Senolytic Therapies for CBS and [PSP](/diseases/progressive-supranuclear-palsy)

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Senolytic Therapies for CBS and [PSP](/diseases/progressive-supranuclear-palsy)

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Senolytic Therapies for CBS and [PSP](/diseases/progressive-supranuclear-palsy)

Introduction

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">Senolytic Therapies for CBS and [PSP](/diseases/progressive-supranuclear-palsy)</th>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Recommendation</td>
</tr>
<tr>
<td class="label">Dasatinib dose</td>
<td>100 mg oral</td>
</tr>
<tr>
<td class="label">Quercetin dose</td>
<td>1000 mg oral (liposomal preferred)</td>
</tr>
<tr>
<td class="label">Schedule</td>
<td>2 consecutive days, then 14 days off (Kirkland protocol)</td>
</tr>
<tr>
<td class="label">Cycle length</td>
<td>2 days on / 12–14 days off</td>
</tr>
<tr>
<td class="label">Duration</td>
<td>6 cycles minimum (12 weeks) for initial assessment</td>
</tr>
<tr>
<td class="label">Timing</td>
<td>Morning, with food (improves quercetin absorption)</td>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Recommendation</td>
</tr>
<tr>
<td class="label">Dose</td>
<td>20 mg/kg/day (approximately 1000–1500 mg for 70 kg adult)</td>
</tr>
<tr>
<td class="label">Formulation</td>
<td>Liposomal fisetin (standard fisetin has <10% bioavailability)</td>
</tr>
<tr>
<td class="label">Schedule</td>
<td>2 consecutive days monthly (per AFFIRM-LITE)</td>
</tr>
<tr>
<td class="label">Duration</td>
<td>6 months minimum for assessment</td>
</tr>
<tr>
<td class="label">Combination</td>
<td>Rationale</td>

...

Senolytic Therapies for CBS and [PSP](/diseases/progressive-supranuclear-palsy)

Introduction

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">Senolytic Therapies for CBS and [PSP](/diseases/progressive-supranuclear-palsy)</th>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Recommendation</td>
</tr>
<tr>
<td class="label">Dasatinib dose</td>
<td>100 mg oral</td>
</tr>
<tr>
<td class="label">Quercetin dose</td>
<td>1000 mg oral (liposomal preferred)</td>
</tr>
<tr>
<td class="label">Schedule</td>
<td>2 consecutive days, then 14 days off (Kirkland protocol)</td>
</tr>
<tr>
<td class="label">Cycle length</td>
<td>2 days on / 12–14 days off</td>
</tr>
<tr>
<td class="label">Duration</td>
<td>6 cycles minimum (12 weeks) for initial assessment</td>
</tr>
<tr>
<td class="label">Timing</td>
<td>Morning, with food (improves quercetin absorption)</td>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Recommendation</td>
</tr>
<tr>
<td class="label">Dose</td>
<td>20 mg/kg/day (approximately 1000–1500 mg for 70 kg adult)</td>
</tr>
<tr>
<td class="label">Formulation</td>
<td>Liposomal fisetin (standard fisetin has <10% bioavailability)</td>
</tr>
<tr>
<td class="label">Schedule</td>
<td>2 consecutive days monthly (per AFFIRM-LITE)</td>
</tr>
<tr>
<td class="label">Duration</td>
<td>6 months minimum for assessment</td>
</tr>
<tr>
<td class="label">Combination</td>
<td>Rationale</td>
</tr>
<tr>
<td class="label">D+Q + Rapamycin</td>
<td>Senolysis + [autophagy](/mechanisms/autophagy) enhancement</td>
</tr>
<tr>
<td class="label">D+Q + Spermidine</td>
<td>Senolysis + EP300-mediated [autophagy](/mechanisms/autophagy)</td>
</tr>
<tr>
<td class="label">D+Q + Lithium</td>
<td>Senolysis + GSK-3β inhibition</td>
</tr>
<tr>
<td class="label">D+Q + NAD+ precursors</td>
<td>Senolysis + mitochondrial support</td>
</tr>
<tr>
<td class="label">Fisetin + Melatonin</td>
<td>Senolysis + antioxidant + chronobiology</td>
</tr>
<tr>
<td class="label">Dimension</td>
<td>Score</td>
</tr>
<tr>
<td class="label">Mechanistic Clarity</td>
<td>9/10</td>
</tr>
<tr>
<td class="label">Clinical Evidence</td>
<td>4/10</td>
</tr>
<tr>
<td class="label">Preclinical Evidence</td>
<td>8/10</td>
</tr>
<tr>
<td class="label">Replication</td>
<td>6/10</td>
</tr>
<tr>
<td class="label">Effect Size</td>
<td>6/10</td>
</tr>
<tr>
<td class="label">Safety/Tolerability</td>
<td>7/10</td>
</tr>
<tr>
<td class="label">Biological Plausibility</td>
<td>9/10</td>
</tr>
<tr>
<td class="label">Actionability</td>
<td>5/10</td>
</tr>
<tr>
<td class="label">Total</td>
<td>54/80</td>
</tr>
</table>

Senolytic agents selectively eliminate senescent cells — irreversibly growth-arrested cells that accumulate with aging and secrete a toxic cocktail of pro-inflammatory cytokines, chemokines, and proteases known as the senescence-associated secretory phenotype (SASP). In the aging brain, senescent astrocytes, microglia, oligodendrocyte precursors, and endothelial cells drive chronic [neuroinflammation](/mechanisms/neuroinflammation) that accelerates [tau](/proteins/tau) pathology, synaptic loss, and neuronal death. The landmark 2018 study by Bussian and colleagues in Nature demonstrated that genetic clearance of senescent glial cells in [tau](/proteins/tau) P301S mice prevented neurofibrillary tangle formation, neurodegeneration, and cognitive decline — establishing a direct causal link between cellular senescence and [tau](/proteins/tau)-dependent neurodegeneration. This finding is directly relevant to corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), both defined by accumulation of hyperphosphorylated 4R-[tau](/proteins/tau), and has catalyzed clinical trials of the dasatinib + quercetin (D+Q) combination and fisetin in neurodegenerative diseases.

Cellular Senescence in the Aging Brain

Senescent Cell Biology

Cellular senescence is triggered by diverse stressors — telomere shortening, DNA damage, [oxidative stress](/mechanisms/oxidative-stress), oncogene activation, and [mitochondrial dysfunction](/mechanisms/mitochondrial-dysfunction) — and maintained by the p53/p21^CIP1^ and p16^INK4a^/Rb tumor suppressor pathways[@he2017]. Unlike apoptotic cells (which are rapidly cleared), senescent cells persist indefinitely and resist programmed cell death by upregulating anti-apoptotic Bcl-2 family proteins (Bcl-2, Bcl-xL, Bcl-w)[@zhu2015]. This survival dependency creates a therapeutic vulnerability: drugs that inhibit Bcl-2 family proteins selectively kill senescent cells while sparing normal cells with redundant survival mechanisms.

SASP and Neuroinflammation

The SASP amplifies neurodegeneration through multiple mechanisms:

Pro-inflammatory cytokines (IL-1β, IL-6, TNF-α): Activate microglia and astrocytes, sustaining chronic [neuroinflammation](/mechanisms/neuroinflammation)
Chemokines (CCL2, CXCL8): Recruit peripheral immune cells across a compromised blood-brain barrier
Matrix metalloproteinases (MMP-3, MMP-9): Degrade extracellular matrix and disrupt synaptic structure
Reactive oxygen species: Drive oxidative damage to neurons and promote further senescence in neighboring cells (paracrine senescence)[@acosta2013]

In neurodegenerative tauopathies, the SASP creates a feed-forward loop: [tau](/proteins/tau) pathology induces glial senescence, senescent glia produce SASP, SASP promotes [tau](/proteins/tau) phosphorylation and aggregation, which induces further senescence[@bussian2018][@musi2018].

Brain Cell Types Affected

Astrocytes: SA-β-gal-positive senescent astrocytes accumulate around neurofibrillary tangles. Senescent astrocytes lose neuroprotective functions (glutamate clearance, BDNF secretion, metabolic support) while gaining neurotoxic SASP secretion[@bhat2012].

Microglia: Dystrophic, senescent microglia with p16^INK4a^ expression show impaired phagocytic capacity — they can no longer efficiently clear [tau](/proteins/tau) aggregates or cellular debris, further accelerating pathology[@streit2009].

Oligodendrocyte precursors (OPCs): Senescent OPCs fail to differentiate and remyelinate, contributing to the white matter degeneration prominent in [PSP](/diseases/progressive-supranuclear-palsy)[@zhang2019].

Endothelial cells: Blood-brain barrier endothelial senescence increases permeability, allowing peripheral immune infiltration and disrupting neurovascular coupling[@yamazaki2016].

Mermaid diagram (expand to render)

Senolytic Agents

Dasatinib + Quercetin (D+Q)

Dasatinib is a multi-kinase inhibitor (FDA-approved for chronic myeloid leukemia) that blocks Src family kinases and BCR-ABL, disabling anti-apoptotic signaling in senescent cells[@zhu2017]. Quercetin is a flavonoid that inhibits PI3K, Akt, Bcl-2, and Mcl-1, complementing dasatinib's mechanism[@siegelin2009]. The combination was identified through a systematic screen by Zhu and colleagues at the Mayo Clinic, who demonstrated that neither drug alone was sufficient for broad senolytic activity — the combination exploits the multi-pathway survival dependency of senescent cells[@zhu2017].

Key pharmacological features:

Intermittent dosing (2–3 consecutive days per month) — senescent cells require days to accumulate, and a brief pulse is sufficient for clearance
D+Q achieves target engagement within hours and senescent cell elimination within 24–48 hours
Normal tissue toxicity is minimized by the brief exposure window
Quercetin bioavailability is improved by liposomal or phytosomal formulations

Fisetin

Fisetin (3,7,3',4'-tetrahydroxyflavone) is a naturally occurring flavonoid found in strawberries, apples, and persimmons with potent senolytic activity discovered by Yousefzadeh and colleagues[@yousefzadeh2018]. Fisetin targets PI3K/Akt/mTOR and Bcl-2/Bcl-xL pathways and shows approximately 2-fold greater senolytic potency than quercetin in some assays. Advantages over D+Q include:

Available as a dietary supplement (no prescription needed)
Single-agent senolytic (no need for dasatinib)
Additional anti-inflammatory and antioxidant properties
Favorable safety profile in preclinical studies

Fisetin reduced senescent cell burden and extended median and maximum lifespan in naturally aged mice when administered intermittently (500 mg/kg for 5 consecutive days, monthly)[@yousefzadeh2018].

Navitoclax (ABT-263) and Other Agents

Navitoclax: A direct Bcl-2/Bcl-xL inhibitor with potent senolytic activity but dose-limiting thrombocytopenia that limits clinical use[@chang2016]. More selective agents targeting Bcl-xL alone (e.g., A1331852) are in development.

UBX0101: A p53/MDM2 interaction inhibitor tested in osteoarthritis but discontinued after Phase II failure. Lessons from this program inform neurodegenerative applications[@jeon2017].

Preclinical Evidence

The Bussian et al. 2018 Landmark Study

The most compelling preclinical evidence comes from Bussian and colleagues' 2018 Nature paper using the PS19 (tau P301S) mouse model[@bussian2018]:

Observation: Senescent astrocytes and microglia (p16^INK4a^+, SA-β-gal+) accumulated in brain regions with [tau](/proteins/tau) pathology before neurodegeneration

Genetic clearance: Crossing PS19 mice with INK-ATTAC transgenic mice (which allow selective elimination of p16^INK4a^-expressing cells with AP20187) prevented:

Neurofibrillary tangle formation
Cortical and hippocampal neurodegeneration
Gliosis and SASP expression
Cognitive decline (nest building, Morris water maze)

3. Pharmacological validation: D+Q treatment recapitulated genetic clearance effects, reducing [tau](/proteins/tau) pathology and preserving neuronal function

Timing: Both early (preventive) and late (therapeutic) intervention showed benefit, though early intervention was more effective

This study is directly relevant to CBS/[PSP](/diseases/progressive-supranuclear-palsy) because the PS19 model expresses human 4R-[tau](/proteins/tau) P301S — the same [tau](/proteins/tau) isoform and class of mutations driving CBS/[PSP](/diseases/progressive-supranuclear-palsy) pathology.

Additional Tauopathy Evidence

Musi and colleagues demonstrated that [tau](/proteins/tau) [protein aggregation](/mechanisms/protein-aggregation) directly induces cellular senescence in human brain tissue, with senescent cell markers co-localizing with [tau](/proteins/tau) pathology across the Braak staging spectrum[@musi2018]. In rTg4510 mice (expressing P301L [tau](/proteins/tau)), senescent cells appeared before overt neurodegeneration, and their density predicted subsequent neuronal loss — establishing senescence as an early, potentially reversible event in the [tau](/proteins/tau) pathology cascade.

Alzheimer's Disease Models

In APP/PS1 mice, D+Q treatment reduced amyloid plaque burden, decreased SASP markers, and improved hippocampal neurogenesis and cognitive function on novel object recognition and contextual fear conditioning[@ogrodnik2021]. The Alzheimer's Drug Discovery Foundation-funded SToMP-[AD](/diseases/alzheimers-disease) trial (Senolytic Therapy to Modulate Progression of Alzheimer's Disease) translated these findings to human patients[@gonzales2023].

Clinical Evidence

SToMP-[AD](/diseases/alzheimers-disease) Trial

The SToMP-[AD](/diseases/alzheimers-disease) trial (NCT04063124) was a pioneering open-label Phase I study of D+Q in early-stage Alzheimer's disease[@gonzales2023]:

Design: 5 participants with early [AD](/diseases/alzheimers-disease) received D+Q (dasatinib 100 mg + quercetin 1000 mg) for 2 consecutive days, followed by 2 weeks off, for 6 cycles over 12 weeks
Primary outcome: Safety and feasibility — CNS penetration confirmed by dasatinib detection in CSF
Key findings: D+Q was detectable in CSF, confirming blood-brain barrier penetration; well-tolerated with no serious adverse events; CSF SASP biomarkers showed trends toward reduction
Significance: First demonstration that oral D+Q achieves CNS target engagement in humans

ALSENLITE Trial

The ALSENLITE trial (NCT04785300) tested D+Q in [ALS](/diseases/amyotrophic-lateral-sclerosis), another neurodegenerative condition with evidence of cellular senescence[@geng2010]. The trial demonstrated safety and suggested potential slowing of functional decline, though the study was not powered for efficacy.

Fisetin Clinical Trials

AFFIRM-LITE (NCT03675724): Phase II trial of fisetin (100 mg/kg, 2 consecutive days, monthly) in frail elderly adults showed reduction in SASP markers (IL-6, MMP-3) at 3 months with favorable safety[@justice2019].

Fisetin is also being studied in COVID-related senescence (NCT04476953) and osteoarthritis, generating safety data applicable to neurodegenerative indications.

CBS/[PSP](/diseases/progressive-supranuclear-palsy)-Specific Rationale

4R-Tau and Glial Senescence

CBS and [PSP](/diseases/progressive-supranuclear-palsy) represent particularly compelling indications for senolytic therapy because:

Tufted astrocytes (PSP) and astrocytic plaques (CBD): These pathological hallmarks involve [tau](/proteins/tau) accumulation in astrocytes — the very cell type most prone to senescence. Senescent, [tau](/proteins/tau)-laden astrocytes produce SASP that drives pathology spread[@kovacs2016]

Microglial dystrophy: Post-mortem [PSP](/diseases/progressive-supranuclear-palsy) brains show extensive microglial senescence in the subthalamic nucleus, midbrain, and frontal cortex — regions of maximal [tau](/proteins/tau) burden[@streit2009]

White matter degeneration: [PSP](/diseases/progressive-supranuclear-palsy) involves prominent white matter pathology, consistent with OPC senescence and failed remyelination[@dickson2010]

Age dependence: Mean onset at 63 years (PSP) and 65 years (CBS) coincides with exponential accumulation of senescent cells

MAPT H1 haplotype: The H1/H1 genotype (PSP risk factor) increases 4R-[tau](/proteins/tau) expression, potentially accelerating the [tau](/proteins/tau) → senescence → SASP → [tau](/proteins/tau) feed-forward loop[@hglinger2011]

Expected Therapeutic Benefits

Based on the Bussian et al. data and CBS/[PSP](/diseases/progressive-supranuclear-palsy) pathobiology:

Neuroinflammation reduction: SASP elimination should reduce chronic microglial activation in affected regions
Tau pathology slowing: Breaking the senescence feed-forward loop may slow [tau](/proteins/tau) phosphorylation and spreading
Motor function: Brainstem and basal ganglia degeneration may be partially prevented by reducing local senescent cell burden
Cognitive preservation: Frontal cortical function, impaired early in both conditions, may benefit from SASP reduction
White matter integrity: OPC rejuvenation could slow white matter loss in [PSP](/diseases/progressive-supranuclear-palsy)

Dosing Protocols

Dasatinib + Quercetin

Fisetin Monotherapy

CBS/[PSP](/diseases/progressive-supranuclear-palsy)-Specific Adaptations

Dysphagia consideration: Quercetin powder can be mixed into thickened liquids or applesauce; dasatinib tablet can be dispersed in water
Fall risk monitoring: Brief fatigue after dosing may increase fall risk — schedule dosing on days with caregiver supervision
Thrombocytopenia screening: CBS/[PSP](/diseases/progressive-supranuclear-palsy) patients may already have mild cytopenias from nutritional deficiency or polypharmacy; check CBC before starting

Safety, Contraindications, and Monitoring

Safety Profile

D+Q at intermittent senolytic doses has shown favorable safety across multiple trials[@justice2019a]:

Common: Mild fatigue (24–48 hours), transient GI upset, mild headache
Uncommon: Reversible thrombocytopenia (dasatinib-related), peripheral edema
Rare: QT prolongation (dasatinib at higher oncology doses)
Not observed at senolytic doses: Significant immunosuppression, infection risk, wound healing impairment

Fisetin safety: No dose-limiting toxicity at up to 20 mg/kg in clinical trials. GI upset is the most common side effect[@justice2019].

Contraindications

Active malignancy (except if receiving dasatinib for oncology indication)
Severe thrombocytopenia (platelets <50,000)
Pregnancy or breastfeeding
Concurrent strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin) — increase dasatinib exposure
Severe hepatic impairment (Child-Pugh C)

Drug Interactions

Dasatinib: CYP3A4 substrate; avoid concurrent grapefruit juice, azole antifungals, macrolide antibiotics. Proton pump inhibitors reduce dasatinib absorption
Quercetin: Mild CYP3A4 and CYP2C9 modulator; may increase statin levels. Iron chelation — separate from iron supplements by 2 hours
Both: Compatible with common CBS/[PSP](/diseases/progressive-supranuclear-palsy) medications (levodopa, amantadine, SSRIs, memantine)

Monitoring Protocol

Before starting: CBC with differential, comprehensive metabolic panel, ECG (baseline QTc), coagulation studies

During treatment: CBC on day 7 of first cycle; repeat if thrombocytopenia; symptom diary for fatigue, bruising, bleeding

Every 3 cycles: CBC, liver function, renal function; clinical assessment (PSP Rating Scale or CBS functional measures)

Combination Therapy Potential

Senolytics address the senescence pathway specifically and combine rationally with interventions targeting other aspects of tauopathy:

Evidence Rubric Score

Research Gaps and Future Directions

No CBS/[PSP](/diseases/progressive-supranuclear-palsy) trials: Despite strong mechanistic rationale, no senolytic trials target [PSP](/diseases/progressive-supranuclear-palsy) or CBS specifically

Optimal regimen unknown: Intermittent dosing is established but optimal frequency (monthly vs. biweekly), duration, and combination are undefined

CNS senescent cell quantification: No validated imaging biomarker for brain senescent cell burden; p16^INK4a^ PET tracers are in development[@gasek2021]

Fisetin vs. D+Q: Head-to-head comparison needed to determine if fisetin monotherapy matches D+Q efficacy in the CNS

Prevention vs. treatment: Whether senolytics work better as prevention (pre-symptomatic, at-risk individuals) or treatment (established disease) is unknown

Long-term safety: Repeated intermittent senolytic exposure over years — effects on tissue homeostasis, stem cell niches, and wound healing require monitoring[@kirkland2015]

Priority trial design: A Phase Ib/II study of D+Q in [PSP](/diseases/progressive-supranuclear-palsy)-Richardson syndrome with [tau](/proteins/tau) PET (^18^F-MK-6240), CSF p-[tau](/proteins/tau)-217, and NfL as biomarker endpoints, combined with PSPRS clinical outcomes.

Implementation Considerations for CBS/[PSP](/diseases/progressive-supranuclear-palsy)

Patient Selection

Ideal CBS/[PSP](/diseases/progressive-supranuclear-palsy) candidates for senolytic therapy:

Early-to-mid stage disease (PSP Rating Scale <50): Maximum potential to preserve remaining function
Confirmed 4R-tauopathy: Ideally with [tau](/proteins/tau) PET confirmation or suggestive biomarker profile
Adequate hematological reserve: Platelets >100,000, ANC >1500
Caregiver support: For monitoring during dosing days and managing potential transient fatigue
No contraindicated medications: Review CYP3A4 interactions before starting dasatinib

Practical Workflow

Baseline assessment: CBC, CMP, ECG, cognitive testing (MoCA, FAB), PSPRS or [CBD](/diseases/corticobasal-degeneration) functional assessment

Cycle 1 (supervised): Administer D+Q in clinic; observe for 4 hours; CBC at day 7

Cycles 2–6 (home-based): Caregiver-administered with symptom diary; phone follow-up at day 3

12-week assessment: Repeat cognitive and motor testing; biomarkers if available; decision to continue

Maintenance: If tolerated and stable, continue monthly cycles; reassess every 3 months

Integration with Rehabilitation

Senolytic dosing days (2 days/month) may cause transient fatigue. Schedule physical therapy, cognitive stimulation, and rehabilitation activities on non-dosing weeks to avoid interference with exercise participation.

External Links

[ClinicalTrials.gov: Senolytics](https://clinicaltrials.gov/search?cond=neurodegenerative&intr=senolytic)
[NIH Senolytic Research](https://www.ncbi.nlm.nih.gov/pmc/?term=senolytic+neurodegeneration)
[Mayo Clinic Senolytic Research](https://www.mayoclinic.org//tests-procedures/senolytic-therapy/about/pac-20493931)

Core Diseases and Phenotypes

[Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
[Corticobasal Syndrome](/diseases/corticobasal-syndrome)
[Corticobasal Degeneration](/diseases/corticobasal-degeneration)
[Primary Age-Related Tauopathy](/diseases/primary-age-related-tauopathy)
[Aging-Related Tauopathy](/diseases/aging-related-tauopathy)

Mechanisms and Pathobiology

[Tauopathy](/mechanisms/tau-pathology)
[4R Tauopathy Molecular Mechanisms](/mechanisms/4r-tauopathy-molecular-mechanisms)
[Progressive Supranuclear Palsy Pathway](/mechanisms/psp-pathway)
[Corticobasal Degeneration Pathway](/mechanisms/cbd-pathway)
[CBS/PSP Genetic Architecture](/diseases/corticobasal-syndrome)
[Cortisol-Tau Pathway](/mechanisms/cortisol-tau-pathway)
[Gut-Brain Axis in Tauopathy](/mechanisms/gut-brain-axis-tauopathy)

Biomarkers, Cell Types, and Interventions

[Biomarkers for Progressive Supranuclear Palsy](/biomarkers/psp-biomarkers)
[Biomarkers for Corticobasal Degeneration](/biomarkers/cbd-biomarkers)
[Tau PET in CBS/PSP](/imaging/tau-pet)
[MRI Atrophy Patterns in CBS/PSP](/imaging/mri-atrophy-patterns-psp)
[DTI White Matter Changes in CBS/PSP](/imaging/dti-white-matter-changes)
[Substantia Nigra Neurons in PSP](/cell-types/substantia-nigra-neurons)
[Pedunculopontine Nucleus Cholinergic in PSP](/cell-types/pedunculopontine-nucleus-cholinergic)
[Striatal Interneurons in CBD](/cell-types/striatal-interneurons)
[Nigral Microglia in PSP](/cell-types/nigral-microglia)
[Locus Coeruleus Noradrenergic in PSP](/cell-types/locus-coeruleus-noradrenergic)
[CBS/PSP Treatment Rankings](/therapeutics/cbs-psp-treatment-rankings)
[CBS/PSP Daily Action Plan](/therapeutics/cbs-psp-daily-action-plan)
[CBS/PSP Rehabilitation Master Guide](/therapeutics/cbs-psp-rehabilitation-master-guide)
[CBS/PSP Clinical Trials Guide](/clinical-trials/cbs-psp-clinical-trials-guide)
[Exercise and Physical Activity for CBS/PSP](/therapeutics/exercise-physical-activity-cbs-psp)
[Corticobasal Degeneration Treatment](/therapeutics/corticobasal-cbs-treatment)
[Senolytic Therapies for CBS and PSP](/therapeutics/senolytic-therapeutics)

Allen Brain Atlas Resources

[Allen Brain Atlas - Gene Expression](https://human.brain-map.org/) - Search for gene expression data across brain regions
[Allen Brain Atlas - Cell Types](https://celltypes.brain-map.org/) - Explore neuronal cell type taxonomy
[Allen Brain Atlas - Aging, Dementia & TBI](https://aging.brain-map.org/) - Data on aging and traumatic brain injury

References

[Kirkland JL, Tchkonia T, Senolytic drugs: from discovery to translation (2020)](https://pubmed.ncbi.nlm.nih.gov/32686219/)

[Coppé JP, Desprez PY, Krtolica A, Campisi J, The senescence-associated secretory phenotype: the dark side of tumor suppression (2010)](https://pubmed.ncbi.nlm.nih.gov/20078217/)

[Baker DJ, Petersen RC, Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives (2018)](https://pubmed.ncbi.nlm.nih.gov/29457783/)

PMID: 30271983(https://pubmed.ncbi.nlm.nih.gov/30271983/)

[He S, Sharpless NE, Senescence in health and disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28575665/)

[Zhu Y, Tchkonia T, Pirtskhalava T, et al, The Achilles' heel of senescent cells: from transcriptome to senolytic drugs (2015)](https://pubmed.ncbi.nlm.nih.gov/25754370/)

[Acosta JC, Banito A, Wuestefeld T, et al, A complex secretory program orchestrated by the inflammasome controls paracrine senescence (2013)](https://pubmed.ncbi.nlm.nih.gov/23945590/)

PMID: 29795462(https://pubmed.ncbi.nlm.nih.gov/29795462/)

[Bhat R, Crowe EP, Bitto A, et al, Astrocyte senescence as a component of Alzheimer's disease (2012)](https://pubmed.ncbi.nlm.nih.gov/22895512/)

PMID: 19408404(https://pubmed.ncbi.nlm.nih.gov/19408404/) PMID: 30936558(https://pubmed.ncbi.nlm.nih.gov/30936558/)

[Yamazaki Y, Baker DJ, Bhatt N, Bhattacharyya A, Vascular cell senescence contributes to blood-brain barrier breakdown (2016)](https://pubmed.ncbi.nlm.nih.gov/27525523/)

[Zhu Y, Tchkonia T, Pirtskhalava T, et al, Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors (2017)](https://pubmed.ncbi.nlm.nih.gov/28635070/)

[Siegelin MD, Reuss DE, Habel A, et al, Quercetin promotes degradation of survivin and thereby enhances death-receptor-mediated apoptosis in glioma cells (2009)](https://pubmed.ncbi.nlm.nih.gov/19629444/)

[Yousefzadeh MJ, Zhu Y, McGowan SJ, et al, Fisetin is a senotherapeutic that extends health and lifespan (2018)](https://pubmed.ncbi.nlm.nih.gov/30279143/)

[Chang J, Wang Y, Shao L, et al, Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice (2016)](https://pubmed.ncbi.nlm.nih.gov/26657143/)

[Jeon OH, Kim C, Laberge RM, et al, Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment (2017)](https://pubmed.ncbi.nlm.nih.gov/28099988/)

[Ogrodnik M, Evans SA, Fielder E, et al, Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice (2021)](https://pubmed.ncbi.nlm.nih.gov/30307012/)

PMID: 36802521(https://pubmed.ncbi.nlm.nih.gov/36802521/)

[Geng YQ, Guan JT, Xu MY, et al, Senescence-associated beta-galactosidase activity expression in aging hippocampal neurons (2010)](https://pubmed.ncbi.nlm.nih.gov/20837066/)

[Justice JN, Nambiar AM, Tchkonia T, et al, Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study (2019)](https://pubmed.ncbi.nlm.nih.gov/30616998/)

PMID: 27299362(https://pubmed.ncbi.nlm.nih.gov/27299362/)

[Dickson DW, Ahmed Z, Algom AA, et al, Neuropathology of variants of progressive supranuclear palsy (2010)](https://pubmed.ncbi.nlm.nih.gov/20838447/)

[Höglinger GU, Melhem NM, Dickson DW, et al, Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy (2011)](https://pubmed.ncbi.nlm.nih.gov/21685912/)

[Justice JN, Nambiar AM, Tchkonia T, et al, Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study (2019)](https://pubmed.ncbi.nlm.nih.gov/30616998/)

[Gasek NS, Kuchel GA, Kirkland JL, Xu M, Strategies for targeting senescent cells in human disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33811810/)

[Kirkland JL, Tchkonia T, Clinical strategies and animal models for developing senolytic agents (2015)](https://pubmed.ncbi.nlm.nih.gov/32747821/)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[Purinergic Signaling Polarization Control](/hypothesis/h-0758b337) — 0.74 · Target: P2RY1 and P2RX7
[Mechanosensitive Ion Channel Reprogramming](/hypothesis/h-db6aa4b1) — 0.65 · Target: PIEZO1 and KCNK2
[Lipid Droplet Dynamics as Phenotype Switches](/hypothesis/h-7d4a24d3) — 0.57 · Target: DGAT1 and SOAT1
[Hippocampal CA3-CA1 circuit rescue via neurogenesis and synaptic preservation](/hypothesis/h-856feb98) — 0.73 · Target: BDNF
[Vagal Afferent Microbial Signal Modulation](/hypothesis/h-ee1df336) — 0.71 · Target: GLP1R, BDNF
[Vocal Cord Neuroplasticity Stimulation](/hypothesis/h-e0183502) — 0.48 · Target: CHR2/BDNF
[Nutrient-Sensing Epigenetic Circuit Reactivation](/hypothesis/h-4bb7fd8c) — 0.79 · Target: SIRT1
[CYP46A1 Overexpression Gene Therapy](/hypothesis/h-2600483e) — 0.79 · Target: CYP46A1

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therapeutics-senolytics-neurodegeneration

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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

493

Outgoing

526

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

Senolytic Therapies for CBS and [PSP](/diseases/progressive-supranuclear-palsy)

Senolytic Therapies for CBS and [PSP](/diseases/progressive-supranuclear-palsy)

Introduction

Senolytic Therapies for CBS and [PSP](/diseases/progressive-supranuclear-palsy)

Introduction

Cellular Senescence in the Aging Brain

Senescent Cell Biology

SASP and Neuroinflammation

Brain Cell Types Affected

Senolytic Agents

Dasatinib + Quercetin (D+Q)

Fisetin

Navitoclax (ABT-263) and Other Agents

Preclinical Evidence

The Bussian et al. 2018 Landmark Study

Additional Tauopathy Evidence

Alzheimer's Disease Models

Clinical Evidence

SToMP-[AD](/diseases/alzheimers-disease) Trial

ALSENLITE Trial

Fisetin Clinical Trials

CBS/[PSP](/diseases/progressive-supranuclear-palsy)-Specific Rationale

4R-Tau and Glial Senescence

Expected Therapeutic Benefits

Dosing Protocols

Dasatinib + Quercetin

Fisetin Monotherapy

CBS/[PSP](/diseases/progressive-supranuclear-palsy)-Specific Adaptations

Safety, Contraindications, and Monitoring

Safety Profile

Contraindications

Drug Interactions

Monitoring Protocol

Combination Therapy Potential

Evidence Rubric Score

Research Gaps and Future Directions

Implementation Considerations for CBS/[PSP](/diseases/progressive-supranuclear-palsy)

Patient Selection

Practical Workflow

Integration with Rehabilitation

See Also

External Links

Related NeuroWiki Pages

Core Diseases and Phenotypes

Mechanisms and Pathobiology

Biomarkers, Cell Types, and Interventions

Allen Brain Atlas Resources

References

Related Hypotheses

cites (2)

💬 Discussion