Ageing is associated with physiological decline, such as reduced physical function, impaired metabolism, and impeded recovery from injury. Yet, the progression of (biological) ageing varies between individuals, with some suffering from chronic diseases before the age of 60, whilst others live well past 80 in good health. Importantly, lifestyle interventions focused on physical exercise and nutrition can effectively counteract the negative effects of ageing, though the observed benefits appear to vary substantially between individuals. The biological factors underlying the heterogeneity of both ageing and the response to lifestyle interventions are not yet fully understood. Therefore, the general aim of this multi-center project is to study the response heterogeneity of various muscle, gut, and immuno-metabolic health parameters to a combined exercise and nutritional lifestyle intervention, in groups of older adults (≥70 years) with different levels of physical and/or metabolic health. At MUMC+, we will focus on the effects of this intervention compared to standard care in older male and female patients recovering from total knee arthroplasty (TKA). Starting ~1 month after surgery, TKA patients (n=70) will undergo 12 weeks of either standard care (n=20) or a multi-modal lifestyle intervention (n=50). The exercise component consists of supervised, whole-body resistance-type exercise training (3x/week). The nutritional intervention component consists of daily supplementation with a protein-rich, multi-ingredient morning drink and a protein-only evening drink, as well as weekly dietary counselling in line with the Dutch Healthy Diet guidelines. At baseline and after 12 weeks of intervention or standard care, outcomes of muscle, gut, and immuno-metabolic health will be assessed via computed tomography, dual x-ray absorptiometry, strength testing, physical function testing, fecal samples, and blood samples, respectively. Additional outcomes include dietary intake (3-day food diary), physical activity level (accelerometry), and quality of life (questionnaires). Total project duration is estimated at 3 years.