Hypothesis\nThe selective autophagy hierarchy is controlled by a reversible ubiquitin-like modification on autophagy receptors that acts as a priority tag. A specific deubiquitinase (DUB) removes low‑priority tags, allowing high‑priority cargo such as damaged mitochondria to access the core machinery. With age, DUB activity declines, causing low‑priority tags to persist and distort the hierarchy, leading to defective mitophagy, mtDNA release, and chronic type I interferon production.\n\n## Mechanistic Basis\nAutophagy receptors (e.g., NIX, p62, OPTN, FAM134B) compete for limited LC3/GABARAP pools. Their affinity is modulated by ubiquitin chains on both cargo and receptor itself. We propose that a DUB, here termed AUTODEUB1, selectively cleaves K63‑linked ubiquitin on receptors that bind low‑affinity cargos (e.g., lipid droplets, certain protein aggregates). When AUTODEUB1 is active, these receptors are de‑ubiquitinated, lowering their affinity and freeing LC3 for high‑priority receptors (e.g., NIX for mitophagy). Aging reduces AUTODEUB1 expression or activity, resulting in persistent ubiquitination of low‑priority receptors, which outcompete high‑priority ones for LC3, skewing flux toward non‑essential cargo and sparing mitochondria.\n\nThis model explains several observations:\n- In young cells, mitophagy and xenophagy dominate during stress (see [1]).\n- Aged macrophages retain lipid droplets and cholesterol, indicative of misrouted lipophagy ([4]).\n- Cytosolic mtDNA activates cGAS‑STING, driving IFN‑I ([3]).\n- Defective degradation of innate immune signaling kinases removes negative feedback ([5]).\n- Stress‑induced shifts toward ER‑phagy can be temporally distinct ([2]).\n\n## Testable Predictions\n1. AUTODEUB1 levels or activity will be inversely correlated with age across tissues and with markers of mitophagy deficiency (e.g., mitochondrial membrane potential, mtDNA copy number).\n2. Overexpression of AUTODEUB1 in aged macrophages will restore mitophagy priority, reduce cytosolic mtDNA, and lower IFN‑β secretion.\n3. Inhibition of AUTODEUB1 in young cells will phenocopy the aged hierarchy: increased lipophagy and ER‑phagy, decreased mitophagy, and elevated cGAS‑STING signaling.\n4. Mutating the ubiquitin‑acceptor sites on a low‑priority receptor (e.g., OPTN) to prevent ubiquitination will rescue mitophagy in AUTODEUB1‑deficient cells without altering overall autophagy flux.\n\n## Potential Experiments\n- Measure AUTODEUB1 protein and DUB activity in liver, brain, and bone marrow from young (3 mo) and old (24 mo) mice using activity‑based probes; correlate with LC3‑II turnover and mito‑Keima signal.\n- Generate myeloid‑specific AUTODEUB1 knockout mice; assess lipid droplet accumulation (BODIPY staining), mitochondrial ROS, and serum IFN‑α/β levels.\n- Use CRISPR‑a to upregulate AUTODEUB1 in primary human aged macrophages; track mitophagy (mt‑Keima), IFN‑β ELISA, and NLRP3 inflammasome activation (caspase‑1 cleavage).\n- Express ubiquitin‑resistant OPTN mutants in AUTODEUB1‑deficient cells; evaluate LC3 colocalization and mitochondrial clearance via confocal microscopy.\n\nIf these predictions hold, the hypothesis reframes age‑related autophagy failure not as a loss of bulk capacity but as a corrupted priority system, offering a precise node—AUTODEUB1—for therapeutic intervention to restore the autophagy triage and curb inflammaging.