Hypothesis: Chronic mTORC1 activation in aged enterochromaffin progenitors locks them into a proliferative, differentiated state that exhausts serotonin synthesis capacity, and intermittent rapamycin treatment can reset the progenitor pool to restore 5-HT output and gut motility.

Mechanistic rationale

Aging epithelium shows accumulated mTORC1 activity due to persistent nutrient and insulin signaling 2 3. In intestinal crypts, high mTORC1 drives stem cell proliferation toward absorptive lineages, suppressing secretory fate 4. Enterochromaffin (EC) cells arise from secretory progenitors; thus, sustained mTORC1 biasing may divert progenitors away from the EC lineage, reducing EC numbers and mucosal 5-HT as observed in aged or constipated phenotypes 1.

Moreover, EC cells themselves use mTORC1 as a nutrient sensor to couple luminal short‑chain fatty acids (SCFAs) to TPH1 transcription 5 6. When mTORC1 is chronically high, feedback inhibition via S6K1 can blunt SCFA‑FFAR2 signaling, diminishing the nutrient‑dependent boost in TPH1 expression. Consequently, even if SCFAs are present, EC cells fail to up‑regulate serotonin synthesis, contributing to low mucosal 5-HT despite adequate microbial metabolites.

Testable prediction

Intermittent rapamycin dosing (e.g., 5 mg/kg i.p. twice weekly) in aged mice will:

1. Decrease phospho‑S6K1 levels specifically in crypt EC progenitors (identified by Chromogranin A‑GFP reporters) without abolishing basal mTORC1 needed for epithelial renewal.
2. Increase the proportion of Chromogranin A⁺/TPH1⁺ cells in the colon and ileum after 4 weeks, indicating lineage rescue.
3. Elevate mucosal 5-HT measured by HPLC, restore SCFA‑induced TPH1 upregulation ex vivo, and accelerate colonic transit in a slow‑transit constipation model.
4. These effects will be absent in mice lacking FFAR2 in EC cells, confirming that rapamycin’s benefit requires intact SCFA sensing.

Falsifiable outcomes

• If rapamycin reduces EC numbers or 5-HT despite restored progenitor markers, the hypothesis is falsified.
• If EC‑specific mTORC1 inhibition (via Raptor‑fl/‑ crossed to Chromogranin A‑Cre) fails to improve motility, then mTORC1’s role is not lineage‑biased but rather secretory‑cell intrinsic.
• If SCFA supplementation cannot rescue TPH1 expression in rapamycin‑treated aged ECs, then the nutrient‑sensing link is not operative.

Broader implication

Treating mTORC1 not as a binary longevity switch but as a dial that tunes progenitor fate suggests that timed, low‑dose rapamycin could preserve the intestinal civilization of specialized secretory cells while still conferring systemic stress resistance. This reframes anti‑aging strategies: we may not need to abandon cellular specialization altogether, but rather periodically reset the dial to prevent lineage exhaustion.