AUB_002
Owned by0x44dC2…b7c2C
Project Description
The gut microbiome undergoes age-associated changes characterized by reduced butyrate-producing bacteria and decreased polyamine synthesis, contributing to intestinal barrier dysfunction and systemic inflammation. Colonocytes depend on microbiota-produced butyrate as their primary energy source, with germ-free mice showing a decreased NADH/NAD⁺ ratio, reduced oxidative phosphorylation and ATP, AMPK activation, and autophagy; butyrate rescues these deficits as an energy substrate. Spermidine, a natural polyamine that declines with aging, extends lifespan across species by inducing autophagy through eIF5A hypusination and histone deacetylase inhibition. Rapamycin, an mTOR inhibitor with proven geroprotective effects, may potentiate complementary autophagy-inducing and metabolic interventions; combination regimens can exceed monotherapies in selected models. We hypothesize that combining low-dose rapamycin with spermidine, butyrate, and NAD+ precursors will synergistically restore intestinal homeostasis by simultaneously inhibiting mTOR, enhancing autophagy, providing metabolic fuel, and replenishing NAD+ pools. Using human intestinal organoids and fibroblasts, we will test five treatment groups: vehicle control, individual compounds, dual/triple combinations, and quadruple therapy. Primary outcomes are intestinal barrier function measured by transepithelial electrical resistance and FITC-dextran permeability, autophagic flux quantified as LC3-II and p62 turnover with and without bafilomycin A1, and mitochondrial spare respiratory capacity by Seahorse XF. Secondary outcomes are mTOR pharmacodynamics assessed by the p-S6K to total S6K ratio with p-4E-BP1 where applicable, cellular NAD+/NADH by isotope-dilution LC-MS/MS, inflammatory markers IL-6 and IL-8, and cellular senescence markers p16INK4a and SA-β-gal. Exploratory outcomes include epigenetic age clocks, which will be performed only if all primary outcomes meet prespecified success thresholds. This structure aligns outcome hierarchy with the gut-centric mechanism and enables clear go or no go decisions on combination efficacy along the gut mitochondrial mTOR axis.TBD
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TBD
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