Hypothesis Comparison

graph TD
    A["Cellular Senescence Trigger"]
    B["p16INK4a Expression"]
    C["Iron Homeostasis Dysregulation"]
    D["Ferroportin (FPN1) Downregulation"]
    E["TfR1 and DMT1 Upregulation"]
    F["Labile Iron Pool (LIP) Accumulation"]
    G["Fenton Chemistry Activation"]
    H["Hydroxyl Radical Generation"]
    I["GPX4 Expression Reduction"]
    J["SLC7A11 Transporter Dysfunction"]
    K["Glutathione Depletion"]
    L["Lipid Peroxidation Initiation"]
    M["Ferroptosis Pathway Activation"]
    N["Senescence-Associated Secretory Phenotype (SASP)"]
    O["Paracrine Senescence Spreading"]
    P["Tissue Dysfunction and Aging"]

    A -->|"initiates"| B
    B -->|"triggers"| C
    C -->|"reduces export"| D
    C -->|"increases import"| E
    D -->|"accumulates"| F
    E -->|"accumulates"| F
    F -->|"catalyzes"| G
    G -->|"produces"| H
    B -->|"downregulates"| I
    B -->|"impairs"| J
    J -->|"reduces synthesis"| K
    I -->|"loss of protection"| L
    H -->|"initiates"| L
    K -->|"enables"| L
    L -->|"triggers"| M
    M -->|"amplifies"| N
    N -->|"promotes"| O
    O -->|"leads to"| P

    style A fill:#ce93d8
    style B fill:#ce93d8
    style C fill:#4fc3f7
    style D fill:#4fc3f7
    style E fill:#4fc3f7
    style F fill:#ef5350
    style G fill:#ef5350
    style H fill:#ef5350
    style I fill:#81c784
    style J fill:#81c784
    style K fill:#ef5350
    style L fill:#ef5350
    style M fill:#ef5350
    style N fill:#ffd54f
    style O fill:#ffd54f
    style P fill:#ffd54f

graph TD
    A["Cellular Senescence
Astrocytes and Microglia"] -->|"Triggers"| B["SASP Activation
Senescence-Associated
Secretory Phenotype"]
    B -->|"Secretes"| C["Pro-inflammatory
Cytokines
IL-1beta, TNF-alpha, IL-6"]
    B -->|"Releases"| D["Complement Initiators
C1q, C3, C4"]
    B -->|"Produces"| E["Chemokines and
Matrix Proteases
CCL2, MMP3"]
    
    D -->|"Activates"| F["Classical Complement
Pathway Initiation
C1q-C1r-C1s Complex"]
    F -->|"Cleaves"| G["C4 and C2
Formation of
C3 Convertase C4b2a"]
    G -->|"Amplifies"| H["C3 Cleavage
C3a and C3b
Generation"]
    
    H -->|"Forms"| I["C5 Convertase
C4b2a3b Complex
Alternative Pathway Feed-in"]
    I -->|"Generates"| J["C5a Anaphylatoxin
Microglial
Chemotaxis Signal"]
    I -->|"Initiates"| K["Terminal Pathway
C5b-9 Membrane
Attack Complex"]
    
    H -->|"Opsonizes"| L["Synaptic Tagging
C3b Deposition on
Neuronal Synapses"]
    L -->|"Recognized by"| M["Microglial CR3
Complement Receptor 3
CD11b-CD18"]
    M -->|"Triggers"| N["Complement-Mediated
Synaptic Pruning
Phagocytosis"]
    
    J -->|"Activates"| O["Microglial Migration
and Activation
M1 Polarization"]
    O -->|"Enhances"| N
    C -->|"Amplifies"| O
    
    N -->|"Results in"| P["Progressive Synapse Loss
Before Plaque Formation
Early AD Pathology"]
    P -->|"Leads to"| Q["Cognitive Decline
Memory Impairment
Neurodegeneration"]
    
    R["Therapeutic C1q-C3
Inhibition in SASP
Microenvironments"] -->|"Blocks"| D
    R -->|"Prevents"| F
    
    classDef normal fill:#4fc3f7,stroke:#2196f3
    classDef therapeutic fill:#81c784,stroke:#4caf50
    classDef pathology fill:#ef5350,stroke:#f44336
    classDef outcome fill:#ffd54f,stroke:#ff9800
    classDef molecular fill:#ce93d8,stroke:#9c27b0
    
    class A,B,C,D,E normal
    class F,G,H,I,J,K,L,M molecular
    class N,O,P pathology
    class Q outcome
    class R therapeutic