Life leads to death, which is arguably the sole universal characteristic of life. The association between the rate of living and the rate of dying has fascinated biologists for a century, but the principal causes of ageing in humans and other organisms are still not resolved. Life span and rates of senescence vary distinctly, even between closely related species of similar size. Yet, for many organisms an intriguing relation between metabolic rate and lifespan is observed: when summed over lifetime, the metabolic rate per unit body mass is remarkably constant. This relation spans a wide range of organisms from yeast to elephant, and includes humans. Also within species, metabolism seems to be causally related with ageing, since caloric (or dietary) restriction typically enhances life expectancy. Despite intense research efforts, the nature of the relationship between metabolism and ageing remains enigmatic. By establishing a Systems Biology Centre called Energy Metabolism and Ageing (SBC-EMA), we will apply a systems biology approach to shed new light on metabolism, ageing, and their interaction. The metabolic rate of an organism is the result of the complex interplay of biochemical and physiological processes acting at various levels of organisation (mitochondria, cells, tissues, organs). Similarly, the physiological and molecular deterioration that characterizes ageing reflects the failure of networks of interacting cells, tissues and organs. Hence, by their very nature both metabolism and ageing require a systems biology approach in order to achieve a full understanding of their nature and their interaction. To unravel the complex relationship between energy metabolism and lifespan, SBC-EMA will combine large-scale data generation efforts with both data-driven top-down approaches and hypothesis-driven bottom-up approaches. In the first phase of its development, the Centre will focus on two model systems: the yeast Saccharomyces cerevisiae and mice Mus musculus. Metabolism and ageing in unicellular yeast and mice shows many similarities as well as differences, but the existence of a universal relation between metabolic rate and ageing suggests that key mechanisms underlying the ageing process are conserved from microorganisms to humans. We aim to discover these general mechanisms and this is an important motivation to study mouse and yeast next to each other. Yeast allows detailed investigations at the level of cells and organelles and they age rapidly. Moreover, a plethora of ?omics? information and techniques is already available, also within the University of Groningen, and metabolic and signalling pathways have been well characterised. Mice will be used to generate and test hypotheses involving intercellular and inter-organ relationships that are critical in higher organisms including humans. By applying similar manipulations (caloric restriction) in two model systems, we will simultaneously study intracellular (yeast) and higher-order (mice) processes in unprecedented detail with the aim to uncover the fundamental ageing processes shared by all life. This proposal is a joint research initiative of two faculties of the University of Groningen, the Faculty of Mathematics and the Natural Sciences (FMNS) and the Faculty of Medical Sciences (FMS). To achieve our ambitious goal, SBC-EMA brings together leading groups from both faculties, with expertise ranging from biochemistry, (molecular) biology, physiology and medicine to mathematics, statistics, bioinformatics and theoretical biology. The research theme of SBC-EMA builds on a rich history in both energetics and ageing research in both faculties. The University of Groningen has identified Healthy Ageing as one of its central research themes, and has founded the European Research Institute on the Biology of Ageing (ERIBA), which will focus on fundamental aspects of the biology of ageing. SBC-EMA will be physically and scientifically embedded within ERIBA together with other facilities like the Groningen Genomics Coordination Centre. By creating first-class infrastructure and by their recruitment policy, the University already demonstrates its commitment to systems biology. They also show a commitment to this proposal by providing 12 PhD student positions in addition to the positions requested in this proposal. SBC-EMA will be a vibrant Centre where scientists with diverse backgrounds will meet and collaborate on a daily basis to understand the fundamentals of ageing. Although research in SBC-EMA is predominantly fundamental, the topic of (healthy) ageing is of major societal relevance. Our research program on yeast and mice will therefore interact closely with Lifelines (and the complementary Systems Genetics endeavours), which will become the largest longitudinal population study in the Netherlands, involving more than 150,000 individuals. SBC-EMA will also have considerable scientific and educational outreach, by making data and results available to the scientific community, by developing user-friendly systems biology software, and by launching attractive systems biology courses for graduate and postgraduate students.