Family 14: Cell Death and Senescence
Family overview. Cells die via multiple regulated pathways β apoptosis (immunologically silent), necroptosis and pyroptosis (inflammatory, releasing DAMPs), ferroptosis (iron-dependent lipid peroxidation) β or enter senescence (SASP). The balance between these pathways determines whether cell loss is silent or inflammatory.
Concrete mechanisms and ME/CFS evidence:
NK cell apoptosis dysregulation. NK cells from ME/CFS patients show altered apoptotic signalling; impaired turnover may contribute to the accumulation of dysfunctional, exhausted NK cells with shortened telomeres.
Neutrophil apoptosis elevation. Elevated neutrophil apoptosis reported, potentially impairing neutrophil-mediated pathogen clearance and altering the neutrophil turnover dynamics that normally maintain immune balance.
T cell terminal exhaustion (epigenetic). T cells in ME/CFS are epigenetically predisposed toward irreversible terminal exhaustion β distinct from functional exhaustion that resolves on antigen clearance. This state persists even in the absence of ongoing antigenic stimulation.
Immunosenescence and SASP. Features of premature immune aging appear at younger ages than normal: shortened NK cell telomeres, reduced cytotoxic function, pro-inflammatory cytokine profiles consistent with SASP. The SASP amplifies surrounding inflammation and may sustain the chronic inflammatory state (Curriu et al. 2013).
Pyroptosis (theoretical). Gasdermin D-mediated inflammatory cell death following NLRP3 activation is mechanistically consistent with elevated IL-1Ξ² and IL-18 in ME/CFS; directly unstudied.
Ferroptosis (theoretical). Iron-dependent, GPx4-sensitive, lipid-peroxidation-driven cell death is mechanistically plausible given elevated ROS, GPx4 activity evidence (Family 2), and elevated lipid peroxidation; directly unstudied in ME/CFS.
Evidence status: Emerging (immune cell apoptosis and senescence documented; pyroptosis and ferroptosis theoretically plausible but unstudied).
If senescent cells accumulate in vascular endothelium, CNS glia, or immune compartments in ME/CFS, senolytic agents (dasatinib + quercetin, fisetin) might reduce SASP-driven neuroinflammation and vascular dysfunction. This is entirely unstudied in ME/CFS and represents a tractable experimental target with existing clinical-stage compounds.