A registered randomized controlled trial — REPROGRAM — is enrolling 60 adults aged 70+ (30F/30M) to receive three weeks of either Metformin MR 1500mg, Fisetin 100mg, or Spermidine 15mg. The primary endpoint is reduction of senescent cells measured by SA-β-galactosidase activity in abdominal adipose biopsies. Secondary endpoints span ten hallmarks of ageing: autophagy flux, immunosenescence, chronic inflammation, mTOR signalling, epigenetic clock age, DNA damage markers, metabolic dysregulation, stem cell exhaustion, and gut microbiome composition.
What makes this trial architecturally significant is the head-to-head mechanistic comparison — these three compounds operate through distinct pathways. Metformin primarily activates AMPK and suppresses mTOR/mTORC1; Spermidine induces autophagy via hypusination of eIF5A; Fisetin acts as a senolytic flavonoid with BCL-2 inhibitory properties. Until now, human mechanistic data in healthy older adults has been nearly absent — most evidence derives from mouse models or disease-specific cohorts. Three weeks is a deliberately short window, which will test whether these compounds produce measurable biological shifts before clinical endpoints emerge — a smart proxy strategy.
Critical limitations: 60 participants across three arms yields roughly 20 per group, limiting statistical power for secondary endpoints. The absence of a placebo arm is a notable design gap that complicates causal inference. Nevertheless, multi-tissue sampling (blood, adipose, stool) at matched timepoints makes this one of the most comprehensive mechanistic geroprotector trials to date. Incremental in scale, potentially paradigm-shifting in scope.
