TNO leverages “Challenge Approach” to substantiate health claims and improve public health

Published: 04-02-2014

Foods that support or improve cardiovascular health—and thereby help prevent cardiovascular diseases—could have a major social impact. In Europe, diseases of the heart and circulatory system (CVD) are the number-one killer, accounting for more than 4.35 million deaths each year, with substantial associated medical and human costs.

Subtle effects
Proving that a dietary product has beneficial effects on cardiovascular health is not that easy. “The European Food Safety Authority (EFSA) uses strict guidelines for the substantiation of health claims,” says Wim van Hartingsveldt, Business Development Manager Food and Health at TNO in Zeist. “For example, cause/effect and dose/response relationships must be established, as with the approval of pharmaceuticals.”

In the nutrition sector, gathering this evidence is extremely difficult, as evidenced by the large number of health claims rejected by the EFSA. Van Hartingsveldt stresses that “nutrition has subtle, multiple and long-term effects that result from interactions between the range of ingredients present in a diet, and has many targets in tissues and organs in the body. This is in sharp contrast to pharmaceuticals, which are targeted at specific receptors with strong and often immediate effects that can be attributed to only one or a few substances.”

The fact that many health issues, particularly cardiovascular diseases and diabetes, develop gradually over time increases the level of difficulty. “To evaluate whether a food helps prevent such diseases, we need combinations of biomarkers that represent physiological changes at an early stage, when an individual still appears to be healthy,” says Van Hartingsveldt.

Current biomarkers such as LDL cholesterol and blood pressure do not adequately meet this need. Alwine Kardinaal, Coordinator Human Studies and Senior Consultant Nutrition & Health at TNO, explains: “These biomarkers represent only some of the mechanistic pathways causing cardiovascular disease. People who suffer from a heart attack, for example, do not always have high blood cholesterol, and high blood cholesterol does not always result in a heart attack. In the development of cardiovascular diseases, other mechanisms play a role, such as inflammation and changes in blood platelet function.”

The “Challenge Approach”
Together with the food industry and academia, TNO is establishing a new generation of biomarkers that assess health and can predict when health turns into disease. Cardiovascular health is one of the main issues of interest, in addition to metabolic and gastrointestinal health. To achieve its aims, the organization has developed an innovative “Challenge Approach.”

The Challenge Approach starts with a new concept of health, which was launched in 2009 by The Lancet and was also recently published in the British Medical Journal (Huber et al., BMJ 2011; 343:d4361). According to Van Hartingsveldt, “Health has always been regarded as the absence of disease. In the Challenge Approach, health is defined as the body’s ability to adapt to changing circumstances and to show sufficient resilience under conditions of social, physical and emotional disturbance to which we are exposed from time to time.”

“The idea of using a ‘challenge’ to make nutrition effects tangible is not new in itself,” says Van Hartingsveldt. “However, until recently, the sensitive and broad-spectrum analysis techniques needed to do such research were not available. Today, we can make use of state-of-the-art technologies such as nutrigenomics, proteomics and metabolomics, plus the auxiliary bioinformatics that allow us to interpret data and reveal relevant physiological effects.”

Challenge tests are expected to indicate whether people are in optimal health or tend to divert from health. Such observations are based on the body’s capacity to respond to relatively ordinary loading and how fast it recovers. Challenge tests comprise light stresses, such as a single consumption of a high-fat or sugar load, or a minor infection. “You can, for example, measure the increase in levels of inflammatory compounds in the blood after a high-fat consumption, and the time it takes for these levels to return to normal,” Kardinaal explains.

Added value
Over the past few years, TNO has carried out a range of studies that support the Challenge Approach and underline its added value in evaluating dietary effects on health. The research includes studies in both animal models and human volunteers.

One study by Pellis et al. in Metabolomics (2012 April; 8(2):347–359. Published online 2011 May 28. doi: 10.1007/s11306-011-0320-5) introduced the Postprandial Challenge Test (PCT) to quantify the postprandial response of multiple metabolic processes in humans in a standardized manner. The study highlighted the added value of the Challenge Approach, affirming that “a metabolomics based quantification of a standardized perturbation of metabolic homeostasis is more informative on metabolic status and subtle health effects induced by (dietary) interventions, than quantification of the homeostatic situation.” The challenge offered to human volunteers in this study was the consumption of a standardized 500 ml dairy shake containing, respectively, 59, 30 and 12 energy percent lipids, carbohydrates and protein.

TNO has developed animal models, such as the ApoE*3 Leiden mice (Zadelaar et al., Arterioscler Thromb Vasc Bio, 2007; 27, 1706), for inflammation and atherosclerosis that closely mimic processes in humans. “These models are globally unique and have enabled us to establish dietary effects on clinical endpoints, such as atherosclerosis (Verschuren et al., J Nutr, 2011, 141:863-9),” says Kardinaal.

One study, using animal models, investigated the effects of the polyphenol quercetin—present in fruits, vegetables and grains. It was concluded that quercetin reduces the expression of human C-reactive protein and the cardiovascular risk factors serum amyloid A (SAA) and fibrinogen. According to the researchers, these systemic effects, together with local anti-proliferative and anti-inflammatory effects in the aorta, could contribute to the attenuation of atherosclerosis (Kleemann et al., Atherosclerosis, 2011; 218, 44).

Another study using a humanized animal model for atherosclerosis investigated whether an alternating high-cholesterol/cholesterol-free diet can diminish hepatic and renal inflammation and cardiovascular risk factors, when compared to a daily high-cholesterol diet. It was shown that alternate-day calorie restriction was almost as beneficial as daily calorie restriction (Wielinga et al., PloS One, 2011 6(3):e18432.).

A third study using animal models (mice) for inflammation and atherosclerosis evaluated whether an anti-inflammatory mixture could reduce inflammatory risk factors, pro-atherogenic lipids and atherosclerosis. The mixture contained resveratrol (present in grapes), lycopene (found in orange fruits and vegetables such as carrots), catechin (found in high concentrations in green tea), vitamins E and C, and fish oil. The mix strongly reduced levels of plasma cholesterol, triglycerides and SAA. Long-term treatment of the mice receiving the mixture over an extended period dramatically reduced development of atherosclerosis. Additional beneficial outcomes were reduced expression of the vascular inflammation markers and adhesion molecules intercellular adhesion molecule-1 and E-selectin (Verschuren et al., J Nutr 2011, 141, 863).

The same anti-inflammatory mix was used in a human-volunteer study with slightly overweight men who received a high-fat challenge (Bakker et al., AJCN 2010; 91, 1044). Once again, it was demonstrated that the supplement mixture reduced inflammatory processes, oxidative stress and metabolism. This was proven via large-scale profiling of genes, proteins and metabolites in plasma, urine and adipose tissue.

Worldwide adoption

TNO has taken the lead in two extensive European research projects, Nutritech and PhenFlex, that will further exploit the Challenge Approach in health claim substantiation. These projects started in February 2012 and will run for the next four years. The outcomes will be disseminated among stakeholders—including regulatory authorities, the academic world and the food industry—from an early stage.

The Nutritech project aims to develop standardized research methods that will be globally adopted in nutrition research. Receiving €6 million from the European Commission, the project consortium consists of 23 research organizations and universities from across the globe.

PhenFlex aims to accelerate the food industry’s application of the Challenge Approach. The challenge test is being used to measure the responses of different target groups with a goal of creating a database holding cardiovascular and metabolic health data from various target groups, related to the Challenge Approach. This project has five industrial partners—Nestlé, DSM, Danisco, FrieslandCampina and Abbott Nutrition—and is funded with €2.5 million from the Dutch government.

Strong support
Van Hartingsveldt and Kardinaal believe that, once adopted, the Challenge Approach will substantially increase the food industry’s success in the substantiation of health claims and significantly shorten time-to-market of new products.

“In addition to health claims, this approach can also be important for guidelines to improve public health,” says Kardinaal. “Moreover, it will increase the credibility of nutrition research. At present, there are only a few biomarkers available for important issues like cardiovascular health, and these are yet to be universally accepted. With the introduction of the Challenge Test, this will be history.”

TNO research program
TNO’s work on cardiovascular health is part of the organization’s research strategy on Food and Health. One of the goals of this program is to develop methods for the short-term assessment of the health effects of food products. TNO’s ambition is to establish groundbreaking methodologies for the substantiation and assessment of health claims that will be adopted both in the Netherlands and abroad. The organization collaborates with respected universities and research institutes in the Netherlands, Europe and the United States. TNO brings its broad expertise in food and nutrition research, ranging from food chemistry and analytics to nutrigenomics and bioinformatics.

Contact details:
Wim van Hartingsveldt