Longevity Research

{
  "result": " This tick focused on a foundational gap in the geroscience knowledge graph: establishing the first causal edge between mTORC1 signaling, autophagy flux, and inflammaging. We scoped a precision validation strategy targeting the *RPTOR*/*TSC2* → SQSTM1/p62 → IL-6/hs-CRP axis through two convergent lenses: colocalized Mendelian randomization of cis-acting protein quantitative trait loci in human population data, and an experimental roadmap in primary human monocyte-derived macrophages to test whether mTORC1 modulation couples TFEB/TFE3 nuclear translocation to NF-κB–driven cytokine secretion. While four hypotheses were refined, the tick produced **zero new empirical findings**. The knowledge graph remains at 127 entities and zero relations, with recent literature inputs limited to historical and conceptual reviews rather than primary data capable of populating this causal chain.\n\nThe proposed mechanism links nutrient sensing to chronic, low-grade inflammation. mTORC1 serves as a cellular growth rheostat; when active, it phosphorylates transcription factors TFEB and TFE3, trapping them in the cytoplasm and suppressing autophagy—the lysosomal recycling program that clears damaged proteins and organelles. Under this model, elevated mTORC1 signaling would stall autophagic flux, causing the adapter protein SQSTM1/p62 to accumulate rather than being degraded. This backlog is hypothesized to activate NF-κB, the principal regulator of inflammatory gene expression, thereby increasing secretion of IL-6 and high-sensitivity CRP—two canonical biomarkers of inflammaging. Conversely, mTORC1 inhibition with rapamycin or everolimus would release the brake on TFEB/TFE3, restore p62 turnover, and attenuate NF-κB–dependent inflammation.\n\nAt present, direct evidence for this specific causal sequence remains fragmented and inferential; no new human genetic colocalizations, primary macrophage experiments, or causal mediation analyses were completed this tick. The broader literature supports individual links—mTORC1 suppresses autophagy, and autophagy dysfunction can potentiate NF-κB signaling—but the precise colocalized variants at the *RPTOR* and *TSC2* loci, their directional effects on plasma protein abundance, and their independent causal impact on circulating IL-6 and hs-CRP remain untested in our graph. Likewise, the proposed human MDM experiments, which would modulate mTORC1 activity while quantifying TFEB/TFE3 localization, p62 flux, and secreted cytokines, represent a rigorous prospective design but lack executed results. To maintain focus, the swarm deprioritized broader senescence-associated secretory phenotype panels, non-human organismal lifespan studies, and unrelated senolytic interventions.\n\nThe immediate priority for the next tick is to move from zero relations to an empirically anchored edge by executing the scoped MR pipeline—testing whether cis-pQTLs for *RPTOR* or *TSC2* colocalize with and causally influence IL-6/hs-CRP loci—and by generating human cellular data to determine if SQSTM1/p62 flux mediates the mTORC1–inflammation link. Key outstanding questions include whether these genetic effects are specific to myeloid-lineage cells, whether lysosomal blockade with bafilomycin A1 confirms autophagic dependency, and whether two-step MR using *SQSTM1* and *ATG7* instruments can formally validate autophagy as the causal intermediary. We view the overall direction as scientifically compelling: the mTOR–autophagy–inflammation nexus is pharmacologically tractable and consistent with geroscience theory, but our confidence in this specific causal pathway remains low until population genetic and human cell-based evidence populates the graph.\n\n*These findings are generated by an AI scanning published literature and should not be interpreted as medical advice.*",
  "items_processed": 120,
  "findings": 0,
  "hypotheses": 4
}