My research on dietary protein and the regulation of proteostasis in muscle and the whole body during growth and adult maintenance is reviewed. Growth control involves both permissive and regulatory roles of protein acting with genetic determinants and functional demand, to mediate substrate flow into metabolic consumption, energy storage and growth. In 1995 a Protein-Stat hierarchical model for control of the fat-free mass was proposed and is updated here with special emphasis on the skeletal muscle mass. Control is exerted in large part through a central aminostatic appetite mechanism sensing changes in free amino-acid patterns in response to the balance between their supply in relation to their demand. This acts primarily to maintain skeletal muscle mass at a level set by the linear dimensions of the organism, which in turn is controlled by genetic programming and mediated by the developmental hormones acting together with an appropriate anabolic drive deriving from dietary protein. This, together with other important nutrients like zinc, calcium and vitamin D, provides the regulatory stimulus for growth and protein deposition in all tissues. The applicability of this model to childhood growth and development will be described as well as the maintenance of the adult phenotypic muscle mass within populations with protein intakes varying over a wide range, work which resulted in an adaptive metabolic demand model for protein and amino acid requirements and values for apparent adult protein and lysine requirements. Finally current understanding of aminostatic mechanisms of amino-acid sensing in the brain will be reviewed.

Nitrogen balance (NB), the principal methodology used to derive recommendations for human protein and amino acid requirements, has been widely criticised, and calls for increased protein and amino acid requirement recommendations have been made, often on the basis of postprandial amino acid tracer kinetic studies of muscle protein synthesis, or of amino acid oxidation. This narrative review considers our knowledge of the homeostatic regulation of the FFM throughout the diurnal cycle of feeding and fasting and what can and has been learnt from post-prandial amino acid tracer studies, about amino acid and protein requirements. Within the FFM, muscle mass in well fed weight-stable adults with healthy lifestyles appears fixed at a phenotypic level within a wide range of habitual protein intakes. However homoeostatic regulation occurs in response to variation in habitual protein intake, with adaptive changes in amino acid oxidation which influence the magnitude of diurnal losses and gains of body protein. Post-prandial indicator amino acid oxidation (IAAO) studies have been introduced as an alternative to NB and to the logistically complex 24 h [C-13-1] amino acid balance studies, for assessment of protein and amino acid requirements. However, a detailed examination of IAAO studies shows both a lack of concern for homeostatic regulation of amino acid oxidation and major flaws in their design and analytical interpretation, which seriously constrain their ability to provide reliable values. New ideas and a much more critical approach to existing work is needed if real progress is to be made in the area.

A model explaining the dietary-protein-driven post-natal skeletal muscle growth and protein turnover in the rat is updated, and the mechanisms involved are described, in this narrative review. Dietary protein controls both bone length and muscle growth, which are interrelated through mechanotransduction mechanisms with muscle growth induced both from stretching subsequent to bone length growth and from internal work against gravity. This induces satellite cell activation, myogenesis and remodelling of the extracellular matrix, establishing a growth capacity for myofibre length and cross-sectional area. Protein deposition within this capacity is enabled by adequate dietary protein and other key nutrients. After briefly reviewing the experimental animal origins of the growth model, key concepts and processes important for growth are reviewed. These include the growth in number and size of the myonuclear domain, satellite cell activity during post-natal development and the autocrine/paracrine action of IGF-1. Regulatory and signalling pathways reviewed include developmental mechanotransduction, signalling through the insulin/IGF-1-PI3K-Akt and the Ras-MAPK pathways in the myofibre and during mechanotransduction of satellite cells. Likely pathways activated by maximal-intensity muscle contractions are highlighted and the regulation of the capacity for protein synthesis in terms of ribosome assembly and the translational regulation of 5-TOPmRNA classes by mTORC1 and LARP1 are discussed. Evidence for and potential mechanisms by which volume limitation of muscle growth can occur which would limit protein deposition within the myofibre are reviewed. An understanding of how muscle growth is achieved allows better nutritional management of its growth in health and disease.

This chapter explores protein metabolism and its requirements. Proteins are the most diverse of the large macromolecules which provide structure and enable the function of the organism. The protein quality of human diets is predicted by protein or amino acid digestibility and the amino acid score, which is calculated in comparison with an age-related reference amino acid pattern. Many plant-source proteins have amino acid scores comparable to animal-source proteins, and this is because plant foods are chemically diverse. The chapter then explains that global national protein consumption patterns reflect the intake of animal source foods (ASFs) before mentioning the challenge of meeting protein needs with expanding populations in developing countries.

Childhood growth and its sensitivity to dietary protein is reviewed within a Protein-Stat model of growth regulation. The coordination of growth of muscle and stature is a combination of genetic programming, and of two-way mechanical interactions involving the mechanotransduction of muscle growth through stretching by bone length growth, the core Protein-Stat feature, and the strengthening of bone through muscle contraction via the mechanostat. Thus, growth in bone length is the initiating event and this is always observed. Endocrine and cellular mechanisms of growth in stature are reviewed in terms of the growth hormone-insulin like growth factor-1 (GH-IGF-1) and thyroid axes and the sex hormones, which together mediate endochondral ossification in the growth plate and bone lengthening. Cellular mechanisms of muscle growth during development are then reviewed identifying (a) the difficulties posed by the need to maintain its ultrastructure during myofibre hypertrophy within the extracellular matrix and the concept of muscle as concentric "bags" allowing growth to be conceived as bag enlargement and filling, (b) the cellular and molecular mechanisms involved in the mechanotransduction of satellite and mesenchymal stromal cells, to enable both connective tissue remodelling and provision of new myonuclei to aid myofibre hypertrophy and (c) the implications of myofibre hypertrophy for protein turnover within the myonuclear domain. Experimental data from rodent and avian animal models illustrate likely changes in DNA domain size and protein turnover during developmental and stretch-induced muscle growth and between different muscle fibre types. Growth of muscle in male rats during adulthood suggests that "bag enlargement" is achieved mainly through the action of mesenchymal stromal cells. Current understanding of the nutritional regulation of protein deposition in muscle, deriving from experimental studies in animals and human adults, is reviewed, identifying regulation by amino acids, insulin and myofibre volume changes acting to increase both ribosomal capacity and efficiency of muscle protein synthesis via the mechanistic target of rapamycin complex 1 (mTORC1) and the phenomenon of a "bag-full" inhibitory signal has been identified in human skeletal muscle. The final section deals with the nutritional sensitivity of growth of muscle and stature to dietary protein in children. Growth in length/height as a function of dietary protein intake is described in the context of the breastfed child as the normative growth model, and the "Early Protein Hypothesis" linking high protein intakes in infancy to later adiposity. The extensive paediatric studies on serum IGF-1 and child growth are reviewed but their clinical relevance is of limited value for understanding growth regulation; a role in energy metabolism and homeostasis, acting with insulin to mediate adiposity, is probably more important. Information on the influence of dietary protein on muscle mass per se as opposed to lean body mass is limited but suggests that increased protein intake in children is unable to promote muscle growth in excess of that linked to genotypic growth in length/height. One possible exception is milk protein intake, which cohort and cross-cultural studies suggest can increase height and associated muscle growth, although such effects have yet to be demonstrated by randomised controlled trials.

The present paper reviews published literature on the relationship between dietary protein and bone health. It will include arguments both for and against the anabolic and catabolic effects of dietary protein on bone health. Adequate protein intake provides the amino acids used in building and maintaining bone tissue, as well as stimulating the action of insulin-like growth factor 1, which in turn promotes bone growth and increases calcium absorption. However, the metabolism of dietary sulphur amino acids, mainly from animal protein, can lead to increased physiological acidity, which may be detrimental for bone health in the long term. Similarly, cereal foods contain dietary phytate, which in turn contains phosphate. It is known that phosphate consumption can also lead to increased physiological acidity. Therefore, cereal products may produce as much acid as do animal proteins that contain sulphur amino acids. The overall effect of dietary protein on physiological acidity, and its consequent impact on bone health, is extremely complex and somewhat controversial. The consensus is now moving towards a synthesised approach. Particularly, how anabolic and catabolic mechanisms interact; as well as how the context of the whole diet and the type of protein consumed is important.

The nutritional regulation of protein and amino acid balance in human skeletal muscle carried out by the authors with Mike Rennie is reviewed in the context of a simple physiological model for the regulation of the maintenance and growth of skeletal muscle, the "Bag Theory". Beginning in London in the late 1970s the work has involved the use of stable isotopes to probe muscle protein synthesis and breakdown with two basic experimental models, primed-dose continuous tracer infusions combined with muscle biopsies and arterio-venous (A-V) studies across a limb, most often the leg, allowing both protein synthesis and breakdown as well as net balance to be measured. In this way, over a 30 year period, the way in which amino acids and insulin mediate the anabolic effect of a meal has been elaborated in great detail confirming the original concepts of bag filling within the muscle endomysial "bag", which is limited by the "bag" size unless bag enlargement occurs requiring new collagen synthesis. Finally we briefly review some new developments involving (H2O)-H-2 labelling of muscle proteins.

We undertook a systematic review and meta-analysis of published papers assessing dietary protein and bone health. We found little benefit of increasing protein intake for bone health in healthy adults but no indication of any detrimental effect, at least within the protein intakes of the populations studied. This systematic review and meta-analysis analysed the relationship between dietary protein and bone health across the life-course. The PubMed database was searched for all relevant human studies from the 1st January 1976 to 22nd January 2016, including all bone outcomes except calcium metabolism. The searches identified 127 papers for inclusion, including 74 correlational studies, 23 fracture or osteoporosis risk studies and 30 supplementation trials. Protein intake accounted for 0–4% of areal BMC and areal BMD variance in adults and 0–14% of areal BMC variance in children and adolescents. However, when confounder adjusted (5 studies) adult lumbar spine and femoral neck BMD associations were not statistically significant. There was no association between protein intake and relative risk (RR) of osteoporotic fractures for total (RR (random) = 0.94; 0.72 to 1.23, I 2 = 32%), animal (RR (random) = 0.98; 0.76 to 1.27, I 2 = 46%) or vegetable protein (RR (fixed) = 0.97 (0.89 to 1.09, I 2 = 15%). In total protein supplementation studies, pooled effect sizes were not statistically significant for LSBMD (total n = 255, MD (fixed) = 0.04 g/cm 2 (0.00 to 0.08, P = 0.07), I 2 = 0%) or FNBMD (total n = 435, MD (random) = 0.01 g/cm 2 (−0.03 to 0.05, P = 0.59), I 2 = 68%). There appears to be little benefit of increasing protein intake for bone health in healthy adults but there is also clearly no indication of any detrimental effect, at least within the protein intakes of the populations studied (around 0.8–1.3 g/Kg/day). More studies are urgently required on the association between protein intake and bone health in children and adolescents.

John Waterlow was an inspiring clinical and laboratory-based nutritional scientist, who was recognized as paterfamilias of a large, international and influential group of distinguished acolytes. His early work was characterized by study of the nature and clinical management of infantile malnutrition, notably as director of the MRC's Tropical Metabolism Research Unit, which he established in Jamaica in 1954. His London period, from 1970 until and beyond his official retirement in 1982, involved him as Head of the Nutrition Department at the London School of Hygiene & Tropical Medicine. Here he established a Clinical Nutrition and Metabolism Unit to continue his experimental animal and human studies researching protein metabolism; he also assumed the role of the the UK's most influential public health nutritionist, becoming President of the Nutrition Society. Like all great scientists, his work encompassed a very wide range of scientific disciplines, although he modestly described himself as a physiologist, consistent with his primary Cambridge training. Above all, throughout his career, he was happiest as an experimentalist at the bench, from his first assignment studying heat stroke of British troops in the Iraq desert during the Second World War to his measurement of [ 15 N] enrichment in urea as part of his study of whole-body protein turnover just prior to his retirement, working with an isotope ratio mass spectrometer which, like much of the equipment he used, he had largely assembled himself.

The relationship between dietary protein intake and bone health has sparked intense debate for many years, and there is still considerable controversy as to whether protein is an important nutrient for optimising skeletal integrity during the life-cycle. The aim of this study was to undertake an updated systematic review and meta-analysis to fully examine the relationship between dietary protein and bone health in the healthy human adult population following the 2009 protein and bone health meta-analysis publication by Darling et al. (2009). The PUBMED (September 2007 to January 2016) database was electronically searched for relevant studies of healthy adults. A total of 1913 potentially relevant studies using the PUBMED database and 3 hand-searched studies were found. Results of the cohort and cross-sectional surveys; all of the pooled correlation coefficients were positive but mostly not statistically significant (P > 0·05). Hence, the proportion of the variance in bone mineral density BMD) explained by protein intake is unclear (random-effects model used due to high heterogeneity). A meta-analysis of randomised, placebo-controlled trials was conducted and this suggested no statistically significant positive effect of whey protein supplementation on BMD at the femoral neck (random-effects model, P = 0·23) or the total hip (fixed-effects model, P = 0·56). However, a statistically significant effect of whey protein supplementation on femoral neck BMD was found using the fixed-effects model (Mean Difference =−2·03 [−2·44, −1·63] P < 0·001). Nonetheless, the random-effects model was more appropriate due to the considerable heterogeneity found (I = 82 %, P = 0·02). It was not possible to run meta-analyses on total protein, soy protein, animal protein or vegetable protein due to low quality studies, cross-over supplementation study designs used or incompatibility with other studies. Evidence suggesting a deleterious effect of dietary protein on bone health was not found in this analysis – indeed the results demonstrated a positive effect of protein in bone at different sites but no effect of whey protein supplementation on BMD at the femoral neck or total hip. Overall, the strength of evidence suggests a weak beneficial effect of dietary protein on bone health. Further analysis of the available literature is now underway to combine this new (2007–2016) data with respect to our previously published meta-analysis (pre-2007 publications). However, according to the most recent National Diet and Nutrition Survey (NDNS), the UK population surpasses the reference nutrient intake (RNI) for protein and thus, a protein intake increment seems unlikely to provide a further benefit to bone health.

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The regulation of linear growth by nutritional and inflammatory influences is examined in terms of growth-plate endochondral ossification, in order to better understand stunted growth in children. Linear growth is controlled by complex genetic, physiological, and nutrient-sensitive endocrine/paracrine/autocrine mediated molecular signalling mechanisms, possibly including sleep adequacy through its influence on growth hormone secretion. Inflammation, which accompanies most infections and environmental enteric dysfunction, inhibits endochondral ossification through the action of mediators including proinflammatory cytokines, the activin A-follistatin system, glucocorticoids and fibroblast growth factor 21 (FGF21). In animal models linear growth is particularly sensitive to dietary protein as well as Zn intake, which act through insulin, insulin-like growth factor-1 (IGF-1) and its binding proteins, triiodothyronine, amino acids and Zn 2+ to stimulate growth-plate protein and proteoglycan synthesis and cell cycle progression, actions which are blocked by corticosteroids and inflammatory cytokines. Observational human studies indicate stunting to be associated with nutritionally poor, mainly plant-based diets. Intervention studies provide some support for deficiencies of energy, protein, Zn and iodine and for multiple micronutrient deficiencies, at least during pregnancy. Of the animal-source foods, only milk has been specifically and repeatedly shown to exert an important influence on linear growth in both undernourished and well-nourished children. However, inflammation, caused by infections, environmental enteric dysfunction, which may be widespread in the absence of clean water, adequate sanitation and hygiene (WASH), and endogenous inflammation associated with excess adiposity, in each case contributes to stunting, and may explain why nutritional interventions are often unsuccessful. Current interventions to reduce stunting are targeting WASH as well as nutrition.

We undertook a systematic review and meta-analysis of published papers assessing dietary protein and bone health. We found little benefit of increasing protein intake for bone health in healthy adults but no indication of any detrimental effect, at least within the protein intakes of the populations studied. This systematic review and meta-analysis analysed the relationship between dietary protein and bone health across the life-course. The PubMed database was searched for all relevant human studies from the 1st January 1976 to 22nd January 2016, including all bone outcomes except calcium metabolism. The searches identified 127 papers for inclusion, including 74 correlational studies, 23 fracture or osteoporosis risk studies and 30 supplementation trials. Protein intake accounted for 0-4% of areal BMC and areal BMD variance in adults and 0-14% of areal BMC variance in children and adolescents. However, when confounder adjusted (5 studies) adult lumbar spine and femoral neck BMD associations were not statistically significant. There was no association between protein intake and relative risk (RR) of osteoporotic fractures for total (RR(random) = 0.94; 0.72 to 1.23, I2 = 32%), animal (RR (random) = 0.98; 0.76 to 1.27, I2 = 46%) or vegetable protein (RR (fixed) = 0.97 (0.89 to 1.09, I2 = 15%). In total protein supplementation studies, pooled effect sizes were not statistically significant for LSBMD (total n = 255, MD(fixed) = 0.04 g/cm2 (0.00 to 0.08, P = 0.07), I2 = 0%) or FNBMD (total n = 435, MD(random) = 0.01 g/cm2 (-0.03 to 0.05, P = 0.59), I2 = 68%). There appears to be little benefit of increasing protein intake for bone health in healthy adults but there is also clearly no indication of any detrimental effect, at least within the protein intakes of the populations studied (around 0.8-1.3 g/Kg/day). More studies are urgently required on the association between protein intake and bone health in children and adolescents.