFTs, including TNF, IL-1β, and IFN-γ.
“Overlapping expression of pathways implicated in senescence were common across tau-transgenic mice and human brain tissue with NFTs. These included tumor necrosis factor (TNF), interleukin 1β (IL-1β), and interferon gamma (IFN-γ), suggesting that these cells may accelerate neurodegeneration through release of toxic SASP factors.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
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- Premisecitation
NF-κB is the strongest upstream regulator of the NFT-associated gene expression profile.
“NF-κB was the strongest upstream regulator of the NFT-associated gene expression profile.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
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- Premisecitation
In mice, transplanting senescent cells at a ratio of one to 10,000 with healthy cells caused frailty, physical disability, and premature mortality.
“In murine models, transplantation of senescent cells at a ratio of one to 10,000 with healthy cells was sufficient to engender frailty, physical disability, and premature mortality (18).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat Med source
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- Premisecitation
Pathogenic tau propagates neuroinflammation by activating microglia and astrocytes.
“Pathogenic tau propagates neuroinflammation through activation of microglia and astrocytes (33).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Laurent, 2018, Tau and neuroinflammation: what impact for Alzheimer's disease and tauopathies?, Biomed J source
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- Premisecitation
In postmortem Alzheimer's disease brain tissue, NFT-bearing neurons show upregulated senescence-associated genes, including cell survival and inflammation genes, and downregulated apoptosis and cell death genes.
“Transcriptomic analyses of neurons with or without NFTs in postmortem human brain tissue of individuals with AD revealed upregulation of genes associated with cellular senescence in NFT-bearing neurons. These included increased expression of genes related to cell survival and inflammation, as well as downregulation of genes implicated in apoptosis and cellular death.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
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- Premisecitation
Preclinical research provides strong proof-of-concept that tau-induced cellular senescence may be a therapeutic target for Alzheimer's disease.
“Collectively, preclinical research has provided strong proof-of-concept data that tau-induced cellular senescence may be a novel therapeutic target for AD (29, 32).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
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- cites [32] Gerdes, 2020, Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases, Int Rev Neurobiol source
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- Premisecitation
Cellular senescence in the brain is associated with tau-containing neurofibrillary tangles in Alzheimer's disease.
“Previous work by our team identified that cellular senescence in the brain is associated with tau-containing neurofibrillary tangles (NFTs), a hallmark feature of AD that closely correlates with cognitive decline (29).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
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- Premisecitation
Senescent cells accumulate with advancing age across multiple organ systems, including the brain.
“Senescent cells accumulate with advancing age throughout multiple organ systems, including the brain (17, 28).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [17] Tchkonia, 2018, Aging, cell senescence, and chronic disease: emerging therapeutic strategies, JAMA source
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- cites [28] Baker, 2018, Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives, J Clin Invest source
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- Premisecitation
In tau transgenic mice with late-stage pathology, senolytic treatment reduced neurofibrillary tangle density by 35%.
“Histopathological analyses revealed 35% lower NFT density in senolytic treated mice (29).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
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- Premisecitation
An independent study validated that dasatinib plus quercetin clear senescent cells in the brain of a β-amyloid Alzheimer's disease mouse model.
“An independent study conducted by Zhang et al. validated the finding of D+Q clearance of senescent cells in the brain of an β-amyloid model of AD pathology (30).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Zhang, 2019, Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model, Nat Neurosci source
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- Premisecitation
Blood-brain barrier dysfunction occurs early in the neurodegenerative disease cascade.
“As blood brain barrier dysfunction occurs early in the underlying neurodegenerative disease cascade (48), the study medications may be more readily absorbed in our target study population relative to neurologically healthy adults.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [48] Montagne, 2015, Blood-brain barrier breakdown in the aging human hippocampus, Neuron source
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- Premisecitation
Intermittent dosing reduces the risk of medication side effects, which may include dasatinib-associated myelosuppression, fluid retention, hemorrhage, difficulty breathing, and myocardial dysfunction.
“Intermittent dosing regimens have the benefit of reducing the risk of associated medication side effects, which could include D-associated myelosuppression, fluid retention, hemorrhage, difficulty breathing, and myocardial dysfunction (44).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [44] Masiello, 2009, The occurrence and management of fluid retention associated with TKI therapy in CML, with a focus on dasatinib, J Hematol Oncol source
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- Premisecitation
Because senescent cells do not divide and accumulate slowly, senolytic agents do not need to be administered continuously to be effective.
“As senescent cells do not divide and slowly accumulate over a period of weeks to months, senolytic agents do not need to be administered continuously to be effective (20, 29, 43).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [20] Zhu, 2014, Cellular senescence and the senescent secretory phenotype in age-related chronic diseases, Curr Opin Clin Nutr Metab Care source
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- cites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
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- cites [43] Zhu, 2016, Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors, Aging Cell source
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- Premisecitation
Continuous receptor binding, enzyme activity modification, and persistent biochemical pathway modulation are not required for senolytic target engagement.
“Justification for this approach is provided by data demonstrating that senolytic target engagement does not require continuous receptor binding, enzyme activity modification, or persistent modulation of biochemical pathways.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [19] Zhu, 2015, The Achilles' heel of senescent cells: from transcriptome to senolytic drugs, Aging Cell source
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- cites [43] Zhu, 2016, Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors, Aging Cell source
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- Premisecitation
Senescent cells in the brain accumulate over two to four weeks.
“Our preclinical research demonstrated that senescent cells in the brain accumulate over a period of two to four weeks (29).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
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- Interpretationreasoning
The study medications may be absorbed more readily in the AD target population than in neurologically healthy adults.
“As blood brain barrier dysfunction occurs early in the underlying neurodegenerative disease cascade (48), the study medications may be more readily absorbed in our target study population relative to neurologically healthy adults.”
Quote in the paperSubstantial claim - Premisecitation
Senolytics act by temporarily disrupting anti-apoptotic pathways that senescent cells use for survival.
“Instead, their mechanism of action is to temporarily disrupt anti-apoptotic pathways utilized by senescent cells for their survival (19, 43).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [19] Zhu, 2015, The Achilles' heel of senescent cells: from transcriptome to senolytic drugs, Aging Cell source
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- cites [43] Zhu, 2016, Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors, Aging Cell source
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- Premiseown data
A partial decrease of 35% in NFTs was observed as a disease-modifying effect.
“Moreover, disease-modifying effects were observed with a partial (35%) decrease in NFTs, which was consistent with preclinical studies of senolytic treatment for other models of aging and disease (10–16, 18, 19, 30, 54–56).”
Quote in the paperSubstantial claim0 of 9 sources checked- cites [10] Lewis-McDougall, 2019, Aged-senescent cells contribute to impaired heart regeneration, Aging Cell source
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- cites [11] Nath, 2018, The murine dialysis fistula model exhibits a senescence phenotype: pathobiologic mechanisms and therapeutic potential, Am J Physiol Renal Physiol source
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- cites [12] Ogrodnik, 2017, Cellular senescence drives age-dependent hepatic steatosis, Nat Commun source
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- cites [13] Ogrodnik, 2019, Obesity-induced cellular senescence drives anxiety and impairs neurogenesis, Cell Metab source
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- cites [14] Palmer, 2019, Targeting senescent cells alleviates obesity-induced metabolic dysfunction, Aging Cell source
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- cites [15] Roos, 2016, Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice, Aging Cell source
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- cites [16] Schafer, 2017, Cellular senescence mediates fibrotic pulmonary disease, Nat Commun source
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- cites [18] Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat Med source
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- cites [19] Zhu, 2015, The Achilles' heel of senescent cells: from transcriptome to senolytic drugs, Aging Cell source
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- Interpretationreasoning
The SToMP-AD pilot trial's 12-week intermittent administration schedule will be suitable for ablating senescent cells.
“Therefore, we anticipate that the SToMP-AD pilot trial length with intermittent administration over 12 weeks will be suitable for ablating senescent cells.”
Quote in the paperSubstantial claim - Premisecitation
In a prior phase I trial, three doses of D+Q given over eleven days were sufficient to clear senescent cells.
“A prior phase I clinical trial reported that three doses of D+Q administered across eleven days was sufficient to clear senescent cells (34).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34] Hickson, 2019, Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease, EBioMedicine source
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- Premiseown data
Cellular senescence is closely coupled to pathological tau accumulation.
“Our preclinical research demonstrated that pathological tau accumulation is closely coupled to cellular senescence (29).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
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- Premisecitation
NFTs from human AD brain tissue and AD mouse models show overlapping expression of pathways implicated in senescence, providing converging evidence of core senescence markers.
“NFTs derived from both species have overlapping expression of pathways implicated in senescence, providing converging evidence of core senescence markers.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
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- Premisecitation
A SASP composite score had been validated in a phase I trial of intermittent D+Q.
“In addition, our trial will examine changes in SASP utilizing a composite score that was validated in a phase I clinical trial of intermittent D+Q (34).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [34] Hickson, 2019, Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease, EBioMedicine source
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- Premisecitation
D+Q are combined to target senescent cell survival mechanisms more broadly.
“Though there are obvious benefits to being able to repurpose a FDA approved chemotherapeutic medication, D, with a well-established side effect profile (53), there is a need to carefully evaluate safety and the equipoise of treatment in our vulnerable target population, especially as D+Q are utilized in combination to achieve broader targeting of senescent cell survival mechanisms (19).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Zhu, 2015, The Achilles' heel of senescent cells: from transcriptome to senolytic drugs, Aging Cell source
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- Interpretationreasoning
The intermittent dosing strategy may help mitigate some adverse events typically associated with these compounds.
“A unique feature of our trial design that may contribute to the mitigation of some adverse events typically associated with these compounds, is the intermittent dosing strategy being utilized.”
Quote in the paperSubstantial claim
- May combine two claims. 20
- Classified as probably not a substantial claim. 9
May combine two claims.
PremisecitationThe senescence-associated secretory phenotype triggers immune clearance of senescent cells, but as senescent cells accumulate it causes adjacent cells to become senescent.
“The SASP triggers immune cells to clear senescent cells, which is beneficial; however as senescent cells accumulate, the SASP exerts paracrine effects on adjacent cells, becoming the precipitant for broader cellular conversion to the senescent phenotype (17, 20).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [17] Tchkonia, 2018, Aging, cell senescence, and chronic disease: emerging therapeutic strategies, JAMA source
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- cites [20] Zhu, 2014, Cellular senescence and the senescent secretory phenotype in age-related chronic diseases, Curr Opin Clin Nutr Metab Care source
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PremisecitationCellular senescence is induced by stressors such as DNA and mitochondrial damage, telomere shortening, protein accumulation, and metabolic dysfunction.
“Cellular senescence is a dynamic molecular process induced by stressors such as DNA and mitochondrial damage, telomere shortening, protein accumulation and metabolic dysfunction (17, 20).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [17] Tchkonia, 2018, Aging, cell senescence, and chronic disease: emerging therapeutic strategies, JAMA source
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- cites [20] Zhu, 2014, Cellular senescence and the senescent secretory phenotype in age-related chronic diseases, Curr Opin Clin Nutr Metab Care source
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May combine two claims.
PremisecitationCellular senescence is a hallmark of aging and contributes to age-related chronic conditions including Alzheimer's disease.
“Cellular senescence is a hallmark feature of aging and contributes to numerous age-related chronic medical conditions including AD (10–19).”
Quote in the paperSubstantial claim0 of 10 sources checked- cites [10] Lewis-McDougall, 2019, Aged-senescent cells contribute to impaired heart regeneration, Aging Cell source
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- cites [11] Nath, 2018, The murine dialysis fistula model exhibits a senescence phenotype: pathobiologic mechanisms and therapeutic potential, Am J Physiol Renal Physiol source
Not checked in the free run.
- cites [12] Ogrodnik, 2017, Cellular senescence drives age-dependent hepatic steatosis, Nat Commun source
Not checked in the free run.
- cites [13] Ogrodnik, 2019, Obesity-induced cellular senescence drives anxiety and impairs neurogenesis, Cell Metab source
Not checked in the free run.
- cites [14] Palmer, 2019, Targeting senescent cells alleviates obesity-induced metabolic dysfunction, Aging Cell source
Not checked in the free run.
- cites [15] Roos, 2016, Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice, Aging Cell source
Not checked in the free run.
- cites [16] Schafer, 2017, Cellular senescence mediates fibrotic pulmonary disease, Nat Commun source
Not checked in the free run.
- cites [17] Tchkonia, 2018, Aging, cell senescence, and chronic disease: emerging therapeutic strategies, JAMA source
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- cites [18] Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat Med source
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- cites [19] Zhu, 2015, The Achilles' heel of senescent cells: from transcriptome to senolytic drugs, Aging Cell source
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PremisecitationThe senescence-associated secretory phenotype consists of pro-inflammatory cytokines, proteases, chemokines, and extracellular matrix degrading proteins.
“The SASP consists of a noxious secretome comprised of pro-inflammatory cytokines, proteases, chemokines, and extracellular matrix degrading proteins (24–27).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [24] Acosta, 2013, A complex secretory program orchestrated by the inflammasome controls paracrine senescence, Nat Cell Biol source
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- cites [25] Chen, 2015, MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype, Mol Cell source
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- cites [26] Hoare, 2016, NOTCH1 mediates a switch between two distinct secretomes during senescence, Nat Cell Biol source
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- cites [27] Weichhart, 2018, mTOR as regulator of lifespan, aging, and cellular senescence: a mini-review, Gerontology source
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InterpretationcitationThe association between aging and Alzheimer's disease suggests shared molecular and cellular processes that may be treatment targets.
“The strong association between aging and AD suggests overlapping molecular and cellular processes (9), which may serve as viable treatment targets to prevent or alleviate neurodegenerative diseases.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Xia, 2018, Aging and Alzheimer's disease: comparison and associations from molecular to system level, Aging Cell source
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PremisecitationThe burden of senescent cells in the brain increases with advanced age and neurodegenerative diseases and occurs across neurons, microglia, astrocytes, oligodendrocyte precursor cells, and endothelial cells.
“The burden of senescent cells in the brain increases with advanced chronological age and neurodegenerative diseases, and occurs across cell types including neurons, microglia, astrocytes, oligodendrocyte precursor cells, and endothelial cells (28–32).”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [28] Baker, 2018, Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives, J Clin Invest source
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- cites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
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- cites [30] Zhang, 2019, Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model, Nat Neurosci source
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- cites [31] Blasko, 2004, How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes, Aging Cell source
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- cites [32] Gerdes, 2020, Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases, Int Rev Neurobiol source
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PremisecitationMicroglia and astrocytes can acquire a senescent phenotype, promoting diffusion of the senescence-associated secretory phenotype and conversion of healthy cells to senescence.
“Microglia and astrocytes can acquire a senescent phenotype themselves (28, 31, 32), promoting further diffusion of the SASP and the conversion of healthy cells to the senescent phenotype.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [28] Baker, 2018, Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives, J Clin Invest source
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- cites [31] Blasko, 2004, How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes, Aging Cell source
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- cites [32] Gerdes, 2020, Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases, Int Rev Neurobiol source
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PremisecitationAcross six transgenic Alzheimer's disease mouse models, orally administered senolytic drugs ablate brain senescent cells and alleviate Alzheimer's-relevant pathogenesis.
“To date, research conducted across six transgenic AD mouse models has demonstrated that orally administered senolytic drugs ablate senescent cells in the brain and alleviate AD-relevant pathogenesis (28–30, 32).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [28] Baker, 2018, Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives, J Clin Invest source
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- cites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
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- cites [30] Zhang, 2019, Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model, Nat Neurosci source
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- cites [32] Gerdes, 2020, Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases, Int Rev Neurobiol source
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May combine two claims.
PremisecitationDasatinib plus quercetin target multiple senescent cell types and clear senescent cells and alleviate chronic conditions in preclinical models.
“D+Q target multiple senescent cell types; the combination of the two agents has been demonstrated to effectively clear senescent cells and alleviate numerous chronic medical conditions in preclinical models, including physical frailty, muscle weakness, vascular stiffness, osteoporosis, and hepatic stenosis (12–15, 18, 34).”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [12] Ogrodnik, 2017, Cellular senescence drives age-dependent hepatic steatosis, Nat Commun source
Not checked in the free run.
- cites [13] Ogrodnik, 2019, Obesity-induced cellular senescence drives anxiety and impairs neurogenesis, Cell Metab source
Not checked in the free run.
- cites [14] Palmer, 2019, Targeting senescent cells alleviates obesity-induced metabolic dysfunction, Aging Cell source
Not checked in the free run.
- cites [15] Roos, 2016, Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice, Aging Cell source
Not checked in the free run.
- cites [18] Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat Med source
Not checked in the free run.
- cites [34] Hickson, 2019, Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease, EBioMedicine source
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May combine two claims.
PremisecitationDasatinib plus quercetin have been well tolerated and shown benefits in first-in-human trials for other conditions, including idiopathic pulmonary fibrosis and diabetic kidney disease.
“Importantly, D+Q have been well tolerated and demonstrated benefits in first-in-human clinical trials of other conditions (i.e., idiopathic pulmonary fibrosis (40) followed by diabetic kidney disease (34).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [40] Justice, 2019, Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study, EBioMedicine source
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- cites [34] Hickson, 2019, Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease, EBioMedicine source
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May combine two claims.
PremisecitationBoth dasatinib and quercetin penetrate the blood-brain barrier in rodent models, with some supportive data from cancer patients.
“Both D and Q have demonstrated blood-brain barrier penetrance in rodent models with some supportive data in clinical studies of individuals undergoing cancer treatment (41, 42).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [41] Porkka, 2008, Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia, Blood source
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- cites [42] Ishisaka, 2011, Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats, Free Radic Biol Med source
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PremisecitationIn tau transgenic mice, senolytic treatment mitigated ventricular enlargement, aberrant blood flow, and the senescence-associated secretory phenotype.
“Brain MRI indicated that senolytic treatment mitigated pathogenic ventricular enlargement, aberrant blood flow, and the SASP.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
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PremisecitationIn preclinical studies and clinical trials of other age-related conditions, D+Q showed an encouraging safety profile and modest but promising therapeutic outcomes.
“Our pilot study evaluating a novel therapeutic agent for AD is a direct follow-up to the preclinical studies and clinical trials utilizing D+Q for other age-related conditions, which demonstrated an encouraging safety profile coupled with modest but promising therapeutic outcomes (18, 34, 40–42).”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [18] Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat Med source
Not checked in the free run.
- cites [34] Hickson, 2019, Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease, EBioMedicine source
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- cites [40] Justice, 2019, Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study, EBioMedicine source
Not checked in the free run.
- cites [41] Porkka, 2008, Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia, Blood source
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- cites [42] Ishisaka, 2011, Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats, Free Radic Biol Med source
Not checked in the free run.
May combine two claims.
PremisecitationIn an open-label diabetic kidney disease trial, short-term dasatinib plus quercetin reduced adipose senescent cell burden and plasma IL-2 and IL-6 levels.
“Similarly, in an open-label trial of D+Q for diabetic kidney disease, short-term treatment effectively reduced senescent cell burden in adipose tissue and attenuated plasma levels of key SASP factors, including IL-2 and IL-6 (34).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34] Hickson, 2019, Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease, EBioMedicine source
Not checked in the free run.
May combine two claims.
PremisecitationThe first clinical trial of senolytic treatment showed dasatinib plus quercetin was generally well tolerated and suggested improved physical function in idiopathic pulmonary fibrosis.
“The first clinical trial of senolytic treatment, published in 2019, showed D+Q was generally well tolerated and suggested improvements in physical function in an open-label trial for individuals with idiopathic pulmonary fibrosis, a fatal disease, providing encouraging first evidence for further clinical testing (40).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [40] Justice, 2019, Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study, EBioMedicine source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe trial will track adverse events and serious adverse events from screening to the end of the study.
“We will track occurrence of adverse events (AEs) and serious adverse events (SAEs) from the screening visit to the end of the study.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationAdverse events and serious adverse events will be defined according to the International Conference on Harmonization Guidance for Clinical Safety Data Management.
“AEs and SAEs will be defined according to the International Conference on Harmonization Guidance for Clinical Safety Data Management.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites International Conference on Harmonization Guidance for Clinical Safety Data Management
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May combine two claims.
PremisecitationDasatinib and/or quercetin can cross the blood-brain barrier in rodent models and in cancer patients.
“While it has been shown that D and/or Q can cross the blood barrier in rodent models and individuals undergoing cancer treatment, the central nervous system drug penetrance in individuals with AD remains unknown (41, 42).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [41] Porkka, 2008, Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia, Blood source
Not checked in the free run.
- cites [42] Ishisaka, 2011, Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats, Free Radic Biol Med source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe incidence of adverse events and serious adverse events will be reviewed by the UTHSCSA Data Safety Monitoring Board.
“Incidence of AEs and SAEs will be reviewed by the UTHSCSA Data Safety Monitoring Board (DSMB).”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataThe trial is an open-label pilot study of intermittent dasatinib plus quercetin in five older adults with early-stage Alzheimer's disease.
“This initial open-label clinical trial pilots an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage Alzheimer’s disease.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationThere is no universally accepted definition or biomarkers of cellular senescence.
“One of the major challenges to our trial and related studies as this field moves forward is the lack of a universally accepted definition and biomarkers of cellular senescence (57).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [57] DiBattista, 2020, NIA workshop on senescence in brain aging and Alzheimer's disease and its related dementias, GeroScience source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationVarious cellular and molecular features of cellular senescence have been identified in preclinical and clinical trials.
“Preclinical and clinical trials have identified various cellular and molecular features of cellular senescence (58).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [58] Tuttle, 2020, Cellular senescence and chronological age in various human tissues: a systematic review and meta-analysis, Aging Cell source
Not checked in the free run.
May combine two claims.
PremisecitationIntermittent administration of senolytics in other study populations reduces side effects and avoids off-target effects caused by continuous receptor occupancy.
“The intermittent administration of senolytics in other study populations has been shown to attenuate side effects and effectively circumvent potential off-target effects induced by continuous receptor occupancy.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [19] Zhu, 2015, The Achilles' heel of senescent cells: from transcriptome to senolytic drugs, Aging Cell source
Not checked in the free run.
- cites [43] Zhu, 2016, Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors, Aging Cell source
Not checked in the free run.
May combine two claims.
PremisecitationMice treated with senolytics showed reduced tau deposition, and this correlated with favorable clinically relevant outcomes.
“Senolytic treated mice had lower tau deposition, which correlated with favorable clinically relevant outcomes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone givenThe SToMP-AD vanguard will provide the first proof-of-concept AD-relevant data using a senescence-associated pharmacotherapy.
“As such, the SToMP-AD vanguard is critical in that it will provide the first proof-of-concept AD-relevant data utilizing a senescence-associated pharmacotherapy.”
Quote in the paperNot a substantial claim- Rests on an assumption: Cellular senescence has not been examined in clinical trials of aMCI or early-stage AD.
May combine two claims.
PremisecitationCSF tau levels rise before tau PET imaging, suggesting CSF tau may be a sensitive marker of early change.
“CSF tau levels demonstrate elevation prior to tau PET imaging, suggesting that it may be a sensitive marker of early change (59).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [59] Mattsson, 2017, (18)F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer's disease, EMBO Mol Med source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningThe secondary aim's senescence markers were chosen in advance from the literature.
“The senescence markers included in the secondary aim were selected a priori based on the literature.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationDasatinib is an FDA-approved chemotherapeutic medication with a well-established side effect profile.
“Though there are obvious benefits to being able to repurpose a FDA approved chemotherapeutic medication, D, with a well-established side effect profile (53), there is a need to carefully evaluate safety and the equipoise of treatment in our vulnerable target population, especially as D+Q are utilized in combination to achieve broader targeting of senescent cell survival mechanisms (19).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] Sprycel prescribing information, 2018
Not checked in the free run.
The paper relies on this without support.
Cerebrospinal fluid concentrations of dasatinib and quercetin reflect central nervous system penetration of these drugs.
“The primary objective is to evaluate the central nervous system penetration of dasatinib and quercetin through analysis of cerebrospinal fluid collected at baseline and after 12 weeks of treatment.”
The paper relies on this without support.
The central nervous system drug penetrance of D+Q in individuals with AD is unknown.
“While it has been shown that D and/or Q can cross the blood barrier in rodent models and individuals undergoing cancer treatment, the central nervous system drug penetrance in individuals with AD remains unknown (41, 42).”
The paper relies on this without support.
Cellular senescence has not been examined in clinical trials of aMCI or early-stage AD.
“However, as no clinical trials of aMCI and early-stage AD have examined cellular senescence, it is possible that the treatment regimen will affect various cellular and molecular senescence markers, which will be determined though exploratory analyses of a broader panel of senescence markers.”
The paper relies on this without support.
D+Q is the most well-established senolytic.
“Though there are several senolytic compounds which have been identified and are being further studied (e.g., fisetin and other flavonoids) for their associations with improvements in cognition and reductions in AD-relevant pathology (36, 49–52), D+Q was selected for use in this first AD relevant trial as it is the most well established.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The trial was open-label, proof-of-concept, phase I, and single-site.
“As previously described29, the open-label, proof-of-concept, Phase I, single-site pilot study protocol included the completion of 11 study visits over a period of 20–24 weeks (Fig. 1).”
From Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (2023) · cites this paper as [29]
Methods > Study Design (page unavailable) describes this as an open-label pilot and an initial proof-of-concept for a larger phase II trial; it also says all visits will occur at one site. It does not identify SToMP-AD as a phase I trial. The Discussion’s references to phase I trials concern other studies. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe application of senolytics for patients diagnosed with early-stage AD has recently been investigated, yielding preliminary findings that suggest a potential role for these agents in managing neurodegenerative diseases.
“The application of senolytics for patients diagnosed with early-stage AD has recently been investigated, yielding preliminary findings that suggest a potential role for these agents in managing neurodegenerative diseases.79,80”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [79]
The ability of senolytic therapy to modulate progression of AD is being evaluated in a pilot clinical trial.
“The ability of senolytic therapy to modulate the progression of AD is also being evaluated in a pilot clinical trial. 32”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [32]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
The stated drug-free interval does not fit the two-week cycle
MinorTwo dosing days followed by 14 no-drug days make a 16-day cycle. That conflicts with the stated two-week cycle and visits scheduled 14 days apart, affecting the treatment schedule.
“Eligible participants will be administered 100 mg of D (one 100 mg capsule, Sprycel, Bristol Myers Squibb) and 1000 mg of Q (four 250 mg capsules, Thorne Research) daily for two consecutive days followed by a 14-day (+/− 2 day) no-drug period to complete a single cycle.”
“On the first day of each 2-week drug cycle, participants will present to the study site for safety assessments and drug dispensing (weeks 1, 3, 5, 7, 9, 11).”
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“14,27,28 To date, four human studies administering DQ as a combination senolytic therapy have been completed in various populations, including idiopathic pulmonary fi brosis, 29 diabetic kidney disease, 30 age-related osteoporosis, 31 and Alzheimer ’ s disease.”
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Senolytic treatment for low back pain
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“The full study protocol [22], as well as the detailed results from the initial reporting of results of the SToMP-AD trial, have been separately published [16].”
Self-citationThe functional role of cellular senescence during vascular calcification in chronic kidney disease
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Pharmacological interventions in human aging
Petr, M. A., Matiyevskaya, F., Osborne, B., Berglind, M., Reves, S., Zhang, B., Ezra, M. B., Carmona-Marin, L. M., Syadzha, M. F., Mediavilla, M. C., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102213 · Cited by 16 · see citing works
Das, V., Miller, J. H., Goud, A. C., Annadurai, N., Sanctis, J. B. D., Hrubá, L., & Hajdúch, M. (2024) · Medicinal Research Reviews · doi:10.1002/med.22033 · Cited by 15 · see citing works
Gao, L., Yang, X.-N., Dong, Y., Han, Y., Zhang, X., Zhou, X.-L., Liu, Y., Liu, F., Fang, J., Ji, J., et al. (2024) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2024.108751 · Cited by 15 · see citing works
Repair mechanisms of the central nervous system: From axon sprouting to remyelination
Gluck, L., Gerstein, B., & Kaunzner, U. W. (2025) · Neurotherapeutics · doi:10.1016/j.neurot.2025.e00583 · Cited by 14 · see citing works
Gauthier, S. G., Boxer, A. L., Knopman, D. S., Sims, J., Doody, R. S., Aisen, P., Iwatsubo, T., Bateman, R. J., & Vellas, B. J. (2022) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2022.29 · Cited by 14 · see citing works
Senolytic Treatment Improve Small Intestine Regeneration in Aging
Luo, Q., Ye, Y., Guo, W., Zhu, Q., Wang, S.-S., Li, N., Cheng, C.-S., & Fan, G. (2023) · Aging and Disease · doi:10.14336/ad.2023.0920 · Cited by 14 · see citing works
Free radicals in Alzheimer's disease: From pathophysiology to clinical trial results
Viña, J., Borrás, C., & Mas‐Bargues, C. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.09.051 · Cited by 14 · see citing works
The Quest for Eternal Youth: Hallmarks of Aging and Rejuvenating Therapeutic Strategies
Nunkoo, V. S., Cristian, A., Jurcău, A., Diaconu, R. G., & Jurcău, M. C. (2024) · Biomedicines · doi:10.3390/biomedicines12112540 · Cited by 15 · see citing works
Immunosenescence and the Geriatric Giants: Molecular Insights into Aging and Healthspan
Fetarayani, D., Kahdina, M., Waitupu, A., Pratiwi, L., Ningtyas, M. C., Adytia, G. J., & Sutanto, H. (2025) · Medical Sciences · doi:10.3390/medsci13030100 · Cited by 14 · see citing works
Bian, X., Snow, Z. K., Zinn, C. J., Bratulin, A. L., Elhusseiny, K. M., Tchkonia, T., Kirkland, J. L., Zhu, Y., Khosla, S., Kim, S. R., et al. (2026) · EBioMedicine · doi:10.1016/j.ebiom.2026.106124 · Cited by 13 · see citing works
Self-citationTranslating Senotherapeutic Interventions into the Clinic with Emerging Proteomic Technologies
Dey, A. K., Banarjee, R., Boroumand, M., Rutherford, D. V., Strassheim, Q., Nyunt, T., Olinger, B., & Basisty, N. (2023) · Biology · doi:10.3390/biology12101301 · Cited by 12 · see citing works
Millar, C. L., Iloputaife, I., Baldyga, K., Kuo, J., Tchkonia, T., Kirkland, J. L., Travison, T. G., & Lipsitz, L. A. (2023) · Translational Medicine of Aging · doi:10.1016/j.tma.2023.10.004 · Cited by 13 · see citing works
Self-citationThe Critical Role of Biomarkers for Drug Development Targeting the Biology of Aging
Owen, M., Bose, N., Nisenbaum, L., Partrick, K. A., & Fillit, H. M. (2023) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2023.111 · Cited by 13 · see citing works
Sanchez-Rodriguez, L. M., Khan, A. F., Adewale, Q., Bezgin, G., Therriault, J., Arias, J. F., Servaes, S., Rahmouni, N., Tissot, C., Stevenson, J., et al. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1383163 · Cited by 15 · see citing works
From bench to bedside: The critical need for standardized senescence detection
Shah, J., Al-Hashimi, A., Benedetto, M., & Ruchaya, P. J. (2025) · Archives of cardiovascular diseases · doi:10.1016/j.acvd.2024.12.008 · Cited by 13 · see citing works
- Authors
- Gonzales, M. M., Garbarino, V. R., Marques Zilli, E., Petersen, R. C., Kirkland, J. L., Tchkonia, T., Musi, N., Seshadri, S., Craft, S., & Orr, M. E.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Mayo Clinic (US)
- Boston University (US)
- Wake Forest University Health Sciences (US)
- Corresponding author
- Gonzales, Mitzi M.
- Orr, Miranda E.
- ORCID
- Venue
- The Journal of Prevention of Alzheimer's Disease
- Publisher
- Elsevier BV
- Published
- 2022-01
- Volume
- 9
- Issue
- 1
- Pages
- 22-29
- ISSN
- 2274-5807 (ISSN-L)
- PMC
- PMC8612719
- OpenAlex
- W3216516063
- Cited by
- 203
- References
- 65
- Citations by year
- 2026: 34 · 2025: 52 · 2024: 55 · 2023: 41 · 2022: 18 · 2021: 3
- FWCI
- 18.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- The Journal of Prevention of Alzheimer s Disease (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (IK2BX003804)
- National Institute on Aging (R33AG061456, P30AG013319, U24AG059624, R01AG068293, P30AG044271)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- senolytic therapy, Alzheimer's disease, dasatinib, quercetin, cellular senescence, tau accumulation, tauopathy, intermittent dosing, cerebrospinal fluid drug penetration, neuroinflammation, cognitive decline, early Alzheimer's disease, older adults
- MeSH terms
- Dasatinib, Senotherapeutics, Aged, Alzheimer Disease, Animals, Humans, Cellular Senescence, Tauopathies, Mice
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