Advances in Nutrition: An International Review Journal current issue

Perspective: Protein Requirements and Optimal Intakes in Aging: Are We Ready to Recommend More Than the Recommended Daily Allowance?

AbstractThe Dietary Reference Intakes set the protein RDA for persons >19 y of age at 0.8 g protein ⋅ kg body weight−1 ⋅ d−1. A growing body of evidence suggests, however, that the protein RDA may be inadequate for older individuals. The evidence for recommending a protein intake greater than the RDA comes from a variety of metabolic approaches. Methodologies centered on skeletal muscle are of paramount importance given the age-related decline in skeletal muscle mass and function (sarcopenia) and the degree to which dietary protein could mitigate these declines. In addition to evidence from short-term experimental trials, observational data show that higher protein intakes are associated with greater muscle mass and, more importantly, better muscle function with aging. We are in dire need of more evidence from longer-term intervention trials showing the efficacy of protein intakes that are higher than the RDA in older persons to support skeletal muscle health. We propose that it should be recommended that older individuals consume ≥1.2 g protein · kg−1 · d−1 and that there should be an emphasis on the intake of the amino acid leucine, which plays a central role in stimulating skeletal muscle anabolism. Critically, the often-cited potential negative effects of consuming higher protein intakes on renal and bone health are without a scientific foundation in humans.

Perspective: Structure-Function Claims on Infant Formula

AbstractIn the context of a food product label, the term “claim” refers to information that attributes value to the product. The term extends to many different types of information, from product identity, descriptors of intended use, and identification of characteristic properties to the physiologic effects in the body of substances in the food, including the reduction of risk of disease. Food labeling, which includes claims, provides information that consumers want and use to improve their diets. Consumers prefer short statements on the front label claims to longer, more detailed information, including ingredients statements and a nutrition panel. Three types of claims are permitted in the United States. Nutrient content claims describe the level of the nutrient in the food relative to an established daily value, e.g., “Excellent source of choline,” and are subject to composition limits for other nutrients, such as total fat, saturated fat, and cholesterol. Health claims describe the relation between a food substance and the risk of disease, e.g., “Adequate calcium and vitamin D throughout life, as part of a well-balanced diet, may reduce the risk of osteoporosis.” They must undergo a premarket evaluation by the FDA to ensure that there is significant scientific agreement about the relation in question. The third type of claim, structure-function (SF) claims, has recently come under scrutiny, particularly regarding their use on infant formula. Such claims represent a food's effect on the structure or function of the body for maintenance of good health and nutrition. These claims must be truthful and not misleading, but are not subject to premarket approval before use. The purpose of this perspective is to describe the origins and unique niche of SF claims, and to comment on recent proposals to further regulate such claims on infant formula.


AbstractMolybdenum, a trace element essential for micro-organisms, plants, and animals, was discovered in 1778 by a Swedish chemist named Karl Scheele. Initially mistaken for lead, molybdenum was named after the Greek work molybdos, meaning lead-like. In the 1930s, it was recognized that ingestion of forage with high amounts of molybdenum by cattle caused a debilitating condition. In the 1950s, the essentiality of molybdenum was established with the discovery of the first molybdenum-containing enzymes. In humans, only 4 enzymes requiring molybdenum have been identified to date: sulfite oxidase, xanthine oxidase, aldehyde oxidase, and mitochondrial amidoxime-reducing component (mARC). Sulfite oxidase, an enzyme found in mitochondria, catalyzes oxidation of sulfite to sulfate, the final step in oxidation of sulfur amino acids (cysteine and methionine). Xanthine oxidase converts hypoxanthine to xanthine, and further converts xanthine to uric acid, preventing hypoxanthine, formed from spontaneous deamination of adenine, from leading to DNA mutations if paired with cytosine in place of thymine. Aldehyde oxidase is abundant in the liver and is an important enzyme in phase 1 drug metabolism. Finally, mARC, discovered less than a decade ago, works in concert with cytochrome b5 type B and NAD(H) cytochrome b5 reductase to reduce a variety of N-hydroxylated substrates, although the physiologic significance is still unclear. In the case of each of the molybdenum enzymes, activity is catalyzed via a tricyclic cofactor composed of a pterin, a dithiolene, and a pyran ring, called molybdenum cofactor (MoCo) (1).

Microbiome-Mediated Effects of the Mediterranean Diet on Inflammation

AbstractThe Mediterranean diet pattern is increasingly associated with improved metabolic health. Two mechanisms by which consuming a Mediterranean diet pattern may contribute to improved metabolic health are modulation of the gastrointestinal (GI) microbiota and reduction of metabolic endotoxemia. Metabolic endotoxemia, defined as a 2- to 3-fold increase in circulating levels of bacterial endotoxin, has been proposed as a cause of inflammation during metabolic dysfunction. As the largest source of endotoxins in the human body, the GI microbiota represents a crucial area for research on strategies for reducing endotoxemia. Diets high in saturated fat and low in fiber contribute to metabolic endotoxemia through several mechanisms, including changes in the GI microbiome and bacterial fermentation end products, intestinal physiology and barrier function, and enterohepatic circulation of bile acids. Thus, the Mediterranean diet pattern, rich in unsaturated fats and fiber, may be one dietary strategy to reduce metabolic endotoxemia. Preclinical studies have demonstrated the differential effects of dietary saturated and unsaturated fats on the microbiota and metabolic health, but human studies are lacking. The role of dietary fiber and the GI microbiome in metabolic endotoxemia is underinvestigated. Clinical research on the effects of different types of dietary fat and fiber on the GI microbiota and GI and systemic inflammation is necessary to determine efficacious dietary strategies for reducing metabolic endotoxemia, inflammation, and subsequent metabolic disease.

Impact of Double-Fortified Salt with Iron and Iodine on Hemoglobin, Anemia, and Iron Deficiency Anemia: A Systematic Review and Meta-Analysis

AbstractDouble-fortified salt (DFS) containing iron and iodine has been proposed as a feasible and cost-effective alternative for iron fortification in low- and middle-income countries (LMICs). We conducted a systematic review and meta-analysis from randomized and quasi-randomized controlled trials to 1) assess the effect of DFS on biomarkers of iron status and the risk of anemia and iron deficiency anemia (IDA) and 2) evaluate differential effects of DFS by study type (efficacy or effectiveness), population subgroups, iron formulation (ferrous sulfate, ferrous fumarate, and ferric pyrophosphate), iron concentration, duration of intervention, and study quality. A systematic search with the use of MEDLINE, EMBASE, Cochrane, Web of Science, and other sources identified 221 articles. Twelve efficacy and 2 effectiveness studies met prespecified inclusion criteria. All studies were conducted in LMICs: 10 in India, 2 in Morocco, and 1 each in Côte d'Ivoire and Ghana. In efficacy studies, DFS increased hemoglobin concentrations [standardized mean difference (SMD): 0.28; 95% CI: 0.11, 0.44; P < 0.001] and reduced the risk of anemia (RR: 0.59; 95% CI: 0.46, 0.77; P < 0.001) and IDA (RR 0.37; 95% CI: 0.25, 0.54; P < 0.001). In effectiveness studies, the effect size for hemoglobin was smaller but significant (SMD: 0.03; 95% CI: 0.01, 0.05; P < 0.01). Stratified analyses of efficacy studies by population subgroups indicated positive effects of DFS among women and school-age children. For the latter, DFS increased hemoglobin concentrations (SMD: 0.32; 95% CI: 0.03, 0.60; P < 0.05) and reduced the risk of anemia (SMD: 0.48; 95% CI: 0.34, 0.67; P < 0.001) and IDA (SMD: 0.37; 95% CI: 0.25, 0.54; P < 0.001). Hemoglobin concentrations, anemia prevalence and deworming at baseline, sample size, and study duration were not associated with effect sizes. The results indicate that DFS is efficacious in increasing hemoglobin concentrations and reducing the risk of anemia and IDA in LMIC populations. More effectiveness studies are needed.

Effects of Iodized Salt and Iodine Supplements on Prenatal and Postnatal Growth: A Systematic Review

AbstractHypothyroidism due to iodine deficiency can impair physical development, most visibly in the marked stunting of myxedematous cretinism caused by severe in utero iodine deficiency. Whether iodine repletion improves growth in noncretinous children is uncertain. Therefore, the aim of our systematic review was to assess the effects of iodine fortification or supplementation on prenatal and postnatal growth outcomes in noncretinous children. Following Cochrane methods and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) reporting guidelines, we searched 10 databases including 2 Chinese databases (latest search February 2017). We included randomized and nonrandomized controlled trials (RCTs; non-RCTs), controlled before-after (CBA) studies, and interrupted time-series studies in pregnant women and children (≤18 y), which compared the effects of iodine (any form, dose, regimen) to placebo, noniodized salt, or no intervention on prenatal and postnatal growth outcomes. We calculated mean differences with 95% CIs, performed random-effects meta-analyses, and assessed the quality of evidence with the use of GRADE (Grading of Recommendations Assessment, Development and Evaluation). We included 18 studies (13 RCTs, 4 non-RCTs, 1 CBA) (n = 5729). Iodine supplementation of severely iodine-deficient pregnant women increased mean birthweight [mean difference (MD): 200 g; 95% CI: 183, 217 g; n = 635; 2 non-RCTs] compared to controls, but the quality of this evidence was assessed as very low. Iodine repletion across the other groups showed no effects on primary growth outcomes (quality of evidence mostly low and very low). Meta-analyses showed a positive effect in moderate-to-mildly iodine-deficient schoolchildren on insulin-like growth factor-1 (MD: 38.48 ng/mL; 95% CI: 6.19, 70.76 ng/mL; n = 498; 2 RCTs, low-quality evidence) and insulin-like growth factor binding protein-3 (MD: 0.46 μg/mL; 95% CI: 0.25, 0.66 μg/mL; n = 498; 2 RCTs, low-quality evidence). In conclusion, we identified few well-designed trials examining the effects of iodine repletion on growth. We are uncertain whether prenatal iodine repletion increases infant growth. Postnatal iodine repletion may improve growth factors but has no clear effects on somatic growth. Our systematic review was registered with PROSPERO as CRD42014012940.

Clinical Outcomes Related to the Gastrointestinal Trophic Effects of Erythropoietin in Preterm Neonates: A Systematic Review and Meta-Analysis

AbstractErythropoietin (EPO) plays an important role in the development and maturation of the gastrointestinal tract. Recombinant EPO (rEPO) has been used to prevent anemia of prematurity. The gastrointestinal trophic effects of EPO may reduce feeding intolerance and necrotizing enterocolitis (NEC) in preterm neonates. The aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the effects of rEPO on clinical outcomes such as feeding intolerance, stage II or higher NEC, any stage NEC, sepsis, retinopathy of prematurity, and bronchopulmonary dysplasia in preterm neonates. Twenty-five RCTs (intravenous: 13; subcutaneous: 10; enteral: 2; n = 4025) were eligible for inclusion. Meta-analysis of data from 17 RCTs (rEPO compared with placebo) with the use of a fixed-effects model showed no significant effect of rEPO on stage II or higher NEC (RR: 0.87; 95% CI: 0.64, 1.19; P = 0.39). Meta-analysis of data from 25 RCTs (rEPO compared with placebo) showed that rEPO significantly decreased the risk of any stage NEC [cases/total sample: 120/2058 (5.83%) compared with 146/1967 (7.42%); RR: 0.77; 95% CI: 0.61, 0.97; P = 0.03]. Only one RCT reported on time to full feedings. Meta-analysis of data from 15 RCTs showed a significant reduction in late-onset sepsis after rEPO administration (RR: 0.81; 95% CI: 0.71, 0.94; P = 0.004). Meta-analysis of 13 RCTs showed no significant effect of rEPO on mortality, retinopathy of prematurity, and bronchopulmonary dysplasia. Prophylactic rEPO had no effect on stage II or higher NEC, but it reduced any stage NEC, probably by reducing feeding intolerance, which is often labeled as stage I NEC. Adequately powered RCTs are required to confirm these findings.

Mechanisms by Which Dietary Fatty Acids Regulate Mitochondrial Structure-Function in Health and Disease

AbstractMitochondria are the energy-producing organelles within a cell. Furthermore, mitochondria have a role in maintaining cellular homeostasis and proper calcium concentrations, building critical components of hormones and other signaling molecules, and controlling apoptosis. Structurally, mitochondria are unique because they have 2 membranes that allow for compartmentalization. The composition and molecular organization of these membranes are crucial to the maintenance and function of mitochondria. In this review, we first present a general overview of mitochondrial membrane biochemistry and biophysics followed by the role of different dietary saturated and unsaturated fatty acids in modulating mitochondrial membrane structure-function. We focus extensively on long-chain n–3 (ω-3) polyunsaturated fatty acids and their underlying mechanisms of action. Finally, we discuss implications of understanding molecular mechanisms by which dietary n–3 fatty acids target mitochondrial structure-function in metabolic diseases such as obesity, cardiac-ischemia reperfusion injury, obesity, type 2 diabetes, nonalcoholic fatty liver disease, and select cancers.

Modeling the Western Diet for Preclinical Investigations

AbstractRodent models have been invaluable for biomedical research. Preclinical investigations with rodents allow researchers to investigate diseases by using study designs that are not suitable for human subjects. The primary criticism of preclinical animal models is that results are not always translatable to humans. Some of this lack of translation is due to inherent differences between species. However, rodent models have been refined over time, and translatability to humans has improved. Transgenic animals have greatly aided our understanding of interactions between genes and disease and have narrowed the translation gap between humans and model animals. Despite the technological innovations of animal models through advances in genetics, relatively little attention has been given to animal diets. Namely, developing diets that replicate what humans eat will help make animal models more relevant to human populations. This review focuses on commonly used rodent diets that are used to emulate the Western dietary pattern in preclinical studies of obesity and type 2 diabetes, nonalcoholic liver disease, maternal nutrition, and colorectal cancer.

The History and Future of Dietary Guidance in America

AbstractEvidence-based dietary guidance in the United States has progressed substantially since its inception >100 y ago. This review describes the historical development and significance of dietary guidance in the United States, including the Dietary Guidelines for Americans (DGAs), and emphasizes the foundations upon which they were developed, the process in the formation of past and current guidelines, and present and future applications. Dietary guidance during the first half of the 20th century was focused primarily on food groups in a healthy diet, food safety, safe food storage, and the role of some minerals and vitamins in the prevention of disease. This was punctuated by World War II messaging to reduce food waste and increase food storage. In 1980, the first DGA report was released, and later, the USDA and the Department of Health and Human Services (HHS) were given a mandate for reissuance and reassessment every 5 y. An ad hoc advisory committee made up of nongovernmental experts was established for each edition to review the scientific evidence and provide content recommendations to the Secretaries of the USDA and the HHS. Wording was changed from negative (avoid) to positive (choose) and emphasis was increasingly placed on reducing the prevalence of overweight and obesity and prevention of chronic diseases. Today, the DGAs guide all federally funded feeding and educational programs, including food policies, food assistance programs, and consumer education programs, as well as these programs at the regional, state, and local levels. Additional users include dietitians and other health professionals, food service personnel, food and beverage manufacturers, schools, and day care facilities. Currently, the DGAs are intended for individuals aged ≥2 y. Future editions of the DGAs will include guidance for infants and children <2 y, as well as pregnant women.

Perspective: Challenges and Controversial Issues in the Dietary Guidelines for Americans, 1980–2015

AbstractSince 1980, every edition of the Dietary Guidelines for Americans (DGAs) has recommended increased consumption of fruits, vegetables, and whole grains, but reduced consumption of saturated fat, sugars, and sodium and, therefore, their primary food sources. Every edition has generated controversy, mainly from producers of foods affected by “eat less” recommendations, particularly meat. Objections to the 2015 DGAs focused on environmental as well as scientific issues, but also on purported conflicts of interest among members of the Dietary Guidelines Advisory Committee. On this basis, critics induced Congress to authorize the National Academy of Medicine (NAM) to review the process of drawing up the guidelines. The NAM's 2017 reports should strengthen the process, but as long as science continues to support advice to reduce consumption of targeted foods, the guidelines will continue to elicit political controversy.

Obesity Interventions for Older Adults: Diet as a Determinant of Physical Function

AbstractThroughout the world, a high prevalence of obesity in older populations has created a new phenotype of frailty: the obese, functionally frail older adult. The convergence of the obesity epidemic with global graying will undoubtedly increase the prevalence of this concern. Barriers to treatment include ambiguities about the appropriate level of obesity that should trigger an intervention, due to age-related physiologic changes and a lack of consensus on specific criteria and cutoffs. Moreover, obesity interventions for this population have been limited by concerns about negative effects on lean mass, bone mineral density, and even mortality. However, newly reported approaches for restoring physical function by obesity reduction have shown good short-term efficacy. Because the majority of these interventions have used exercise as part of the treatment, this review focuses specifically on current understanding of the discrete effects of dietary interventions for geriatric obesity with regards to functional outcomes on tests including the Short Physical Performance Battery, the Physical Performance Test, and the Western Ontario and McMaster Universities Osteoarthritis Index. The literature showed roughly equal benefits to function from a weight reduction diet or exercise regimen, although neither modality was as efficacious alone as the 2 combined. Only 1 of 3 studies of protein intake during weight loss showed a positive effect of protein on function, but findings to date are too limited to prove or disprove a protein benefit. We conclude that although diet and exercise should be combined whenever possible, it remains important to further investigate the beneficial and likely unique effects that calorie restriction and/or nutrient modification can provide, particularly for obese and functionally frail older populations.

Perspective: Total, Added, or Free? What Kind of Sugars Should We Be Talking About?

AbstractThere is consistent public guidance to limit sugars intakes. However, WHO recommendations are for “free” sugars, whereas some other guidance documents and public discussion focus on “added” sugars, and globally most food labeling states “total” sugars. Total sugars comprise all mono- and disaccharides, regardless of source, whereas both added and free sugars exclude the sugars that naturally occur in dairy products and intact fruit and vegetables. Definitions of added and free sugars differ mainly in their respective exclusion or inclusion of sugars in juiced or pureed fruit and vegetables. To date, there has been little evidence-based analysis of the scientific basis for these different sugar classifications or implications of their adoption for consumer communication and nutrition labeling. Evidence of discriminating relations of total compared with added or free sugars with weight gain or energy intake, type 2 diabetes, and dental caries was identified from recent systematic reviews and meta-analyses. The relations were weakest for total sugars and most consistent for dietary sources corresponding to free sugars (including sugars added to and in fruit juices). Consideration of these health outcomes suggests that the emphasis for intake monitoring, public health guidance, and consumer communication should be on free sugars. However, at present, the adoption of free sugars for these purposes would also carry challenges related to implementation, including consumer understanding, consensus on specifications, and current (labeling) regulations.

Perspective: Cardiovascular Responses to Sugar-Sweetened Beverages in Humans: A Narrative Review with Potential Hemodynamic Mechanisms

AbstractCardiovascular diseases are still the primary cause of mortality worldwide, with high blood pressure and type 2 diabetes as major promoters. Over the past 3 decades, almost in parallel with the rise in cardiovascular disease incidence, the consumption of sugar-sweetened beverages (SSBs) has increased. In this context, SSBs are potential contributors to weight gain and increase the risk for elevations in blood pressure, type 2 diabetes, coronary heart disease, and stroke. Nevertheless, the mechanisms underlying the cardiovascular and metabolic responses to SSBs, in particular on blood pressure, are poorly understood. We discuss and propose potential mechanisms underlying differential effects of sugars on postprandial blood pressure regulation; provide evidence for additional molecular contributors, i.e., fibroblast growth factor 21, towards sugar-induced cardiovascular responses; and discuss potential cardiovascular neutral sugars. Furthermore, we explore whether pre-existing glucose intolerance in humans exacerbates the cardiovascular responses to SSBs, thus potentially aggravating the cardiovascular risk in already-susceptible individuals.

Can Curcumin Counteract Cognitive Decline? Clinical Trial Evidence and Rationale for Combining ω-3 Fatty Acids with Curcumin

AbstractThe rate of cognitive decline in the elderly is highly variable. One potential factor contributing to accelerated cognitive decline is chronic systemic inflammation, because it has been linked to cognitive impairment and increased dementia risk. Certain lifestyle factors, such as excess body weight and sedentary behavior, can exacerbate a proinflammatory state in older adults, resulting in chronic low-grade inflammation. Supplementing the diet with curcumin, an anti-inflammatory polyphenolic compound from the curry spice turmeric, is a potential approach to prevent accelerated cognitive decline by counteracting chronic inflammatory processes. Although the anti-inflammatory effects of curcumin are well established, the potential cognitive benefits of curcumin were discovered more recently. Several animal and epidemiologic studies on the effect of curcumin supplementation on cognition showed promising results; however, randomized controlled trials in humans are limited. In this review, we identified 5 randomized controlled trials, of which only 2 observed a beneficial effect of curcumin supplementation on cognition by improving working memory. By critically examining the methodologies of those studies, we identified some limitations, one of which is that none of the studies explored the possibility that anti-inflammatory mechanisms were mediating cognitive benefits (i.e., no study tested participants with low-grade inflammation or measured inflammatory biomarkers). Other factors influencing the likelihood of conclusive outcomes include choice of study population (cognitively unimpaired compared with impaired), study duration, curcumin dose and its bioavailability, and neurocognitive test battery. On the basis of these findings, we offer recommendations for future studies to examine the potential cognitive benefits of curcumin in humans, which include evaluating its effects on cerebral endothelial vasodilator function and boosting its cognitive effects by combining it with long-chain omega-3 (n–3) fatty acids.

Bone Health following Bariatric Surgery: Implications for Management Strategies to Attenuate Bone Loss

AbstractBariatric surgery (BS) is an effective treatment for morbid obesity and its associated comorbidities. Following such a procedure, however, patients are at risk of developing metabolic bone disease owing to the combination of rapid weight loss, severely restricted dietary intake, and reduced intestinal nutrient absorption. Patients undergoing malabsorptive procedures are at a higher risk of postoperative bone health deterioration than those undergoing restrictive procedures; however, studies have demonstrated negative skeletal consequences of restrictive procedures as well. The clinical practice guidelines of some international associations have previously addressed preoperative evaluation and postoperative clinical care in order to maintain bone health in BS patients. Nevertheless, some issues regarding bone health in BS patients remain unclear owing to the lack of relevant randomized clinical trials, including doses of nutritional supplements pre- and post-BS. This review summarizes the current data regarding the skeletal consequences of BS and its mechanisms, with an emphasis on the preventive strategies and nutritional care that may be warranted in order to attenuate bone deterioration following BS.