Regulatory Network Inference of Induced Senescent Midbrain Cell Types Reveals Cell Type-Specific Senescence-Associated Transcriptional Regulators

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 6, 2025

Abstract Cellular senescence of brain cell types has become an increasingly important perspective for both aging and neurodegeneration, specifically in the context Parkinson’s Disease (PD). The characterization classical hallmarks is a widely debated topic, whereby which phenotype being investigated, such as type, inducing stressor, and/or model system, extremely aspect to consider when defining senescent cell. Here, we describe type-specific profile through investigation various canonical markers five human midbrain lines using chronic 5-Bromodeoxyuridine (BrdU) treatment DNA damage-induced senescence. We used principal component analysis (PCA) subsequent regulatory network inference define unique common profiles well revealed senescence-associated transcriptional regulators (SATRs). Functional one identified regulators, transcription factor AP4 (TFAP4), further highlights type-specificity expression hallmarks. Our data indicates that SATRs modulate induced key play role PD.

Язык: Английский

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NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathway

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Апрель 10, 2025

Background Age-related decline in nicotinamide adenine dinucleotide (NAD+)—a central regulator of cellular metabolism, DNA repair, and immune homeostasis—is strongly associated with physiological dysfunction. Nicotinamide mononucleotide (NMN), a potent NAD+ precursor, shows promise counteracting aging-related pathologies, particularly neurodegenerative decline. Methods An aging model was established mice through 8-week D-galactose (D-gal) exposure, followed by NMN oral supplementation. Behavioral outcomes (open field test, Morris water maze) were analyzed alongside oxidative stress markers (SOD, CAT, AGEs), inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10), neurotransmitters (LC-MS/MS). Apoptotic activity (TUNEL, p16/p21), mitochondrial regulators (Sirt1, p-AMPK, PGC-1α), intestinal barrier integrity (HE/AB-PAS staining) evaluated. Sirt1 dependency confirmed using inhibitor Ex527. Results restored locomotor spatial memory D-gal without altering body weight. Mechanistically, synergistically attenuated systemic inflammation, elevating antioxidant enzymes CAT) IL-10 while suppressing pro-inflammatory IL-6) AGEs. Cortical/hippocampal analyses revealed reduced apoptosis (TUNEL + cells) senescence (p16, p21), enhanced function via Sirt1/AMPK/PGC-1α activation p-AMPK). concurrently preserved mucosal architecture, mitigating D-gal-induced disruption. Crucially, all benefits abolished inhibition, confirming pathway specificity. Conclusion Our findings establish as multifaceted therapeutic agent that preserves neurocognitive homeostasis models orchestrating antioxidative, anti-inflammatory, antiapoptotic responses activation. This work provides translational insights into NAD+-boosting strategies for age-related disorders.

Язык: Английский

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Defining and characterizing neuronal senescence, ‘neurescence’, as GX arrested cells

Trends in Neurosciences, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

Язык: Английский

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Senescent brain cell types in Alzheimer's disease: Pathological mechanisms and therapeutic opportunities

Neurotherapeutics, Год журнала: 2025, Номер 22(3), С. e00519 - e00519

Опубликована: Янв. 6, 2025

Cellular senescence is a cell state triggered by programmed physiological processes or cellular stress responses. Stress-induced senescent cells often acquire pathogenic traits, including toxic secretome and resistance to apoptosis. When form faster than they are cleared the immune system, accumulate in tissues throughout body contribute age-related diseases, neurodegeneration. This review highlights evidence of brain their role Alzheimer's disease (AD), leading cause dementia older adults. We also discuss progress challenges senotherapies, pharmacological strategies clear mitigate effects, which hold promise as interventions for AD related dementias (ADRD).

Язык: Английский

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Protocol for a pilot clinical trial of the senolytic drug combination Dasatinib Plus Quercetin to mitigate age-related health and cognitive decline in mental disorders

F1000Research, Год журнала: 2025, Номер 13, С. 1072 - 1072

Опубликована: Март 5, 2025

Background Major depressive disorder (MDD) and schizophrenia are linked to accelerated aging leading reduced lifespan, health span cognitive decline. Cellular senescence, in which cells lose proliferative capacity develop a senescence-associated secretory phenotype (SASP), plays role this process. Emerging research suggests that the senolytic regimen of dasatinib+quercetin (D+Q) reduces senescent cells, potentially mitigating age-related This pilot study aims assess feasibility safety D+Q older adults with schizophrenia, schizoaffective disorder, treatment-resistant depression (TRD). Methods single-center will recruit 30 participants total aged 50 years or schizophrenia/schizoaffective 60 TRD; difference age limits is because individuals biologically about 10 than general population owing metabolic burden. Each participant receive two consecutive days 100 mg oral dasatinib plus 1250 quercetin at baseline weeks one through three, (i.e., on, five off ) along lifestyle risk management education. Questionnaires assessments measure function as well psychiatric baseline, week 10, year. Magnetic Resonance Imaging (MRI) structural functional brain weeks. Blood sampling for SASP testing occur seven time points: four, Conclusion evaluate D+Q’s potential counteract TRD. Trial registration Dasatinib Plus Quercetin Accelerated Aging Mental Disorders registered on ClinicalTrials.gov: NCT05838560; posted May 1, 2023.

Язык: Английский

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Design and development of Dasatinib nanoemulsions for ocular delivery: In vitro characterization, biocompatibility, and Ex vivo ocular irritation study

International Journal of Pharmaceutics, Год журнала: 2025, Номер unknown, С. 125504 - 125504

Опубликована: Март 1, 2025

Язык: Английский

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Senescent cell reduction does not improve recovery in mice under experimental autoimmune encephalomyelitis (EAE) induced demyelination

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Апрель 7, 2025

Язык: Английский

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The Mechanistic Link Between Tau-Driven Proteotoxic Stress and Cellular Senescence in Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(22), С. 12335 - 12335

Опубликована: Ноя. 17, 2024

In Alzheimer's disease (AD), tau dissociates from microtubules (MTs) due to hyperphosphorylation and misfolding. It is degraded by various mechanisms, including the 20S proteasome, chaperone-mediated autophagy (CMA), 26S macroautophagy, aggrephagy. Neurofibrillary tangles (NFTs) form upon impairment of aggrephagy, eventually, ubiquitin chaperone valosin-containing protein (VCP) heat shock 70 kDa (HSP70) are recruited sites NFTs for extraction ubiquitin-proteasome system (UPS)-mediated degradation. However, degradation in neurons allows be secreted into extracellular space. Secreted can monomers, oligomers, paired helical filaments (PHFs), which seeding competent pathological that endocytosed/phagocytosed healthy neurons, microglia, astrocytes, oligodendrocyte progenitor cells (OPCs), oligodendrocytes, often causing proteotoxic stress eventually triggers senescence. Senescent secrete senescence-associated secretory phenotype (SASP) factors, trigger cellular atrophy, decreased brain volume human AD. molecular mechanisms senescence not entirely understood an emerging area research. Therefore, this comprehensive review summarizes pertinent studies provided evidence sequential degradation, failure, mechanistic link between tau-driven

Язык: Английский

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Genetic risk factors for late-onset Alzheimer’s disease drive senescence in female tauopathy mice

Neuron, Год журнала: 2024, Номер 112(23), С. 3811 - 3813

Опубликована: Дек. 1, 2024

Язык: Английский

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From Bench to Bedside: Translating Cellular Rejuvenation Therapies into Clinical Applications

Cells, Год журнала: 2024, Номер 13(24), С. 2052 - 2052

Опубликована: Дек. 12, 2024

Cellular rejuvenation therapies represent a transformative frontier in addressing age-related decline and extending human health span. By targeting fundamental hallmarks of aging—such as genomic instability, epigenetic alterations, mitochondrial dysfunction, cellular senescence—these aim to restore youthful functionality cells tissues, offering new hope for treating degenerative diseases. Recent advancements have showcased range strategies, including reprogramming, senolytic interventions, restoration, stem cell-based approaches, gene-editing technologies like CRISPR. Each modality has demonstrated substantial potential preclinical models is now being cautiously explored early-stage clinical trials. However, translating these from the laboratory practice presents unique challenges: safety concerns, delivery precision, complex regulatory requirements, ethical considerations, high costs impede widespread adoption. This review examines current landscape rejuvenation, highlighting key advancements, risks, strategies needed overcome hurdles.

Язык: Английский

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