REPROGRAM Trial Tests Three Geroprotectors in Older Adults to Reverse Biological Aging
A UK trial gives adults 70+ metformin, fisetin, or spermidine for 3 weeks to measure changes in senescent cells and other hallmarks of aging.
Resumen
The REPROGRAM trial is a three-arm randomized study enrolling 60 healthy adults aged 70 and older to evaluate whether a three-week course of metformin MR (1500 mg), fisetin (100 mg), or spermidine (15 mg) can measurably reduce biological markers of aging. The primary endpoint is the number of senescent cells in abdominal adipose tissue, measured by SA-β-galactosidase activity in biopsies. Secondary endpoints span a broad multi-omic panel covering autophagy, immunosenescence, chronic inflammation, mTOR signaling, epigenetic aging clocks, DNA damage, metabolic dysregulation, stem cell exhaustion, and gut microbiome composition. This is a protocol paper describing rationale and design; results are pending.
Resumen detallado
Aging reduces resilience to physiological stressors such as surgery and infection, and this vulnerability is believed to stem from interconnected biological mechanisms known as the hallmarks of aging. Geroprotectors—drugs proposed to slow or partially reverse these hallmarks—have shown promise in animal models and some human data, but rigorous mechanistic trials in healthy older adults remain scarce. The REPROGRAM study was designed to fill this gap.
The trial randomizes 60 participants (30 female, 30 male, all aged 70+) to one of three geroprotectors: metformin MR 1500 mg daily, fisetin 100 mg daily, or spermidine 15 mg daily, each administered over three weeks. These agents were selected based on favorable safety profiles in older populations and published evidence of engagement with hallmarks of aging. Participants undergo extensive clinical characterization at baseline, including physical function, cognitive assessment, and frailty scoring.
The primary research question asks whether three weeks of treatment reduces the burden of senescent cells in abdominal adipose tissue, quantified by SA-β-galactosidase (SA-β-GAL) staining in biopsies taken at baseline and post-intervention. This primary endpoint was chosen because cellular senescence is a central, druggable hallmark and adipose tissue is accessible, rich in senescent cells in older adults, and functionally relevant to systemic inflammation.
Beyond senescence, the study collects blood, adipose biopsies, and stool at both timepoints to profile autophagy flux, immune cell phenotypes (immunosenescence), circulating inflammatory cytokines, mTOR pathway activity, DNA damage markers, metabolomics, epigenetic age via DNA methylation clocks, stem cell exhaustion markers, and gut microbiome composition via metagenomics. EEG is also used to assess brain electrophysiological changes as a functional readout of cognitive resilience. This breadth of endpoints positions REPROGRAM as a discovery platform capable of revealing which hallmarks each geroprotector engages most strongly.
The trial has received ethical approval (24/LO/0549) and is registered with ISRCTN (47919839). It is funded by a Wellcome Leap Dynamic Resilience Award co-funded by Temasek Trust. As a protocol paper, no results are yet available. Findings will be published in peer-reviewed gerontology journals and shared with participants. If successful, REPROGRAM could provide the human mechanistic evidence needed to justify larger efficacy trials of these compounds for extending healthspan in older adults.
Hallazgos clave
- Three-week interventions with metformin, fisetin, or spermidine are being tested in 60 adults aged 70+ in a randomized trial.
- Primary endpoint is reduction of senescent cells (SA-β-GAL) in abdominal adipose biopsies pre- and post-treatment.
- Secondary measures span 10+ hallmarks of aging including epigenetic clocks, immunosenescence, autophagy, and gut microbiome.
- EEG is included as a novel functional readout of brain electrophysiological resilience alongside molecular endpoints.
- This is a protocol paper; no efficacy results are yet available, but the design enables head-to-head mechanistic comparison of three geroprotectors.
Metodología
Randomized three-arm parallel-group trial in 60 adults aged 70+ (30F/30M) receiving metformin MR 1500 mg, fisetin 100 mg, or spermidine 15 mg for three weeks. Samples collected at baseline and post-intervention include blood, abdominal adipose biopsies, and stool, analyzed via multi-omic platforms alongside EEG and clinical assessments.
Limitaciones del estudio
This is a protocol paper only; no outcome data are available yet. The three-week intervention window is short and may be insufficient to detect changes in some slowly evolving hallmarks. With 20 participants per arm, the study is powered for biological effect detection rather than clinical outcomes, limiting generalizability.
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