Immuun-fitheid: interindividuele variatie en identificatie van nutriënten die hierop aangrijpen
Aging is known to associate with ‘immunosenescence’ defining a gradually increasing dysfunction of the immune system. Both the presence of a chronic state of low grade inflammation or ‘inflammaging’ as well as a deterioration of acute immune responses are often observed in elderly individuals suggestive of a reduction in immune cell fitness. Nutritional interventions have been adopted as a popular strategy to improve immune function and ultimately health. One of the biggest challenges for the nutritional sector is the high variability in response to nutrition which is especially the case for nutritional studies targeting immune cell function. We hypothesize that this may largely be caused by differences in immune cell fitness between subjects. To increase effectiveness of dietary interventions, the first challenge is to distinguish those individuals with immune dysfunction from those that are immunologically fit. Recent insights from the field of immunology have revealed that energy metabolism of innate immune cells is a key factor in determining immunological fitness and functionality.
The first aim of this project is to screen and subsequently identify immunologically unfit and fit individuals by using an new approach based on both the metabolic and functional properties of easily accessible circulating monocytes. Within this project we will develop an ex vivo screening tool that only requires a person’s blood sample and ex vivo lab work to measure immune fitness. The second aim of this project is to examine whether certain nutrients can improve immune cell fitness in these immunologically unfit subjects.
In addition to an increase in life expectancy, the number of elderly individuals in the Netherlands is increasing steadily with almost 3.1 million elderly individuals (age > 65) in 2016. Hence, strategies to promote healthy aging are urgently needed, both from a societal as well as from and economical point of view. We believe that effectively targeting immunosenescence will be of great benefit, yet this requires identification of those elderly individuals with reduced immune cell function. This project aims to identify those individuals and to subsequently increase immune cell fitness using nutritional interventions. The determination of ‘biomarkers’ for immune health are very much needed to support modern nutritional research and can enable a personalized health approach to better and more specifically advice food consumers. This project will contribute to the development innovations in the area of optimized nutritional formulations /supplements targeting immune senescence and scientific health claim substantiation for aging populations.
WP1. Ex vivo immune fitness screening potency of nutrients
Time table: execution A: Q1 2019 B: Q4 2020
Milestones: Candidate nutrients for human intervention study identified
Objective I: To optimize the ex vivo screening tool and to screen and select nutrients on their capacity to change immune fitness.
A. The ex vivo screening of immune cell fitness is up and running and very suitable to screen human subjects and a small subsets of nutrients. To obtain a faster and more standardized ex vivo analyses of immune fitness we will start with a further optimization of this tool. A detailed description of ex vivo screening is given in WP2. Briefly, this approach exists of the isolation of circulating monocytes that will be directly assessed ex vivo. Both metabolic and immunological parameters of the human monocytes will be defined and used to calculate a fitness score of the cell.
B. In the second phase of the project when we have identified the most important pathways/routes affected in immune unfit individuals in WP2 we will use the ex vivo tool to screen multiple nutrients to identify nutrients that improve immune cell fitness. Candidate nutrients/ingredients will be selected based on their potential capacity to improve pathways/routes affected in immune unfit individuals and will be shortlisted from literature or current research interest of the companies involved. Via this screening tool we will identify the most potent nutrients that will be selected for further investigation in the human intervention study (WP3).
To valorise the ex vivo tool, a SOP will be made and the most promising biomarker of immune unfit individuals will be further developed to enable usage in an immunoassay
WP2. Human characterisation study
Time table: Q1 2019-Q4 2020
Milestones: METC approval, study finished, lab analyses finished, draft manuscript ready
Objective II: To characterize immunologically unfit and fit individuals.
To identify immunologically unfit and fit individuals, we will isolate circulating monocytes of 50 young individuals ( 50 years). The young will be used as a reference measurement. These cells will be used to determine immune fitness state using detailed metabolic and functional characterization ex vivo as described in in the addendum and WP1. The metabolic and functional readouts will allow us to identify individuals with fit immune cells, yet also distinguish those with aberrant metabolic responses that will be classified as unfit immune cells (for more details see in the addendum). As ageing is associated with chronic inflammation and increased infection rate we will link immune fitness to chronic inflammation and infection rate as functional outcome measures.
If the proposed assessment of immune fitness is not able to precisely distinguish immune fit and unfit individuals we will continue with comprehensive phenotyping (RNAseq of the monocytes) of the most extreme responding individuals (fit/unfit), allowing improved disentangling of the two groups. As a budgetary consequence the human intervention study proposed in WP3 will have two instead of the proposed three intervention arms if this strategy is pursued
WP3 Human nutrient intervention study
Time table: Q1 2020- Q4 2021
Milestones: : METC approval, study finished, lab analyses finished, draft manuscript ready
Objective III: Proof of principle study to examine the power of the selected candidate nutrients to improve immune cell fitness in immunologically unfit individuals
In a proof of concept study the two most promising immune modulating nutrients identified in WP1B will be examined on the potency to affect immune fitness in humans. To enable comparison within a person a randomized, placebo controlled cross-over intervention study will be executed to assess the acute effects of nutrients on immune fitness. The study population will exist of 20 immune unfit and 10 immune fit men and women age above 50 years. The latter will be included as a healthy reference group. Immune fitness state will be assessed as described in WP2 and the addendum of WP2. Before and one to six hours after nutrient intake blood circulating monocytes will be isolated and immune fitness will be determined. Effects on immune fitness will be compared between both nutrients and the placebo group and compared to the response in the immune fit reference group.