Hypothesis

Rapamycin extends lifespan by activating a famine‑response transcriptional program that specifically rejuvenates epithelial barrier tissues through stem‑cell niche remodeling, while in non‑barrier tissues it chiefly slows damage accumulation.

Mechanistic rationale

Both rapamycin and caloric restriction suppress mTORC1, leading to ULK1/ATG13 dephosphorylation and autophagy induction 2. However, nutrient scarcity also activates the FOXO‑TFEB axis, which drives lysosomal biogenesis and expression of stem‑cell‑supportive factors such as Wnt3a and Notch ligands in the intestinal crypt and oral mucosa 5. We propose that this FOXO‑TFEB‑dependent program is engaged only when mTORC1 inhibition coincides with low intracellular amino acid levels, a condition that rapamycin mimics but does not fully replicate in metabolically active tissues like muscle or brain. In barrier epithelia, the transient drop in mTORC1 signaling lifts repression of Paneth‑cell‑derived Wnt, expanding the stem‑cell pool and enhancing tissue repair, which manifests as periodontal bone regeneration and a youthful microbiome 5. In contrast, tissues lacking this niche feedback rely on autophagy alone to clear damaged proteins, resulting in a slower accrual of damage without genuine rejuvenation.

Testable predictions

1. Stem‑cell activity: In aged mice treated with rapamycin, lineage‑tracing of Lgr5+ intestinal stem cells will show a higher symmetric division rate compared with pair‑fed controls, an effect abolished by intestinal‑specific Raptor knockout (mTORC1 loss) or by pharmacological inhibition of FOXO (e.g., AS1842856).
2. Barrier‑tissue rejuvenation: Rapamycin will increase expression of Wnt3a and DLL4 in the crypt and gingival epithelium, detectable by qPCR and immunofluorescence, while similar increases will not be observed in skeletal muscle or hippocampus.
3. Damage markers: γH2AX foci and SASP IL‑6 levels will decline in oral mucosa and intestinal villi after rapamycin treatment, but will remain unchanged in liver and kidney, indicating tissue‑specific damage reversal.
4. Nutrient‑signal dependence: Adding a leucine bolus to rapamycin‑treated mice will blunt the stem‑cell proliferative response and the reduction in senescence markers, confirming that low amino acid signaling is required for the rejuvenative arm.
5. Lifespan contribution: Mice with barrier‑tissue‑specific Raptor deletion will recapitulate the lifespan extension of rapamycin despite systemic mTORC1 activity being intact elsewhere, suggesting that the longevity benefit is driven largely by niche rejuvenation in barrier tissues.

Potential falsification

If rapamycin fails to increase stem‑cell symmetric division or niche factor expression in barrier tissues, or if these changes occur equally in non‑barrier organs, the hypothesis that lifespan extension stems from a tissue‑specific famine‑response program would be refuted. Conversely, if systemic mTORC1 inhibition alone (without nutrient‑signal mimicry) yields identical stem‑cell effects, the nutrient‑scarcity mimicry premise would be weakened.