The gut-to-brain axis drives lifespan extension, yet we lack epigenomic maps of the intestinal cells that produce the key metabolites. I hypothesize that age‑dependent loss of YY1‑mediated super‑enhancer–promoter loops in intestinal stem cells (ISCs) directly diminishes transcription of SCFA transporters and lipid‑desaturase enzymes, cutting the supply of gut‑derived signals that sustain brain health. Restoring YY1 activity in ISCs should rescue butyrate uptake, reestablish vagal afferent signaling, and extend lifespan even when brain‑centric interventions fail.

First, we predict that aged ISCs show reduced H3K27ac enrichment at super‑enhancers controlling Slc5a8 (the sodium‑butyrate cotransporter) and Fads2 (a fatty‑acid desaturase) compared with young ISCs. This predicts a >50 % drop in allele‑specific expression of these genes in sorted Lgr5+ ISCs from 24‑month mice versus 3‑month controls, measurable by ATAC‑seq and RNA‑seq (see chromatin changes in aged muscle MSCs [3][4]). Second, we anticipate that fecal and portal‑vein butyrate concentrations will fall proportionally, leading to diminished activation of vagal afferents (reduced c‑Fos in the nucleus tractus solitarius) and lower hippocampal BDNF levels. Third, we expect that conditional overexpression of YY1 specifically in ISCs (using Villin‑CreERT2;Rosa26‑YY1) in aged mice will restore Slc5a8/Fads2 expression, normalize butyrate flux, improve vagal signaling, and extend median lifespan by ~15 % relative to littermate controls, without altering neuronal YY1 levels.

Falsifiable outcomes: If YY1 overexpression fails to increase butyrate transporter expression or does not rescue vagal activity and longevity, the hypothesis is refuted. Conversely, if pharmacological butyrate supplementation in YY1‑deficient ISC mice restores brain phenotypes despite the epigenetic defect, it would suggest the metabolite acts downstream of YY1, refining the model.

Mechanistically, YY1 may recruit p300/CBP to maintain open chromatin at enhancer‑promoter hubs; its loss permits HDAC‑mediated compaction, silencing transporter genes. Notably, butyrate itself inhibits HDACs, creating a potential positive feedback loop where microbial butyrate sustains YY1‑dependent enhancer activity—a circuit that collapses with age‑associated microbiome shifts. Testing this loop requires measuring HDAC activity in ISCs before and after butyrate exposure in vitro.

By positioning YY1‑driven enhancer architecture as the gatekeeper of gut‑derived longevity signals, this hypothesis shifts the focus from brain‑centric to gut‑centric interventions, offering a concrete, epigenetically grounded target for extending healthspan.

[1] https://www.youtube.com/watch?v=xwvpbmlYQR0 [2] https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2788843 [3] https://pmc.ncbi.nlm.nih.gov/articles/PMC12155207/ [4] https://pmc.ncbi.nlm.nih.gov/articles/PMC12740102/