Resistance exercise training (RET) is effective at increasing skeletal muscle strength and mass, attributes desired for optimal athletic performance and mitigating muscle wasting disorders e.g sarcopenia. Skeletal muscle hypertrophy is underpinned by cumulative post-exercise increases in muscle protein synthesis (MPS) driven by acute increases in translational efficiency (e.g. mTOR-signaling) and a chronic increase in synthetic capacity (ribosomal biogenesis). However, RET-induced hypertrophy1, acute RET-induced MPS2 and ribosomal gene expression3, are blunted in older (O) vs. younger (Y) individuals. Here, we tested the hypothesis that age-related “anabolic resistance” is reflected in chronic deficits in MPS (using D2O approaches) and ribosomal biogenesis. Ten young (Y: 23±1y) and ten older (O: 69±3y) men undertook 6-wks unilateral-RET (6×8 reps, 75%-1RM 3.wk-1). Vastus Lateralis muscle thickness (MT), architecture, maximal voluntary contraction (MVC) and 1-repetition maximum (1-RM) were assessed regularly with DXA at baseline (0-wks) and completion (6-wks). After bilateral baseline muscle biopsies, subjects consumed 150ml D2O then 50ml.wk-1 with biopsies at 3/6-wk 60-90 min post-RET to temporally quantify MPS, mRNA/protein targets (qRT-PCR and immunoblotting /ELISA) and total RNA/DNA concentrations. After 6-wks RET, 1-RM increased in Y (+35±4% P<0.01) and O (+25±3% P<0.01), yet MVC increased in Y (70o +29±6% P<0.01) but not O (+8±3% P=NS). Similarly, quadriceps mass increased at 6-wks in Y only (Y: +4±1% P<0.01 vs. O: +1±0.3% P=0.3). This was consistent with blunted increases in MT (Y: +8±1 and +11±2%, P<0.01 vs. O: +2.6 ±1 and +3.5 ±2%, P=0.08 at 3 and 6-wks, respectively). Basal MPS did not differ between age groups (Y: 1.35±0.1%.d-1 vs. O: 1.39±0.1%.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: 1.50±0.09%.d-1 P=0.1). Markers of ribosomal biogenesis and translational capacity increased only in Y ug RNA/ug DNA at 3 (Y: 0.47±0.05 to 0.62±0.05 P<0.01 vs. O: 0.53±0.05 to 0.56±0.04) and 6-wks (Y: 0.64±0.03 P<0.01 vs O: 0.57±0.04). Similarly, only Y displayed acute exercise induced C-MYC mRNA/protein and p70S6K1Thr389 phosphorylation; in addition O exhibited attenuated basal testosterone (Y: 3.6±0.2 ng/ml vs. O: 2.6±0.2 ng/ml P<0.05), IGF-1 (Y: 155.1± 16 ng/ml vs. O: 84.2±8 ng/ml P<0.01) but not myostatin concentrations. Finally, following a bout of RET (60-90 min), serum testosterone increased only in Y (post-RE: 3.93±0.2 ng/ml P<0.05). RET-induced muscle hypertrophy was blunted in O, likely the result of cumulative deficits in MPS and translational efficiency, ribosomal biogenesis and anabolic capacity, and unfavorable anabolic hormone profiles. Age-related anabolic resistance is thus multi-factorial.