Hypothesis

Aged cells actively suppress autophagy by routing TFEB to lysosomes for degradation, linking mTORC1 hyperactivity to inflammasome‑driven SASP persistence.

Mechanistic rationale

• mTORC1 phosphorylates TFEB on serine residues, promoting its cytoplasmic retention and exposing a degron recognized by the lysosomal chaperone‑mediated autophagy receptor LAMP2A.mTORC1 hyperactivation
• Concurrently, age‑related decline in AMPK and SIRT1 reduces inhibitory phosphorylation of mTORC1 and fails to deacetylate ATG proteins, tipping the balance toward TFEB lysosomal targeting.AMPK/SIRT1 decline
• Lysosomal acidification and cathepsin activity then degrade sequestered TFEB, lowering nuclear TFEB levels below the threshold required for autophagy gene transcription.Epigenetic silencing of autophagy genes
• Loss of TFEB‑driven lysosomal biogenesis impairs autophagosome‑lysosome fusion, causing accumulation of damaged mitochondria that release mtDNA and activate the cGAS‑STING pathway, amplifying NF‑κB‑mediated SASP.SASP and autophagy threshold model
• The resulting inflammatory milieu further activates mTORC1 via IL‑6/JAK/STAT signaling, creating a feed‑forward loop that sustains TFEB loss and autophagy suppression.Young plasma restores autophagy

Testable predictions

1. In aged murine liver, inhibiting lysosomal proteolysis with leupeptin will increase TFEB half‑life and restore nuclear TFEB without altering mTORC1 activity.
2. Genetic ablation of LAMP2A in senescent fibroblasts will attenuate SASP IL‑6 and IL‑8 secretion despite persistent mTORC1 activation.
3. Administration of a TFEB‑stabilizing peptide that blocks LAMP2A interaction will reduce SASP markers and improve tissue function in progeroid mice, an effect abolished by concomitant mTORC1 activation.
4. Young plasma transfer will fail to rescue autophagy in aged animals if lysosomal degradation is genetically enhanced, indicating that reversal depends on TFEB stability rather than mere mTORC1 inhibition.

Falsifiability

If lysosomal inhibition does not elevate nuclear TFEB or if SASP remains unchanged when TFEB degradation is blocked, the hypothesis that active TFEB lysosomal degradation underlies autophagy suppression would be refuted, favoring a model of purely translational or transcriptional blockade.

Therapeutic implication

It's hypothesized that targeting the LAMP2A‑TFEB interaction offers a node to uncouple autophagy suppression from inflammasome activation without globally inhibiting mTORC1, which may preserve anabolic signaling needed for tissue repair. We're optimistic that small‑molecule inhibitors of LAMP2A‑TFEB binding or gene‑silencing approaches could be evaluated in aged models for reduction of SASP and improvement of metabolic homeostasis. Combining such agents with intermittent rapamycin dosing might synergistically restore autophagic flux while minimizing immunosuppressive side effects.