Mitochondria-endoplasmic reticulum contact sites (MERCS) coordinate calcium shuttling, mitochondrial fission-fusion dynamics, lipid trafficking, and the unfolded protein response (UPR). This review systematically maps five MERCS-linked axes — calcium overload, fission-fusion imbalance, inflammatory amplification, lipid dysregulation, and unresolved ER stress — as hypothesized upstream drivers of microglial senescence, characterized by p16INK4a upregulation, SA-β-gal activity, and SASP secretion that sustains chronic neuroinflammation in Alzheimer's disease. A four-tier evidence-grading framework distinguishes dystrophic, disease-associated (DAM), and bona-fide senescent microglia using transcriptomic and proteomic data.
The framework here is intellectually rigorous but the authors' own evidence audit is sobering: over 90% of mechanistic data derives from non-microglial cell models, meaning MERCS dysfunction in microglia specifically remains an evidence-thin hypothesis requiring direct in-vivo validation. The acknowledgment that APOE/TREM2 signaling and MERCS engage in bidirectional crosstalk — rather than a clean linear cascade — reflects genuine biological complexity that most AD pathway papers flatten. This matters because senolytics targeting p16INK4a-positive microglia are gaining traction clinically, yet without confirmed MERCS causality in human microglia, combinatorial strategies risk being mechanistically untethered. Translational barriers — poor blood-brain barrier penetration, off-target neurotoxicity, and APP/PS1 models lacking tauopathy — are honestly flagged. As a review, this is a conceptually generative but speculative contribution; incremental for the longevity field until in-vivo microglial MERCS data emerges.