Hypothesis

Acarbose extends lifespan primarily in male mice by increasing colonic butyrate, which activates an androgen‑receptor‑dependent hepatic FGF21 signaling cascade that promotes autophagy and reduces inflammation; females lack sufficient androgen signaling to translate the butyrate signal into comparable FGF21 upregulation, explaining the observed sex dimorphism.

Mechanistic Model

1. Microbiome shift – Acarbose inhibition of α‑glucosidase delivers more resistant starch to the colon, enriching butyrate‑producing taxa (e.g., Lactobacillus, Bifidobacterium) and raising fecal butyrate【4†L1-L3】.
2. Butyrate signaling – Butyrate reaches the portal circulation, acts as a histone deacetylase inhibitor and activates GPR109A on enteroendocrine cells, stimulating secretion of GLP‑1 and peptide YY【6†L1-L2】.
3. Androgen receptor cross‑talk – In males, testicular androgen receptors (AR) are highly expressed in hepatocytes; butyrate‑induced HDAC inhibition increases AR transcriptional activity, leading to up‑regulation of the fibroblast growth factor 21 (Fgf21) gene【7†L1-L4】.
4. FGF21 effects – Hepatic FGF21 stimulates autophagy via AMPK‑ULK1 signaling, improves insulin sensitivity, and suppresses NF‑κB‑driven inflammation, collectively extending healthspan【3†L1-L3】.
5. Female limitation – Lower circulating testosterone and reduced hepatic AR expression blunt the butyrate‑AR‑FGF21 axis, so the same microbiome shift yields only modest metabolic improvement and a small lifespan gain.

Testable Predictions

• Prediction 1: Castrated male UM‑HET3 mice treated with acarbose will show a loss of the lifespan extension seen in intact males, while ovariectomized females will not be further affected.
• Prediction 2: Hepatic‑specific knockdown of androgen receptor in males will abolish acarbose‑induced Fgf21 mRNA elevation and attenuate the longevity benefit.
• Prediction 3: Supplementing female mice with a physiological dose of testosterone (or a selective AR agonist) together with acarbose will rescue the male‑level increase in fecal butyrate‑correlated FGF21 expression and extend median lifespan to ≈20%.
• Prediction 4: Pharmacological inhibition of butyrate production (e.g., with antibiotics targeting Lactobacillus/Bifidobacterium) will prevent the acarbose‑induced rise in hepatic FGF21 and erase the sex‑specific survival advantage.

Each prediction can be evaluated in the ITP framework using survival analysis, liver RNA‑seq, and hormone measurements, providing a clear falsifiable route: if any of the interventions fail to modify the sex‑specific lifespan outcome, the hypothesis is refuted.

References

[1] JAX ITP page – acarbose sex‑specific effects [2] March 2026 ITP update – negative compounds [3] Acarbose mechanism – glucose‑insulin blunting [4] Microbiome and SCFA changes – butyrate elevation [5] Reversibility of microbiome shifts [6] Human prediabetic trial – SCFA increase [7] Sex dimorphism discussion – baseline microbiome [8] Human translation uncertainty