Hypothesis

Core proposition

Acarbose extends lifespan by increasing colonic butyrate, which activates a vagal‑to‑liver FGF21 hormetic axis. This signal mimics a persistent nutrient‑scarcity state without reducing caloric intake, and its magnitude is modulated by sex‑dependent intestinal barrier integrity and estrogen‑regulated butyrate transport.

Mechanistic pathway

1. Acarbose inhibits intestinal α‑glucosidases → more undigested carbs reach the colon → microbiota ferment them to produce butyrate and other SCFAs【https://pmc.ncbi.nlm.nih.gov/articles/PMC8190416/】.
2. Colonic butyrate enters the portal circulation and stimulates vagal afferents expressing FFAR2/3 receptors, triggering a neuroendocrine signal to the hypothalamus【https://gethealthspan.com/science/article/acarbose-and-rapamycin-longevity】.
3. Vagal signaling upregulates hepatic FGF21 expression via a CRF‑dependent cascade, raising circulating FGF21 levels (observed opposite to true caloric restriction)【https://digitalcommons.library.uab.edu/etd-collection/1257/】.
4. Elevated FGF21 activates adipose lipolysis and ketogenesis, reinforcing a perceived energy‑deficit state and engaging downstream stress‑resistance pathways (AMPK, SIRT1) that prolong lifespan【https://pmc.ncbi.nlm.nih.gov/articles/PMC3954939/】.
5. The hormetic loop is sustained as long as acarbose is present, creating a continuous “false scarcity” cue.

Sex specificity

• Estradiol enhances expression of the monocarboxylate transporter MCT1 in intestinal epithelium, increasing butyrate uptake in females and thereby blunting the vagal signal【https://pmc.ncbi.nlm.nih.gov/articles/PMC6413665/】.
• Consequently, males experience a stronger vagal‑FGF21 response, translating into a larger lifespan extension (up to 22 % vs ~5 % in females)【https://gethealthspan.com/science/article/acarbose-and-rapamycin-longevity】.
• Ovariectomy or estrogen‑receptor antagonism in females should raise colonic butyrate spillover and mimic the male phenotype.

Testable predictions

• Vagotomy (subdiaphragmatic) in male mice treated with acarbose will abolish the increase in hepatic FGF21 and the lifespan benefit, without affecting gut microbiome changes.
• Pharmacological blockade of hepatic FGFR2/β‑Klotho complex (using an antagonist antibody) will prevent acarbose‑induced lifespan extension while leaving microbiota alterations intact.
• Female mice given an estrogen receptor antagonist (e.g., fulvestrant) alongside acarbose will show a male‑like rise in hepatic FGF21 and a proportional increase in median lifespan.
• Butyrate supplementation (sodium butyrate) in germ‑free mice colonized with a butyrate‑producing strain should recapitulate the vagal‑FGF21 axis and extend lifespan, even in the absence of acarbose.
• Metabolomic profiling will reveal that acarbose‑treated males have higher portal butyrate concentrations and lower circulating insulin/IGF‑1 than females, correlating with FGF21 levels.

Potential falsifications

If any of the following occur, the hypothesis is weakened:

• Vagotomy does not reduce hepatic FGF21 or lifespan extension in acarbose‑treated males.
• Hepatic FGFR2/β‑Klotho blockade fails to impact lifespan despite confirmed target engagement.
• Estrogen antagonism in females does not raise hepatic FGF21 or lifespan to male levels.
• Direct butyrate supplementation fails to stimulate vagal signaling or lifespan extension.
• Portal butyrate levels do not differ between sexes despite opposite lifespan outcomes.

This framework shifts the focus from “mimicking scarcity” to a definable gut‑brain‑liver endocrine axis that translates microbial metabolism into a sex‑specific hormetic cue, offering concrete intervention points to dissect whether life extension stems from simulated adversity or from activating a conserved longevity program.