Hypothesis

Cold exposure extends lifespan by reshaping the gut microbiome to increase short‑chain fatty acid (SCFA) production, which stimulates enteroendocrine L‑cells to release glucagon‑like peptide‑1 (GLP‑1). GLP‑1 activates vagal afferents that relay signals to the nucleus tractus solitarius, dampening HPA‑axis drive and reducing neuroinflammation. If this bottom‑up cascade is required, then interrupting vagal afferent signaling or GLP‑1 receptor activity will abolish the longevity benefit of cold exposure, whereas central manipulations alone will not reproduce it.

Mechanistic rationale

• Cold stress (e.g., 4 °C water immersion) shifts the murine microbiome toward taxa that ferment fiber to butyrate and propionate (3).
• Elevated luminal SCFAs bind FFAR2/FFAR3 on L‑cells, triggering GLP‑1 secretion into the portal circulation and onto nearby vagal afferents (1).
• Vagal afferents convey GLP‑1–mediated signals to the nucleus tractus solitarius, which inhibits corticotropin‑releasing hormone neurons, lowering glucocorticoid tone and microglial activation.
• Reduced glucocorticoid exposure preserves hippocampal integrity and dampens inflammaging, thereby extending lifespan.

Testable predictions

1. Vagal transection (subdiaphragmatic vagotomy) in mice undergoing chronic cold exposure will not show the lifespan increase seen in sham‑operated cold‑exposed controls, while sham mice will retain the benefit.
2. GLP‑1 receptor antagonism (e.g., exendin‑(9‑39)) administered during cold exposure will block the extension of median survival without affecting core temperature or brown‑fat activation.
3. Oral butyrate supplementation at doses that mimic cold‑induced luminal concentrations will recapitulate the longevity benefit in mice kept at thermoneutrality, and this effect will be lost after vagal ablation.
4. Central overexpression of GLP‑1 in the hypothalamus will not extend lifespan unless vagal afferents are intact, demonstrating that the brain cannot substitute for missing gut‑derived signals.

Falsifiability

If any of the above manipulations fail to alter the lifespan outcome as predicted—for instance, if vagotomy does not diminish cold‑induced longevity or if butyrate feeding fails to extend life in warm‑housed animals—the hypothesis would be refuted. Conversely, confirmation of the predicted dependencies would support a bottom‑up model in which gut‑originating signals set the brain’s homeostatic baseline for aging interventions.