PROMETHEUS clinical trial protocol: tailoring healthy ageing with lifestyle and nutraceuticals

Abstract The d emographic shift toward an older population is accelerating the prevalence of age-related diseases. Precision geromedicine represents a paradigm shift in targeting the biological processes of ageing to optimise health and healthspan, which likely requires multimodal tailored interventions. PROMETHEUS, as part of the XPRIZE healthspan semi-finalist competition, is an 8-week feasibility and exploratory study including 20 middle-aged-to-older participants who received a multimodal intervention comprising fundamental and augmented interventions. The fundamental interventions include sleep and dietary recommendations; supplementation with whey protein, creatine, and fucoidan; supervised exercise with an exergaming component (dual-task cognitive-physical training); motivational interviewing; and cognitive behavioural therapy. The augmented intervention is further personalised based on predefined gerotypes, reflecting individual ageing patterns beyond chronological age. At baseline, urolithin A, nicotinamide mononucleotide, and/or multivitamin-multimineral were prescribed to participants based on their muscle mass, VO 2 peak, and cognitive performance. At mid-intervention, interventions were adjusted based on individual response, including dose escalation and/or the addition of ergothioneine for inadequate improvement in cognition. Primary outcomes include measures of muscle strength and mass, immune function and cognitive performance, and feasibility indicators such as adherence and trial completion. Secondary outcomes include assessments of other biological, clinical, and digital biomarkers of ageing, as well as qualitative indicators of motivation and personal values. This study is aimed at investigating the recruitment feasibility, safety, adherence, and exploratory outcome trajectories of a multimodal, personalised precision geromedicine intervention protocol based on individual participant’s baseline characteristics and interim responses. These findings will also inform the design of a subsequent 12-month, randomised controlled trial evaluating personalised lifestyle and nutraceutical strategies with the potential to incorporate repurposed pharmacological agents to optimise age-related health outcomes.