Physical activity in the form of exercise or increasing the plasma availability of essential amino acids (EAA) by exogenous supply (orally or intravenously) or via oral protein sources stimulates skeletal muscle anabolism. Mechanistically, EAA-induced increases in muscle protein synthesis (MPS) are initiated after AA-transportation into the muscle cell whereupon leucine indirectly activates the mechanistic target of rapamycin complex-1 (mTORc1), independent of proximal insulin signaling (phosphatidylinositol 3-kinase (PI3K)) pathways. Similarly, exercise also stimulates mTORc1 signaling via mechano-mediated routes, again largely independent of proximal insulin signalling. Subsequent downstream mTORc1 signaling enhances translational initiation via activation of mTORc1 substrates (e.g. p70S6K1, 4EBP1) culminating in ribosomal assembly, polyribosome formation and increased MPS. In terms of kinetics, skeletal muscles are receptive to the anabolic effects of EAA for only a short period, equating to ~2 h in the rested state (even after ~50 g EAA-rich protein), thereafter becoming refractory despite continued EAA availability and mTORc1 signalling. This phenomenon has been termed “muscle-full”, whereby muscles intrinsically sense “excess” EAA and divert them toward oxidation. Episodes of physical activity (i.e., exercise) are able to delay the “muscle-full” signal to facilitate muscle adaptation (e.g. cellular remodelling/ hypertrophy) in accordance to the demands of the exercise activity imposed e.g. resistance vs. endurance. Intake of nutrition also provides a second route for muscle anabolism via suppression of muscle protein breakdown (MPB). This occurs independently to direct effects of EAA on MPB since EAA supply under insulin clamped conditions (postabsorptive ~5μU.ml-1) is insufficient to suppress MPB. Instead, the release of insulin in response to nutrition causes suppression of MPB (~15μU.ml-1 provides ~50% suppression). On this basis, the robust insulin secretagogue properties of EAA are likely sufficient to increase plasma insulin enough to supress MPB, and maximise nutrient-driven muscle anabolism even in the absence of carbohydrates. To facilitate delivery of AA and insulin to the myocellular-capillary interface, nutrients also modulate peripheral vascular function. Indeed, while insulin is known to increase blood flow to skeletal muscle, certain AA (e.g. arginine, the precursor for nitric oxide) can also enhance muscle microvascular flow. Therefore, an appreciation of the co-ordination between endocrine pancreas, peripheral vasculature, and muscle cells is needed to understand the anabolic effects of AA and the nature of any interactions with exercise in terms of muscle protein anabolism. In terms of ageing, it has been demonstrated that the transient anabolic effects of exercise and/or EAA are blunted in older age (vs. younger groups) providing evidence for the existence of so-called ‘anabolic resistance’. While this phenomenon has been proven in both pre-clinical and clinical scenarios as an “all-cause” mechanism of skeletal muscle atrophy, how much this relates to inactivity in older-aged individuals remains to be definitively determined. Nevertheless, this has lead to suggestion that strategies aimed at increasing dietary EAA-intake or enhancing the anabolic effects of exercise/nutrition represent important foci in treating sarcopenia. To summarise, optimal nutritional strategies for older individuals need to be viewed in the context of the gut-vascular-pancreas-muscle axis and in terms of interactions with physical activity; only comprehension of all these facets will afford full exploitation of the anabolic efficacy of nutrition and exercise in sarcopenia. Finally, a better comprehension of the metabolic and molecular basis of other facets of ageing muscles, beyond those occurring in protein metabolism (e.g. ectopic lipids, satellite cells dysfunction), are needed to generate a more holistic appreciation of the effects of ageing on skeletal muscle in relation to deleterious functional and metabolic outcomes.