Research Paper

A combined lifestyle intervention induces a sensitization of the blood transcriptomic response to a nutrient challenge

Authors

Thies Gehrmann (0000-0003-4666-5406, T.Gehrmann@lumc.nl)^1,2,*, Marian Beekman (0000-0003-0585-6206, m.beekman@lumc.nl)¹, Joris Deelen (0000-0003-4483-3701, Joris.Deelen@age.mpg.de)^1,3,4, Linda Partridge (0000-0001-9615-0094, Partridge@age.mpg.de)^3,5, Ondine van de Rest (0000-0002-4632-7418, ondine.vanderest@wur.nl)⁶, Leon Mei (0000-0001-7920-3967, H.Mei@lumc.nl)^1,7, Yotam Raz (0000-0001-9628-632X, Y.Raz@lumc.nl)¹, Lisette de Groot (0000-0003-2778-2789, Lisette.degroot@wur.nl)⁶, Ruud van der Breggen (0000-0003-2110-6069, r.van_der_breggen@lumc.nl)¹, Marcel J.T. Reinders (0000-0002-1148-1562, M.J.T.Reinders@tudelft.nl)^1,2,8, Erik B. van den Akker (0000-0002-7693-0728, E.B.van_den_akker@lumc.nl)^1,2,8, P.Eline Slagboom (0000-0002-2875-4723, P.Slagboom@lumc.nl)^1,3,4,*

¹Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Einthovenweg 20, 2333ZC Leiden, The Netherlands

²Leiden Computational Biology Center, Einthovenweg 20, 2333ZC Leiden, The Netherlands

³Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany

⁴Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

⁵Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, Darwin Building, 104 Gower St, London WC1E 6AD, UK

⁶Division of Human Nutrition, Wageningen University, Stippeneng 4, Building 124, 6708 WE Wageningen, The Netherlands

⁷Sequencing Analysis Support Core, Department of Biomedical Data Sciences, Leiden University Medical Center, Einthovenweg 20, 2333ZC Leiden, The Netherlands

⁸Delft Bioinformatics Lab, Delft University of Technology, Van Mourik Broekmanweg 6, 2628 XE Delft, The Netherlands

^*Corresponding authors

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Abstract

The global population is growing older. As age is a primary risk factor of (multi)morbidity, there is a need for novel indicators to predict, track, treat and prevent the development of disease. Lifestyle interventions have shown promising results in improving the health of participants and reducing the risk for disease, but in the elderly population, such interventions often show less reliable or subtle effects on health outcomes. This is further complicated by a poor understanding of the homeodynamics and the molecular effects of lifestyle interventions, by which their effects of a lifestyle intervention remain obscured. In the Growing Old Together (GOTO) study, we examined the responses of 164 healthy, elderly men and women to a 13-week combined physical and dietary lifestyle intervention. In addition to collecting blood samples at a fasted state, we sampled blood also 30 minutes following a standardized meal. This allows us to investigate an intervention response not only in the traditional fasted state, but also in the blood metabolic and cellular responses to a nutrient challenge. We investigated the transcriptomic and metabolomic responses to this nutrient challenge, how these responses relate to each other, and how this response is affected by the lifestyle intervention. We find that the intervention has very little effect on the fasted blood transcriptome, but that the nutrient challenge induces a large translational inhibition, and an innate immune activation, which together comprise a cellular stress response that is stimulated by the intervention. A sex-specific analysis reveals that although the same set of genes respond in the same direction in both males and females, the magnitude of these effects differ, and are modulated differently by the intervention. On the other hand, the metabolomic response to the nutrient challenge is largely unaffected by the intervention, and the correlation between the metabolomic nutrient response and transcriptomic modules indicates that the change in transcriptomic response to the nutrient challenge is independent from a change in cellular metabolomic environment. This work constitutes a glance at the acute transcriptomic stress response to nutrient intake in blood, and how a lifestyle intervention affects this response in healthy elderly, and may lead to the development of novel biomarkers to capture the phenotypic flexibility of health.