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 effectiveThis 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 monthsIntegration 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.
See Also
- [Corticobasal Syndrome](/diseases/corticobasal-syndrome)
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
- [Senolytic Agents](/treatments/senolytic-agents)
- [Apoptosis in Neurodegeneration](/mechanisms/apoptosis-neurodegeneration)
- [Cellular Senescence](/mechanisms/cellular-senescence)
- [Neuroinflammation](/mechanisms/neuroinflammation-pathway)
- [Aging and Neurodegeneration](/mechanisms/aging-neurodegeneration)
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)
Related NeuroWiki Pages
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
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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/)
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[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/)
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[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) — <span style="color:#81c784;font-weight:600">0.74</span> · Target: P2RY1 and P2RX7
- [Mechanosensitive Ion Channel Reprogramming](/hypothesis/h-db6aa4b1) — <span style="color:#81c784;font-weight:600">0.65</span> · Target: PIEZO1 and KCNK2
- [Lipid Droplet Dynamics as Phenotype Switches](/hypothesis/h-7d4a24d3) — <span style="color:#ffd54f;font-weight:600">0.57</span> · Target: DGAT1 and SOAT1
- [Hippocampal CA3-CA1 circuit rescue via neurogenesis and synaptic preservation](/hypothesis/h-856feb98) — <span style="color:#81c784;font-weight:600">0.73</span> · Target: BDNF
- [Vagal Afferent Microbial Signal Modulation](/hypothesis/h-ee1df336) — <span style="color:#81c784;font-weight:600">0.71</span> · Target: GLP1R, BDNF
- [Vocal Cord Neuroplasticity Stimulation](/hypothesis/h-e0183502) — <span style="color:#ffd54f;font-weight:600">0.48</span> · Target: CHR2/BDNF
- [Nutrient-Sensing Epigenetic Circuit Reactivation](/hypothesis/h-4bb7fd8c) — <span style="color:#81c784;font-weight:600">0.79</span> · Target: SIRT1
- [CYP46A1 Overexpression Gene Therapy](/hypothesis/h-2600483e) — <span style="color:#81c784;font-weight:600">0.79</span> · Target: CYP46A1
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