Providence St. Joseph Health Providence St. Joseph Health Digital Commons

Articles, Abstracts, and Reports

5-1-2017

Optimal nutrition and the ever-changing dietary landscape: a conference report.

A Shao

A Drewnowski

D C Willcox

L Krämer

Christopher G Lausted Institute for Systems Biology, Seattle, Washington, United States of America.

See next page for additional authors

Follow this and additional works at: https://digitalcommons.psjhealth.org/publications

Part of the Genetics and Genomics Commons, and the Medical Nutrition Commons

Recommended Citation Shao, A; Drewnowski, A; Willcox, D C; Krämer, L; Lausted, Christopher G; Eggersdorfer, M; Mathers, J; Bell, J D; Randolph, R K; Witkamp, R; and Griffiths, J C, "Optimal nutrition and thev e er-changing dietary landscape: a conference report." (2017). Articles, Abstracts, and Reports. 1569. https://digitalcommons.psjhealth.org/publications/1569

This Article is brought to you for free and open access by Providence St. Joseph Health Digital Commons. It has been accepted for inclusion in Articles, Abstracts, and Reports by an authorized administrator of Providence St. Joseph Health Digital Commons. For more information, please contact [email protected]. Authors A Shao, A Drewnowski, D C Willcox, L Krämer, Christopher G Lausted, M Eggersdorfer, J Mathers, J D Bell, R K Randolph, R Witkamp, and J C Griffiths

This article is available at Providence St. Joseph Health Digital Commons: https://digitalcommons.psjhealth.org/ publications/1569 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 DOI 10.1007/s00394-017-1460-9

SUPPLEMENT

Optimal nutrition and the ever‑changing dietary landscape: a conference report

A. Shao1 · A. Drewnowski2 · D. C. Willcox3 · L. Krämer4 · C. Lausted5 · M. Eggersdorfer6 · J. Mathers7 · J. D. Bell8 · R. K. Randolph9 · R. Witkamp10 · J. C. Griffths11

Published online: 5 May 2017 © The Author(s) 2017. This article is an open access publication

Abstract The feld of nutrition has evolved rapidly over the cellular and molecular levels. This approach has appropri- past century. Nutrition scientists and policy makers in the ately expanded in recent years to become more holistic with developed world have shifted the focus of their efforts from the aim of understanding the role of nutrition in the broader dealing with diseases of overt nutrient defciency to a new context of dietary patterns. Ultimately, this approach will paradigm aimed at coping with conditions of excess—calo- culminate in a full understanding of the dietary landscape— ries, sedentary lifestyles and stress. Advances in nutrition a web of interactions between nutritional, dietary, social, science, technology and manufacturing have largely eradi- behavioral and environmental factors—and how it impacts cated nutrient defciency diseases, while simultaneously fac- health maintenance and promotion. ing the growing challenges of obesity, non-communicable diseases and aging. Nutrition research has gone through a Keywords Aging · Big data · Bioactives · Biomarkers · necessary evolution, starting with a reductionist approach, Dietary patterns · Dietary supplements · Longevity · driven by an ambition to understand the mechanisms Micronutrients · Obesity · Overfed · Phytonutrients · responsible for the effects of individual nutrients at the Sarcopenic obesity · Systems approaches · Undernourished · Wellness

This is the seventh CRN-International conference report. Previous conference reports were published in Regulatory Toxicology and Pharmacology [103], and for the last fve years, From reductionism to holism: the evolution in the European Journal of Nutrition [1, 16, 67, 70, 71]. of nutrition science

* J. C. Griffths Compared to the classical natural sciences (chemistry, [email protected] physics and mathematics) nutrition science is a relatively 1 Herbalife Nutrition, Los Angeles, CA, USA new discipline. In the early twentieth century, the pub- lic health challenges around nutrition mainly focused on 2 University of Washington, Seattle, WA, USA communicable diseases and overt nutrient defciencies, at 3 Okinawa International University, Ginowan, Japan the time major determinants of a short life expectancy. To 4 Technische Universität Braunschweig, Brunswick, Germany address these concerns, the scientifc focus of the time was 5 Institute for Systems Biology, Seattle, WA, USA devoted to vitamins and essential minerals to combat the 6 DSM Nutritional Products, Kaiseraugst, Switzerland effects of malnutrition. During this time, scientists believed that single nutrients 7 Newcastle University, Newcastle upon Tyne, UK could cure or reverse particular diseases. This concept was 8 University of Westminster, London, UK readily accepted by the scientifc and medical communities 9 Amway Global Discovery, Buena Park, CA, USA because it was simple and based on three premises [95]: 10 Wageningen University, Wageningen, The Netherlands 11 Council for Responsible Nutrition-International, Washington, 1. A simple cause–effect relationship exists between a DC, USA particular nutrient and a specifc effect or disease.

1 3 S2 Eur J Nutr (2017) 56 (Suppl 1):S1–S21

2. Symptoms of a specifc nutrient defciency can be contributed to a paradox of obesity combined with under- physiologically explained in terms of the role played nutrition. Populations have become overfed, but undernour- by the respective nutrient. ished [78]. 3. Providing the nutrient in the diet can prevent, and in In the 1980s and 1990s, nutrition science entered an many cases reverse, the defciency disease. era during which the ‘magic bullet’ was sought using a reductionist approach. This has been referred to as ‘greedy This paradigm was appropriate for addressing the then reductionism’: challenges of overt nutrient defciency. However, through …in their eagerness for a bargain, in their zeal to the course of the twentieth century the situation changed explain too much too fast, scientists and philoso- rapidly, especially in developing nations. Public health and phers… underestimate the complexities, trying to nutrition challenges, which had been rooted in defciency, skip whole layers or levels of theory in their rush to shifted to challenges resulting from excess. By the mid- fasten everything securely and neatly to the founda- to-late twentieth century, major public health challenges tion [30]. transitioned from communicable diseases and malnutri- tion as the major cause of mortality, to lifestyle-related Nutrients were included in drug-like randomized con- chronic diseases [7]. These contemporary challenges are trolled trials, the most notable were the studies in which due to a combination of poor diet, reduced physical activ- vitamin E and/or beta-carotene were given to lifelong ity, rapidly aging population, rapidly expanding population, smokers or asbestos workers, with the ill-conceived hypoth- climate change and food security issues. The reductionist esis that these nutrients could reverse decades of smoking research model has proven to be ill-suited to address these or asbestos exposure [90, 107]. In an effort to uncover the challenges. magic bullet, scientists inappropriately studied nutrients in In response to the growing challenges of non-commu- a drug-like context. Unlike drugs, nutrients do not function nicable diseases, public and private investments in science in isolation and have benefcial effects on multiple tissues and research grew dramatically and have achieved some and organ systems; a narrow focus on a single or ‘primary’ important benefcial milestones. outcome measure is not practical and does not ft the nutri- tional context [50]. • Advances in understanding the role of diet and nutrition Perpetuated by a reductionist approach on single macro- in the etiology of chronic diseases. and micronutrients, scientists have similarly spent countless • Advances in cellular and molecular biology, and bio- resources satisfying the demand for the nutrition ‘villain’ and chemistry to allow for a better understanding of macro ‘hero.’ Heroes include substances such as anti-oxidants, fber, and micronutrient metabolism and mechanisms of protein and probiotics, while the maligned villains include action. saturated fat, refned carbohydrates, trans-fat, salt and sugar. • Advances in identifcation of nutrients linked to chronic In studying the effects of nutrients in isolation, premature disease; for example, calcium, folate, vitamin D, conclusions have been reached, resulting in the inevitable omega-3 fatty acids and dietary fber. ‘fip-fopping’ on whether particular nutrients are benefcial • Advances in the discovery, study, and use of other bio- or harmful. This, in turn, has led to enormous consumer con- active substances found in foods, such as isofavones, fusion and frustration. The problem with this reductionist carotenoids, anthocyanins and catechins. approach is that, in emphasizing specifc nutrients, it fails to • Advances in the understanding of the impact of the take into account that food components interact in complex microbiome on immunity, obesity and cognitive func- ways to give rise to emergent properties of diets that are not tion. explicable at the level of individual chemical parts. • Advances in the various ‘omics’ technologies: genom- During that time span, the perspective of nutrition ics, transcriptomics, proteomics and metabolomics, research has changed from a reductionist approach focus- along with epigenetics. ing on specifc nutrients, to a complex systems-based sci- ence domain. According to the defnition of nutrition However, despite these advances, from a public health science for the twenty-frst century from The Giessen Dec- perspective, the emphasis on a healthy diet and lifestyle has laration, an important international workshop sponsored not had the anticipated impact. Imbalanced diet and poor by the International Union of Nutritional Sciences and the lifestyle have emerged as major contributors to early death World Health Policy Forum: ‘Nutrition science is defned [128] coinciding with a global obesity epidemic [46] and as the study of food systems, foods and drinks, and their proliferation of co-morbidities such as type II diabetes [47]. nutrients and other constituents; and of their interactions The nutrition imbalance, where nutrient adequacy is wors- within and between all relevant biological, social and envi- ening while energy (calorie) excess continues to rise, has ronmental systems’ [108].

1 3 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 S3

Nutrition research is now described as a feld which Undernourished but overfed: the social integrates a variety of disciplines, including biology, physi- and economic considerations ology, sociology, economics, politics and environment [19]. Researchers are now calling for the consideration of Global diets have become rich in calories but can be poor environmental sustainability when addressing nutrition in some essential nutrients. More and more people are questions of public health signifcance [5]. To grasp these becoming overweight and obese while failing to meet dynamic and highly intertwined connections and interac- dietary nutrient requirements. As a result, overweight tions, a systems approach is now being advocated, which and nutrient defciencies, the latter sometimes known as incorporates transdisciplinary models for food and nutrition ‘hidden hunger’, are both viewed as different forms of security. Such an approach aims to reduce complexity by malnutrition. revealing key interactions that infuence the outcomes of Ideally, each food calorie ought to be the dietary vec- interest [48]. In other words, a systems approach can help tor for essential micronutrients, e.g., vitamins and miner- to identify common causal factors underlying the otherwise als. It was long assumed that dietary nutrients and calo- seemingly opposing challenges of malnutrition and obe- ries went together. However, that relation has now been sity (population is undernourished, but overfed), which are uncoupled by the emergence in the modern food supply occurring with more regularity around the world. of low-cost empty calories from refned grains, added The recognition of the need for an interdisciplinary sugars and added fats. If low-cost fats and sweets pro- approach to nutrition research has fortunately made its vide dietary energy but no nutrients, then eating more way to the Federal research agenda in the United States. food provides no further nutritional benefts. The link The National Nutrition Research Roadmap released by the between energy consumption and nutrient intake is bro- Interagency Committee on Human Nutrition Research [56] ken. The low cost of empty calories has made it possible includes highly relevant research questions targeting areas to become undernourished but overfed. such as behavioral, lifestyle, social, cultural, economic, Dietary advice has not kept pace with the basic eco- occupational and environmental factors that impact food nomics of food-choice behavior. The Dietary Guidelines choices. The report highlights the importance of environ- for Americans 2015–2020 have restated the traditional mental sustainability and social science as it pertains to position that all nutritional needs should be met primarily maintaining healthy eating patterns. from nutrient-dense foods. The recognized components Technology now allows use of ‘small data’ at the indi- of healthy eating patterns were fresh vegetables, legumes, vidual level to drive personalization of diets [129]. Hand- whole fruits whole grains, fat-free or low-fat dairy, sea- held devices now assist consumers allowing them to under- food, lean meats and poultry, as well as nuts and seeds. stand their own nutrient and health status and to make Other expert panels have gone further in recommending choices. Biomarkers of nutrition status are replacing intake that all dietary nutrients should come from wholesome assessment as the basis for identifying dietary gaps. Rec- ‘real’ foods, preferably local, fresh, unprocessed, and ommendations for healthy dietary patterns are compliment- organic. The 2015 Dietary Guidelines did allow that, in ing, and in some cases replacing those for specifc foods some cases, fortifed foods and dietary supplements could and nutrients [111]. These advancements are part of the be useful in providing selected nutrients that might oth- evolution from linking health benefts to specifc nutri- erwise be consumed in less than recommended amounts ents at specifc doses to understanding the broader dietary [111]. landscape that impacts health including food policy, food Underconsumed nutrients of greatest public health choices, culture, environment, dietary patterns, social/psy- concern were identifed as calcium, potassium, dietary chological factors, home/workplace/school and economy. fber and vitamin D. Iron, underconsumed by adolescent Despite a number of challenges and setbacks, nutrition girls and adult women, was another nutrient of public science has developed signifcantly over time (and will con- health concern. The suggested remedy was to shift to eat- tinue). The scientifc focus of nutrition had narrowed with a ing patterns with more vegetables, fruits, whole grains reductionist approach and subsequently (now) expanded to and dairy. Vegetables, fruit juices and dairy are important be more holistic. It is now recognized that the study of nutri- sources of potassium; vegetables and whole grains supply tion involves more than the biology of nutrients, but encom- fber; whereas dairy is the principal source of both cal- passes the integration of other scientifc disciplines, includ- cium and vitamin D. ing social, political and environmental sciences. Nutrition Although sustainable food production was an issue, recommendations and policy need to continue to evolve in the wide disparities in food prices, seemingly, were not. parallel with advances in science and technology to provide The nutritive value of foods is often related to their per solutions to contemporary public health challenges. calorie cost [33, 34]. Among the chief food sources of

1 3 S4 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 potassium, the Dietary Guidelines listed low-cost baked 100 kcal, 100 g or serving size. Typically, nutrient-rich potato but also wild Atlantic salmon, Swiss chard and foods are those that contain more nutrients than calories. pomegranate juice. Among fber sources were a wide The so-called qualifying nutrients have included protein, variety of beans and ready-to-eat cereals but also avoca- fber, and a variety of vitamins and minerals, including dos, artichokes and raspberries. Calcium was provided those of public-health concern. Disqualifying nutrients by milk and cheese and by various fortifed ready-to-eat have typically included fat, sugar and sodium. Nutrient cereals. Only pregnant women were advised to take an profling is the technique used to separate foods that are iron supplement when recommended by a healthcare pro- energy-dense from those that are nutrient-rich [32, 35]. vider. Other supplements were not mentioned. Nutrient profling has also been used to assess nutri- Yet, it is food prices and diet costs that mediate the ents per unit cost and the environmental cost of nutrient observed links between poverty, obesity and micronutri- production. ent defciencies [26, 80]. The following arguments can be The more nutrient-rich foods not only did cost more made. per calorie, but the price disparity between energy-dense First, the current hierarchy of food prices is such that and nutrient-rich foods has continued to grow. Tracking energy-dense refned grains, added sugars, and vegetable the cost of a market basket of 384 foods from 2004 to oils have become the least expensive sources of concen- 2016 has shown that prices have increased the most for trated dietary energy, as measured in calorie per unit cost meat, poultry and seafood, fresh produce and whole fruit. [33, 34]. Total diets composed of energy-dense foods tend Whereas, processed fats and sweets cost only 30% more to be cheaper per calorie than low energy density diets than they did 20 years ago; the cost of fresh produce has built around the recommended healthier options [26]. In more than doubled. As might be expected, energy-dense such studies, food energy density was measured in terms of processed foods, including many grain-based desserts, kcal/100 g, whereas dietary energy density was measured provide palatable calories at low cost. in terms of cost per 1800 or 2000 kcal. The shift to cheap energy-dense foods can lead to over- As shown in Fig. 1, energy density of foods is deter- eating due to diminished satiety signals. Whereas, veg- mined by their moisture content. This is because water pro- etables and whole fruit can be bulky but low in energy, vided bulk and weight but no energy and no nutrients. In dry foods provide concentrated energy in small volume. general, energy-dense foods are foods that are dry. Those Whereas, carrots provide 40 kcal/100, the energy density foods are associated with lower per calorie costs. Not by of a bar of chocolate can be several times higher, around coincidence, grains, fats and sweets provided calories at 500 kcal/100 g. In multiple clinical studies, energy-dense low cost, as did sugar sweetened beverages. foods and energy-dense diets have been linked to overeat- By contrast, the more nutrient-rich meat, poultry, fsh, ing and weight gain. vegetables and fruit were more expensive. Nutrient den- Thus, the observed links between poverty and obesity sity of foods has been measured in terms of nutrients per may be mediated, in part, by the low cost of energy-dense foods and reinforced by the high palatability of sugar and fat. In the US, population subgroups with less edu- cation and lower incomes had lower food expenditures and lower quality diets. Those groups were least likely to consume the recommended nutrient-rich foods and were more likely to suffer from micronutrient defcien- cies, notably for the nutrients of public health concern. It has been well documented elsewhere that groups of lower socioeconomic status were also more likely to be obese [26]. As a result, populations in developed countries suf- fer from the dual burden of malnutrition: micronutri- ent deficiencies and overweight. Both conditions are linked to socioeconomic disparities and are most prev- alent among population subgroups with low economic resources and high poverty rates. Improving the nutri- Fig. 1 Relation between mean cost per 100 kcal in US dollars and water content of foods in g/100 g. Data are for 1387 foods from the ent-to-calorie ratio, rather than focusing on calories USDA Food and Nutrient Database for Dietary studies (FNDDS 2.0) alone, may be an effective strategy for obesity preven- aggregated by major food groups tion and control.

1 3 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 S5

Dietary patterns and longevity: insights from the the traditional Okinawan diet differs in some key areas. oldest old in Okinawa In particular, the staple food of the Okinawan diet was neither polished white rice nor other grains but many The proportion of worldwide mortality from chronic varieties of colorful sweet potatoes. age-associated disease is projected to reach two-thirds Okinawan sweet potatoes have several interest- of all deaths by 2030 [126]. This global increase in dis- ing nutritional characteristics that may have anti-aging ease burden from cardiovascular disease (CVD), can- effects. For example, sporamin comprises most of the cer, diabetes and other chronic age-associated diseases total protein in the edible tuberous root. The biological refects an aging population, as well as social and eco- functions of sporamin include strong free-radical inhibi- nomic changes, including lifestyle changes and a global tory and scavenging activity [99]. In light of the strong nutrition transition to dietary patterns that are more connection between infammation and aging, or ‘infam- energy-dense but poor in some essential nutrients (see maging’, as termed by Franceschi and colleagues [40], “Undernourished but overfed: the social and economic it is of particular interest that the sweet potato has sig- considerations”, this article). Despite these challenges, nifcant anti-infammatory properties from multiple phy- effective public health policy and program implementa- tonutrients that include phenolic acids, favonols, antho- tion can do much to mitigate this risk and help people cyanins and carotenoids [124]. In addition to its strong remain healthy as they age. anti-infammatory effects, sweet potatoes are also good Refecting the potential for preventive public health sources of B vitamins, including folate, thiamine, ribofa- efforts, the World Health Organization (WHO) has esti- vin, and vitamin B6. Folate and vitamin B6 help convert mated that 80% of coronary heart diseases and type-2 homocysteine into harmless cysteine. Since high homo- diabetes, as well as 40% of cancers could be prevented cysteine levels are associated with an increased risk of by better management of three health behaviors: dietary cardiovascular disease, it is also of considerable interest habits, physical activity and the use of tobacco products that low homocysteine levels accompany the low CVD [126]. Of these three risk factors, dietary habits may mortality in Okinawa [4]. have become the most important modifable risk factor Once regarded derisively as a ‘poor farmer’s food’ by in many nations, as suggested by a recent study in the those in the upper classes, sweet potatoes now are highly United States, that assessed 17 major risk factors. Com- recommended for their health-enhancing properties with position of the diet made up the largest cluster of risk fac- recommendations coming from the American Heart tors responsible for death (26%) and the highest percent- Association, the American Cancer Society, as well as the age of disability-adjusted life years lost at 14% [83]. Center for Science in the Public Interest (CSPI) [122]. Because nutritional issues play such a key role in a In fact, the CSPI recently ranked the sweet potato as the wide range of age-associated diseases, the potential for ‘healthiest of all vegetables’, mainly for its high content better dietary habits to improve health outcomes in aging of dietary fber and protein, anti-oxidant vitamins A and populations is great. The Okinawans are of special inter- C, potassium, iron, calcium and low levels of saturated est to this topic, as they have been celebrated as the long- fat, sodium and cholesterol [122]. Moreover, most of est lived of the Japanese since prefectural data became these nutrients are the very same that are lacking in the available, and nutritional factors may have played a key American (or ‘Westernized’) diet. role in this healthy aging phenomenon, with low rates Traditional Okinawan cuisine revolves around steamed of cardiovascular disease (and some cancers) mirroring sweet potatoes, simmered or steamed green leafy and/or WHO estimates of what may be potentially achieved by yellow root vegetables, and soy (e.g., miso soup, tofu, preventive public health efforts [105]. miso favorings), which accompanies almost every meal. Much of the longevity advantage in Okinawa is Smaller servings of fsh or lean meats favored with herbs thought to be related to a healthy lifestyle and this and spices, often accompany these staples [124]. Other includes the traditional diet, which is calorie-poor, yet characteristics that defne the Okinawan diet include nutritionally dense, particularly with regard to phytonutri- a taste for bonito favored broths, and the liberal use of ents with potential caloric restriction (CR) mimetic prop- herbs and spices in place of salt. erties [122]. Although many similarities exist between Ten characteristics of the traditional Okinawa diet: the traditional Okinawan and Japanese dietary patterns, including the high intake of vegetables; the abundance of 1. low-caloric intake, soy products such as tofu, natto and miso; the low intake 2. high-vegetable consumption (particularly yellow of fats and oils; the heavy reliance on seafood and sea- root and green leafy vegetables and seaweeds), weeds; and the minimal consumption of dairy products, 3. high consumption of legumes (mostly soybean),

1 3 S6 Eur J Nutr (2017) 56 (Suppl 1):S1–S21

4. moderate consumption of seafood (more in coastal not experience CR suggests otherwise [119]. Population- areas), wide CR was over by the 1960s, and generations thereaf- 5. low consumption of meat (mostly lean pork), ter have had a higher BMI across all age strata, as well as 6. little to no dairy products, more metabolic syndrome and worse cardiovascular risk 7. low-fat intake (high mono and polyunsaturated/satu- factors than other Japanese. The life expectancy advantage rated fat ratio), for Okinawans, which used to be the highest in Japan for 8. low-glycemic load, all ages, is now seen only in older ages, consistent with a 9. high-fber intake, residual CR-related cohort effect in older Okinawans [120]. 10. moderate alcohol consumption. In addition to CR, several nutritional factors are thought to be important for Okinawan longevity. For example, the Research suggests that dietary patterns associated with a health properties of particular foods from the traditional reduced risk of chronic age-associated disease are vegetable Okinawan diet may mimic the biological effects of CR, and fruit heavy (therefore phytonutrient rich) but reduced acting as caloric restriction ‘mimetics’. CR-mimetics are in meat, refned grains, saturated fat, sugar and salt [122]. compounds that provide the physiological beneft of CR Many characteristics of the traditional Okinawan diet are without the need for restriction of calories. The traditional shared with other healthy dietary patterns, including tradi- Okinawan diet appears to be a rich source of CR-mimetics tional Asian diets (especially Japanese), native Hawaiian [119]. In the Okinawan language, the term nuchi gusui, (taro and sweet potatoes), Mediterranean (both vegetable literally means ‘food is medicine’ and refects the cul- heavy), and the researcher designed dietary approaches to tural context wherein commonly consumed dietary items, stop hypertension (DASH) and portfolio (cholesterol low- including foods, herbs and spices are also used as folk ering) diets [119]. Overall, the important shared features of medicines. Common items that play dual roles as both tra- these healthy dietary patterns include: high intake of unre- ditional medicines and foods include sweet potatoes (pulp, fned carbohydrates, moderate protein intake with emphasis skin and leaves), bitter melon, multiple green leafy vegeta- on vegetables and legumes, fsh, and lean meats as sources, bles, ginger, turmeric, mugwort (Artemisia vulgaris), pep- and a healthy fat profle (higher in mono/polyunsaturated pers (Piper hancei) and carotenoid-rich marine foods (such fats, lower in saturated fat; rich in omega-3). Additionally, as seaweeds), among others [119]. the lower caloric density and higher amounts of fber from We may ask why Okinawa appears to have so many such plant-based diets results in lower caloric intake, a food items with medicinal properties, but climate may lower glycemic load and a higher intake of phytonutrients; offer a scientifc basis for this phenomenon. Compounds all important for minimizing risk for age-associated disease that have potential CR-mimetic properties, such as carot- (cardiovascular disease in particular) and maximizing odds enoids, favonoids and other phytochemicals, are synthe- for healthy aging and longevity. The oldest old in Okinawa sized by plants to help scavenge free radicals formed due may also have had a longevity dividend from mild caloric to stress from extremes of heat, cold, insects, UV light or restriction and an unusually high amount of foods with other threats that are common to sub-tropical Okinawa. potential CR-mimetic effects. These mostly shared dietary Murakami et al. [82] investigated typical food items from characteristics reduce the risk for chronic age-associated Okinawa and compared them to food items from mainland disease and promote healthy aging and longevity through Japan and found that foods from Okinawa had, on aver- multiple mechanisms, including reduced infammation and age, stronger free radical scavenging properties. Of over oxidative stress. one hundred food items tested for anti-oxidative and anti- Recent studies of humans who practice CR (up to nitrosative activity, many were shown to be promising anti- 15 years) have shown adaptations consistent with the model infammatory agents, with implications for the prevention organism data, that is, lower risk for CVD and cancer, and of infammation-associated carcinogenesis, especially two biomarker changes suggestive of slower aging [118]. The kinds of turmeric, wild Okinawan turmeric (Curcuma aro- Okinawans have long been of interest to CR researchers matica) and Okinawan zedoary (Curcuma zedoaria); and because they may represent the best human example of a ‘Botanbofu’ or ‘Sakuna’ as it is known in Okinawa (Peuce- naturally calorically restricted population (with optimal danum japonicum). nutrition) and the study of their lifespan, healthspan, mor- The most common compounds (polyphenols, favo- tality and morbidity patterns could provide important infor- noids and similar compounds) can initiate a cellular mation on the long-term effects of CR in humans [120]. stress response and induce benefcial molecular adapta- Some researchers have argued that the Okinawans achieved tions that are collectively known as ‘hormesis’ or a poten- a long life expectancy for genetic (or other) reasons, but tially important mechanism for the health-enhancing the rapid disappearance of the CR phenotype, as well as effects of caloric restriction [94]. Moreover, Davinelli the longevity disadvantage in younger Okinawans who did et al. [27] proposed that phytohormetic stress resistance

1 3 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 S7 also involves the activation of nuclear factor erythroid Systems approaches for defning the dietary 2-related factor 2 (Nrf2) signaling, a central regulator landscape of the adaptive response to oxidative stress, which may partly account for CR’s anti-aging effects. Uptake and metabolism of food is a highly complex pro- Hormetic phytochemicals have received much atten- cess and requires the coordinated interaction of cells, tis- tion for their potential pro-longevity effects and abil- sues and organs to establish homeostasis in multi-cellular ity to act as potent activators of sirtuins (upstream of organisms. Already minor disturbances in this interaction FOXO3 (i.e., Forkhead Box O3, a protein coding gene, can cause disease or malfunction of the whole system. the deregulation of which is involved with tumorigene- On the other hand, the metabolism has to be prepared to sis; and a variant is associated with longevity)), the most act on various fuel types and thus to convert various types notable among them being resveratrol [75]. Interestingly, of nutrients into energy, biomass, and at the same time to several of these compounds that are found in Okinawan build up a storage pool for periods of fasting. plants, such as chebulagic acid (a resveratrol derivative) Systems approaches in the feld of nutrition aim to and sequiterpenoids, seem to be even more potent than understand the complex interplay of fux, metabolism, resveratrol, at least in terms of some anti-aging proper- utilization, and regulation of nutrients from exogenous ties, such as the ability to inhibit reactive oxygen species and endogenous origin in whole nutritional systems [69]. (ROS) and nitric oxide (NO) [85]. Many are also potent In this context, stable-isotopes are a valuable and non- activators of FOXO3 transcription, a key transcription invasive tool to profle the dynamics of metabolite turno- factor from the insulin-IGF-1 signaling pathway [29]. ver of (I) specifc metabolic pathways of interest [24] and FOXO3 appears essential for caloric restriction to exert (II) on a whole organism scale [18, 52, 61]. In this con- its benefcial effects [121, 123], and allelic variation in tribution, we discuss the application and value of stable- the FOXO3 gene is strongly associated with human lon- isotope labeling in the feld of nutrition. gevity [121]. In fact, this fnding has been replicated in To warrant the immediate and stable availability of multiple independent populations and is one of only two energy even under high load conditions where complete consistently replicated genes associated with human lon- carbohydrate oxidation is too slow or even not possible, gevity [31]. Finally, and importantly, there are numer- the body must ensure that production and clearance of ous promising food compounds from the traditional metabolites such as glucose, lactic acid or alanine are Okinawan diet that have been shown to modulate FOXO3 balanced. In humans and other mammals, the Cori cycle expression [119] and research is currently underway with is a metabolic pathway that allows glucose homeostasis the purpose of identifying the most promising candidates and involves the concerted action of central organs as it with therapeutic potential. recycles alanine or lactic acid produced by glucose-con- In summary, older Okinawans consumed a diet con- suming tissues back to glucose. Lactic acid and/or ala- sistent with mild caloric restriction and rich in foods with nine produced in metabolically active tissues are trans- CR-mimetic effects, including the staple sweet potato, ferred into the blood stream and transported to the liver. marine-based carotenoid-rich foods, such as seaweeds, The liver takes up lactic acid and alanine, and recycles and a myriad of herbs and spices. A CR-like phenotype two of these molecules back to glucose in an energy- can be witnessed in older Okinawans which includes consuming fashion (gluconeogenesis). The so-assembled smaller stature, less age-associated disease, longer aver- glucose is secreted back into the blood stream. Hepatic age and maximum lifespan and longer healthspan. gluconeogenesis is, thus, essential for plasma glucose Moreover, the epidemiological evidence supports a link homeostasis, and when deregulated can be a cause for between mild caloric restriction, CR-mimetic foods com- hyperglycemia, especially in type 2 diabetes mellitus monly consumed in the traditional diet, and the healthy [24]. aging phenomenon in Okinawa [120]. Biological path- The dynamics of gluconeogenesis in vivo can be ways through which caloric restriction (and CR-mimet- revealed by oral administration of 13C-stable-isotope- ics) operate are currently being better characterized and labeled glucose and time-resolved blood sampling. the insulin-IGF-1 signaling (IIS) pathway appears to be We developed a protocol to extract polar metabolites critical. FOXO3 is a major regulatory gene in the IIS from dried blood spots (DBS) and apply gas chroma- pathway and acts as a transcription factor that induces tography coupled with mass spectrometry (GC–MS) to changes in gene expression in many downstream target acquire mass spectrometric data for plasma metabolites. genes in response to biological stress. It is activated by To extract pure mass-spectra from these complex data, CR and CR-mimetic compounds commonly found in the we apply the ion-chromatographic deconvolution algo- traditional Okinawan diet. This may have profound impli- rithm of our MetaboliteDetector software [53]. Finally, cations for healthy aging and longevity. based on the deconvoluted mass-spectra, we correct the

1 3 S8 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 compound spectra for naturally occurring stable-isotopes determination of isotopic enrichment patterns of plasma and determine mass isotopomer distributions (MIDs) for metabolites of interest (Fig. 2). target metabolites. These time-resolved enrichment pat- As shown in Fig. 2, depending on the origin of the terns in combination with absolute concentrations of the labeled metabolite, different mass isotopomers can be target metabolites both obtained from DBS sampling detected. For example, glutamate can be synthesized from and GC–MS measurement are used as input for a sim- starch hydrolysis via glucose, glycolysis, and TCA cycle ple mathematical ordinary differential equations (ODE) metabolism and two labeled carbon atoms from glucose model. By solving the equation system, we are able to are conserved. In this case, the molecular mass of gluta- determine quantitative and robust values for glucose pro- mate is increased by 2 U (M2 isotopologue). On the other duction (GP) and gluconeogenesis (GNG). hand, glutamate appears as a hydrolysis product of protein While already providing exact and quantitative meta- resulting in a fully labeled glutamate molecule. In this case, bolic turnover rates for metabolites directly involved in its molecular mass is increased by 5 U (M5 isotopologue). glucose metabolism, such a ‘small system’ does not high- Combining these data with information of the composi- light other parts of whole body homeostasis, as for exam- tion of the applied food product, a biochemical pathway ple, metabolism of amino acids. To address this limitation, model can generate quantitative information on the dynam- we are extending our focus to include quantitative fux data ics of the postprandial response [36]. Such approaches to for more metabolites. For this purpose, we follow the fate profle multifaceted systems result in the generation of of fully 13C-labeled food products after ingestion by human high amounts of complex data. Therefore, computer-based individuals. The application of labeled nutrients has been tools and programs as well as high quality statistical anal- reported for various applications, e.g., the investigation of ysis are increasingly important for deriving meaningful postprandial response [36], and is mostly based on food conclusions. products from 13C-labeled plants like wheat, rice, potato or Nutrition is highly infuencing our personal health, and 13 algae grown in a saturated CO2 atmosphere. Due to the it was recognized that dietary interventions in disease are fact that all 12C carbon atoms are substituted by 13C iso- important to support clinical therapy. Therefore, the gen- topes, every molecule has an increased molecular mass. eration of innovative systems approaches in the feld of In case of wheat and rice, the major molecule types are nutrition will be essential. As the analytical techniques starch and protein. Therefore, the digestion and metabo- and the computer tools improve, the extension of systems lism of these bio-polymers can be traced by time-resolved approaches by stable-isotope driven techniques adds inval- plasma sampling, subsequent GC–MS measurement, and uable information on the dynamical scale [52, 61].

Fig. 2 Fully 13C-labeled food products based on, e.g., wheat, rice or potato are composed of 13C-labeled starch and 13C-labeled protein. The labeled hydrolysis products, labeled glucose (black) and free labeled amino acids (red) enter metabo- lism and enrichment patterns in the plasma metabolites, meas- ured by GC–MS. Lac lactate, Ala alanine, OxAc oxaloacetate, Cit citrate, aKG alpha-ketoglu- tarate, Glu glutamate, LDH lactate dehydrogenase, PDH pyruvate dehydrogenase, CS citrate synthase, Aco aconitase, IDH isocitrate dehydrogenase, GDH glutamate dehydrogenase

1 3 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 S9

Bringing a ‘big data’ component to the wellness inform health decisions by providing actionable hypoth- discussion eses chosen to optimize wellness and minimize disease. The second is patient-data integration that will uncover As healthcare becomes more data-rich and proactive, it biological networks defning health, and that are per- will focus more on maintaining and enhancing well- turbed in early disease stages. Through an understanding ness rather than just reacting to disease. The Institute of these differences, fundamental insights will be gained for Systems Biology in Seattle (ISB) recently launched [54]. the large-scale ‘100K Wellness Project’ that integrates A few highly motivated members of the nascent quanti- genomics, proteomics, transcriptomics, microbiomes, fed self movement have started collecting their own data and clinical chemistries along with wearable devices to clouds. Larry Smarr (UC San Diego) is one such pioneer. monitor wellness and disease. This project has begun After establishing solid baselines, he noticed an unex- with a proof-of-concept pilot study in a set of 108 indi- plained spike in his circulating C-reactive protein (CRP) viduals, the ‘Pioneer 100 Project,’ completed this past levels—an indicator of infammation. On sharing this with year. The interpretation of these data led the participants his physician, he was asked, ‘Do you have a symptom?’ to actionable fndings in the areas of medicine, exercise, and, when he answered in the negative, was sent away and nutrition. without treatment. Shortly after, he did indeed experience Current systems for dealing with health issues remain an acute, dangerous event that required urgent care [102]. mostly reactive, with patients reporting to their clinic Michael Snyder (Stanford University) is another. In his once symptoms are fully developed. This is a major single test subject (not offcially identifed), he observed impediment to the early diagnosis of complex diseases. a number of distinct changes in blood biomarkers, refect- Few physiological and biochemical parameters are meas- ing pathways activated by viral infections and also by the ured routinely, and only after long intervals, so changes onset of diabetes. Proteomic data indicated the onset of might not be identifed until many months after the ini- an elevated glucose response, following shortly after a tial stages of disease. Furthermore, parameters vary respiratory syncytial virus infection [23]. Taken by itself, greatly depending on time of day, gender, genetics, age, this could be mere coincidence, but once comparable data exercise schedule, environment, and many other factors. clouds are shared by thousands of individuals, real statisti- These sparse measurements are then typically compared cal analysis becomes possible. to reference ranges determined from large population The ultimate goal is to gather comprehensive genetic and averages that may not be entirely relevant. As a result, physiological data, regularly, for a large number of peo- it is very diffcult to accurately determine if a signifcant ple, over a long period of time. The objective is to observe health transition has occurred in a particular individual. all measurable changes that occur as individual transition Today, it is not generally possible to predict when we will between disease and healthy states and vice versa. Towards become ill. this goal, ISB recruited volunteers to the ‘Pioneer 100 Pro- What if this were not the case? Imagine if one could ject’. This pilot project tested the feasibility of collecting learn how many years he or she were away from a spe- and interpreting multifaceted data for multiple individu- cifc illness. No one can avoid every risk factor for every als, providing them with real-time feedback from the data, disease, but much can be done if one knows what to pri- and coaching them on ways to improve their health and oritize. Good doctors always remind their patients to wellness. eat healthy and exercise. But what are the right foods? ISB successfully enrolled 108 volunteers, or ‘Pioneers’, What are the right exercises? Only by engaging health- into an IRB-approved study led by Profs. Leroy Hood and care consumers as active participants who provide both Nathan Price. Pioneers ranged in age from their 20s to health-related data and insights into pathophysiology can over 88 years and were approximately balanced between biomedical innovation accelerate. male and female. The study ran for 9 months in 2014. This new scientifc wellness strategy is described as Each pioneer had their whole genome sequenced and pro- personalized, predictive, preventive, and participatory vided blood, urine, saliva samples at 3-month intervals for (P4) medicine. The participatory component describes metabolomic, proteomic, and additional chemical analy- patients, researchers, physicians, and the entire health- sis. The gut microbiota were also surveyed three times by care community joining together to make health main- 16S rRNA sequencing. Participants engaged in continual tenance and the practice of medicine as highly proactive self-tracking and lifestyle monitoring via digital pedom- activities. Implementation requires two central activities. eters and questionnaires. A registered dietitian served as The frst is the establishment for each individual of a a ‘wellness coach’ to share and interpret results with the ‘dense, dynamic data cloud’ consisting of billions of data participants. A physician reviewed all data before sharing points. Computational analysis of these data clouds will [93].

1 3 S10 Eur J Nutr (2017) 56 (Suppl 1):S1–S21

Correlations between genetic predispositions and meas- role of nutrition and micronutrients, to reduce risks of urements were found for both simple traits and complex chronic conditions and disability, and to delay the onset of phenotypes. For example, by integrating previously identi- non-communicable diseases. This provides a trifold beneft: fed genetic variants, each with a small effect on elevated for the individual, for the society, and for healthcare system LDL cholesterol risk, individualized risk scores were cal- and costs [41, 100]. culated. Increasing baseline LDL cholesterol levels were Most of the world’s population has inadequate intake of found to correlate with increasing genetic risk. Cohort- one or more of the essential vitamins and minerals. While level statistics on all measurements also revealed that the vitamin and mineral defciency, and inadequacy are often largely ‘healthy’ volunteers had a high rate of initial lab seen as problems in developing countries it is less recog- results outside of normal range. Based on these results, all nized as an issue, also in developed countries [63]. Vita- of the pioneers received actionable recommendations from mins and minerals are cofactors for proteins and enzymes their coaching phone calls. At the fnal time point, out-of- of metabolism or have other essential functions in our body. range measurements had dropped in diabetes, cardiovascu- A varied and balanced diet should provide enough of all of lar disease, infammation, and nutritional categories. Two the vitamins and minerals; however, an unbalanced diet pioneers had genetic variants putting them at severe risk provides calories but not enough of the vitamins and miner- for hemochromatosis—a potentially life-threatening excess als. Insuffcient vitamins and minerals result in a defciency of blood iron. In fact, both had elevated iron and ferritin disease, while the consequences of inadequacy are more levels and neither were previously aware of this condition. diffcult to diagnose. The Triage theory by Dr. Bruce Ames By the end of the study, both had their iron levels under posits that, because of recurrent shortages of vitamins and control and affected family members were made aware of minerals during evolution, natural selection developed a their risk. strategic-rationing response to moderate shortages so that Even in a relatively small cohort of 108 individuals, the the scarce nutrient is preferentially retained by proteins that study uncovered proto-disease states, nutrient defciencies, are essential for short-term survival and reproduction [6, and unhealthy heavy metal levels. During the course of this 45]. In contrast, proteins needed for long-term health and study, the participants were thoroughly engaged by provid- to defend against the diseases associated with aging, are ing questionnaire data, biosamples for analysis, discuss- starved for vitamins, and thus are disabled. Since the dam- ing the fndings and the health recommendations with the age from moderate defciency is insidious, its importance wellness coach, and participating in pioneer social events. for long-term health is not clinically apparent. Mechanis- Pioneer feedback provided three consistent messages. First, tic, genetic, and epidemiological evidence suggests that the participants understood that their genome does not control metabolic trade-off accelerates aging-associated malfunc- their health destiny. Second, the provided data enhanced tions and diseases, such as cancer, cardiovascular disease, their ability to take control of their health. Finally, many immune dysfunction, and cognitive decline [45]. people are less healthy than they think—each pioneer had The following example summarizes the beneft of essen- multiple actionable possibilities for enhancing their health. tial nutrients for a healthy life which could result in appro- priate changes, characterized by health and vitality of the individual, and a positive impact on healthcare and the The role of supplements to support a healthy life attendant economic costs. Nutrition is a complex topic and so are its felds of application; nevertheless, a signifcant According to the WHO, globally, life expectancy is increas- scientifc and medical consensus exists as to the importance ing in the majority of countries [126]. Living longer is not of an appropriate level of micronutrient intake throughout the issue anymore but living longer healthy and better is the life course to support growth, foster health, and prevent the challenge. The proportion of people aged over 60 years the onset of disease. Appropriate micronutrient intake (vita- is growing faster than any other age group. Consequently, mins and minerals)—as part of a balanced diet and in com- from 2000 until 2050, the proportion of the global popu- bination with fortifed food and supplements—encourages lation over 60 years will double from approximately 11 to health and well-being [8, 43]. 22%. This can be interpreted as a success story for public Micronutrient defciencies and inadequate micronutri- health policies and for socioeconomic development, but ent intake compared to recommendations can have seri- at the same time it also challenges societies to adapt and ous health consequences for individuals; they also have a overcome the health and economic burden of aging and wider impact on societies, economies, and healthcare and non-communicable diseases. ‘Healthy’ refers to physical, welfare systems. Healthcare costs are a signifcant part of mental, and social well-being as indicated in the WHO def- the gross domestic product (GDP), expenditures have risen inition of health [126, 127]. Lifelong health promotion is signifcantly; a 10% increase in non-communicable diseases the opportunity, with a clear emphasis on the fundamental results in a 0.5% reduction in annual economic growth [41,

1 3 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 S11

100]. There is growing evidence from food intake surveys increasingly reported to be related to protecting essential that a suffcient intake of micronutrients has not reached in fatty acids from lipid peroxidation, cognitive function, many countries compared to the recommendations. Reasons reducing the risk of Alzheimer’s disease, and reducing the for this are changes in lifestyle, different eating patterns negative health implications of fatty liver disease. However, with a higher share of outdoor eating and an increase of the intake of vitamin E is generally low across all regions processed foods. As the insuffcient intake does not result in worldwide; the population intakes for α-tocopherol and immediate consequences for a person, the impact and long- vitamin E are below the recommended 15 mg/day for men term effects on health and well-being are often neglected and women in the US as well as other Western countries, [110]. like Germany, the United Kingdom, and the Netherlands A map indicating the vitamin D status in different coun- [92]. A minimum serum level of 12 µmol/L α-tocopherol tries and populations showed a surprisingly low vitamin is needed to avoid defciencies in the human body. Further- D and initiated a call to act for evidence-based programs more, results from several observational, prospective stud- of vitamin D fortifcation of foods for the general popula- ies suggest a serum tocopherol concentration of 30 µmol/L tion and/or supplementation in risk groups. An inadequate and above to have benefcial effects on human health in the status in vitamin D impacts several body functions [57, 68, feld of cardiovascular disease, some types of cancer, and 113]. The classic role of vitamin D is connected to bone mortality. Additionally, data from the 2003–2006 National health: vitamin D is essential for the uptake and for the Health and Nutrition Examination Survey (NHANES) transportation of calcium, next to other factors like vitamin show mean α-tocopherol concentrations below the optimal K. There are a number of emerging health benefts con- concentration for the total population and non-supplement nected to an adequate vitamin D status, for example mus- users. Apart from differences in α-tocopherol concentration cle strength and the risk of falling in advanced age; vita- between supplement and non-supplement users, a higher min D strengthens the immune system and reduces the risk proportion of younger rather than older adults had subop- for multiple sclerosis. It also has an impact on the risk for timal α-tocopherol concentrations. Therefore, despite low cardiovascular diseases because it reduces high blood pres- incidence of overt vitamin E defciency many American sure, and it reduces the risk of some cancers as it inhib- adults have suboptimal α-tocopherol status even when sup- its or reduces cell proliferation. An analysis of published plementing their diet [86, 92]. population-based studies in Europe, where the 25-hydroxy- There is a robust literature suggesting that the health vitamin D status was measured in blood, demonstrated benefts of the long chain omega-3 fatty acids, eicosap- for many countries a status below the desired level. There entaenoic acid (EPA, 20:5n3) and docosahexaenoic acid are different recommendations in place: the Institute of (DHA, 22:6n3) for human use. Blood levels of EPA and Medicine in the US recommends a status of 50 nmol/L or DHA vary across the globe, with most of the countries higher for the general population as optimal; the authori- and regions of the world having levels that are considered ties in Europe, the International Osteoporosis Foundation, as low to very low [37, 39]. The very low to low range of the Endocrine Society and other organizations recommend blood EPA and DHA may have implications for the indi- a status of 75 nmol/L or higher. A number of human studies vidual as well as for the society because of higher risks indicate that a blood level of 75 nmol/L 25-hydoxy-vita- for non-communicable diseases, in particular cardiovas- min D and higher is optimal for reducing the risk of bone cular diseases and cognitive decline. A recent meta-analy- fractures, improving muscle strength and reducing risk for sis, to date, the most comprehensive quantitative analysis diseases like diabetes, multiple sclerosis and some can- of its kind within the peer reviewed biomedical literature, cers. There is currently only one country in Europe which showed a signifcant decrease of CHD risk in people with is in the desirable level of 75 nmol/L 25-hydoxy-vitamin elevated TG and LDL cholesterol levels by supplementa- D; this is Finland. Some countries are in the range between tion with omega-3 fatty acids [3, 77, 89]. It is necessary to 50 and 75 nmol/L and the general population in countries, consume signifcantly more than 250 mg of omega-3 fatty for example, Germany, Switzerland, and Italy are even acids per day to be classifed as having a high EPA/DHA below 50 nmol/L. For elderly, there are no data available status, resulting in a blood level required to achieve cardi- which are representative for a complete country. An assess- ovascular benefts. This optimal level can be achieved by ment for Germany has indicated that supplementation of eating fatty fsh rich in omega-3, like salmon or cod sev- elderly—assuming a risk reduction for fractures by 20%— eral times a week [89]. As many people cannot or will not would result in healthcare cost reduction of 580–780 mil- have a diet heavy in marine foods, food supplements and lion Euros every year [41, 68, 100]. fortifed foods are the most convenient and cost effective Vitamin E is an essential nutrient; it is a powerful anti- way to ensure that the optimal level is achieved. The very oxidant and has been recognized as being vital for preserv- low to low range of blood EPA and DHA levels may have ing the integrity of the cell membrane [86]. Vitamin E is implications on the global risk for chronic disease as well

1 3 S12 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 as healthcare costs, with a recent study fnding that regu- Nutrition and healthy aging: towards the lar consumption of omega-3 supplements in the range of development of personalized interventions 1000 mg/day could save €12.9 billion a year in healthcare costs related to CVD-related events in the European Union In most countries, average human lifespan is increasing at alone [41, 68, 100]. approximately 2 years per decade. However, these addi- The consensus concerning the value of appropriate tional life years are often burdened by poor health, this is micronutrient intake is based on a robust body of evidence not an inevitable consequence of aging. The aging pro- and several powerful nutritional and economic models. cess is plastic and there is good evidence that nutrition is a It is, however, critical to develop models that address the major determinant of how well we age [62] and of risk of complexities of micronutrient interventions. age-related disease and disability [84]. The challenge is to The extensive scientifc knowledge currently available improve eating patterns (and other lifestyle factors) to max- needs to be translated into cost-effective, practical pub- imize healthy aging. However, conventional approaches lic health solutions. These may include fortifcation and/ to changing eating patterns have often produced modest or supplementation. The health and economic benefts of improvements only [65], which are diffcult to sustain. fortifcation or supplementation with certain micronutri- Additionally, because of optimistic bias, people are often ents, e.g., vitamin A (to reduce infant mortality), iodine (to resistant to dietary change. reduce goiter), vitamin D (primarily against rickets), and The worldwide obesity epidemic attests to the diffculty folic acid (primarily to reduce neural tube defects), is clear. in changing dietary choices in healthy ways. However, in The economic return of fortifcation varies from 1:24 for recent years, there has been growing interest in the use vitamin A fortifcation; to 1:46 for multivitamins (Copen- of personalized nutrition (PN) approaches to help people hagen Consensus); up to 1:200 for iodine fortifcation. adopt healthier eating patterns. The PN approach is predi- Many countries in the world already have mandatory for- cated on the idea that individuals will be more motivated to tifcation programs in place involving these micronutrients. make appropriate and sustained dietary changes if they per- The absence of such programs (for example for folic acid ceive that the advice and support offered is ‘personalized’ and vitamin D), is an unacceptable gap in our public health and, therefore, more directly relevant to each individual. system and should be scrutinized in the light of the over- The Food4Me PN intervention trial, tested the hypoth- whelming evidence of the proven benefts of fortifcation/ esis that personalizing nutrition advice would produce big- supplementation programs involving these micronutrients ger and more appropriate changes in eating patterns and [8, 38, 110]. markers of health [21]. This large-scale intervention study The above points should receive the urgent attention recruited 1609 adults (aged 18–79 years) across seven of the public health, as well as the nutrition community, European countries and randomized them to (i) conven- policy makers, patient organizations, health insurers and tional dietary advice (control) or to PN advice based on: other stakeholders, and next steps should be taken to give (ii) individual baseline diet; (iii) individual baseline diet a healthy diet a higher priority. The implementation of food plus phenotype; or (iv) individual baseline diet plus phe- fortifcation programs, the development of nutrient-rich, notype plus genotype. Participants were recruited via the energy-balanced foods and supplementation programs are internet using the Food4Me website (http://food4me.org/) all rated as important steps towards a healthy life [38]. So, [21, 22], the intervention was delivered via the web and by in summary, healthy nutrition and reduction of healthcare e-mail and the participants used this website to upload die- costs are realistic objectives. A healthy diet including food tary and other data. Participants collected buccal swabs (for fortifcation and use of supplements providing all nutrients DNA extraction and genotyping) and blood samples (dried is more infuential than genetic factors to decrease morbid- blood spots for metabolite assay) at home and posted them ity, to support quality of life and healthy aging. Successful to the recruiting centers. examples demonstrate that people understand the impor- At 6-month follow-up, participants randomized to the tance of eating healthy, however, that realization requires PN arms of the intervention had bigger improvements in support and education. In communities where integrated eating patterns than those in the conventional dietary advice programs have taken place, dramatic improvements in (control) group but there was no evidence of added advan- quality of life, healthier life and lower healthcare costs tage of using phenotypic or genetic information to tailor the are reported. Relevant stakeholders should act together to personalized dietary advice [22]. The Food4Me Study also develop and implement programs for healthy nutritional showed the potential benefts of using an internet-based solutions to provide all essential nutrients and improve the platform to recruit participants and to deliver PN across quality of life; solutions are available. multiple countries. This offers opportunities for scaling-up

1 3 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 S13 intervention delivery and, potentially, for improved cost- muscles as potential markers of sarcopenia [59, 116], but effectiveness [20]. these have not been fully validated. Lifestyle-based interventions are likely to be more In many instances of sarcopenia, reduced muscle mass is effective if they are offered during signifcant life-stage associated with increased fat mass, a condition known as sar- transitions when participants may be more receptive to copenic-obesity [10]. Sarcopenic-obesity, has been described change. In respect of healthy aging, retirement is a major as ‘the confuence of two epidemics’ [97], with a combination intervention opportunity which has been exploited in of reduced muscle mass coupled with signifcant metabolic developing living, easting, activity and planning (LEAP), dysregulation. The reported prevalence of sarcopenic-obesity an internet-based platform designed to deliver personal- varies widely, ranging from 3.6 to 94% [9]. Moreover, despite ized advice to help individuals improve diet, physical the fact that in many cases the apparent ‘volume of muscle’ activity and social roles/connections and so age more may appear unchanged or even increased, there is an addi- healthily [87]. A recently completed pilot study shows tional burden of obesity in the elderly as decline in physical that this intervention was well-received by participants function reduces muscle quality [114]. Recently, it has been in the retirement transition with high participant reten- proposed that magnetic resonance imaging (MRI) techniques tion [66]. This was further evidence that internet (digital) could play a signifcant role for a more objective diagnosis approaches are effective in engaging participants and in of sarcopenic-obesity [81], as they allow full body composi- delivering PN. tion analysis during a single examination, including ectopic fat depots. Indeed, recent studies suggest that the sarcopenic- Sarcopenic‑obesity: a view from the inside obesity phenotype should include ectopic fat depots such as the liver, pancreas and muscle. Both intra- Modern lifestyle choices are leading to a plethora of meta- (within muscle cells) and extra- (between muscle cells) bolic conditions and phenotypes. Excess calorie intake, myocellular fat have been shown to increase as a con- coupled with an ever increasing sedentary lifestyle has sequence of aging, inactivity, obesity and poor dietary brought about an increase in overall adipose tissue mass, choices [72, 109]. This, in turn, may underpin the dete- as well as adverse distribution. Modern imaging methods rioration in ’muscle quality’ observed with this pheno- have helped to identify an ever increasing number of body type. This is clearly illustrated in Fig. 3, where increas- composition sub-phenotypes, all of which appear to have ing fat infiltration across muscle groups can be observed distinct disease risk. One such phenotype is the so-called with aging, in the absence of changes in ‘muscle vol- sarcopenic-obesity, with an aberrant muscle mass content ume’. Thus, understanding the contribution of ectopic and abnormal fat distribution. This phenotype, contrary to fat accumulation may be particularly relevant to sar- classical sarcopenia, which is especially observed in the copenic-obesity since there is a significant association older populations, appears to arise as a direct consequence between intermuscular fat accumulation and decline in of the current obesogenic environment that modern humans gait speed, independent of thigh area [13]. This suggests have created for themselves. that measurements of muscle quality/composition may Sarcopenia describes the age-related gradual decline in be pivotal. muscle mass and function [96]. The consequences of sarco- In conclusion, our current obesogenic environment, penia are evident in the quality of life of many older subjects, characterized by access to calorie rich foods coupled to leading to frailty, fractures, disability and mortality [76]. The uncontrolled levels of inactivity, is leading to the propa- etiology of sarcopenia is not fully understood, but includes gation of a sarcopenic-obesity phenotype across the pop- physical inactivity, chronic diseases, infammation, and poor ulation and across the generations. The advent of sophis- nutrition. Currently, there is no universal method for deter- ticated high-throughput imaging systems are allowing the mining sarcopenia; however, options include the use of the development of a more detailed and reproducible defni- relative appendicular skeletal muscle mass; lowest two quin- tion and measurement of sarcopenic-obesity, thus, deter- tiles of relative muscle mass or ratios of appendicular fat-free mining its impact on health. mass or whole body fat-free mass to height squared or skele- tal muscle/body weight 100 [25]. The lack of techniques to × directly measure ‘muscle mass’ has signifcantly limited the Plant‑based dietary patterns, chronic disease risk, objective and reproducible assessments of sarcopenia. Most and healthy longevity: an emerging paradigm studies today tend to use dual-energy X-ray absorptiometry for phytonutrients and health promotion (DXA) or bioelectrical impedance (BIA), although neither measure ‘muscle quality’. Some researchers have suggested Over the past two decades, epidemiological studies have the use of specifc muscles such as the psoas or masseter shown a consistent inverse relationship between fruit and

1 3 S14 Eur J Nutr (2017) 56 (Suppl 1):S1–S21

Fig. 3 Axial MR images from the lower leg of 5 volunteers, showing typical changes arising as a result of the normal aging process. This includes both a reduction in the proportion of ‘muscle mass’ and the ‘quality’ of the muscle, with a visible increase in the amount of inter- muscular fat deposited

vegetable intake and risk for chronic disease, and are the suggest a protective role against other chronic diseases basis for the WHO recommendation for adults to con- that are less often associated with mortality. sume at least 400 g/day fruit and vegetables. In the same A new paradigm for plant-based dietary patterns, phy- timeframe, other epidemiological research has identi- tonutrients, and health promotion comes from a selection fed dietary patterns featuring an abundance and variety of literature focused on four emerging areas of science: (i) of plant foods as a common characteristic in populations plant-based dietary patterns in cohorts experiencing healthy that experience exceptionally healthy longevity. The longevity, (ii) plant-based diets and wellness outcomes, (iii) Okinawan and Mediterranean style diets are two well- advances in understanding the biology of aging, and (iv) known examples (see “Dietary patterns and longevity: phytonutrient interactions with aging mechanisms. insights from the oldest old in Okinawa”, this article). Selected Okinawan and Mediterranean populations have As these two bodies of research have developed, rapid been documented to experience unusually healthy longev- advances have been made in understanding the biology ity. Interestingly, these populations have plant-based die- of aging. This emerging research suggests that the age- tary patterns that are well studied in terms of their protec- related decline in cells, tissues and organs underlies the tive effects against chronic disease. These populations not onset of many chronic diseases. Studies in animal models just survive to old age, they do so with high quality health suggest that interventions that slow the rate of aging hold until late in life. More recently, the National Geographic potential to both reduce the risk for chronic disease, and Society has sponsored a body of ethnographic research also promote health. The provocative potential connec- that features a selected few demographic groups around the tions between these areas of research have been the basis world, all of which experience unusually healthy longev- for science at the bench, as well as in the clinic, to char- ity similar to the Okinawan and Mediterranean populations. acterize the composition, assimilation and metabolism of These have collectively been named ‘Blue Zones’. Interest- plant food nutrient components, and their effects on bio- ingly, plant-based dietary patterns rich in fruits, vegetables, logical mechanisms of aging. whole grains, and legumes are a feature of the Blue Zones, Two prominent examples of science focused on the in addition to active lifestyle, and other health promoting role of plant-based dietary patterns for reducing and man- behaviors. aging chronic diseases come from Wang et al. [117] and Emerging wellness outcomes research in humans Boeing et al. [17]. Wang et al. demonstrated an inverse suggests that plant foods hold potential to promote relationship between the hazard ratio for all-cause mor- health and function of different organ systems. Green tality and fruit and vegetable consumption. Higher con- leafy vegetable consumption has been associated with sumption of fruits and vegetables was signifcantly asso- improvements of heart rate variability measures, which ciated with a lower risk of all-cause mortality. There was may reduce the risk of cardiovascular disease through a threshold around fve servings of fruits and vegetables these favorable changes in cardiac autonomic function a day, after which the risk of all-cause mortality did not [91]. Strong inverse associations were found between reduce further. Boeing et al. summarized the strength of plant-based anthocyanin intake and age-related decline evidence behind fruit and vegetable intake and specifc in lung function as determined by forced vital capacity chronic diseases. The conclusions from this work suggest [74]. There is evidence that increased fruit and vegeta- that increased fruit and vegetable intake is likely protec- ble intake has a positive impact on immune function as tive against cardiovascular disease and cancer, and also determined by antibody response to vaccination [45] as

1 3 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 S15 well as an inverse association with 4-year weight change is one rendering of the emergent paradigm for the role of [14]. Vegetables having both higher fber and lower gly- diet, specifcally phytonutrients, to favorably infuence all cemic load were more strongly inversely associated with of these outcomes. weight change compared to lower-fber, higher-glycemic- Evaluation of the evidence as a whole supports the role load vegetables. Intake of fruits, vegetables, fsh, whole of plant-based dietary patterns in promoting healthy lon- grains, legumes and dairy products is associated with gevity and suggests that there is an opportunity to intercept improved bone mineral density [28]. individual health trajectories with a healthy plant-based A developing body of evidence in in vitro and animal dietary pattern, with the result being improved health and model systems has identifed several mechanisms that function throughout life. There are, however, important are thought to play important roles in aging. The primary considerations in this paradigm. First, phytonutrients are mechanistic pathways result in reduced oxidative stress, not likely to act alone as individual compounds, but as a suppressed low-grade chronic infammation and induction collective family of nutrient compounds. Second, dietary of autophagy [101]. We have explored botanical extracts for patterns are more powerful lenses with which one can their ability to infuence one or more of these pathways. We examine healthy longevity with respect to individual foods. evaluated the effects of turmeric, quercetin, and rosemary No single food is likely to exert healthy longevity. Third, extracts on the activation of the nuclear erythroid 2-related physical activity is most likely a large infuencing factor for factor 2–anti-oxidant responsive element (Nrf2–ARE) sign- healthy longevity. Fourth, the gastrointestinal microbiota aling pathway. Alone, each of these botanicals had mod- undoubtedly play a role in the assimilation of dietary com- est Nrf2 activation. When combined, however, there was a ponents, as well as in the manifestation of end-physiologi- surprising synergistic activation. This result is not only an cal effects. example of the ability of selected phytonutrients to infu- ence aging mechanisms favorably, but also an illustration of the potential for them to interact within a given pathway Defning optimum nutrition: dynamic biomarkers [79]. to capture the complexity of health Advances in understanding the biology of aging suggest that the origins of chronic disease may lie in the age-related Notwithstanding an increasing interest in specifc diets to decline in cell, tissue and organ function. The schematic manage, reverse or even cure disease, the primary goal of shown in Fig. 4 depicts a synthesis of current working healthy nutrition is to maintain optimal health and to prevent models for the relationship between mechanisms of aging, disorders [15, 44, 51]. Although this might only seem like a age-related functional decline and chronic disease. Early in marginal difference, starting from the perspective of health, life, the majority of cells and tissues in the body reside at instead of disease, requires different ways of thinking and the far left hand side of this schematic. With the passage of new approaches. Interestingly, many aspects of modern time, however, the number of cells and tissues that exhibit ‘healthcare’ are rather forms of ‘disease management’. It compromised function rises such that there is a decline in is perfectly understandable that this situation has evolved functional capacity at the tissue and organ level. This pro- since health is intangible, variable, and diffcult to predict. cess proceeds, if unimpeded, to pathology and the manifes- At the same time, and irrespective of its precise defnition, tation of disease. there is general consensus that optimal health not only con- Phytonutrients interact with aging mechanisms such that stitutes one of the most important values in our life, but also they hold potential to confer healthy longevity. Figure 4 is a major determinant of social and economic stability. It is depicts some proposed areas where phytonutrients conceiv- also clear that diet is one of the main lifestyle factors deter- ably can infuence the rate of aging, but also promote func- mining physical and even mental health. However, faced tional capacity and reduce the risk for chronic disease. This with diffculties to capture the effects of diet and nutritional

Fig. 4 Schematic of current working models for the relation- ships between mechanisms of aging, age-related functional decline and chronic disease. The proposed interactions between these mechanisms and phytonu- trients are depicted by green text

1 3 S16 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 interventions and their multifactorial character, many clini- approach’ is used, meaning that multiple biomarkers, pref- cians and policy makers struggle with the practical impact erably of different integration levels (e.g., gene, protein, and feasibility of dietary measures. Effects of nutrition are metabolite, but also a physiological response, images, etc.) subtle, complex and generally occurring very slowly. This are analyzed at different time points and integrated into complexity not only poses important scientifc questions, models [11]. Such combinations of health biomarkers are but also fuels ongoing discussions, trends, and hypes in the often different from the classical disease biomarkers. Fur- feld of nutrition and health. To address the knowledge gaps, thermore, ‘stress’ or ‘challenge’ tests are used to measure several initiatives involving academic and industrial part- the fexibility and resilience of health. Such tests measure ners have been launched to develop new views and method- the response to a metabolic, physical, psychological or ologies. Their focus is not only on measuring health effects, immunological stressor. Different biochemical, physiologi- but also on trial design including the role of randomized cal or psychological endpoints are in use, which are indica- controlled trials (RCTs), statistics, and methodology to tive of specifc processes [104]. For example, a metabolic accurately measure dietary intake. These developments are challenge test measures the response to a standardized meal supported by the rapid progress made in -omics technolo- or beverage that provides a carbohydrate or fat ‘load’ [60, gies, data management, statistics, and micro-electronics. 104, 125]. Next to metabolic stress tests, a laboratory can Biomarkers for health are key in this process. also apply physical challenge tests [58]. These tests, apply- In many ways, modern medicine and nutrition science ing a strenuous exercise protocol on a bicycle ergometer, have drifted apart. Medicine has developed into a pre- generate effects on immune function and intestinal per- dominantly disease-oriented discipline, and in its wake meability, which in turn can be used to investigate poten- the ‘one disease—one target—one drug paradigm’ has tially positive effects of dietary interventions, probiotics, become a dominating principle. Understandably, this has etc. Other challenge tests apply vaccination, experimental consequences for thinking, training, and the way of doing infection [106] or psychological stress [73, 98]. research. In this respect the RCT is the golden standard to, Although these concepts are increasingly acknowl- for example, demonstrate the effcacy of therapeutic drugs. edged as the way forward in nutritional science, they have However, it is clear that nutrients behave differently from not made life easier in every respect. Their development is medicinal compounds. Unlike most medicines, single nutri- often hampered by complexity and costs. Inter-individual ents are involved in numerous endogenous processes and differences in responses can be quite large, and standardi- part of complex molecular networks regulating their avail- zation and data exchange between labs is not always easy. ability, formation and degradation. As a result, their dose Another disadvantage is that these tests usually only pro- (or concentration) response curves, often U-shaped, are vide information on the resilience of a limited domain of generally composed of multiple effect relationships. Acute health (improvement) indicators such as metabolic health, effects or ‘quick wins’ are far less obvious than with phar- intestinal health, immune health, etc. Last but not least, maceuticals. Another important point is that RCTs have their extrapolation to perceivable consumer benefts often often little usefulness or may not even be possible when remains diffcult. studying the effect of diet and (or) specifc nutrients [15, An interesting development will be the possibility to 42, 51]. To understand and quantify the way nutrition acts move challenge test approaches out of the conventional lab in improving, stabilizing or restoring health, better working environment. Thanks to the rapid developments in ‘weara- defnitions of ‘health’ were needed that take into account ble’ technologies for continuous collection of health param- it’s dynamic, multi-dimensional and time-dependent char- eters [64], it is anticipated that a new generation of chal- acter. These defnitions have in common the ability to con- lenge tests can be developed and incorporated into systems tinuously adapt in varying circumstances. An example is for total health monitoring with ‘real life’ challenges. Pro- ‘the ability to adapt and self-manage in the face of social, vided that technical problems with data integration will be physical, and emotional challenges’ [55]. This paradigm solved, such methodology would also enable further inter- dates back to the classical physiological, or even older disciplinary integration, for example between physiology, principles of homeostasis. Nutrition plays important roles epidemiology, geo-informatics, microbiology, consumer in maintaining or even strengthening a proper physiologi- behavior, etc. cal bandwidth or fexibility (resilience). This has also been The generally subtle effects of diet and nutrition on called ‘phenotypic fexibility’, being the resultant of the health require methods and biomarkers that capture the individual’s genotype, his/her physiological and psycho- dynamics and complexity of physiological resilience. Tech- logical state at a particular point it time, his/her microbi- nological developments are moving extremely fast, offer- ota, etc. [112, 115]. Within this context, the (often gradual) ing exciting new ways to measure systems fexibility under onset of disease starts when and where adaptive processes real life conditions. Although still many technological and fail. To measure these dynamic processes, a ‘systems IT challenges lie ahead [2, 49] these ‘living lab’ approaches

1 3 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 S17 are likely to offer new ways for nutrition-related health however, it is highlighting opportunities and setting the optimization, self-empowerment, and to develop new prod- stage for more robust discussion and broader and deeper ucts and services. recommendations.

Acknowledgements This conference report summarizes the presen- Conclusion tations and outcomes of the meeting entitled ‘Optimal Nutrition and the Ever-Changing Dietary Landscape’ held on December 2, 2016, in Hamburg, Germany. The event was organized by the Council for The CRN-International Scientifc Symposium and this arti- Responsible Nutrition-International (www.crn-i.ch). The opinions cle focus on ‘Optimal Nutrition,’ a subject that is nebulous expressed, herein, are those of the authors; this conference report is and fraught with a myriad of defnitions, boundaries, cave- not a consensus statement; therefore, some authors may not agree with all opinions expressed. The following individuals assisted in ats, and nuances. The ten recognized experts offered their the preparation of various portions of this conference report and are personal perspectives on this most challenging theme. Def- hereby acknowledged as follows: Richard Allsopp (Institute for Bio- nitionally, ‘optimal’ would be deemed the ‘most desirable genesis Research, University of Hawaii, Honolulu, HI, USA); Gus- or satisfactory, most favorable, most effective’ and would tavo Glusman (Institute for Systems Biology, Seattle, WA, USA); Leroy Hood (Institute for Systems Biology, Seattle, WA, USA); be the ‘selection of a best element (with regard to some cri- Karsten Hiller (Technische Universität Braunschweig, Abteilung terion) from some set of available alternatives’, and ‘nutri- für Bioinformatik und Biochemie Braunschweig Integrated Centre tion’ would be the ‘act or process of nourishing or being of Systems Biology (BRICS), Braunschweig, Germany); E Louise nourished; specifcally; the sum of the processes by which Thomas (Research Centre for Optimal Health, Department of Life Sciences, Faculty of Science and Technology, University of West- an animal or plant takes in and utilizes food substances’. minster, London UK); Nathan D. Price (Institute for Systems Biol- However, even when seeking the most desirable process ogy, Seattle, WA, USA); Matt Runyon (Amway Global Discovery, of nourishment, one must then consider that what may be Buena Park, CA, USA); Makoto Suzuki (Okinawa International Uni- optimal for one person or one region, may not be translat- versity, Ginowan, Japan and University of the Ryukyus, Nishihara, Japan); Bradley J Willcox (Kuakini Medical Center, Honolulu, HI, able across the spectrum of human idiosyncrasies. USA and Department of Geriatric Medicine, University of Hawaii, Historically, the presence or absence of a disease was the Honolulu, HI, USA). measure of how poorly or how successfully one was enter- ing older age. However, that concept is being reevaluated Compliance with ethical standards and redefned and ‘functional ability’ is becoming the new rubric. A combination of the intrinsic capacity (physical Confict of interest A Drewnowski, D.C. Willcox, L. Krämer, C. Lausted, M. Eggersdorfer, J. Mathers, J. Bell, R.K. Randolph, R. and mental) that an individual can rely on, relevant envi- Witkamp and J.C. Griffths had their travel expenses reimbursed by ronmental factors, and the interactions between the individ- CRN-I. J. Mathers serves on the advisory board for Estavayer Lait ual and these characteristics is how WHO recommendsde- S.A., Switzerland. A. Shao, M. Eggersdorfer and R.K. Randolph are fning ‘healthy aging’ [12, 88]. A geriatric population that employees of their respective companies, Herbalife Nutrition, DSM Nutritional Products and Amway Corporation. A. Drewnowski has is characterized by high prevalence of ‘frailty’, i.e., a pro- received grants, honoraria, and consulting fees from numerous food, gressive age-related deterioration in physiological systems beverage, and ingredient companies and from other commercial and that result in extreme vulnerability to stressors that in turn nonproft entities with an interest in nutrient density of individual increase the risk of multiple adverse outcomes, to the indi- foods, meals, and total diets. vidual as well as to the personal and public healthcare sys- tems through increased dependence, has the potential for Open Access This article is distributed under the terms of the Crea- extreme personal, familial, governmental and societal costs tive Commons Attribution 4.0 International License (http://crea- tivecommons.org/licenses/by/4.0/), which permits unrestricted use, in time and money. In the twenty-frst century, most peo- distribution, and reproduction in any medium, provided you give ple can expect to live well into their 60s and 70s (and even appropriate credit to the original author(s) and the source, provide a older). In 2015, the WHO estimated that global life expec- link to the Creative Commons license, and indicate if changes were tancy at birth was 71.4 years (http://www.who.int/gho/ made. mortality_burden_disease/life_tables/situation_trends/en/). However, the quality of the growing number of added years of life expectancy is highly dependent upon and affected, References for better or worse, by each individual’s ‘health’. 1. Aggett PJ, Hathcock J, Jukes D, Richardson DP, Calder PC, This year’s proceedings article offers insights into sys- Bischoff-Ferrari H, Nicklas T, Mühlebach S, Kwon O, Lewis J, tems approaches, tracking and analyzing ‘big data’, use Lugard MJF, Prock P (2012) Nutrition issues at Codex: health of key nutritional and dietary supplements, personalized claims, nutrient reference values and WTO agreements: a con- interventions, dealing with obesity (visible and invis- ference report. Eur J Nutr. doi:10.1007/s00394-012-0306-8 2. Ala-Korpela M, Davey-Smith G (2016) Metabolic profling– ible), use of dynamic biomarkers and other perspec- multitude of technologies with great research potential, but tives. It is not the ultimate answer or defnitive roadmap; (when) will translation emerge? Int J Epidemiol 45:1311–1318

1 3 S18 Eur J Nutr (2017) 56 (Suppl 1):S1–S21

3. Alexander D, Miller P, Van Elswyk M, Kuratko CN, Bylsma the prevention of chronic diseases. Eur J Nutr 51(6):637–663. LC (2017) A meta-analysis of randomized trials and prospec- doi:10.1007/s00394-012-0380-y tive cohort studies of eicosapentaenoic and docosahexaenoic 18. Brunengraber H, Kelleher JK, Des Rosiers C (1997) Applica- long chain omega-3 fatty acids and coronary heart disease tions of mass isotopomer analysis to nutrition research. Ann risk. Mayo Clin Proc 92:15–29 Rev Nutr 17:559–596 4. Alfthan G, Aro A, Gey KF (1997) Plasma homocysteine and 19. Cannon G, Leitzmann C (2005) The new nutrition science cardiovascular disease mortality. Lancet 349(9049):397 project. Public Health Nutr 8(6A):673–694 5. Allison DB, Bassaganya-Riera J, Burlingame B, Brown 20. Celis-Morales C, Lara J, Mathers JC (2015) Person- AW, le Coutre J, Dickson SL, Vögele C (2015) Goals in alising nutritional guidance for more effective behav- nutrition science 2015-2020. Front Nutr 2:26. doi:10.3389/ iour change. Proc Nutr Soc 74(2):130–138. doi:10.1017/ fnut.2015.00026 S0029665114001633 6. Ames BN (2006) Low micronutrient intake may accelerate 21. Celis-Morales C, Livingstone KM, Marsaux CF, Forster H, the degenerative diseases of aging through allocation of scarce O’Donovan CB, Woolhead C, Macready AL, Fallaize R, Navas- micronutrients by triage. Proc Natl Acad Sci USA 103:17589– Carretero S, San-Cristobal R, Kolossa S, Hartwig K, Tsirigoti 17594. doi:10.1073/pnas.0608757103 L, Lambrinou CP, Moschonis G, Godlewska M, Surwiłło A, 7. Anjana RM, Ali MK, Pradeepa R, Deepa M, Datta M, Grimaldi K, Bouwman J, Daly EJ, Akujobi V, O’Riordan R, Unnikrishnan R, Mohan V (2011) The need for obtaining Hoonhout J, Claassen A, Hoeller U, Gundersen TE, Kaland accurate nationwide estimates of diabetes prevalence in India: SE, Matthews JN, Manios Y, Traczyk I, Drevon CA, Gibney rationale for a national study on diabetes. Indian J Med Res ER, Brennan L, Walsh MC, Lovegrove JA, Alfredo Martinez 133:369–380 J, Saris WH, Daniel H, Gibney M, Mathers JC (2015) Design 8. BAPEN (2014) Malnutrition matters. British Association and baseline characteristics of the Food4Me study: a web- for Parenteral and Enteral Nutrition (BAPEN), Redditch. based randomised controlled trial of personalised nutrition in http://www.bapen.org.uk/pdfs/toolkit-for-commisioners.pdf. seven European countries. Genes Nutr 10(1):450. doi:10.1007/ Accessed 23 May 2017 s12263-014-0450-2 9. Batsis JA, Barre LK, Mackenzie TA, Pratt SI, Lopez-Jimenez 22. Celis-Morales C, Livingstone KM, Marsaux CF, Macready AL, F, Bartels SJ (2013) Variation in the prevalence of sarcopenia Fallaize R, O’Donovan CB, Woolhead C, Forster H, Walsh MC, and sarcopenic obesity in older adults associated with differ- Navas-Carretero S, San-Cristobal R, Tsirigoti L, Lambrinou ent research defnitions: dual-energy X-ray absorptiometry data CP, Mavrogianni C, Moschonis G, Kolossa S, Hallmann J, from the National Health and Nutrition Examination Survey Godlewska M, Surwiłło A, Traczyk I, Drevon CA, Bouwman J, 1999-2004. J Am Geriatr Soc 61:974–980 van Ommen B, Grimaldi K, Parnell LD, Matthews JN, Manios 10. Baumgartner RN (2000) Body composition in healthy aging. Y, Daniel H, Martinez JA, Lovegrove JA, Gibney ER, Brennan Ann N Y Acad Sci 904:437–448 L, Saris WH, Gibney M, Mathers JC, Food4Me Study (2016) 11. Bayle M-L, Wopereis S, Bouwman J, Ommen B, Scalbert A, Effect of personalized nutrition on health-related behaviour Pujos-Guillot E (2012) Semi-targeted metabolomic approaches change: evidence from the Food4me European randomized con- to validate potential markers of health for micronutrients: ana- trolled trial. Int J Epidemiol. doi:10.1093/ije/dyw186 lytical perspectives. Metabolomics 8(6):1114–1129 23. Chen R, Mias GI, Li-Pook-Than J, Jiang L, Lam HY, Chen 12. Beard JR, Offcer A, de Carvalho A, Sadana R, Pot AM, Michel R, Miriami E, Karczewski KJ, Hariharan M, Dewey FE, J-P, Lloyd-Sherck P, Epping-Jordan J, Peeters GM, Mahanani Cheng Y, Clark MJ, Im H, Habegger L, Balasubramanian WR, Thiyagarajan JA, Chatterji S (2016) The world report on S, O’Huallachain M, Dudley JT, Hillenmeyer S, Harak- ageing and health: a policy framework for healthy ageing. Lan- singh R, Sharon D, Euskirchen G, Lacroute P, Bettinger K, cet 387:2145–2154 Boyle AP, Kasowski M, Grubert F, Seki S, Garcia M, Whirl- 13. Beavers KM, Beavers DP, Houston DK, Harris TB, Hue TF, Carrillo M, Gallardo M, Blasco MA, Greenberg PL, Snyder Koster A, Newman AB, Simonsick EM, Studenski SA, Nicklas P, Klein TE, Altman RB, Butte AJ, Ashley EA, Gerstein M, BJ, Kritchevsky SB (2013) Associations between body compo- Nadeau KC, Tang H, Snyder M (2012) Personal omics profl- sition and gait-speed decline: results from the Health, Aging, ing reveals dynamic molecular and medical phenotypes. Cell and Body Composition study. Am J Clin Nutr 97:552–560 148(6):1293–1307 14. Bertoia ML, Mukamal KJ, Cahill LE, Hou T, Ludwig DS, 24. Consoli A, Nurjhan N, Reilly JJ Jr, Bier DM, Gerich JE (1990) Mozaffarian D, Willett WC, Hu FB, Rimm EB (2015) Mechanisms of increased gluconeogenesis in noninsulin- Changes in intake of fruits and vegetables and weight change dependent diabetes mellitus. J Clin Invest 86:2038–2045 in United States men and women followed for up to 24 years: 25. Cruz-Jentoft AJ, Landi F, Schneider SM, Zúñiga C, Arai H, analysis from three prospective cohort studies. PLoS Med Boirie Y, Chen LK, Fielding RA, Martin FC, Michel JP, Sie- 12(9):e1001878. doi:10.1371/journal.pmed.1001878 ber C, Stout JR, Studenski SA, Vellas B, Woo J, Zamboni M, 15. Biesalski HK, Aggett PJ, Anton R, Bernstein PS, Blumberg J, Cederholm T (2014) Prevalence of and interventions for sarco- Heaney RP, Henry J, Nolan JM, Richardson DP, van Ommen penia in ageing adults: a systematic review. Report of the Inter- B, Witkamp RF, Rijkers GT, Zöllner I (2011) 26th Hohenheim national Sarcopenia Initiative (EWGSOP and IWGS). Age Age- Consensus Conference, September 11, 2010 Scientifc substan- ing 43:748–759 tiation of health claims: evidence-based nutrition. Nutrition 26. Darmon N, Drewnowski A (2015) Contribution of food prices 27:S1–S20 and diet cost to socioeconomic disparities in diet quality and 16. Biesalski HC, Erdman JW, Hathcock J, Ellwood K, Beatty health: a systematic review and analysis. Nutr Rev 73(10):643– S, Johnson E, Marchioli R, Lauritzen L, Rice HB, Shao A, 660. doi:10.1093/nutrit/nuv027 Griffths J (2013) Nutrient reference values for bioactives: 27. Davinelli S, Willcox DC, Scapagnini G (2012) Extending new approaches needed? A conference report. Eur J Nutr. healthy ageing: nutrient sensitive pathway and centenarian pop- doi:10.1007/s00394-013-0503-0 ulation. Immun Ageing 9:9 17. Boeing H, Bechthold A, Bub A, Ellinger S, Haller D, Kroke 28. de Jonge EAL, Kiefte-de Jong JC, de Groot LCPGM, Voort- A, Leschik-Bonnet E, Müller MJ, Oberritter H, Schulze M, man T, Schoufour JD, Zillikens MC, Hofman A, Uitterlin- Stehle P, Wat B (2012) Critical review: vegetables and fruit in den AG, Franco OH, Rivadeneira F (2015) Development of

1 3 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 S19

a food group-based diet score and its association with bone 46. Global prevalence of overweight in adults in 2014 (2015) mineral density in the elderly: the Rotterdam study. Nutrients http://gamapserver.who.int/gho/interactive_charts/ncd/risk_ 7(8):6974–6990. doi:10.3390/nu7085317 factors/overweight/atlas.html. Accessed 23 Mar 2017 29. de Magalhaes JP, Wuttke D, Wood SH, Plank M, Vora C 47. Global report on diabetes (2016) http://apps.who.int/iris/ (2012) Genome-environment interactions that modulate bitstream/10665/204871/1/9789241565257_eng.pdf?ua 1. aging: powerful targets for drug discovery. Pharmacol Rev Accessed 23 Mar 2017 = 64:88–101 48. Hammond RA, Dubé L (2012) A systems science perspective 30. Dennett D (1995) Darwin’s dangerous idea: evolution and the and transdisciplinary models for food and nutrition security. meanings of life. Simon & Schuster, New York Proc Natl Acad Sci USA 109(31):12356–12363. doi:10.1073/ 31. Donlon TA, Curb JD, He Q, Grove JS, Masaki KH, Rodriguez pnas.0913003109 B, Elliott A, Willcox DC, Willcox BJ (2012) FOXO3 gene 49. Hart T, Xie L (2016) Providing data science support for sys- variants and human aging: coding variants may not be key tems pharmacology and its implications to drug discovery. players. J Gerontol A 67:1132–1139 Expert Opin Drug Discov 11:241–256 32. Drewnowski A (2009) Defning nutrient density: development 50. Heaney RP (2008) Nutrients, endpoints, and the problem of and validation of the Nutrient Rich Foods Index. J Am Coll proof. J Nutr 138(9):1591–1595 28(4):421S–426S 51. Heaney RP (2012) The nutrient problem. Nutr Rev 33. Drewnowski A (2010) The cost of US foods as related to 70:165–169 their nutritive value. Am J Clin Nutr 92(5):1181–1188. 52. Hellerstein MK (2004) New stable isotope-mass spectromet- doi:10.3945/ajcn.2010.29300 ric techniques for measuring fuxes through intact metabolic 34. Drewnowski A (2013) New metrics of affordable nutrition: pathways in mammalian systems: introduction of moving pic- which vegetables provide most nutrients for least cost? J Acad tures into functional genomics and biochemical phenotyping. Nutr Diet 113(9):1182–1187. doi:10.1016/j.jand.2013.03.015 Metab Eng 6:85–100 35. Drewnowski A, Fulgoni VL 3rd (2014) Nutrient den- 53. Hiller K, Hangebrauk J, Jäger C, Spura J, Schreiber K, sity: principles and evaluation tools. Am J Clin Nutr 99(5 Schomburg D (2009) MetaboliteDetector: comprehensive Suppl):1223S–1228S Analysis Tool for targeted and nontargeted GC/MS based 36. Eelderink C, Moerdijk-Poortvliet TC, Wang H, Schepers M, metabolome analysis. Anal Chem 81:3429–3439 Preston T, Boer T, Vonk RJ, Schierbeek H, Priebe MG (2012) 54. Hood L, Price ND (2014) Demystifying disease, democratiz- The glycemic response does not refect the in vivo starch ing health care. Sci Transl Med 6(225):225ed5 digestibility of fber-rich wheat products in healthy men. J 55. Huber M, Knottnerus JA, Green L, van der Horst H, Jadad Nutr 142:258–263 AR, Kromhout D, Leonard B, Lorig K, Loureiro MI, van der 37. Eggersdorfer M (2016) Mapping public health benefts of Meer JW, Schnabel P, Smith R, van Weel C, Smid H (2011) adequate omega-3 levels. http://www.nutri-facts.org/en_US/ How should we defne health? BMJ 343:d4163 news/Mapping-Public-Health-Benefts-of-Adequate-Omega- 56. Interagency Committee on Human Nutrition Research (2016) 3-Levels.html. Accessed 23 Mar 2017 National Nutrition Research Roadmap 2016‒2021: advanc- 38. Eggersdorfer M, Kraemer K, Ruel M, Van Ameringen ing nutrition research to improve and sustain health. https:// M, Biesalski HK, Bloem M, Chen J, Lateef A, Mannar V www.nal.usda.gov/sites/default/files/fnic_uploads/2016- (2013) The road to good nutrition. Karger, Basel. ISBN 03-30-ICHNRNNRR(2).pdf. Accessed 23 Mar 2017 978-3-318-02549-1 57. International Osteoporosis Foundation (2017) Vitamin D. 39. Food Supplements Europe (2016) Healthcare cost savings of https://www.iofbonehealth.org/osteoporosis-musculoskeletal- omega 3 food supplements in the European Union. http://www. disorders/osteoporosis/prevention/vitamin-d. Accessed 23 foodsupplementseurope.org/sites/0023/uploads/content/hccs- Mar 2017 omega-3/hccs-omega-3-summary.pdf. Accessed 23 Mar 2017 58. Janssen-Duijghuijsen LM, Mensink M, Lenaerts K, Fie- 40. Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, dorowicz E, van Dartel DAM, Mes JJ, Luiking YC, Keijer J, Ottaviani E, De Benedictis G (2000) Infamm-aging. An evolu- Wichers HJ, Witkamp RF, van Norren K (2016) The effect tionary perspective on immunosenescence. Ann N Y Acad Sci of endurance exercise on intestinal integrity in well-trained 908:244–254 healthy men. Physiol Rep 4(20):e12994 41. Freijer K, Tan SS, Koopmanschap MA, Meijers JM, Halfens 59. Jones KI, Doleman B, Scott S, Lund JN, Williams JP (2015) RJ, Nuijten MJ (2013) The economic costs of disease related Simple psoas cross-sectional area measurement is a quick and malnutrition. Clin Nutr 32:136–141 easy method to assess sarcopenia and predicts major surgical 42. Gallagher AM, Meijer GW, Richardson DP, Rondeau V, Skarp complications. Colorectal Dis 17:O20–O26 M, Stasse-Wolthuis M, Tweedie GC, Witkamp R, International 60. Kardinaal AF, van Erk MJ, Dutman AE, Stroeve JH, van de Life Sciences Institute Europe Functional Foods Task Force Steeg E, Bijlsma S, Kooistra T, van Ommen B, Wopereis S (2011) A standardised approach towards PROving the eff- (2015) Quantifying phenotypic fexibility as the response to a cacy of foods and food constituents for health CLAIMs (PRO- high-fat challenge test in different states of metabolic health. CLAIM): providing guidance. Br J Nutr 106(Suppl 2):S16–S28. FASEB J 29:4600–4613 doi:10.1017/S0007114511003618 61. Kelleher JK (2001) Flux estimation using isotopic tracers: 43. García OP, Long KZ, Rosado JL (2009) Impact of micronutri- common ground for metabolic physiology and metabolic ent defciencies on obesity. Nutr Rev 67:559–572. doi:10.111 engineering. Metab Eng 3:100–110 1/j.1753-4887.2009.00228 62. Kiefte-de Jong JC, Mathers JC, Franco OH (2014) Nutri- 44. Georgiou NA, Garssen J, Witkamp RF (2011) Pharma-nutrition tion and healthy ageing: the key ingredients. Proc Nutr Soc interface: the gap is narrowing. Eur J Pharmacol 651:1–8 73(2):249–259. doi:10.1017/S0029665113003881 45. Gibson A, Edgar JD, Neville CE, Gilchrist SECM, McKin- 63. Krebs-Smith SM, Guenther PM, Subar AF, Kirkpatrick SI, ley MC, Patterson CC, Young IS, Woodside JV (2012) Effect Dodd KW (2010) Americans do not meet federal dietary recom- of fruit and vegetable consumption on immune function in mendations. J Nutr 140:1832–1838 older people: a randomized controlled trial. Am J Clin Nutr 64. Kuehn BM (2016) Wearable biosensors studied for clinical 96(6):1429–1436. doi:10.3945/ajcn.112.039057 monitoring and treatment. JAMA 316:255–257

1 3 S20 Eur J Nutr (2017) 56 (Suppl 1):S1–S21

65. Lara J, Hobbs N, Moynihan PJ, Meyer TD, Adamson AJ, by a combination of botanical extracts. Planta Med Int Open Errington L, Rochester L, Sniehotta FF, White M, Mathers 3(02):e27–e30. doi:10.1055/s-0036-158516 JC (2014) Effectiveness of dietary interventions among 80. Monsivais P, Aggarwal A, Drewnowski A (2012) Are socio- adults of retirement age: a systematic review and meta- economic disparities in diet quality explained by diet cost? analysis of randomized controlled trials. BMC Med 12:60. J Epidemiol Commun Health 66(6):530–535. doi:10.1136/ doi:10.1186/1741-7015-12-60 jech.2010.122333 66. Lara J, O’Brien N, Godfrey A, Heaven B, Evans EH, Lloyd S, 81. Müller MJ, Geisler C, Pourhassan M, Glüer CC, Bosy-Westphal Moffatt S, Moynihan PJ, Meyer TD, Rochester L, Sniehotta FF, A (2014) Assessment and defnition of lean body mass def- White M, Mathers JC (2016) Pilot randomised controlled trial ciency in the elderly. Eur J Clin Nutr 68:1220–1227 of a web-based intervention to promote healthy eating, physi- 82. Murakami A, Ishida H, Kobo K, Furukawa I, Ikeda Y, Yonaha cal activity and meaningful social connections compared with M, Aniya Y, Ohigashi H (2005) Suppressive effects of usual care control in people of retirement age recruited from Okinawan food items on free radical generation from stimulated workplaces. PLoS ONE 11(7):e0159703. doi:10.1371/journal. leukocytes and identifcation of some active constituents: impli- pone.0159703 cations for the prevention of infammation-associated carcino- 67. LeDoux MA, Appelhans KR, Braun LA, Dziedziczak D, Liu L, genesis. Asian Pac J Cancer Prev 6:437–448 Osiecki H, Wyszumiala E, Griffths JC (2015) A quality dietary 83. Murray CJ, US Burden of Disease Collaborators (2013) The supplement: before you start and after it’s marketed—a conference State of US Health, 1990-2010: burden of diseases, inju- report. Eur J Nutr 54:S1–S8. doi:10.1007/s00394-014-0827-4 ries, and risk factors. JAMA 310(6):591–608. doi:10.1001/ 68. Lotters FJ, Lenoir-Wijnkoop I, Fardellone P, Rizzoli R, Rocher jama.2013.13805 E, Poley MJ (2013) Dairy foods and osteoporosis: an exam- 84. Murray CJ, Richards MA, Newton JN, Fenton KA, Anderson ple of assessing the health-economic impact of food products. HR, Atkinson C, Bennett D, Bernabé E, Blencowe H, Bourne Osteoporos Int 24:139–150 R, Braithwaite T, Brayne C, Bruce NG, Brugha TS, Burney P, 69. Lu DX (2014) Systems nutrition: an innovation of a scientifc Dherani M, Dolk H, Edmond K, Ezzati M, Flaxman AD, Flem- system in animal nutrition. Front Biosci 6:55–61 ing TD, Freedman G, Gunnell D, Hay RJ, Hutchings SJ, Ohno 70. Lupton JR, Atkinson SA, Chang N, Fraga CG, Levy J, Messina SL, Lozano R, Lyons RA, Marcenes W, Naghavi M, Newton M, Richardson DP, van Ommen B, Yang Y, Griffths JC, Hath- CR, Pearce N, Pope D, Rushton L, Salomon JA, Shibuya K, cock J (2014) Exploring the benefts and challenges of estab- Vos T, Wang H, Williams HC, Woolf AD, Lopez AD, Davis lishing a DRI-like process for bioactives. Eur J Nutr 53:S1–S9. A (2013) UK health performance: fndings of the Global Bur- doi:10.1007/s00394-014-0666-3 den of Disease Study 2010. Lancet 381(9871):997–1020. 71. Lupton JR, Blumberg JB, L’Abbe M, LeDoux M, Rice HB, von doi:10.1016/S0140-6736(13)60355-4 Schacky C, Yaktine A, Griffths JC (2016) Nutrient reference 85. Nguyen BC, Taira N, Tawata S (2014) Several herbal com- value: non–communicable disease endpoints—a conference pounds in Okinawa plants directly inhibit the oncogenic/aging report. Eur J Nutr. doi:10.1007/s00394-016-1195z kinase PAK-1. Drug Discov Ther 8:238–244 72. Marcus RL, Addison O, Kidde JP, Dibble LE, Lastayo PC 86. NIH Offce of Dietary Supplements (2017) Vitamin E. https:// (2010) Skeletal muscle fat infltration: impact of age, inactivity, ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/. and exercise. J Nutr Health Aging 14:362–366 Accessed 23 Mar 2017 73. McCrea CE, West SG, Kris-Etherton PM, Lambert JD, Gaugler 87. O’Brien N, Heaven B, Teal G, Evans EH, Cleland C, Moffatt TL, Teeter DL, Sauder KA, Gu Y, Glisan SL, Skulas-Ray AC S, Sniehotta FF, White M, Mathers JC, Moynihan P (2016) (2015) Effects of culinary spices and psychological stress on Integrating evidence from systematic reviews, qualitative postprandial lipemia and lipase activity: results of a randomized research, and expert knowledge using co-design techniques crossover study and in vitro experiments. J Transl Med 13:7 to develop a web-based intervention for people in the retire- 74. Mehta AJ, Cassidy A, Litonjua AA, Sparrow D, Vokonas P, ment transition. J Med Internet Res 18(8):e210. doi:10.2196/ Joel Schwartz J (2016) Dietary anthocyanin intake and age- jmir.5790 related decline in lung function: longitudinal fndings from the 88. Offcer A (2016) World Report on ageing and health. http://apps. VA Normative Aging Study. Am J Clin Nutr 103(2):542–550. who.int/iris/bitstream/10665/186463/1/9789240694811_eng. doi:10.3945/ajcn.115.121467 pdf. Accessed 23 Mar 2017 75. Mercken EM, Carboneau BA, Krzysik-Walker SM, de Cabo 89. O’Keefe JH, Jacob D, Lavie CJ (2017) Omega-3 fatty acid ther- R (2012) Of mice and men: the benefts of caloric restriction, apy: the tide turns for a fsh story. Mayo Clin Proc 92:1–3 exercise, and mimetics. Ageing Res Rev 11:390–398 90. Omenn GS, Goodman G, Thornquist M, Grizzle J, Rosenstock 76. Metter EJ, Talbot LA, Schrager M, Conwit R (2002) Skeletal L, Barnhart S, Glass A (1994) The beta-carotene and retinol muscle strength as a predictor of all-cause mortality in healthy effcacy trial (CARET) for chemoprevention of lung cancer in men. J Gerontol A 57:B359–B365 high risk populations: smokers and asbestos-exposed workers. 77. Mietus-Snyder ML, Shigenaga MK, Suh JH, Shenvi SV, Lal A, Cancer Res 54(7 Suppl):2038s–2043s McHugh T, Olson D, Lilienstein J, Krauss RM, Gildengoren 91. Park SK, Tucker KL, O’Neill MS, Sparrow D, Pantel S, Voko- G, McCann JC, Ames BN (2012) A nutrient-dense, high-fber, nas PS, Hu H, Schwartz J (2009) Fruit, vegetable, and fsh con- fruit-based supplement bar increases HDL cholesterol, particu- sumption and heart rate variability: the Veterans Administra- larly large HDL, lowers homocysteine, and raises glutathione in tion Normative Aging Study. Am J Clin Nutr 89(3):778–786. a 2-wk trial. FASEB J 26:3515–3527. doi:10.1096/fj.11-201558 doi:10.3945/ajcn.2008.26849 78. Miller GD, Drewnowski A, Fulgoni V, Heaney RP, King J, 92. Péter S, Friedel A, Roos FF, Wyss A, Eggersdorfer M, Hoff- Kennedy E (2009) It is time for a positive approach to dietary mann K, Weber P (2016) A systematic review of global alpha- guidance using nutrient density as a basic principle. J Nutr tocopherol status as assessed by nutritional intake levels and 139(6):1198–1202. doi:10.3945/jn.108.100842 blood serum concentrations. Int J Vitam Nutr Res 14:1–21. 79. Missler SR, Rajgopal A, Roloff SJ, Scholten JD, Burns CR, Pat- doi:10.1024/0300-9831/a000281 terson JA, Pusateri DJ, Gellenbeck KW, Stern NP, Randolph 93. Price ND, Magis AT, Earls JC, Glusman G, Levy R, Lausted RK, Lin Y, Chuang J, Kazlova V, Fast DJ (2016) Synergistic CG, McDonald DT, Kusebauch U, Moss CL, Zhou Y, Qin S, activation of the Nrf2-ARE oxidative stress response pathway Moritz RL, Brogaard K, Omenn GS, Lovejoy JC, Hood L

1 3 Eur J Nutr (2017) 56 (Suppl 1):S1–S21 S21

(2017) Mining dense, dynamic, personal data clouds of 108 113. van Schoor NM, Lips P (2011) Worldwide vitamin D status. Best humans over 9 months. Nat Biotech (in press) Pract Res Clin Endocrinol Metab 25(4):671–680. doi:10.1016/j. 94. Rattan SI (2012) Rationale and methods of discovering beem.2011.06.007 hormetins as drugs for healthy ageing. Expert Opin Drug Disc 114. Villareal DT, Banks M, Siener C, Sinacore DR, Klein S (2004) 7:439–448 Physical frailty and body composition in obese elderly men and 95. Raubenheimer D, Simpson SJ (2016) Nutritional ecology women. Obes Res 12:913–920 and human health. Annu Rev Nutr 36:603–626. doi:10.1146/ 115. Vis D, Westerhuis J, Jacobs D, van Duynhoven JM, Wopereis S, annurev-nutr-071715-051118 van Ommen B (2014) Analyzing metabolomics-based challenge 96. Rosenberg IH (1997) Sarcopenia: origins and clinical rel- tests. Metabolomics 1:50–63 evance. J Nutr 127:990S–991S 116. Wallace JD, Calvo RY, Lewis PR, Brill JB, Shackford SR, Sise 97. Roubenoff R (2004) Sarcopenic-obesity: the confuence of MJ, Sise CB, Bansal V (2017) Sarcopenia as a predictor of mor- two epidemics. Obes Res 12:887–888 tality in elderly blunt trauma patients: comparing the masseter to 98. Schrieks IC, Joosten MM, Klöpping-Ketelaars WAA, Wit- the psoas using computed tomography. J Trauma Acute Care Surg kamp RF, Hendriks HFJ (2016) Moderate alcohol consump- 82:65–72 tion after a mental stressor attenuates the stress response. 117. Wang X, Ouyang Y, Liu J, Zhu M, Zhao G, Bao W, Hu FB (2014) Alcohol 57:29–34 Fruit and vegetable consumption and mortality from all causes, 99. Senthilkumar K, Manivasagan P, Venkatesan J, Kim SK cardiovascular disease, and cancer: systematic review and dose- (2013) Brown seaweed fucoidan: biological activity and response meta-analysis of prospective cohort studies. BMJ apoptosis, growth signaling mechanism in cancer. Int J Biol 349:g4490. doi:10.1136/bmj.g4490 Macromol 60:366–374 118. Weiss EP, Fontana L (2011) Caloric restriction: powerful protec- 100. Shanahan C, de Lorimier R (2013) Smart prevention—health tion for the aging heart and vasculature. Am J Physiol Heart Circ care cost savings resulting from the targeted use of dietary Physiol 301:H1205–H1219 supplements. http://www.crnusa.org/sites/default/fles/pdfs- 119. Willcox BJ, Willcox DC (2014) Calorie restriction, calorie restric- hccs/SmartPrevention-fullreport0913.pdf. Accessed 23 Mar tion mimetics, and healthy aging in Okinawa: controversies and 2017 clinical implications. Curr Opin Clin Nutr Metab Care 17:51–58 101. Si H, Liu D (2014) Dietary antiaging phytochemicals and 120. Willcox BJ, Willcox DC, Todoriki H, Fujiyoshi A, Yano K, He mechanisms associated with prolonged survival. J Nutr Bio- Q, Curb JD, Suzuki M (2007) Caloric restriction, the traditional chem 25(6):581–591. doi:10.1016/j.jnutbio.2014.02.001 Okinawan diet, and healthy aging: the diet of the world’s longest- 102. Smarr L (2012) Quantifying your body: a how-to guide from lived people and its potential impact on morbidity and life span. a systems biology perspective. Biotechnol J 7(8):980–991 Ann N Y Acad Sci 1114:434–455 103. Somogyi A, Hathcock J, Biesalski HK, Blumberg JB, Antoine 121. Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki JM, Edwards G, Prock P (2011) Scientifc issues related to KH, Willcox DC, Rodriguez B, Curb JD (2008) FOXO3A geno- Codex Alimentarius goals: a review of principles with exam- type is strongly associated with human longevity. Proc Natl Acad ples. Reg Toxicol Pharmacol 60:161–164 Sci USA 105(37):13987–13992. doi:10.1073/pnas.0801030105 104. Stroeve JH, Wietmarschen H, Kremer BH, Ommen B, Wopereis 122. Willcox DC, Willcox BJ, Todoriki H, Suzuki M (2009) The S (2015) Phenotypic fexibility as a measure of health: the opti- Okinawan diet: health implications of a low-calorie, nutrient- mal nutritional stress response test. Genes Nutr 10(3):459 dense, anti-oxidant-rich dietary pattern low in glycemic load. J 105. Suzuki M, Willcox BJ, Willcox DC (2001) Implications from Am Coll Nutr 28(Suppl):500S–516S and for food cultures for cardiovascular disease: longevity. Asia 123. Willcox DC, Willcox BJ, Yasura S, Ashitomi I, Suzuki M (2012) Pac J Clin Nutr 10:165–171 Gender gap in health span and life expectancy in Okinawa: health 106. Ten Bruggencate SJ, Frederiksen PD, Pedersen SM, Floris- behaviours. Asian J Gerontol Geriatr 7:49–58 Vollenbroek EG, Lucas-van de Bos E, van Hoffen E, Wejse 124. Willcox DC, Scapagnini G, Willcox BJ (2014) Healthy aging PL (2016) Dietary milk-fat-globule membrane affects resist- diets other than the Mediterranean: a focus on the Okinawan diet. ance to diarrheagenic Escherichia coli in healthy adults in a Mech Ageing Dev 136:148–162 randomized, placebo-controlled, double-blind study. J Nutr 125. Wopereis S, Wolvers D, van Erk M, Gribnau M, Kremer B, van 146:249–255 Dorsten F, Boelsma E, Garczarek U, Cnubben N, Frenken L, van 107. The Alpha-Tocopherol, Beta Carotene Cancer Prevention der Logt P, Hendriks HF, Albers R, van Duynhoven J, van Ommen Study Group (1994) The effect of vitamin E and beta caro- B, Jacobs DM (2013) Assessment of infammatory resilience in tene on the incidence of lung cancer and other cancers in male healthy subjects using dietary lipid and glucose challenges. BMC smokers. N Engl J Med 330(15):1029–1035. doi:10.1056/ Med Genomics 6:44 NEJM199404143301501 126. World Health Organization (2005) Preventing chronic diseases: a 108. The Giessen Declaration (2005) Public Health Nutr 8(6A):783–786 vital investment: WHO global report. WHO Press, Geneva. http:// 109. Thomas EL, Parkinson JR, Frost GS, Goldstone AP, Doré CJ, www.who.int/chp/chronic_disease_report/contents/en/. Accessed McCarthy JP, Collins AL, Fitzpatrick JA, Durighel G, Taylor-Rob- 23 Mar 2017 inson SD, Bell JD (2012) The missing risk: mRI and MRS pheno- 127. World Health Organization (2007) Global age-friendly cities. typing of abdominal adiposity and ectopic fat. Obesity 20:76–87 World Health Organisation, Geneva. http://www.who.int/age- 110. Troesch B, Eggersdorfer M, Weber P (2012) 100 years of ing/publications/Global_age_friendly_cities_Guide_English.pdf. vitamins: adequate intake in the elderly is still a matter of Accessed 23 Mar 2017 concern. J Nutr 142:979–980 128. World Health Organization (2015) Noncommunicable diseases. 111. U.S. Department of Health and Human Services and U.S. Fact sheet. World Health Organisation, Geneva. http://www.who. Department of Agriculture (2015) 2015–2020 dietary guide- int/mediacentre/factsheets/fs355/en/. Accessed 23 Mar 2017 lines for Americans, 8th edn. http://health.gov/dietaryguide- 129. Zeevi D, Korem T, Zmora N, Israeli D, Rothschild D, Wein- lines/2015/guidelines/. Accessed 23 Mar 2017 berger A, Segal E (2015) Personalized nutrition by prediction 112. van Ommen B, van der Greef J, Ordovas JM, Daniel H (2014) of glycemic responses. Cell 163(5):1079–1094. doi:10.1016/j. Phenotypic fexibility as key factor in the human nutrition and cell.2015.11.001 health relationship. Genes Nutr 9:423

1 3