While new molecular targets and pharmacological therapeutics (e.g. SARMS, myostatin inhibitors) to enhance muscle protein synthesis (MPS) and muscle mass have arisen over past years, the most proven, safe intervention to mitigate muscle wasting remains exercise-induced musculoskeletal loading i.e. resistance exercise training (RET). That said, we have shown that acute RET-induced increases in MPS and chronic muscle hypertrophy are blunted in older (O) vs. younger (Y) individuals1,2. Moreover, while the etiology of sarcopenia and age-related “exercise resistance” (NB. also seen in some young people) remain poorly defined, it could be conjectured chronic deficits in MPS and associated imbalances in anabolic/catabolic factors (i.e. testosterone/IGF-1/myostatin/mTORc1-signalling) may drive these phenotypes. We hypothesized blunted hypertrophic responses to RET would be associated with impaired chronic MPS (using our newly developed heavy water (D2O) methods3) and that this would be accompanied by hormonal and anabolic signalling deficits. Ten young (Y: 23±1y) and ten older (O: 69±3 y) men undertook 6-wks supervised progressive unilateral RET (i.e. one-leg knee-extensor: 6×8 reps, 75%-1RM 3.wk-1). In both legs: Vastus Lateralis muscle thickness, architecture, maximal voluntary contraction (MVC) and 1-repetition maximum (1-RM) were assessed at intervals with DXA at baseline (0-wks) and completion (6-wks). After baseline testing, subjects consumed 150ml D2O (70-Atom%) with a further 50ml.wk-1; bi-lateral biopsies and blood samples were taken ~90 min post exercise at 0/3/6-wk to temporally quantify rested and exercised anabolic signalling (mTORc1) and MPS via GC-Pyrolysis-IRMS: MPS=(%.d-1)=-Ln((1-[APEAla/APEP])/t))×100. We also collected blood samples at baseline and following the first bout of unilateral RET, to quantify systemic hormones (i.e. myostatin, IGF-1, testosterone; ELISA). Physical activity and food-intake were monitored via accelerometry and diet diaries, respectively. After 6-wks RET, 1-repetition maximum (RM) had increased 35±4% P<0.01 in Y and 25±3% in O P<0.01, while maximal voluntary contraction (MVC) increased at various joint angles in Y (e.g. 70o 29± 6% P<0.01) but not O (8±3% P=NS). Similarly, quadriceps mass assessed by DXA increased only in Y (Y: 4±1% P<0.01 vs. O: 1±0.3% P=0.3). This was also consistent with blunted increases in muscle thickness (Y: 8±1 and 11±2%, P<0.01 vs. O: 2.6 ±1 and 3.5±2%, P=0.07 at 3 and 6-wks, respectively). Basal MPS was not different between groups (Y: 1.35±0.08%.d-1 vs. O: 1.38±0.09%.d-1). In contrast, reflecting early hypertrophy, MPS increased in Y but not O after 3-wks RET (Y: 1.61±0.1%.d-1 P<0.01 vs. O: 1.53±0.09%.d-1 P=0.1). Again, matching hypertrophic responses, MPS was not enhanced [over basal] 3-6wks in either group (Y: 1.29±0.11%.d-1 and O: 1.39±0.15%.d-1). Basal concentrations of myostatin did not differ with ageing (Y: 4563±403 pg/ml vs. O: 3781±373 pg/ml), while Y presented with greater testosterone (Y: 3.6±0.2 ng/ml vs. O: 2.6±0.2 ng/ml P<0.05) and IGF-1 (Y: 155.1± 16 ng/ml vs. O: 84.2±8 ng/ml P<0.01) concentrations. Following the first bout of RET, serum testosterone increased but this occurred only in Y (post-RET: 3.93±0.2 ng/ml P<0.05). During the study, neither protein (Y: 1.7±0.1 g (kg.FFM.d)-1 vs. O: 1.4±0.1 g (kg.FFM.d)-1 P=0.1) nor caloric (Y: 44±5 Kcal (kg.FFM.d)-1 vs. O: 35±6 Kcal (kg.FFM.d)-1 P=0.1) intake significantly differed with age. However, Y subjects were more habitually active: 76573±7521 vs. 50313±6996 activity counts.d-1 (P<0.05). As such, hypertrophic responses to RET in Y predominate in early stages of RET i.e. ~3-wks, underpinned by sustained increases in MPS; in contrast hypertrophic adaptations are blunted in older age as a result of chronic deficits in MPS. Moreover, in agreement with previous work4 we observed lower testosterone and IGF-1 in O, and speculate this contributes to blunted hypertrophy, and by extension, sarcopenia; in contrast, myostatin was unaltered by age. Further, we have shown D2O is a powerful tool to acquire long-term measures of MPS with potential to study multiple substrates (myofibrillar, mitochondria, satellite cells). Coupled to the relative ease in the application and minimal invasiveness, D2O holds promise for unraveling the role of muscle substrate synthesis in muscle wasting and for investigating the efficacy of anabolic/anti-catabolic interventions. In future, it is crucial we embrace heterogeneous mechanisms of human muscle wasting (e.g. in ageing, ICU, sarcopenia, cachexia syndromes etc) and that one-size will not fit all for treatments. Finally, there are big challenges associated physical therapies, beyond exercise resistance i.e. adherence, application to some populations (e.g. ICU, severe illness, disability) rendering pursuit of adjuvant therapies crucial.