REPROGRAM: REsilience PROmotion with GeRoprotectors: AssessMent of biological effect: Rationale and protocol for a trial of biological effect.

<h4>Background</h4>Ageing is associated with reduced resilience to physiological stressors such as infection and surgery. This reduced resilience is believed to be underpinned by the hallmarks of ageing, the key biological mechanisms driving the aged phenotype. Geroprotectors are drugs that are proposed to slow down the ageing process and promote longevity and healthspan(definition). Despite this, mechanistic studies in healthy older adults are lacking.<h4>Methods and analysis</h4>This trial will test the hypothesis that geroprotectors targeted towards biological mechanisms associated with poor resilience can reverse these pathways within a three-week period. Three geroprotectors with a good safety profile in older adults and evidence of effect on the hallmarks of ageing will be administered to 60 (30 female; 30 male) adults 70 + . Participants will be randomised to one of three arms (Metformin MR 1500 mg, Fisetin 100 mg or Spermidine 15 mg). Participants will be extensively clinically characterised at baseline. Blood, abdominal adipose tissue and stool samples will be taken at baseline and following the three-week intervention. The primary research question will answer whether a three-week course of Metformin, Spermidine, or Fisetin reduce the number of senescent cells as measured by SA-β-GAL in adipose biopsies in healthy older volunteers. Additionally, there will be assessment of the effect of the geroprotectors on other hallmarks of ageing, including autophagy(definition), immunosenescence, chronic inflammation, dysregulated mTOR(definition) signalling, epigenetic age, DNA damage, dysregulated metabolism, stem cell exhaustion and microbial composition.<h4>Ethics and dissemination</h4>Ethical approval is in place (24/LO/0549). The main trial report and any sub-studies will be published in high impact peer-reviewed gerontology journals, presented at academic conferences and through a series of public engagement events. Participants enrolled in the study will be informed of the results by a written summary.<h4>Trial registration</h4>REPROGRAM was registered with ISRCTN on 10/09/24. ISRCTN47919839. Available at https://www.isrctn.com/search?q=47919839.