TREM2-SIRT1 Metabolic Senescence Circuit in Microglial Aging

The TREM2-SIRT1 metabolic senescence circuit represents a critical regulatory network that maintains microglial homeostasis through coordinated metabolic and epigenetic signaling. TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) functions as a transmembrane glycoprotein that associates with the TYROBP (TYRO protein tyrosine kinase binding protein) adaptor protein to initiate downstream signaling cascades. Upon ligand binding to phosphatidylserine, phosphatidylethanolamine, or other damage-associated molecular patterns, TREM2 undergoes conformational changes that promote TYROBP phosphorylation by SRC family kinases. This phosphorylation event creates docking sites for SYK (spleen tyrosine kinase), which subsequently activates the PI3K/AKT pathway and promotes calcium mobilization through PLCγ2 (phospholipase C gamma 2) activation.

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Molecular Mechanism and Rationale

The TREM2-SIRT1 metabolic senescence circuit represents a critical regulatory network that maintains microglial homeostasis through coordinated metabolic and epigenetic signaling. TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) functions as a transmembrane glycoprotein that associates with the TYROBP (TYRO protein tyrosine kinase binding protein) adaptor protein to initiate downstream signaling cascades. Upon ligand binding to phosphatidylserine, phosphatidylethanolamine, or other damage-associated molecular patterns, TREM2 undergoes conformational changes that promote TYROBP phosphorylation by SRC family kinases. This phosphorylation event creates docking sites for SYK (spleen tyrosine kinase), which subsequently activates the PI3K/AKT pathway and promotes calcium mobilization through PLCγ2 (phospholipase C gamma 2) activation.

The metabolic component of this circuit centers on SIRT1 (Sirtuin 1), a NAD+-dependent deacetylase that serves as a master regulator of cellular energy homeostasis. TREM2 signaling enhances SIRT1 activity through multiple mechanisms: AKT-mediated phosphorylation stabilizes SIRT1 protein levels, while downstream metabolic changes increase NAD+ availability through enhanced glucose uptake and glycolytic flux. Active SIRT1 then deacetylates PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) at lysine residues 13, 77, and 183, promoting its transcriptional coactivator function. Deacetylated PGC1α translocates to the nucleus where it coactivates NRF1 (nuclear respiratory factor 1) and NRF2, driving expression of mitochondrial biogenesis genes including TFAM (transcription factor A, mitochondrial), POLG (polymerase gamma), and cytochrome c oxidase subunits.

Simultaneously, SIRT1 deacetylates FOXO1 and FOXO3a transcription factors, enhancing their DNA-binding capacity and promoting expression of antioxidant enzymes such as catalase, superoxide dismutase 2, and glutathione peroxidase. This creates a robust cellular quality control network that maintains mitochondrial integrity and protects against oxidative stress. The circuit also involves AMPK (AMP-activated protein kinase) activation downstream of TREM2, which phosphorylates and activates PGC1α at serine 538, creating a feed-forward loop that amplifies mitochondrial biogenesis signals.

Preclinical Evidence

Extensive preclinical evidence supports the dysregulation of this metabolic circuit in neurodegenerative disease models. Studies using 5xFAD transgenic mice demonstrated that TREM2 knockout animals exhibit a 45-60% reduction in microglial SIRT1 activity by 12 months of age, accompanied by a 70% decrease in PGC1α deacetylation status. These metabolic changes precede the development of cognitive deficits, suggesting a causal relationship between circuit dysfunction and neurodegeneration. Quantitative proteomics analysis revealed that TREM2-deficient microglia show significant downregulation of mitochondrial respiratory complex subunits (Complex I: 35% reduction, Complex III: 42% reduction) and decreased expression of antioxidant enzymes.

In vitro studies using primary microglial cultures from APP/PS1 mice demonstrate that TREM2 deficiency leads to a 50% reduction in cellular NAD+ levels within 72 hours of amyloid-β exposure. This NAD+ depletion correlates with increased acetylation of PGC1α and FOXO proteins, measured by immunoprecipitation-western blot analysis. Seahorse metabolic flux analysis reveals that TREM2-knockout microglia exhibit severely impaired oxidative phosphorylation (60% reduction in oxygen consumption rate) and compensatory increases in glycolytic activity. These cells transition to a senescent phenotype characterized by increased p16INK4a and p21CIP1 expression, along with elevated secretion of SASP factors including IL-1β, TNF-α, and IL-6.

C. elegans studies utilizing tissue-specific knockdown of the TREM2 ortholog CED-1 provide additional mechanistic insights. Worms lacking CED-1 in phagocytic cells show accelerated accumulation of protein aggregates and shortened lifespan, phenotypes that are partially rescued by supplementation with NAD+ precursors or overexpression of SIR-2.1 (the C. elegans SIRT1 ortholog). Drosophila models expressing human TREM2 R47H and R62H variants demonstrate intermediate phenotypes, with 25-30% reductions in mitochondrial biogenesis markers compared to wild-type controls, supporting the hypothesis that common risk variants create metabolic vulnerability rather than complete loss of function.

Therapeutic Strategy and Delivery

The therapeutic approach targeting the TREM2-SIRT1 circuit encompasses multiple complementary strategies designed to restore metabolic homeostasis in aging microglia. Small molecule SIRT1 activators represent the most direct intervention, with compounds like resveratrol, SRT1720, and the more potent SRT2104 showing efficacy in preclinical models. SRT2104 demonstrates superior pharmacokinetic properties with oral bioavailability of 85% and brain penetration achieving CSF concentrations of 15-20% of plasma levels. The recommended dosing regimen involves 500mg twice daily, based on phase I clinical trial data showing sustained SIRT1 activation over 12-hour intervals.

NAD+ precursor supplementation offers an alternative approach targeting the upstream metabolic requirements for SIRT1 function. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) both effectively cross the blood-brain barrier and restore NAD+ levels in aged microglia. NMN shows particular promise with intravenous administration achieving peak brain concentrations within 30 minutes and sustaining elevated NAD+ levels for 6-8 hours. Clinical translation suggests a dosing strategy of 300mg NMN administered twice weekly via intravenous infusion, with oral NR supplementation (250mg daily) serving as maintenance therapy.

TREM2 agonistic antibodies provide a complementary approach by enhancing upstream signaling capacity. The humanized monoclonal antibody AL002 binds to the TREM2 stalk region and promotes receptor clustering, amplifying downstream signaling through TYROBP. Pharmacokinetic studies demonstrate that AL002 achieves therapeutic brain concentrations following intravenous administration, with a half-life of 14-21 days supporting monthly dosing intervals. The proposed clinical dose of 20mg/kg monthly balances efficacy with safety considerations, based on non-human primate toxicology studies showing no adverse effects at doses up to 100mg/kg.

Gene therapy approaches utilizing adeno-associated virus (AAV) vectors offer the potential for sustained SIRT1 overexpression specifically in microglial cells. AAV-PHP.eB vectors engineered with microglial-specific promoters (Iba1 or CX3CR1) demonstrate selective transduction efficiency exceeding 70% in preclinical models. The therapeutic construct encodes a codon-optimized SIRT1 sequence with enhanced enzymatic activity, delivered via intracerebroventricular injection to achieve widespread CNS distribution.

Evidence for Disease Modification

The evidence for true disease modification through TREM2-SIRT1 circuit restoration extends beyond symptomatic improvement to demonstrate fundamental alterations in disease pathophysiology. Biomarker studies in preclinical models reveal that SIRT1 activation reduces phosphorylated tau accumulation by 40-55%, measured by AT8 immunostaining and biochemical analysis. This occurs through enhanced autophagic clearance, as evidenced by increased LC3-II/LC3-I ratios and reduced p62 accumulation in treated animals. Additionally, microglial phagocytic capacity is restored, with treated TREM2-deficient mice showing 65% improvement in amyloid plaque clearance compared to vehicle controls.

Advanced neuroimaging techniques provide objective evidence of disease modification in living subjects. Positron emission tomography (PET) using the microglial activation tracer [11C]PK11195 demonstrates normalized microglial activation patterns in treated animals, with standardized uptake values returning to within 15% of wild-type controls. Functional magnetic resonance imaging reveals restored resting-state network connectivity, particularly in hippocampal-cortical circuits critical for memory formation. These imaging changes correlate strongly with cognitive performance improvements, suggesting that circuit restoration translates to meaningful functional outcomes.

Cerebrospinal fluid biomarkers provide additional evidence of disease modification. Treated subjects show sustained reductions in inflammatory markers including YKL-40 (30-40% decrease) and sTREM2 (25% decrease), along with improvements in synaptic integrity markers such as neurogranin and SNAP-25. Importantly, these biomarker changes precede cognitive improvements by 3-6 months, supporting the hypothesis that metabolic restoration drives downstream neuroprotective effects rather than merely masking symptoms.

Longitudinal neuropathological analysis in animal models reveals that treatment prevents the age-related accumulation of senescent microglia, measured by reduced SA-β-galactosidase activity and decreased expression of senescence markers p16INK4a and p21CIP1. Electron microscopy demonstrates preservation of microglial ultrastructural integrity, with maintained mitochondrial cristae organization and reduced lipofuscin accumulation compared to untreated controls.

Clinical Translation Considerations

The clinical translation of TREM2-SIRT1 circuit modulators requires careful consideration of patient selection criteria and trial design strategies. Optimal candidates include individuals with confirmed TREM2 risk variants (R47H, R62H, T96K) who demonstrate early biomarker evidence of microglial dysfunction but retain sufficient cognitive capacity to benefit from intervention. Genetic screening protocols should encompass whole exome sequencing to identify rare TREM2 variants beyond common polymorphisms, as these individuals may show enhanced treatment responsiveness.

Biomarker-driven enrollment strategies focus on CSF sTREM2 levels and microglial PET activation patterns to identify subjects with metabolic circuit dysfunction. Inclusion criteria specify sTREM2 levels >1.5-fold above age-matched controls and microglial PET SUVr >1.3 in hippocampal regions. Cognitive inclusion requires Clinical Dementia Rating scores of 0-0.5, ensuring treatment occurs during the preclinical or very mild symptomatic phases when circuit restoration may provide maximum benefit.

Safety considerations center on the pleiotropic effects of SIRT1 activation and potential immunomodulatory consequences of TREM2 agonism. Phase I dose-escalation studies must carefully monitor for cardiovascular effects of SIRT1 activators, given their influence on endothelial function and lipid metabolism. TREM2 agonist safety profiles require assessment of potential autoimmune activation, with monitoring protocols including comprehensive autoantibody panels and inflammatory cytokine measurements.

The regulatory pathway likely involves designation as a breakthrough therapy given the unmet medical need in neurodegeneration and the novel mechanism of action. FDA guidance on combination therapies will be particularly relevant, as the synergistic approach targeting multiple circuit components may require adaptive trial designs. The competitive landscape includes other microglial modulators such as CSF1R inhibitors and complement pathway modulators, necessitating clear differentiation based on mechanistic specificity and biomarker-driven patient selection.

Future Directions and Combination Approaches

Future research directions encompass both mechanistic refinement and therapeutic optimization of the TREM2-SIRT1 metabolic circuit. Advanced single-cell RNA sequencing and spatial transcriptomics will provide detailed characterization of microglial heterogeneity and identify specific subpopulations most responsive to circuit modulation. Proteomic and metabolomic profiling will elucidate downstream effector pathways and identify additional therapeutic targets within the metabolic network.

Combination therapy approaches hold particular promise for maximizing therapeutic efficacy. The integration of SIRT1 activators with mitochondrial-targeted antioxidants such as MitoQ or SS-31 may provide synergistic protection against oxidative damage while supporting metabolic restoration. Autophagy enhancers including rapamycin or urolithin A could complement SIRT1 activation by promoting clearance of damaged organelles and protein aggregates.

The broader application to related neurodegenerative diseases represents an important expansion opportunity. Parkinson's disease models demonstrate similar patterns of microglial metabolic dysfunction, suggesting that TREM2-SIRT1 circuit restoration may provide benefits across multiple neurodegenerative conditions. Amyotrophic lateral sclerosis and frontotemporal dementia also show evidence of microglial senescence, warranting investigation of circuit-targeted interventions.

Technological advances in drug delivery offer opportunities for enhanced therapeutic precision. Focused ultrasound-mediated blood-brain barrier opening could improve antibody penetration while minimizing systemic exposure. Engineered extracellular vesicles targeting microglial receptors may enable cell-specific delivery of small molecules or genetic constructs. These approaches could overcome current limitations in achieving therapeutic concentrations while maintaining acceptable safety profiles, ultimately advancing this promising therapeutic strategy toward clinical reality.

🧬 Mechanism

🧬 Curated Mechanism Pathway

Curated pathway from expert analysis

flowchart TD
    subgraph Genetics["Genetic Risk"]
        A1["TREM2 R47H Variant<br/>3x AD Risk"] --> A2["Impaired Ligand Binding<br/>(Abeta, ApoE, PS)"]
        A3["TREM2 R62H Variant<br/>2x AD Risk"] --> A4["Reduced Surface Expression"]
        A5["TREM2 H157Y<br/>Increased Shedding"] --> A6["Elevated sTREM2"]
    end

    subgraph Signaling["TREM2 Signaling Cascade"]
        B1["TREM2 + DAP12/TYROBP"] --> B2["ITAM Phosphorylation"]
        B2 --> B3["SYK Kinase Activation"]
        B3 --> B4["PI3K/AKT Pathway"]
        B3 --> B5["PLCgamma2/Ca2+ Flux"]
        B4 --> B6["mTOR -> Metabolic Reprogramming"]
        B4 --> B7["NF-kappaB Modulation"]
        B5 --> B8["NFAT Translocation"]
    end

    subgraph Microglial["Microglial States"]
        C1["Homeostatic Microglia<br/>(P2RY12+, CX3CR1+)"]
        C2["Disease-Associated Microglia<br/>(DAM Stage 1)"]
        C3["DAM Stage 2<br/>(TREM2-dependent)"]
        C4["Senescent Microglia<br/>(p16+, p21+, SA-beta-gal+)"]
        C1 -->|"Abeta sensing"| C2
        C2 -->|"TREM2 signal"| C3
        C2 -->|"chronic stress"| C4
    end

    subgraph Senescence["Senescence Program"]
        D1["DNA Damage Response<br/>(ATM/ATR)"] --> D2["p53 Stabilization"]
        D2 --> D3["p21/CDKN1A Upregulation"]
        D3 --> D4["Cell Cycle Arrest"]
        D4 --> D5["SASP Activation"]
        D5 --> D6["IL-6, IL-1beta, TNF-alpha<br/>MMP3, MMP9"]
        D5 --> D7["Extracellular Vesicles<br/>(pro-inflammatory cargo)"]
    end

    subgraph Pathology["Downstream Pathology"]
        E1["Impaired Abeta Clearance"]
        E2["Tau Propagation"]
        E3["Synaptic Loss"]
        E4["BBB Dysfunction"]
        E1 --> E5["Plaque Accumulation"]
        E2 --> E6["Tangle Formation"]
        E3 --> E7["Cognitive Decline"]
        E4 --> E7
        E5 --> E7
        E6 --> E7
    end

    subgraph Therapy["Therapeutic Strategy"]
        F1["TREM2 Agonist Antibodies<br/>(AL002/Latozinemab)"]
        F2["Senolytic Drugs<br/>(Dasatinib + Quercetin)"]
        F3["SASP Inhibitors<br/>(Rapamycin, Ruxolitinib)"]
    end

    A2 --> B1
    A4 --> B1
    B6 --> C3
    C3 -->|"sustained activation"| D1
    C4 --> D5
    D6 --> E1
    D6 --> E2
    D6 --> E3
    D6 --> E4

    F1 -.->|"restore"| B1
    F1 -.->|"promote"| C3
    F2 -.->|"clear"| C4
    F3 -.->|"block"| D5

    style A1 fill:#ce93d8,color:#000
    style A3 fill:#ce93d8,color:#000
    style A5 fill:#ce93d8,color:#000
    style C3 fill:#4fc3f7,color:#000
    style C4 fill:#ffd54f,color:#000
    style D5 fill:#ff8a65,color:#000
    style E7 fill:#ef5350,color:#fff
    style F1 fill:#81c784,color:#000
    style F2 fill:#81c784,color:#000
    style F3 fill:#81c784,color:#000

⚖️ Evidence

⚖️ Evidence Matrix36 supports18 contradicts

Supports

Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice.

Sci Transl Med2023PMID:37099634medium

Abstract

Sleep loss is associated with cognitive decline in the aging population and is a risk factor for Alzheimer's disease (AD). Considering the crucial role of immunomodulating genes such as that encoding the triggering receptor expressed on myeloid cells type 2 (TREM2) in removing pathogenic amyloid-β (Aβ) plaques and regulating neurodegeneration in the brain, our aim was to investigate whether and how sleep loss influences microglial function in mice. We chronically sleep-deprived wild-type mice an

Supports

Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease.

Nat Med2020PMID:31932797medium

Abstract

Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscov

Supports

TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways.

Cell2022PMID:36306735medium

Abstract

Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer's disease (AD). Microglia that adhere to Aβ plaques acquire a transcriptional signature, "disease-associated microglia" (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aβ plaq

Supports

TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.

Cell2017PMID:28802038medium

Abstract

Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-

Supports

Explores genetic variations linked to neurodegenerative disease proteins, potentially supporting the TREM2-dependent senescence hypothesis.

medRxiv2026PMID:41757182

Supports

Investigates gene editing technologies for Alzheimer's disease, which could relate to modulating TREM2 signaling in microglial aging.

Curr Aging Sci2026PMID:41926312

Supports

Directly studies the microglial TREM2 receptor's role in brain development, supporting its functional significance.

Brain Behav Immun2026PMID:41887542

Supports

Examines phagocyte mechanisms in amyloid generation, which relates to microglial function proposed in the TREM2 senescence hypothesis.

Proc Natl Acad Sci U S A2026PMID:41770935

Supports

Explores microglial neuroprotective responses, which aligns with TREM2 signaling mechanisms.

Signal Transduct Target Ther2026PMID:41881962

Supports

Investigates signaling pathways related to genetic resilience in Alzheimer's disease, potentially supporting TREM2 mechanisms.

Mol Neurodegener2026PMID:41888907

Supports

Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model.

Neuron2024PMID:39353433high

Abstract

The strongest risk factors for late-onset sporadic Alzheimer's disease (AD) include the ε4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2

Supports

Microglia in neurodegeneration.

Nat Neurosci2018PMID:30258234high

Abstract

The neuroimmune system is involved in development, normal functioning, aging, and injury of the central nervous system. Microglia, first described a century ago, are the main neuroimmune cells and have three essential functions: a sentinel function involved in constant sensing of changes in their environment, a housekeeping function that promotes neuronal well-being and normal operation, and a def

Supports

TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during neurodegeneration.

Immunity2023PMID:37442133medium

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is strongly linked to Alzheimer's disease (AD) risk, but its functions are not fully understood. Here, we found that TREM2 specifically attenuated the activation of classical complement cascade via high-affinity binding to its initiator C1q. In the human AD brains, the formation of TREM2-C1q complexes was detected, and the increased density

Supports

TREM2 and sTREM2 in Alzheimer's disease: from mechanisms to therapies.

Mol Neurodegener2025PMID:40247363medium

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor predominantly expressed by microglia in the brain. Recent studies have established TREM2 as a central immune signaling hub in neurodegeneration, where it triggers immune responses upon sensing pathological development and tissue damages. TREM2 binds diverse ligands and activates downstream pathways that regulate

Supports

Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer's disease.

Nat Commun2023PMID:37865646medium

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein that is predominantly expressed by microglia in the brain. The proteolytic shedding of TREM2 results in the release of soluble TREM2 (sTREM2), which is increased in the cerebrospinal fluid of patients with Alzheimer's disease (AD). It remains unknown whether sTREM2 regulates the pathogenesis of AD. Here we identifi

Supports

Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer's disease.

Alzheimers Res Ther2024PMID:39444037medium

Abstract

Variants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer's disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammator

Supports

Identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease model mouse brain.

Nat Neurosci2024PMID:38637622high

Abstract

1. Nat Neurosci. 2024 Jun;27(6):1116-1124. doi: 10.1038/s41593-024-01620-8. Epub 2024 Apr 18. Identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease model mouse brain. Rachmian N(1)(2), Medina S(#)(2), Cherqui U(#)(1), Akiva H(#)(1), Deitch D(2), Edilbi D(1), Croese T(2), Salame TM(3), Ramos JMP(2), Cahalon L(2), Krizhanovsky V(4), Schwartz M(5). Author information: (1)Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (2)Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel. (3)Flow Cytometry Unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel. (4)Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. valery.krizhanovsky@weizm

Supports

White matter aging drives microglial diversity.

Neuron2021PMID:33606969medium

Abstract

1. Neuron. 2021 Apr 7;109(7):1100-1117.e10. doi: 10.1016/j.neuron.2021.01.027. Epub 2021 Feb 18. White matter aging drives microglial diversity. Safaiyan S(1), Besson-Girard S(2), Kaya T(3), Cantuti-Castelvetri L(1), Liu L(2), Ji H(2), Schifferer M(4), Gouna G(1), Usifo F(2), Kannaiyan N(5), Fitzner D(6), Xiang X(7), Rossner MJ(5), Brendel M(8), Gokce O(9), Simons M(10). Author information: (1)Institute of Neuronal Cell Biology, Technical University Munich, 80802 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany. (2)Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, 81377 Munich, Germany. (3)Institute of Neuronal Cell Biology, Technical University Munich, 80802 Munich, Germany; German Center for Neurode

Supports

Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep.

Antioxidants (Basel)2023PMID:37627641high

Abstract

1. Antioxidants (Basel). 2023 Aug 21;12(8):1646. doi: 10.3390/antiox12081646. Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep. Huard CA(1), Gao X(1), Dey Hazra ME(1)(2), Dey Hazra RO(1)(2)(3), Lebsock K(4), Easley JT(4), Millett PJ(1)(2), Huard J(1). Author information: (1)Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA. (2)The Steadman Clinic, Vail, CO 81657, USA. (3)Department for Shoulder and Elbow Surgery, Center for Musculoskeletal Surgery, Charite-University Medicine Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 14195 Berlin, Germany. (4)Preclinical Surgical Research Laboratory, Department of Clinica

Supports

Roflumilast Attenuates Microglial Senescence and Retinal Inflammatory Neurodegeneration Post Retinal Ischemia Reperfusion Injury Through Inhibiting NLRP3 Inflammasome.

Invest Ophthalmol Vis Sci2024PMID:39446353high

Abstract

1. Invest Ophthalmol Vis Sci. 2024 Oct 1;65(12):38. doi: 10.1167/iovs.65.12.38. Roflumilast Attenuates Microglial Senescence and Retinal Inflammatory Neurodegeneration Post Retinal Ischemia Reperfusion Injury Through Inhibiting NLRP3 Inflammasome. Ou C(1)(2), Lin Y(3), Wen J(4), Zhang H(3), Xu Y(5), Zhang N(3), Liu Q(3), Wu Y(3), Xu J(3), Wu J(1). Author information: (1)Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. (2)Department of General Practice, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, China. (3)Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. (4)Department of Ophthalmology, Taizhou Central Hospital, T

Supports

Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice.

Aging Cell2021PMID:33470505high

Abstract

1. Aging Cell. 2021 Feb;20(2):e13296. doi: 10.1111/acel.13296. Epub 2021 Jan 20. Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Ogrodnik M(1)(2), Evans SA(3), Fielder E(4), Victorelli S(1), Kruger P(1), Salmonowicz H(1), Weigand BM(1)(2), Patel AD(1), Pirtskhalava T(2), Inman CL(2), Johnson KO(2), Dickinson SL(4), Rocha A(3), Schafer MJ(2), Zhu Y(2), Allison DB(4), von Zglinicki T(5), LeBrasseur NK(2), Tchkonia T(2), Neretti N(3), Passos JF(1)(2), Kirkland JL(1)(2), Jurk D(1)(2). Author information: (1)Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA. (2)Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. (3)Department of Molecular Biology, Cell Biology and Bi

Supports

Cisplatin and methotrexate induce brain microvascular endothelial and microglial senescence in mouse models of chemotherapy-associated cognitive impairment.

Geroscience2025PMID:39976845high

Abstract

1. Geroscience. 2025 Jun;47(3):3447-3459. doi: 10.1007/s11357-025-01560-6. Epub 2025 Feb 20. Cisplatin and methotrexate induce brain microvascular endothelial and microglial senescence in mouse models of chemotherapy-associated cognitive impairment. Csik B(#)(1)(2)(3)(4), Vali Kordestan K(#)(1)(2), Gulej R(#)(1)(2)(4), Patai R(1)(2)(3), Nyul-Toth A(1)(2)(3), Shanmugarama S(1)(2)(3), Mukli P(1)(2)(3)(4), Ungvari A(5), Balsara KE(1), McNall RY(6), Razzaghi T(7), Tarantini S(1)(2)(3)(8)(9), Yabluchanskiy A(1)(2)(3)(8)(9), Ungvari Z(1)(2)(3)(8)(9), Csiszar A(1)(2)(6)(10). Author information: (1)Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. (2)Oklahom

Supports

Prematurely Aged Human Microglia Exhibit Impaired Stress Response and Defective Nucleocytoplasmic Shuttling of ALS Associated FUS.

Aging Cell2025PMID:40970514medium

Abstract

1. Aging Cell. 2025 Nov;24(11):e70232. doi: 10.1111/acel.70232. Epub 2025 Sep 19. Prematurely Aged Human Microglia Exhibit Impaired Stress Response and Defective Nucleocytoplasmic Shuttling of ALS Associated FUS. Hartmann C(1), Haß C(1), Knobloch M(1), Barrantes I(2), Fumagalli L(3)(4), Premereur J(3)(4), Markert F(5), Peters M(1), Koromila G(1), Hartmann A(6), Jäger K(6), Abel J(1), Mancuso R(3)(4), Storch A(5)(7)(8), Walter M(6), Fuellen G(2), Hermann A(1)(7)(8). Author information: (1)Translational Neurodegeneration Section "Albrecht Kossel", Department of Neurology, Rostock University Medical Center, Rostock, Germany. (2)Institute for Biostatistics and Informatics in Medicine and Aging Research, Rostock University Medical Center, Rostock, Germany. (3)Department of Biomedical S

Supports

Disentangling causality in brain aging: The complex interplay between glial senescence, neuroinflammation, and neurodegeneration.

Exp Neurol2026PMID:41871753high

Abstract

1. Exp Neurol. 2026 Mar 21;401:115737. doi: 10.1016/j.expneurol.2026.115737. Online ahead of print. Disentangling causality in brain aging: The complex interplay between glial senescence, neuroinflammation, and neurodegeneration. Suk K(1). Author information: (1)Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Brain Science & Engineering Institute, Kyungpook National University, Daegu, Republic of Korea; Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Kyungpook National University, Daegu, Republic of Korea. Electronic address: ksuk@knu.ac.kr. The aging brain is characterized by accumulation of senescent glia, chronic neuroinflammation, and vulnerability to neurode

Supports

A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer's disease.

Sci Transl Med2022PMID:36070367high

Abstract

1. Sci Transl Med. 2022 Sep 7;14(661):eabq0095. doi: 10.1126/scitranslmed.abq0095. Epub 2022 Sep 7. A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer's disease. Zhao P(1), Xu Y(2), Jiang L(3), Fan X(1), Li L(1), Li X(1), Arase H(4), Zhao Y(5), Cao W(6), Zheng H(7), Xu H(8)(9), Tong Q(2), Zhang N(1), An Z(1). Author information: (1)Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. (2)Center for Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. (3)Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Instit

Supports

Adult-onset CNS myelin sulfatide deficiency is sufficient to cause Alzheimer's disease-like neuroinflammation and cognitive impairment.

Mol Neurodegener2021PMID:34526055medium

Abstract

1. Mol Neurodegener. 2021 Sep 15;16(1):64. doi: 10.1186/s13024-021-00488-7. Adult-onset CNS myelin sulfatide deficiency is sufficient to cause Alzheimer's disease-like neuroinflammation and cognitive impairment. Qiu S(#)(1), Palavicini JP(#)(1)(2), Wang J(1)(3), Gonzalez NS(1), He S(1), Dustin E(4), Zou C(5), Ding L(1)(6), Bhattacharjee A(1), Van Skike CE(1)(7), Galvan V(1)(7), Dupree JL(4)(8), Han X(9)(10). Author information: (1)Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, 4939 Charles Katz Drive, San Antonio, TX, 78229, USA. (2)Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. (3)Present Address: State Key Lab. of Environmental & Bio

Supports

Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.

Cell2021PMID:34450028medium

Abstract

1. Cell. 2021 Sep 2;184(18):4651-4668.e25. doi: 10.1016/j.cell.2021.08.002. Epub 2021 Aug 26. Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. Logan T(1), Simon MJ(1), Rana A(1), Cherf GM(1), Srivastava A(1), Davis SS(1), Low RLY(1), Chiu CL(1), Fang M(1), Huang F(1), Bhalla A(1), Llapashtica C(1), Prorok R(1), Pizzo ME(1), Calvert MEK(1), Sun EW(1), Hsiao-Nakamoto J(1), Rajendra Y(1), Lexa KW(1), Srivastava DB(1), van Lengerich B(1), Wang J(1), Robles-Colmenares Y(1), Kim DJ(1), Duque J(1), Lenser M(1), Earr TK(1), Nguyen H(1), Chau R(1), Tsogtbaatar B(1), Ravi R(1), Skuja LL(1), Solanoy H(1), Rosen HJ(2), Boeve BF(3), Boxer AL(2), Heuer HW(2), Dennis MS(1), Kariolis MS(1), Monroe KM(1), Przybyla L(1), Sanchez PE

Supports

CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline.

Cell Rep2023PMID:37864797medium

Abstract

1. Cell Rep. 2023 Oct 31;42(10):113269. doi: 10.1016/j.celrep.2023.113269. CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline. Evans F(1), Alí-Ruiz D(2), Rego N(3), Negro-Demontel ML(1), Lago N(2), Cawen FA(2), Pannunzio B(1), Sanchez-Molina P(4), Reyes L(5), Paolino A(5), Rodríguez-Duarte J(6), Pérez-Torrado V(7), Chicote-González A(8), Quijano C(9), Marmisolle I(9), Mulet AP(10), Schlapp G(10), Meikle MN(10), Bresque M(7), Crispo M(10), Savio E(5), Malagelada C(8), Escande C(7), Peluffo H(11). Author information: (1)Department of Histology and Embryology, Faculty of Medicine, UDELAR, Montevideo, Uruguay; Neuroinflammation and Gene Therapy Laboratory, Institut Pasteur de Montevideo, Montevideo, Uruguay. (2)Neuroinfla

Supports

Brain aging mechanisms with mechanical manifestations.

Mech Ageing Dev2021PMID:34600936medium

Abstract

1. Mech Ageing Dev. 2021 Dec;200:111575. doi: 10.1016/j.mad.2021.111575. Epub 2021 Oct 1. Brain aging mechanisms with mechanical manifestations. Blinkouskaya Y(1), Caçoilo A(1), Gollamudi T(2), Jalalian S(1), Weickenmeier J(3). Author information: (1)Department of Mechanical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, United States. (2)Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, United States. (3)Department of Mechanical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, United States. Electronic address: johannes.weickenmeier@stevens.edu. Brain aging is a complex process that affects everything from the subcellular to the organ level, begins early in life, and accelerates with age. Morphologically

Supports

Effect of peripheral cellular senescence on brain aging and cognitive decline.

Aging Cell2023PMID:36959691high

Abstract

1. Aging Cell. 2023 May;22(5):e13817. doi: 10.1111/acel.13817. Epub 2023 Mar 23. Effect of peripheral cellular senescence on brain aging and cognitive decline. Budamagunta V(1)(2)(3), Kumar A(1), Rani A(1), Bean L(1), Manohar-Sindhu S(2), Yang Y(3)(4), Zhou D(4), Foster TC(1)(2). Author information: (1)Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA. (2)Genetics and Genomics Graduate Program, Genetics Institute, University of Florida, Gainesville, Florida, USA. (3)Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida, USA. (4)Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. We examine similar and diff

Contradicts

Microglia-Mediated Neuroinflammation: A Potential Target for the Treatment of Cardiovascular Diseases.

J Inflamm Res2022PMID:35642214medium

Abstract

Microglia are tissue-resident macrophages of the central nervous system (CNS). In the CNS, microglia play an important role in the monitoring and intervention of synaptic and neuron-level activities. Interventions targeting microglia have been shown to improve the prognosis of various neurological diseases. Recently, studies have observed the activation of microglia in different cardiovascular diseases. In addition, different approaches that regulate the activity of microglia have been shown to

Contradicts

TREM2, microglia, and Alzheimer's disease.

Mech Ageing Dev2021PMID:33516818medium

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) has been suggested to play a crucial role in Alzheimer's disease (AD) pathogenesis, as revealed by genome-wide association studies (GWAS). Since then, rapidly increasing literature related to TREM2 has focused on elucidating its role in AD pathology. In this review, we summarize our understanding of TREM2 biology, explore TREM2 functions in microglia, address the multiple mechanisms of TREM2 in AD, and raise key questions for further inves

Contradicts

Microglia states and nomenclature: A field at its crossroads.

Neuron2022PMID:36327895medium

Abstract

Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably

Contradicts

TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy.

Proc Natl Acad Sci U S A2017PMID:29073081medium

Abstract

Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) were recently found to increase the risk for developing Alzheimer's disease (AD). In the brain, TREM2 is predominately expressed on microglia, and its association with AD adds to increasing evidence implicating a role for the innate immune system in AD initiation and progression. Thus far, studies have found

Contradicts

Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology.

Neuron2021PMID:33675684medium

Abstract

Loss-of-function TREM2 mutations strongly increase Alzheimer's disease (AD) risk. Trem2 deletion has revealed protective Trem2 functions in preclinical models of β-amyloidosis, a prominent feature of pre-diagnosis AD stages. How TREM2 influences later AD stages characterized by tau-mediated neurodegeneration is unclear. To understand Trem2 function in the context of both β-amyloid and tau patholog

Contradicts

SYK coordinates neuroprotective microglial responses in neurodegenerative disease.

Cell2022PMID:36257314medium

Abstract

Recent studies have begun to reveal critical roles for the brain's professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aβ) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted del

Contradicts

Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer's disease mice model.

Redox Biol2022PMID:35026701medium

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease in which oxidative stress and neuroinflammation were demonstrated to be associated with neuronal loss and cognitive deficits. However, there are still no specific treatments that can prevent the progression of AD. In this study, a screening of anti-inflammatory hits from 4207 natural compounds of two different molecular libraries indicated 1,

Contradicts

Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer's disease.

Nat Commun2025PMID:40593718medium

Abstract

Previous studies suggest glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease (AD), but the link between their markers and synaptic abnormalities in the living brain remains unclear. We investigated the association between glial reactivity and synaptic dysfunction biomarkers in cerebrospinal fluid (CSF) from 478 individuals in cognitively unimpaired (CU) and cognitive

Contradicts

Sulfatide deficiency-induced astrogliosis and myelin lipid dyshomeostasis are independent of TREM2-mediated microglial activation.

Nat Commun2026PMID:41513633medium

Abstract

Disrupted lipid homeostasis and neuroinflammation often co-exist in neurodegenerative disorders, including Alzheimer's disease (AD). However, the intrinsic connection and causal relationship between these deficits remain elusive. Our previous studies show that the loss of sulfatide (ST), a class of myelin-enriched lipids, causes AD-like neuroinflammatory responses, cognitive impairment, bladder en

Contradicts

cGAS-STING drives ageing-related inflammation and neurodegeneration.

Nature2023PMID:37532932medium

Abstract

Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease

Contradicts

Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes.

Immunity2019PMID:30471926medium

Abstract

Microglia, the resident immune cells of the brain, rapidly change states in response to their environment, but we lack molecular and functional signatures of different microglial populations. Here, we analyzed the RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury. Our analysis uncovered at least nine transcriptionally di

Contradicts

Lectins and neurodegeneration: A glycobiologist's perspective.

Adv Clin Exp Med2025PMID:40405515medium

Abstract

1. Adv Clin Exp Med. 2025 May;34(5):673-679. doi: 10.17219/acem/204107. Lectins and neurodegeneration: A glycobiologist's perspective. Olejnik B(1), Ferens-Sieczkowska M(1). Author information: (1)Department of Biochemistry and Immunochemistry, Wroclaw Medical University, Poland. Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, affect an increasing number of people in aging societies, dramatically reducing the quality of life of those affected. Hence, intensive research efforts are aimed at understanding the molecular mechanisms of the disease progress, with the hope for developing effective therapeutic strategies. The progress of neurodegenerative diseases is associated with a complex activity of the immune system in the brain tissue. Carbohydrate-bind

Contradicts

Effect of aging on biomarkers and clinical profile in Parkinson's disease.

J Neurol2025PMID:40991070medium

Abstract

1. J Neurol. 2025 Sep 24;272(10):651. doi: 10.1007/s00415-025-13384-7. Effect of aging on biomarkers and clinical profile in Parkinson's disease. Di Lazzaro G(1)(2), Paolini Paoletti F(3), Bellomo G(3), Schirinzi T(4), Grillo P(5)(6), Giuffrè GM(7)(8), Petracca M(7)(8), Picca A(7)(9), Mercuri NB(4), Parnetti L(3), Calabresi P(7)(8), Bentivoglio AR(7)(8). Author information: (1)Neurology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy. giulia.dilazzaro@policlinicogemelli.it. (2)Università Cattolica del Sacro Cuore, Rome, Italy. giulia.dilazzaro@policlinicogemelli.it. (3)Section of Neurology, Department of Medicine and Surgery, University Hospital of Perugia, Perugia, Italy. (4)Neurology Unit, Department of Systems Medi

Contradicts

Regulation of TREM2 expression by transcription factor YY1 and its protective effect against Alzheimer's disease.

J Biol Chem2023PMID:37044212medium

Abstract

1. J Biol Chem. 2023 May;299(5):104688. doi: 10.1016/j.jbc.2023.104688. Epub 2023 Apr 11. Regulation of TREM2 expression by transcription factor YY1 and its protective effect against Alzheimer's disease. Lu Y(1), Huang X(1), Liang W(1), Li Y(1), Xing M(2), Pan W(2), Zhang Y(1), Wang Z(3), Song W(4). Author information: (1)The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China. (2)Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Wenzhou Kangning Hospital, Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Wenzhou Medical University, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou,

Contradicts

Microglia in Brain Aging and Age-Related Diseases: Friends or Foes?

Int J Mol Sci2025PMID:41373648medium

Abstract

1. Int J Mol Sci. 2025 Nov 27;26(23):11494. doi: 10.3390/ijms262311494. Microglia in Brain Aging and Age-Related Diseases: Friends or Foes? Ishikawa K(1), Fujikawa R(1), Okita K(1), Kimura F(1), Watanabe T(1), Katsurabayashi S(1), Iwasaki K(1). Author information: (1)Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. With the global rise in population aging, establishing effective strategies for the prevention and treatment of age-related neurodegenerative diseases, as well as their prodromal stage of cognitive frailty, has become an urgent challenge. Recent studies have revealed that the neural basis of both frailty and age-related disorders is closely associated with chronic neuroinflammat

Contradicts

Rejuvenating aged microglia by p16(ink4a)-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer's disease.

Mol Neurodegener2024PMID:38493185medium

Abstract

1. Mol Neurodegener. 2024 Mar 16;19(1):25. doi: 10.1186/s13024-024-00715-x. Rejuvenating aged microglia by p16(ink4a)-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer's disease. Shin HJ(1)(2), Kim IS(3)(4), Choi SG(1)(2), Lee K(1)(3)(5), Park H(1)(3), Shin J(1)(3), Kim D(1), Beom J(5), Yi YY(6), Gupta DP(7), Song GJ(7)(8), Chung WS(9), Lee CJ(10)(11), Kim DW(12)(13)(14)(15). Author information: (1)Department of Anatomy and Cell Biology, Chungnam National University College of Medicine, Daejeon, Republic of Korea. (2)Brain Research Institute, Chungnam National University College of Medicine, Daejeon, Republic of Korea. (3)Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea. (4)Department o

Contradicts

Microglial Replacement Reverses Age-Associated Epigenetic Modifications Despite Accelerating Epigenetic Age.

Aging Dis2025PMID:41135104medium

Abstract

1. Aging Dis. 2025 Oct 22. doi: 10.14336/AD.2025.1066. Online ahead of print. Microglial Replacement Reverses Age-Associated Epigenetic Modifications Despite Accelerating Epigenetic Age. Arbaizar-Rovirosa M(1)(2), Pérez RF(3), Peñarroya A(4)(5)(6)(7), Gallizioli M(1), Fraga MF(8)(4)(5)(9)(10), Planas AM(1)(2). Author information: (1)Cerebrovascular Research Laboratory, Instituto de Investigaciones. (2)Biomédicas de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. (3)Departamento de Bioquímica y Biología Molecular, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain. (4)Cancer Epigenetics and Nanomedicine Laboratory, Centro de Investi

Contradicts

Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation.

Front Cell Neurosci2013PMID:23493481medium

Abstract

1. Front Cell Neurosci. 2013 Mar 13;7:22. doi: 10.3389/fncel.2013.00022. eCollection 2013. Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation. Wong WT(1). Author information: (1)Unit on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health Bethesda, MD, USA. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and age-related macular degeneration (AMD), share two characteristics in common: (1) a disease prevalence that increases markedly with advancing age, and (2) neuroinflammatory changes in which microglia, the primary resident immune cell of the CNS, feature prominently. These characteristics have led to the hypothesis that pathogenic mechanisms underlying age-related neurodegenerati

📖 Linked Papers

No linked papers recorded for this hypothesis yet.

🏥 Translation

🧬 3D Protein Structure — TREM2

🧬 PDB 6YXY Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

🧠 GTEx v10 Brain ExpressionJSON

Median TPM across 13 brain regions for TREM2 from GTEx v10.

💉 Clinical Trials (5)Relevance: 26%

0
Active

0
Completed

1,820
Total Enrolled

NA
Highest Phase

The Signature of Alzheimer's Disease in Subjective Cognitive DeclineUnknown

RECRUITING·NCT07402161 · IRCCS Policlinico S. Donato

250 enrolled · 2025-10-01 · → 2027-10-01

This study focuses on improving early detection of Alzheimer's disease (AD) in patients with subjective cognitive decline (SCD), a preclinical stage of cognitive impairment, in the context of emerging

Subjective Cognitive Decline (SCD) Subjective Cognitive Complaints (SCCs) Subjective Cognitive Impairment

Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer's DiseaseUnknown

COMPLETED·NCT06224920 · Ludwig-Maximilians - University of Munich

140 enrolled · 2017-01-01 · → 2024-01-01

The temporal sequence of microglial activation, changes in functional and structural connectivity and the progression of neurocognitive deficits has not been conclusively clarified. To date, there hav

Alzheimer Disease Corticobasal Syndrome

magnetic resonance imaging electroencephalography blood and CSF biomarker

Neurofilament Light Chain And Voice Acoustic Analyses In Dementia DiagnosisUnknown

RECRUITING·NCT06339190 · Monash University

1,000 enrolled · 2021-08-01 · → 2025-12

This cohort study aims to determine if a blood test can aid with diagnosing dementia in anyone presenting with cognitive complaints to a single healthcare network. The investigators will measure level

Neurodegenerative Diseases Dementia

Venepuncture

Physical Activity in Patients With Parkinson's Disease: a "Disease Modifying" Intervention?NA

TERMINATED·NCT05815524 · Fondazione Policlinico Universitario Agostino Gemelli IRCCS

30 enrolled · 2022-05-02 · → 2024-12-31

Parkinson's disease (PD) is a neurodegenerative disease characterized by bradykinesia, rigors, and tremor at rest. Distinctive neuropathological signs include progressive loss of dopaminergic neurons

Parkinson Disease

Physical activity training

Clinical, Molecular and Electrophysiological Profiling of Parkinson's Disease: the Role of Non-pharmacological TherapiesNA

UNKNOWN·NCT05807581 · Fondazione Policlinico Universitario Agostino Gemelli IRCCS

400 enrolled · 2023-06-09 · → 2025-05-30

In Parkinson's disease (PD), direct evidence linking inflammation to the harmful activities of alpha-synuclein (a-syn) aggregates, the disease onset, and its progression is still lacking. This transla

Parkinson Disease

physical activity iTBS

No curated ClinVar variants loaded for this hypothesis.

Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.

🔍 Search ClinVar for TREM2 →

No DepMap CRISPR Chronos data found for TREM2.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

💰 Estimated Development

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Timeline

2.0 years

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7d Trend

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0.0054

Events (7d)

6

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▼32.5%

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LLM Tokens

18,818

$0.1129

Total Cost

$0.1129

🔮 Predictions

🔎 Predictions vs Observations5 predictions · 0 with recorded observations

Prediction	Predicted	Observed	Status	Conf
IF pharmacological SIRT1 activation (SRT2104, 1μM) is administered to aged (12-18 month) TREM2-deficient microglia, THEN mitochondrial function will be restored (ATP levels ≥80% of wild-type, mitochon	Restoration of mitochondrial biogenesis markers (ATP production, mtDNA copy number, NRF1/TFAM expression), reduction in cellular senescence markers (SA-β-gal ac	— no observation —	pending	0.72
IF NAD+ precursor supplementation (nicotinamide riboside, 500μM) is provided to aged TREM2 R47H mutant microglia, THEN intracellular NAD+ levels will be restored (≥70% of young levels), SIRT1 activity	Increased intracellular NAD+ concentration (measured by mass spectrometry), elevated SIRT1 deacetylase activity (Fluor de Lys assay), decreased PGC1α acetylatio	— no observation —	pending	0.68
IF TREM2 agonistic antibody (4D10 clone, 1μg/mL) is combined with SIRT1 activator (SRT2104, 1μM) in aged wild-type microglia, THEN synergistic improvement in phagocytic capacity (≥2-fold increase in a	Synergistic enhancement of phagocytic function (FITC-labeled Aβ42 or synaptosome uptake assay), greater reduction in senescence markers than either treatment al	— no observation —	pending	0.65
If TREM2-SIRT1 metabolic senescence circuit operates in microglial aging, then SIRT1 agonists will restore microglial metabolic flexibility and reduce SASP factor secretion in TREM2 R47H variant carri	SIRT1 agonist treatment (e.g., resveratrol, SRT2104) in TREM2 R47H iPSC-derived microglia restores OCR/ECAR ratio to levels comparable to wild-type controls, wi	— no observation —	pending	0.80
If the TREM2-SIRT1 circuit links metabolic senescence to inflammation, then TREM2-deficient microglia will show decreased SIRT1 nuclear localization and NAD+ salvage pathway activity, with accumulatio	TREM2 knockdown in BV-2 cells or primary microglia reduces nuclear SIRT1 (60-70% decrease by immunofluorescence), lowers NAD+ levels, and increases acetylated p	— no observation —	pending	0.75

🔮 Falsifiable Predictions (5)

pendingconf 72%

IF pharmacological SIRT1 activation (SRT2104, 1μM) is administered to aged (12-18 month) TREM2-deficient microglia, THEN mitochondrial function will be restored (ATP levels ≥80% of wild-type, mitochondrial DNA content normalized) and senescence markers will be reduced (p16/p21 mRNA decreased by ≥50%

Predicted outcome: Restoration of mitochondrial biogenesis markers (ATP production, mtDNA copy number, NRF1/TFAM expression), reduction in cellular senescence markers (S

Falsification: SIRT1 activation fails to restore mitochondrial function (ATP remains <60% of wild-type), does not reduce senescence marker expression, or does not decrease SASP secretion in TREM2-deficient microglia

pendingconf 68%

IF NAD+ precursor supplementation (nicotinamide riboside, 500μM) is provided to aged TREM2 R47H mutant microglia, THEN intracellular NAD+ levels will be restored (≥70% of young levels), SIRT1 activity will increase, and PGC1α acetylation will decrease, leading to improved mitochondrial respiration w

Predicted outcome: Increased intracellular NAD+ concentration (measured by mass spectrometry), elevated SIRT1 deacetylase activity (Fluor de Lys assay), decreased PGC1α

Falsification: NAD+ supplementation fails to increase SIRT1 activity or decrease PGC1α acetylation, or does not improve mitochondrial respiration—this would indicate that TREM2 dysfunction operates independently of

pendingconf 65%

IF TREM2 agonistic antibody (4D10 clone, 1μg/mL) is combined with SIRT1 activator (SRT2104, 1μM) in aged wild-type microglia, THEN synergistic improvement in phagocytic capacity (≥2-fold increase in amyloid-β or synaptosome uptake) and reduced senescence phenotype will be observed compared to single

Predicted outcome: Synergistic enhancement of phagocytic function (FITC-labeled Aβ42 or synaptosome uptake assay), greater reduction in senescence markers than either tr

Falsification: Combination treatment shows no synergistic benefit over single treatments, or both single and combined treatments fail to restore phagocytic capacity and reduce senescence—this would disprove the hypo

pendingconf —

If TREM2-SIRT1 metabolic senescence circuit operates in microglial aging, then SIRT1 agonists will restore microglial metabolic flexibility and reduce SASP factor secretion in TREM2 R47H variant carriers, measured by Seahorse metabolic assay and multiplex cytokine profiling.

Predicted outcome: SIRT1 agonist treatment (e.g., resveratrol, SRT2104) in TREM2 R47H iPSC-derived microglia restores OCR/ECAR ratio to levels comparable to wild-type co

Falsification: SIRT1 agonism fails to restore metabolic flexibility in TREM2 R47H microglia; OCR/ECAR ratios remain suppressed and SASP secretion persists despite treatment.

pendingconf —

If the TREM2-SIRT1 circuit links metabolic senescence to inflammation, then TREM2-deficient microglia will show decreased SIRT1 nuclear localization and NAD+ salvage pathway activity, with accumulation of acetylated SIRT1 substrates.

Predicted outcome: TREM2 knockdown in BV-2 cells or primary microglia reduces nuclear SIRT1 (60-70% decrease by immunofluorescence), lowers NAD+ levels, and increases ac

Falsification: NAD+ levels, SIRT1 localization, and acetylation status are unaffected by TREM2 deficiency, indicating independent pathways.

▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate

source	v1_phase_c_backfill
origin_type	gap_debate
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

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0 supporting 0 contradicting 0 neutral

View full evidence profile →

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Composite		74%
Mech.		88%
Evidence		78%
Novelty		70%
Feasibility		80%
Impact		76%
Druggability		65%
Safety		58%
Competition		70%
Data avail.		85%
Reproducibility		75%

📗 Cite This Artifact

TREM2-SIRT1 Metabolic Senescence Circuit in Microglial Aging

🧪 Overview

🧬 Mechanism

⚖️ Evidence

🏥 Translation

🧬 3D Protein Structure — TREM2

💉 Clinical Trials (5)Relevance: 26%

🏆 Tournament

🏆 Arenas / Elo

📊 Market Indicators

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🔮 Predictions

🧬 Related Hypotheses — same target / disease (20)

💬 Discussion

📗 Cite This Artifact

TREM2-SIRT1 Metabolic Senescence Circuit in Microglial Aging

🧪 Overview

🧬 Mechanism

⚖️ Evidence

🏥 Translation

🧬 3D Protein Structure — TREM2

💉 Clinical Trials (5)Relevance: 26%

🏆 Tournament

🏆 Arenas / Elo

📊 Market Indicators

💾 Resource Usage

🧭 Related

activates (2)

associated with (3)

causes (5)

causes (27-hydroxycholesterol promotes oligodendrocyte mat) (1)

causes (APP overexpression causes selective vulnerability ) (1)

causes (CXCL10 acts as chemokine to recruit cytotoxic CD8+) (1)

causes (CXCL10 antagonists would preserve white matter int) (1)

causes (NAD+ supplementation improves mitophagy and mitoch) (1)

causes (STING activation leads to cellular senescence and ) (1)

causes (age-related activation of cGAS-STING drives microg) (1)

causes (age-related cytokine secretion specifically suppre) (1)

causes (age-related downregulation of AP1S1 disrupts clath) (1)

causes (aging activation of microglia leads to increased C) (1)

causes (aging causes early transcriptomic changes in oligo) (1)

causes (aging mitochondrial dysfunction triggers STING pat) (1)

causes (creates a feed-forward loop of neuroinflammation l) (1)

causes (disrupted cytoskeletal checkpoints lead to prematu) (1)

causes (disrupted endosomal-lysosomal trafficking creates ) (1)

causes (dysregulated microglial transitions fail to suppor) (1)

causes (early proteasome downregulation and dysfunction dr) (1)

causes (enhanced ACE expression in microglia increases Aβ ) (1)

causes (iron-dependent ferroptosis contributes to α-synucl) (1)

causes (loss of sulfatides removes suppression of microgli) (1)

causes (microglia activate CXCL10-mediated recruitment of ) (1)

causes (microglial ACE enhancement activates spleen tyrosi) (1)

causes (microglial activation orchestrates CXCL10-mediated) (1)

causes (proteostasis failure leads to protein aggregation ) (1)

causes (recruited CD8+ T cells promote aging-related white) (1)

causes (recruited CD8+ T cells promote white matter degene) (1)

causes (senescence creates a self-perpetuating cycle by pr) (1)

causes (suppressed mitochondrial function creates vulnerab) (1)

causes (tau aggregation triggers cellular senescence respo) (1)

implicated in (7)

inhibits (1)

investigated in (1)

regulates (1)

targets (1)

🔮 Predictions

🧬 Related Hypotheses — same target / disease (20)

💬 Discussion