Acarbose extends lifespan in male ITP mice by delaying carbohydrate digestion and reshaping the gut microbiome, which elevates colonic short‑chain fatty acids (SCFAs) that correlate with longevity [1][2][5][6]. We hypothesize that these SCFAs—particularly butyrate—act as histone deacetylase (HDAC) inhibitors in intestinal stem cells, increasing acetylation of shelterin complex genes (e.g., TRF2, POT1) and thereby stabilizing telomere chromatin. This epigenetic tightening reduces the informational entropy of telomeric DNA, slowing the stochastic loss of telomeric repeats that occurs independently of cell‑division count. Consequently, telomere length is maintained not as a mitotic counter but as a fidelity metric of biological information processing.

Sex differences arise because estrogen signaling modulates the expression of SCFA receptors (GPR41/43, GPR109A) and telomerase activity. In males, lower basal estrogen yields higher receptor density, amplifying butyrate‑driven HDAC inhibition and telomere protection, which explains the pronounced male‑specific lifespan extension (up to 22%) when acarbose is given alone [1]. Females exhibit higher estrogen, which down‑regulates these receptors and favors alternative metabolic pathways, attenuating the SCFA‑telomere link and resulting in a modest 5% benefit. When rapamycin is added, mTOR inhibition broadly enhances autophagy and reduces inflammatory cytokine IL‑6, overriding the receptor disparity and equalizing telomere preservation across sexes, thereby abolishing the sex gap in combination therapy [7].

Testable predictions: (1) Male mice treated with acarbose from 4 months will show increased telomere length and reduced γH2AX foci in colonic crypt stem cells compared with untreated controls; this effect will be absent in GPR43‑knockout males. (2) Pharmacological blockade of HDAC activity (e.g., with trichostatin A) will mimic acarbose’s telomere‑preserving effect, whereas HDAC over‑expression will negate it. (3) Supplementing females with a physiological dose of estradiol will diminish acarbose‑induced telomere stabilization, while androgen supplementation in castrated males will enhance it. (4) Metabolomic profiling will reveal elevated butyrate‑dependent histone acetylation marks (H3K9ac, H3K27ac) at telomere‑associated gene promoters exclusively in responders.

If acarbose fails to lengthen telomeres or if telomere length changes do not correlate with SCFA levels, receptor status, or HDAC inhibition, the hypothesis is falsified. Conversely, confirming these links would reframe telomeres as dynamic informational buffers whose integrity is governed by microbial metabolites and hormonal milieu, positioning aging as a manageable entropy‑regulation problem rather than an immutable mitotic timer.