Key developments at WUR

Researching the links between healthy ageing and nutrition

Nutrition & Health is one of the key subject areas of Wageningen University and Research Centre (WUR). Its “Division of Human Nutrition” has a broad expertise and outstanding facilities for academic education and research in this field. Research is performed at various levels. The molecular level is studied in cell systems. In addition, controlled dietary interventions at the individual level, as well as observational studies at the population level, are frequently carried out. By integrating the expertise from chairs in “Nutrition and Health,” “Nutrition and Epidemiology” and “Nutrition, Metabolism and Genomics,” surplus value is being created. Most projects belong to one of the following five research themes:

• Diet and other lifestyle factors in human health and disease

• Cellular and physiologic mechanisms that support health

• Prevention of cardiovascular and gastrointestinal diseases

• Obesity-related syndromes in developed countries

• Micronutrient malnutrition in developing countries and the elderly

Three examples of the Division’s research domains are being presented here.

Nutrition and ageing

In Europe, the US and Japan, population ageing, due to an increased life expectancy, combined with a decline in birth rates, is a challenge for social/economic and health policy. The nutrition of mature and aged subjects is often inadequate (because of deficiency or excess), which may lead to premature or pathological senescence. Ageing is associated with an increased risk for chronic diseases such as cancer and cardiovascular diseases. Other conditions related to ageing are, for instance, osteoporosis, sarcopenia (i.e. the progressive decline in skeletal muscle mass and function), and cognitive decline.

Professor Lisette de Groot is studying nutrition as a determinant in successful ageing in various ways. “Adequate nutrition plays a major role in a healthy lifestyle that maintains bodily and mental functioning, whereas inadequate nutrition contributes to a loss of function and to the development and progression of disease,” de Groot indicates. Inadequate nutritional intake is one of the dominant causes of malnutrition in older persons. Unintentional weight loss is often the first warning signal, with dehydration, anorexia, sarcopenia or malabsorption as the underlying cause. In collaboration with Professor Kees de Graaf, De Groot performed a large cluster-randomized trial in 5 Dutch nursing homes to study the effect of mealtime ambiance, as a stimulus for appetite, in order to prevent or treat anorexia. Positive effects on overall quality of life, daily energy intake, and body weight were reported (Nijs et al., J Am Med Dir Assoc 2009;10:226-229). “The results indicate that mealtime ambiance may act as an appetite stimulus and should be considered as one aspect of a nutritional care plan in nursing homes,” says De Groot.

In addition to these social aspects, De Groot studies special dietary recommendations in relation to the ageing process, including those involving fortified foods and/or supplements. A committee of the Health Council of the Netherlands, in which De Groot participated, recommended additional Vitamin D for all women over 50, and men over 70 years of age (Towards an adequate intake of Vitamin D; Health Council of the Netherlands, 2008; publication no. 2008/15), based on bone quality status. De Groot and her colleagues are currently investigating the role of Vitamin B12 in bone health. Mechanistic and epidemiological research, as well as intervention trials, are carried out in order to provide clarity on the necessity of supplementation for elderly people.

Another research topic of De Groot et al. involves the suggested effect of fish and marine polyunsaturated fatty acids (PUFAs), like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with respect to prevention of age-related cognitive decline, and prevention of impaired mental well-being. However, in older people without a clinical diagnosis of dementia or depression, no effect of supplementation of EPA and DHA was found in a 26-week randomized, double-blind, placebo-controlled trial (Van de Rest et al., Am J Clin Nutr 2008; 88:706-713). Yet, gene expression profiles in human white blood cells did show a less inflammatory and a less atherogenic status upon this fish oil supplementation (Bouwens et al., Am J Clin Nutr 2009; 90:415-424), indicating that metabolic changes have occurred during this supplementation period. According to De Groot, more research in this respect is needed. She explains, “for instance, focused on more sensitive groups than the healthy persons assessed in this trial, such as subjects with Mild Cognitive Impairment, subjects with a suboptimal PUFA status, or subjects with a specific genetic makeup (APOE genotype) would be productive. Furthermore, long-term supplementation for years instead of weeks should be studied as well.”

De Groot values international partnerships. The longitudinal SENECA Study (Survey in Europe on Nutrition and the Elderly: a Concerted Action) was designed to assess differences in dietary and lifestyle factors among elderly Europeans, and to identify factors that contribute to healthy ageing. Approximately 2,600 elderly people from 8 countries were included in this study, from which data was collected three times between 1988 and 1999. “In general, dietary intake of the elderly was sufficient, but tended to decline over time,” de Groot explains. This was reflected in data on their nutritional status. Potential concerns were identified in relation to Vitamin D and Vitamin B12, where dietary intake levels may not suffice because of reduced synthesis capacity (Vitamin D) or reduced absorption (Vitamin B12) (De Groot et al., J of Gerontology 2004;12:1277-1284). Data from this SENECA study and from the HALE project (Healthy Ageing: a Longitudinal Study in Europe), for example, also showed that high plasma concentrations of carotene are associated with both lower mortality from all causes and lower mortality from cancer in the elderly (Buijsse et al., Am J Clin Nutr 2005; 82:879-886).

Among other things, de Groot is currently participating in EURRECA: The EURopean micronutrient RECommendations Aligned Network of Excellence. This project runs from 2007 until the end of 2011, and seeks to establish clear guidelines for assessing the validity of reported micronutrient intakes among vulnerable population groups, including the elderly. The Network is made up of 34 partners based in 17 countries, drawn not only from nutrition science but also from industry, consumer groups, national nutrition societies, and the health professions. Priority micronutrients on which the Network concentrates include folic acid, Vitamin D and iron. In addition to the elderly, other vulnerable groups such as pregnant and lactating women, children, persons on low incomes, and migrant populations are within EURRECA’s focus. EURRECA will not only consider nutrition science advice, but also policy implications, and applications that take into account national, social, cultural and ethical differences.

Nutrition and diabetes

The prevalence of metabolic syndrome and the related syndrome, diabetes, is strongly increasing. At the moment, more than 220 million people worldwide suffer from diabetes. The World Health Organization predicts that the prevalence of diabetes will double between 2005 and 2030. Type 2 diabetes results from the body’s ineffective use of insulin. Over time, diabetes can damage the heart, blood vessels, eyes, kidneys and nerves. Type 2 diabetes is the major form of diabetes present in 90% of all patients. “Lifestyle adjustments, in particular a healthy diet, regular physical activity, and the maintenance of a normal body weight can help postpone or even prevent the development of diabetes,” says professor Edith Feskens.

Feskens mentions a domino effect: abdominal obesity leading to insulin resistance which, in turn, leads to metabolic syndrome, followed by diabetes and its consequent conditions such as coronary heart disease and kidney failure. Hyperactivity of abdominal fat cells seems to be the starting point of this cascade. Production of hormones and neurotransmitters by these cells leads, among other things, to raised insulin resistance, chronic inflammation, and deterioration of vascular function.

Professor Edith Feskens focuses on several aspects of this. “Identification of factors that influence plasma glucose levels might improve our understanding of the pathogenesis of diabetes,” Feskens explains. Studies on genetic polymorphisms, taking into account gene/environment interactions (nutrigenomics, for example) are carried out by the Division of Human Nutrition. A recent study among 3,244 subjects within the Doetinchem Cohort suggests that the effect of the PPARGC1A gene, which is involved with both fatty acid oxidation and glucose metabolism, is modified by a person’s Body Mass Index. This was suggested by the fact that the Ser/Ser genotype of PPARGC1A was associated with lower glucose levels in lean subjects, but with higher glucose levels in obese people (Povel et al., Int J Obesity 2010; Feb 2 [Epub ahead of print]).

Apart from this molecular type of work, Feskens also focuses on dietary pattern analysis in relation to diabetes. “I am not only interested in what people actually eat, but also in when, how often, and, for instance, the rate of eating.” Feskens continues: “The traditional approach to investigate diet/disease interactions is by studying single dietary components. For diseases like diabetes, the effect of the overall diet should be taken into account as well.” Feskens and her colleagues conducted a randomized parallel controlled-feeding trial in 60 non-diabetics with mild abdominal obesity, comparing three energy-intake controlled diets: one diet high in monounsaturated fatty acids; the second being a Mediterranean diet (rich in monounsaturated fatty acids, as well); and the third diet containing a high level of saturated fatty acids. Effects on insulin sensitivity and serum lipids were measured. In conclusion, the diet high in monounsaturated fatty acids, as well as the Mediterranean diet, improved serum lipids, which may reduce cardiovascular risks. In contrast to other studies, however, no beneficial effect of the Mediterranean diet was seen with respect to insulin sensitivity (Bos et al., Nutr Metab Cardiovasc Dis. 2009 Aug 17 [Epub ahead of print]), which requires further attention.

In another prospective study, neither a previously suggested protective effect of fish eating, nor a protective effect of EPA and DHA intake on the development of type 2 diabetes, could be demonstrated (Van Woudenbergh et al., Diabetes Care 2009 32(11):2021-6 Epub 2009 Aug 12). Both studies illustrate that this type of dietary pattern research is complex and that further research is needed.

In collaboration with Chinese groups, Feskens studied four dietary patterns for their effect on newly diagnosed glucose tolerance abnormalities among Chinese adults (He et al., Diabetes Care 2009;32:1972-1976). Impaired glucose tolerance is an intermediate condition in the transition between normality and diabetes. It became clear that dietary patterns and food factors are associated with the presence of glucose tolerance abnormalities in China, even independent of obesity. Feskens is hopeful that “Analysis of the dietary patterns and food factors involved will provide the basis for future prevention studies.”

In the Netherlands, a study called “Study on Lifestyle Intervention and Impaired Glucose Tolerance Maastricht” (SLIM) was conducted, which showed a sustained beneficial effect of a lifestyle intervention program, based on Dutch dietary guidelines for a healthy diet, as well as on advice with respect to the level of physical activity (Roumen et al., Diabetic Medicine 2008;25:597-605). Feskens indicates that, among other things, dietary composition improved (less fat intake), and enthusiastically adds that a beneficial effect on glucose tolerance and insulin sensitivity in a population at high risk for type 2 diabetes was observed. Regarding the success of this study, Feskens emphasizes, “After three years, the difference between groups was associated with more than a 50% reduction in the incidence of diabetes.”

Diet and cancer

One third of the Dutch population is faced with the diagnosis of cancer in their lifetime. Factors associated with cancer include smoking, lack of physical activity, being overweight, and excessive alcohol use. Endogenous as well as external factors, such as exposure to chemicals, cigarette smoke, radiation, viruses and alcohol, may damage DNA and cause mutations in genes. Apart from mutations, epigenetic changes – for example, changes in the methylation pattern of genes – may lead to cancer by. undesirably, switching on or off cancer-related genes.

Various forms of cancer exist, each with its own incidence and characteristics. For example, colorectal cancer is the third most common cancer worldwide, with 945,000 new cases and 492,000 deaths, annually. International variation in diet and colorectal cancer rates suggest that diet is an important factor to take into account. Established risk factors are being overweight, using alcohol, and eating red and processed meat. On the other hand, dairy products and plant products seem to reduce the risk for colorectal cancer.

Professor Ellen Kampman studies the role of our diet in relation to carcinogenesis in various ways. One of the spearheads of her research is cancer prevention, studying the role of nutrition in (epi)genetic changes. “There are indications that a healthy diet has favorable effects on the risk of epigenetic changes, albeit scientific insights are far from complete,” Kampman says. Kampman and her coworkers have demonstrated that supplementation with high doses of folic acid and Vitamin B12 may not favorably influence promoter methylation of selected genes in the colonic mucosa of individuals with a history of colorectal adenoma (Van den Donk et al., J Nutr 2007; 137: 2114-2120). In contrast, beneficial effects of dietary folate intake with respect to cancer have been reported in literature. The research by Kampman et al. underscores the need for further studies to determine whether or not synthetic folic acid supplementation may be as effective as dietary folate from green leafy vegetables in cancer prevention. The appropriate form of folate, dose, timing, as well as the target group, need to be established. Kampman goes on to say: “Together with the group of Professor Lisette de Groot, we are now evaluating whether supplementation with a moderate dose of folic acid and Vitamin B12 among elderly with high homocysteine levels is favorably influencing DNA methylation.”

The effect of food compounds on relevant molecular events in the colon and rectum are studied in human observational studies or in randomized, placebo-controlled intervention studies. The genetic variation within the population may be important, as well. In a study on glutathione S-transferase (GST) activity linked to fruit and vegetable consumption, both the genetic variation and recent consumption of fruits and vegetables appeared to influence the GST enzyme system. Fruit and vegetable consumption affected individual rectal GST isoenymes, which might affect detoxification capacity of tissues (Tijhuis et al., Carcinogenesis 2007;28:848-857). Within the framework of the second World Cancer Research Fund report, a meta-analysis on prospective cohort studies to evaluate the association between fish consumption or n-3 fatty acids and colorectal cancer incidence or mortality was conducted, since results from epidemiologic studies were inconsistent. Fish consumption, and possibly n-3 fatty acids, may reduce colorectal carcinogenesis, particularly if the intake of fish is relatively large (Geelen et al., Am J Epidemiol 2007; 166:1116-1125). Extra consumption of fish once a week corresponds to a 4 percent lower risk of colorectal cancer. However, most of the observational studies do not discriminate between the effects of oil-rich and lean fish. Therefore, a randomized controlled trial was conducted within the framework of the SEAFOODPLUS EU project. Subjects (n=242) at an increased risk of colorectal cancer and those with no macroscopic signs of disease were randomly allocated to receive dietary advice, plus either two additional weekly portions of salmon or cod, or only dietary advice, for six months. The results of this intervention did not provide strong evidence for the beneficial effects of fish consumption on markers of colorectal carcinogenesis (Pot et al., Am J Clin Nutr 2009;90:354-361). Furthermore, colorectal genotoxicity (Pot et al., J Nutr 2010;140:371-376), levels of cytokines and chemokines in colonic biopsies and feces, and fecal calprotectin were also not markedly changed after fish consumption. Only serum C–reactive protein (CRP) levels demonstrated a statistically significant decrease after consumption of salmon and cod compared with dietary advice alone (Pot et al., Am J Clin Nutr 2009;90:354-361).

Another spearhead of Kampman’s research is the relationship between overweight, in particular, abdominal fat and cancer risk. Kampman underlines the enormous impact of weight management in relation to cancer prevention by indicating that a 10% reduction in overall cancer incidence could be achieved if overweight could be successfully combatted in our society. When estimated for specific forms of cancer, such as breast cancer, colorectal cancer, and endometrium cancer, the percentage of reduction could be even higher when the percentage of body fat is kept at a desirable level. “Most people are insufficiently aware that a healthy lifestyle in this respect diminishes their risk of cancer appreciably,” Kampman adds. Possible mechanisms involved in this relationship between abdominal fat and cancer risk, such as hormone metabolism, the role of growth factors, and the development of insulin resistance, are studied within Kampman’s group. For example, the effect of lycopene supplementation in relation to colorectal cancer risk is being studied, taking the possible mechanism via the Insulin-like Growth Factor (IGF) system into account (Vrieling et al., Am J Clin Nutr 2007;86:1456-1462).

A third research domain involves the diet of cancer patients. “On the one hand, we are gaining much knowledge about the role of nutrition in the development of cancer, but on the other hand, we know very little about the optimal diet for cancer patients,” says Kampman. “Cancer patients often ask their practitioner or other experts for advice about a sound diet and/or nutritional supplements, in order to keep their quality of life as high as possible, and to reduce the risk of recurrence of the cancer,” Kampman observes. “But which diet would be optimal for them, and would they be able to eat this diet when they are weak and sick, for example, when undergoing chemotherapy,” she continues. Furthermore, not much is known about the effectiveness and possible risks of nutritional supplements for cancer patients. Several collaborative studies are ongoing to address these issues. A cohort study involving 1,000 patients with colorectal cancer is currently being carried out in collaboration with the Radboud University Medical Centre, and hospital” “De Gelderse Vallei.” An additional project among breast cancer survivors which she is planning to conduct, focuses on weight gain of many breast cancer patients after undergoing chemo or hormone therapy. “We would like to know why this weight gain occurs,” Kampman says. Together with colleague professor Kees de Graaf, she would like to study alterations in taste and smell sensations, and food preferences among these patients as a result of cancer treatment.

The above-described internationally oriented, integrative research at the Division of Human Nutrition shows that healthy ageing is intimately linked to nutrition. For instance, adequate weight management can reduce the risk of developing various common types of cancer and diabetes. Obviously, only a selection of the work of the Division could be presented here. For further information, please check their website or get in touch.

Professor Ellen Kampman		Professor Lisette de Groot