Hypothesis\n\nAcarbose extends male lifespan by increasing colonic butyrate production, which activates hepatic FGF21 signaling to inhibit mTORC1 in an androgen‑dependent manner.\n\n## Mechanistic Rationale\n\n- It's known that acarbose blocks α‑glucosidase, delivering undigested starch to the colon where it fuels SCFA‑producing bacteria, raising butyrate levels 3.\n- Butyrate, a histone deacetylase inhibitor, can upregulate Fgf21 expression in hepatocytes via PPARα activation 4.\n- Hepatic FGF21 acts as an endocrine hormone that suppresses mTORC1 signaling, mimicking caloric restriction and rapamycin effects 8.\n- Male mice have higher androgen receptor activity in liver, which synergizes with FGF21 to further dampen mTORC1, whereas females lack this amplification, explaining the modest lifespan gain.\n\n## Testable Predictions\n\n1. Germ‑free or antibiotic‑treated male mice fed acarbose will show no increase in fecal butyrate, no hepatic FGF21 rise, and no lifespan extension.\n2. Oral butyrate supplementation in germ‑free males on acarbose will rescue FGF21 upregulation and lifespan benefit.\n3. Liver‑specific Fgf21 knockout males will abolish acarbose‑mediated mTORC1 inhibition and longevity, despite normal microbiome shifts.\n4. Castration of males will reduce the acarbose‑induced lifespan effect to female‑level levels, while androgen replacement in females will enhance it.\n5. Pharmacologic inhibition of HDAC (e.g., with sodium butyrate) will mimic acarbose’s effect on FGF21 only when the microbiome is intact.\n\n## Potential Confounds and Controls\n\n- Ensure diet starch content is constant; high‑starch diets amplify microbiome shifts 2.\n- Monitor food intake and body weight to rule out caloric restriction as a confounder.\n- Use sex‑matched controls and verify hormone levels via serum testosterone/estradiol assays.\n- Include rapamycin co‑treatment groups to test whether the acarbose‑butyrate‑FGF21 axis acts independently or additively to mTOR inhibition.\n\n## Falsification\n\nIf any of the following occurs, the hypothesis is falsified:\n- Acarbose extends lifespan in germ‑free males.\n- Butyrate supplementation fails to raise hepatic FGF21 in intact males.\n- Liver Fgf21 knockout does not affect acarbose‑induced longevity.\n- Manipulating androgen status does not alter the sex‑specific magnitude of lifespan extension.