Hypothesis

Telomeres function as a dynamic readout of cellular informational entropy, integrating microbiome‑derived short‑chain fatty acids (SCFAs) via NAD+-dependent sirtuin signaling to adjust chromatin stability and DNA repair capacity. Under acarbose treatment, elevated colonic propionate increases hepatic NAD+ levels, activating SIRT1, which deacetylates telomere‑associated proteins (e.g., TRF2) and promotes a controlled telomere shortening that reflects a lower‑entropy metabolic state. This adaptive telomere remodeling enhances stress resistance and extends lifespan, whereas in humans the same SCFA exposure overwhelms NAD+ buffering, leading to net telomere attrition without the compensatory sirtuin activation, thus appearing as accelerated aging.

Predictions

1. In acarbose‑treated mice, hepatic NAD+ and SIRT1 activity will rise concurrently with propionate elevation, and telomere shortening will correlate with increased SIRT1‑dependent deacetylation of shelterin components.
2. Pharmacologic inhibition of SIRT1 (e.g., EX527) will block the lifespan‑extending effect of acarbose despite preserving propionate levels and will abolish the telomere‑shortening signal.
3. Propionate supplementation alone will recapitulate the mouse telomere dynamics and lifespan extension, but only when NAD+ biosynthesis is intact; NAD+ depletion will prevent telomere changes and longevity benefits.
4. In human leukocytes from diabetic patients on acarbose, NAD+ levels will be unchanged or decreased, and SIRT1 activity will not increase, explaining the observed telomere shortening without longevity benefit.

Experimental Approach

• Treat cohorts of male C57BL/6 mice with acarbose, propionate, or vehicle, with/without EX527 or NAD+ precursor (NR) supplementation. Measure colonic SCFA, hepatic NAD+, SIRT1 activity, telomere length (qFISH), shelterin acetylation, and survival.
• Parallel human PBMC study: collect leukocytes from diabetic patients before and after 6 months of acarbose, quantify NAD+/NADH, SIRT1 activity, telomere length, and inflammatory markers.
• Use single‑cell RNA‑seq to assess transcriptomic noise as a proxy for informational entropy; predict reduced noise in mice with acarbose‑induced telomere shortening and elevated SIRT1.

Falsifiability If SIRT1 inhibition does not diminish acarbose‑mediated lifespan extension, or if telomere length manipulation (via telomerase overexpression) fails to alter the metabolic benefits, the hypothesis that telomeres encode metabolic informational entropy via sirtuin signaling would be refuted.

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