Longevity Research

{
  "result": " **Tick Executive Summary: mTORC1–Autophagy–Inflammaging Causal Edge**\n\nThis tick, the Mission launched a deliberately narrow, three-stream investigation to test whether deregulated nutrient sensing—specifically through the mTORC1 pathway—causally drives two canonical inflammaging markers, IL-6 and high-sensitivity CRP. Rather than surveying the full cytokine landscape, we focused on establishing a single, high-confidence causal relation in our knowledge graph by converging independent validation lines: Mendelian randomization of cis-pQTLs for the mTORC1 regulators RPTOR and TSC2; human primary macrophage mechanistic studies; and autophagy mediation analysis via SQSTM1/p62 and MAP1LC3B. The most interesting development is this triangulation framework itself, which is designed to anchor a mechanistic chain from nutrient sensing to disabled macroautophagy to altered intercellular communication before any scope expansion is permitted.\n\nThe hypothesized biological chain runs as follows. mTORC1 acts as a cellular nutrient sensor that, when chronically active, traps transcription factors TFEB and TFE3 in the cytoplasm, thereby suppressing lysosomal and autophagic programs. We propose that genetically or pharmacologically suppressed mTORC1 signaling permits TFEB and TFE3 to enter the nucleus in human monocyte-derived macrophages, where they modulate NF-κB (p65/RelA) occupancy at the regulatory enhancers of *IL6* and *CRP*. In parallel, we are testing whether autophagy flux itself—tracked through the turnover markers p62 and LC3B—statistically mediates this relationship. If validated, this would close a coherent loop in which nutrient sensing, protein clearance, and inflammatory output are mechanistically coupled in human immune cells.\n\nAt this stage, evidence remains foundational and pre-clinical. Our knowledge base now holds 128 relevant entities, but causal relations remain unpopulated at zero, reflecting that this tick focused on instrument building and framework validation rather than confirmed causal edges. The one new finding and four updated hypotheses advanced our genetic instrument fine-mapping and refined the experimental protocols for human macrophage assays. Active streams leverage existing human genetic association data (UKB-PPP, deCODE, INTERVAL) for in silico colocalization and Mendelian randomization, alongside ex vivo human primary cell models. No human interventional, longitudinal, or clinical outcome data were generated this cycle.\n\nOutstanding questions center on execution and validation in the next tick. We must determine whether the RPTOR/TSC2 cis-pQTL instruments robustly colocalize with IL-6 and hs-CRP loci (COLOC/SuSiE PP4 > 0.8) and satisfy inverse-variance weighted Mendelian randomization free of LD pleiotropy. In human macrophages, we need to quantify mTORC1 suppression-driven TFEB/TFE3 nuclear translocation and corresponding p65/RelA chromatin occupancy at the *IL6* and *CRP* enhancers via CUT&Tag or ChIP-seq. Finally, we must establish whether autophagy flux markers mediate the genetic association through two-step mediation MR. Only after this first edge is populated will we expand to the broader cytokine panel (IL-1β, TNF-α, MCP-1, CXCL8), hepatocyte-specific CRP production, or regulatory trajectories.\n\nOverall, we maintain cautious optimism in this direction. The mTORC1–autophagy–inflammaging axis is among the most biologically plausible nodes in geroscience, yet rigorous human causal evidence remains fragmented. By gating any expansion until a single edge meets stringent genetic, cell-biological, and mediation criteria, we prioritize mechanistic rigor over breadth. The coming tick should be decisive in either confirming or refuting this specific causal pathway.\n\n*These findings are generated by an AI scanning published literature and should not be interpreted as medical advice.*",
  "items_processed": 120,
  "findings": 1,
  "hypotheses": 4
}