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• W2592278051 abstract "Optimizing dietary amino acid ratios to achieve maximal growth and reproduction has historically required tedious empirical studies. In this issue, Piper et al., 2017Piper M.D. Soultoukis G. Blanc E. Mesaros A. Herbert S. Juricic P. He X. Atanassov I. Salmonowicz H. Yang M. et al.Cell Metab. 2017; 25 (this issue): 610-621Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar present an in silico method of essential amino acid optimization based on the translated portion of an organism’s genome, or exome. Optimizing dietary amino acid ratios to achieve maximal growth and reproduction has historically required tedious empirical studies. In this issue, Piper et al., 2017Piper M.D. Soultoukis G. Blanc E. Mesaros A. Herbert S. Juricic P. He X. Atanassov I. Salmonowicz H. Yang M. et al.Cell Metab. 2017; 25 (this issue): 610-621Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar present an in silico method of essential amino acid optimization based on the translated portion of an organism’s genome, or exome. The fundamental requirement for dietary protein was first demonstrated in 1816 by François Magendie in dogs by their failure to survive exclusively on a non-nitrogenous, “empty” calorie source consisting of sucrose and oil (Magendie, 1816Magendie F. Précis Élémentaire de Physiologie. Chez Mequignon-Marvis, Libraire pour la partie de Médecine, 1816Google Scholar). A century later, the identification and purification of the 20 amino acid (AA) constituents of proteins made possible the use of isolated AAs as the sole protein source. Single AA dropout and add-back studies performed by William Rose during the 1920s to 1950s were used to identify AAs that are essential for growth in rodents. Using nitrogen balance as a readout in man, Rose developed our current dietary recommendations for essential AA (EAA) intake (Rose, 1949Rose W.C. Fed. Proc. 1949; 8: 546-552PubMed Google Scholar). Although an estimated 90% of Americans exceed minimal recommended protein intakes, situations can arise in which protein consumption is reduced and EAAs can become limiting. In people suffering from protein-energy malnutrition, this is most often due to food scarcity, while in management of chronic kidney disease or in industrial animal husbandry, it is purposefully done to limit renal load or feed costs, respectively. Determining the ideal AA composition to prevent EAAs from becoming limiting is challenging due to the complexity of potential interactions between individual AAs (e.g., methionine sparing by cysteine) (Harper et al., 1970Harper A.E. Benevenga N.J. Wohlhueter R.M. Physiol. Rev. 1970; 50: 428-558Crossref PubMed Scopus (792) Google Scholar). It is additionally complicated by effects of different levels of total protein and energy intake. Identifying which EAA may become limiting as protein intake is reduced has historically required tedious empirical studies—until now. In this issue of Cell Metabolism, Piper et al. used an in silico approach to optimize dietary AAs based on their hypothesis that optimal AA requirements are encoded in an organism’s genome (Piper et al., 2017Piper M.D. Soultoukis G. Blanc E. Mesaros A. Herbert S. Juricic P. He X. Atanassov I. Salmonowicz H. Yang M. et al.Cell Metab. 2017; 25 (this issue): 610-621Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). To test this, they translated the nearly 20,000 predicted protein coding genes from Drosophila melanogaster and Mus musculus genomes into AA sequences and derived a relative proportion for each AA based on its prevalence in the entire translated portion, or “exome.” They used these proportions to design an artificial “exome-matched” protein source, which differed markedly in AA composition from natural or laboratory protein sources. The authors then tested the effects of their exome-matched synthetic diet on growth, fecundity, and satiety. Flies fed an exome-matched protein source at relatively low total protein concentrations developed as quickly as flies fed four times more total protein with a “mismatched” AA composition. Female flies on exome-matched protein diets also grew faster and laid more eggs than those on mismatched protein diets normalized for total protein concentrations. While hungry flies preferred the exome-matched diet over traditional mismatched diets, over longer time periods, flies consumed less of the exome-matched diet. Together, these suggested increased satiety rather than aversion. The exome-matched diet also significantly lowered uric acid production and triglyceride accumulation, consistent with improved nitrogen utilization and energy efficiency. Thus, by all these measures, the exome-matched diet is superior to the flies’ natural protein source, yeast, allowing for improved fitness at lower levels of total protein intake (Figure 1). Next, the authors tested their ability to predict the limiting EAA in any given dietary protein source by comparing it to the exome-matched EAA composition. According to their hypothesis, an EAA ratio between mismatched and exome-matched diets below 1 indicates a limiting AA (although, importantly, it doesn’t inform on the total protein level that this may occur). Using this method, arginine and methionine were predicted to be the first and second most limiting EAAs driving different physiological responses between exome-matched and yeast-based protein sources. Titrating arginine alone, or arginine and methionine, into the mismatched diet resulted in a corresponding increase in egg laying. Surprisingly, exome-matched AA ratios weighted according to actual protein expression levels as measured by SILAC proteomics experiments failed to outperform the original genome-based exome predictions. Finally, the authors confirmed the effects of an exome-matched diet at low total protein intake across species boundaries. Despite eating 15% less food per gram body weight, young mice fed over a 15 week period on an exome-matched low (6%)-protein diet relative to a “mismatched” 6% casein-based diet displayed increased growth rate, lean body mass, and cortical and trabecular bone thickness. Furthermore, urinary nitrogen excretion was decreased by over 50%. Interestingly, exome-matched diets performed as well or better for mouse growth at 6% total protein concentration as diets based on empirically derived AA requirements, or on mouse total AA composition as determined in extracts. In conclusion, Piper and colleagues have created an in silico tool to identify balanced AA compositions that can support growth, fecundity, satiety, and nitrogen retention across species boundaries when total protein concentrations are limiting. This fascinating study, with immediate implications for the food industry and potentially for human health, raises a number of important questions. What are the molecular implications of AA mismatch in vivo? AAs are essential for protein translation, but also a plethora of additional processes ranging from neurotransmission to antioxidant defense to energy metabolism. Nonetheless, based on the effects of mismatched protein sources on phenotypes heavily dependent on translation (growth and egg production), it seems likely that general translation can explain most of the benefits of exome matching. Mechanistically, the authors interrogated the potential role of translational control via the TOR pathway and found reduced protein levels of the translational repressor 4EPB1 (but not TOR-dependent phosphorylation) in adult female flies, but not ovariectomized females, upon exome-matched protein feeding. There is thus a great deal yet to be learned regarding the critical AA sensing and effector mechanisms responsible for the differential effects of matched versus mismatched AA sources. Another open question is whether exome matching has health benefits when total dietary protein is not limiting, as is the case for a majority of people with ready access to plant- or animal-based protein sources. While nitrogen retention is improved by AA balance across a range of total protein concentrations, the physiological consequences of this effect are unclear. On the other hand, if satiety is increased by exome matching at high as well as low total AA concentrations, this could have important translational implications with the potential to lower overall food intake (Figure 1). Finally, conventional wisdom holds that dietary restriction maximizes lifespan at the cost of reproduction. Here, lifespan was unique among scored phenotypes in flies: improved upon reduced dietary protein intake and independently of AA ratios (Figure 1). Furthermore, the authors found that lifespan and fecundity were not mutually exclusive, confirming their previous findings (Grandison et al., 2009Grandison R.C. Piper M.D. Partridge L. Nature. 2009; 462: 1061-1064Crossref PubMed Scopus (543) Google Scholar) and leading them to propose the existence of a single dietary optimum for both at a relatively low concentration (10.7%) of exome-matched AAs. Paradoxically, AA mismatch can itself increase lifespan even at moderate protein concentrations. For example, rodents fed a 14% AA diet limited for the EAA methionine (Orentreich et al., 1993Orentreich N. Matias J.R. DeFelice A. Zimmerman J.A. J. Nutr. 1993; 123: 269-274PubMed Google Scholar) live significantly longer, as do yeast (Ruckenstuhl et al., 2014Ruckenstuhl C. Netzberger C. Entfellner I. Carmona-Gutierrez D. Kickenweiz T. Stekovic S. Gleixner C. Schmid C. Klug L. Sorgo A.G. et al.PLoS Genet. 2014; 10: e1004347Crossref PubMed Scopus (153) Google Scholar) and flies (Lee et al., 2014Lee B.C. Kaya A. Ma S. Kim G. Gerashchenko M.V. Yim S.H. Hu Z. Harshman L.G. Gladyshev V.N. Nat. Commun. 2014; 5: 3592PubMed Google Scholar). Different EAA mismatched diets can also improve metabolic fitness and stress resistance via GCN2-dependent AA deprivation signaling (Peng et al., 2012Peng W. Robertson L. Gallinetti J. Mejia P. Vose S. Charlip A. Chu T. Mitchell J.R. Sci. Transl. Med. 2012; 4: 118ra11Crossref PubMed Scopus (114) Google Scholar) or reduced mTORC1 signaling (Hine et al., 2015Hine C. Harputlugil E. Zhang Y. Ruckenstuhl C. Lee B.C. Brace L. Longchamp A. Treviño-Villarreal J.H. Mejia P. Ozaki C.K. et al.Cell. 2015; 160: 132-144Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar). Thus, while the consequences of matched versus mismatched AA composition remain to be fully elucidated, Piper and colleagues have provided us with an invaluable tool to predict these imbalances. Matching Dietary Amino Acid Balance to the In Silico-Translated Exome Optimizes Growth and Reproduction without Cost to LifespanPiper et al.Cell MetabolismMarch 07, 2017In BriefDietary protein is a critical determinant of health, but the empirical determination of optimal amino acid ratios is challenging. Piper et al. show that a consumer’s genome provides a template for optimal dietary amino acid proportions. Low amounts of optimized protein are simultaneously beneficial for appetite, growth, reproduction, and lifespan. Full-Text PDF Open Access" @default.
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• W2592278051 title "Feeding the Genome: In Silico Optimization of Dietary Amino Acid Composition" @default.
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