Objective <p>The combined effects of metabolic status and genetic predisposition on healthy ageing remain unclear. We aimed to investigate the association of metabolic status and genetic predisposition with healthy ageing and life expectancy across obesity levels in the context of predictive, preventive, and personalized medicine (PPPM).</p> Methods <p>Cox regression models were used to examine the relationships of metabolic status and polygenic risk score (PRS) with healthy ageing across obesity levels using data from the UK Biobank. Multistate life tables were used to evaluate life expectancy with and without major chronic diseases, cognitive dysfunction, physical impairment, and mental impairment.</p> Results <p>Compared with individuals with metabolically unhealthy obesity (MUO) and a low PRS for healthy ageing, those with metabolically healthy obesity (MHO) and a high PRS had a significantly increased likelihood of healthy ageing (hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.04, 1.18; <i>P</i> &lt; 0.01). In the low PRS group, individuals with MHO exhibited a greater likelihood of healthy ageing than those with MUO did (HR: 1.08; 95% CI: 1.02, 1.16; <i>P</i> &lt; 0.05). For life expectancy free of major chronic diseases, cognitive dysfunction, physical impairment, and mental impairment, compared with individuals with MUO and a low PRS, those with a metabolically healthy normal weight and a high PRS lived 6.21 (95% CI: 6.02, 6.40) years longer at age 60.</p> Conclusions <p>Collectively, this study proposes a novel and actionable strategy for promoting healthy ageing and extending healthy life expectancy: prioritizing the transition from MUO to MHO for individuals with a low PRS and preserving MHN status for those with a high PRS. These findings inform the formulation of precision prevention strategies that are consistent with PPPM principles.</p> Graphical abstract <p></p>