Physical Activity and Nutrition INfluences In ageing (PANINI): consortium mission statement

decade in poor health. Consequently, there is an urgent need to understand how lifestyle factors can influence age-related changes from gene to society level and how they may be integrated into a net effect of healthy ageing. It is also crucial to develop and validate interventions and health policies to ensure that more of our older adults have a healthy and active later life. This is an urgent and cross-cutting research priority in Europe, and to achieve this, it is vital to increase research capacity in this area to push forward the frontiers of scientific understanding. The Horizon 2020 funded Marie Sklodowska Innovative Training Network—PANINI is addressing this capacity issue by focusing on research and training in two major interacting lifestyle factors with impact at multiple levels, namely, physical activity and nutrition. The aims of PANINI are, therefore, to:


Introduction
Current demographic trends indicate that by the year 2020, almost one in five of the European population will be aged 65 years or over. Although life expectancy is increasing by 2 years per decade, the period of life spent in good health is not keeping pace and most Europeans spend their last 1 3 interaction of physical activity and nutrition through training a network of early stage researchers; 2. develop a standardised toolkit of the best practice measures of physical activity and nutrition; 3. utilise the toolkit across PANINI research projects to develop a shared data set across different European ageing populations; 4. coordinate existing data from collaborators to strengthen the PANINI data set to assess the physical activity and nutritional status interactions in a range of older adult populations; 5. compare novel physical activity and nutritional interventions to improve healthy ageing and assess the potential mechanisms underlying intervention responsiveness; 6. develop an online repository of training material on physical activity and nutrition in older adults for continuing professional development (CPD); 7. create a healthy ageing policy document with key stakeholders.
To promote healthy ageing, it is important to understand the mechanisms underlying unhealthy ageing trajectories. Healthy ageing is defined as optimising opportunities for good health, so that older people can take an active part in society and enjoy an independent and high quality of life (http://www.healthyageing.eu). Ageing is a complex process, but we are beginning to understand how age-related changes in physiological systems influence physical function. Good musculoskeletal function is critical for a healthy and active old age [1], but the musculoskeletal system is significantly affected by ageing, with loss of muscle mass and bone density from midlife resulting in increased physical frailty, falls, fractures, and loss of independence. The aetiology of sarcopaenia (low skeletal muscle mass and function) includes intrinsic factors associated with ageing, but more recently extrinsic modifiable lifestyle factors such as physical activity and nutrition have been suggested as primary drivers [2]. When associated with weight loss, fatigue, weakness, slow walking speed, and physical inactivity, this results in frailty [3]. Thus, early detection through comprehensive multidisciplinary assessment of a range of relevant factors and sensitive biomarkers, and mitigation through targeted interventions is essential [3].
Increased inactivity is a well-recorded feature of ageing humans, with less than half of those over the age of 50 years meeting the recommended guidelines for physical activity, and less than 10% in those over the age of 75 years. Furthermore, ageing is typically associated with a gain in fat mass (adiposity), which with decreased activity can contribute to sarcopaenia, and reduced mobility [4]. However, with ageing, energy intake also decreases, and malnutrition is prevalent [5], particularly in hospitalised patients and older outpatients [6]. Physical activity and optimal nutrition can influence the function of a range of body systems [7,8], which interact in the maintenance of homeostasis and healthy ageing via enhancing quality of life, cognition, muscle mass, decrease fat mass, and modify sarcopaenia. However, data are sparse on energy-protein intake and energy expenditure in less fit older populations or communitydwelling older adults, where the prevalence of undernutrition may be far higher than currently assumed [7]. Consequently, nutritional and exercise requirements of elders to maintain physical and mental function are largely unknown, although the European Society for Clinical Nutrition and Metabolism (ESPEN) [9] have made evidence-based nutrition recommendations and the European College of Sport Science (ECSS) [10] have adapted existing physical activity guidelines for older adults. What is needed are multidimensional data over various populations, extending from midadulthood to old age, which PANINI will collect and analyse through development of its shared database and standardised toolkit of measures detailed below.
Understanding the biology and physiology underlying healthy/unhealthy ageing is an important initial step required before developing and testing physical activity and nutritional interventions. PANINI will address this through focusing on the impact of nutrition and physical activity on mobility, muscle function, endocrine function, cognitive function, and inflammation in ageing at the cell and system level. Dysregulation of mitochondrial function in the muscle is a hallmark of ageing and age-and lifestyle-related diseases and so will be studied in skeletal muscle, applying a system biology approach through the mathematical modelling of metabolism [11]. This will include assessment of the impact of diet and physical activity on metabolic activity across different age groups through the use of the newly generated PANINI data as well as existing data sets of PANINI collaborators, e.g., NU-AGE, MYOAGE, and MUMC+.
Stress hormone changes with ageing relate to significant decrements in mental health and frailty, and increased inflammation, thus cortisol:dehydroepiandrosterone (DHEA) hormone ratios will be measured [12]. The decline in sex steroids in perimenopause can also have dramatic effects on muscle mass and function later on in life [13]. However, few studies have characterized changes in neuromuscular function, level of physical activity, and psychological characteristics in middle-aged women across menopausal stages. These biological and physiological changes will be studied within PANINI. Biological and physiological changes associated with ageing will be examined across a range of older populations of differing frailty phenotype, and novel interventions will be designed to reduce sedentary time, increase activity, and improve physical function. The study of sedentariness, and the development of interventions to reduce this will focus on older adults awaiting surgery and will utilise behaviour change techniques such as individualised feedback, individualised goal setting, and motivational interviewing, as well as environmental modification to encourage reduced sitting time. It will also utilise direct measurement of physical activity and sitting time variables to provide data on sitting time, standing time, stepping time, sit-to-stand transitions, and quantity of sedentary bouts >30 min. These data will be used to inform the design of a definitive trial to reduce sitting time prior to surgery, on selected health outcomes after surgery.
Further, ageing is often accompanied by an increase in systemic inflammation affecting physical and mental function [14], and dietary intake can also influence memory, attention, and learning [15]. Consequently, where possible within PANINI, cognitive function will also be assessed, and in particular, elderly cohorts, detailed food intake, and cognitive function will be assessed longitudinally to assess the impact of dietary choices and changes on cognitive decline. In addition, assessing dietary intake is challenging and subject to bias, but quantitative methods are cost-and labour intensive and only provide a narrow view of nutrients. PANINI will also use a mixed-methods approach that can provide a richer and broader view of food choice and eating behaviours. We will focus specifically on changes in social networks and their influence on dietary intake and physical function and will target under-studied, high-risk groups such as ethnic minorities, allowing us to design appropriate interventions that address barriers and enablers to sustained healthy food choices in old age across a range of populations.
The state of the art for interventions to improve musculoskeletal health is resistance training with/without nutritional supplementation [16], but efficacy is blunted in older adults, so innovative strategies to optimise responsiveness are needed. Physical activity interventions need to be appropriate for older adults across a range of health, frailty, and independence levels, and, as such, must be individually tailored. For example, major surgery induces stress, which combined with bed rest, can be harmful for patients, particularly when frail. Promoting a pro-physical activity and social environment before and during the entire surgical trajectory prevents frailty progression, and has been proven cost effective [17]. One of the barriers to physical activity in frail or recuperating populations is limited mobility and independence. There is evidence to support the effectiveness of chair-based muscle strengthening resistance exercise on muscle function [18]; however, it is not yet known how feasible these interventions are in very frail and dependent older adults, or how effective they are at altering key biomarkers of healthy ageing and well-being such as inflammation. PANINI will refine existing interventions by determining feasibility, effectiveness, and appropriate dose in a range of frail older adult populations including acute inpatients, sedentary older adults, care home residents, and hospital outpatients.
Discovering biomarkers of ageing are a crucial goal in ageing research. Epigenetics are the range of heritable reversible changes in chromatin structure and gene function, which can determine biological ageing and health status. Several candidate genes have been identified that show progressive increases in methylation across the human lifespan, and thus appear to be promising biomarkers [19,20]. However, further research is needed to determine whether gene methylation simply indicates chronological age or correlates with physiological function. Using this state-of-the-art technique, it is possible to develop interventions that could alter biological ageing via effects on epigenetic regulators, such as in FP7 project NU-AGE [21], focusing on the modulatory role of a modified Mediterranean diet on DNA methylation patterns during ageing [21,22]. PANINI will expand this research by also examining methylation of candidate genes that relate to physiological function, and assess the impact of interventions on epigenetic modulation to provide further information on mechanisms of intervention effectiveness across several of the PANINI interventions. DNA methylation analysis of candidate biomarkers will be performed using Sequenom MassArray high-throughput platform and quantitatively analysed for DNA methylation using the EpiTYPER protocol. Candidate target regions will include genomic regions, whose methylation status are ageassociated and are informative of the biological age of an individual, according to published and proprietary data.
Finally, PANINI will explore the relevance of individual genetic background for the development of sarcopenic/frail phenotypes and for the success of nutritional and physical interventions. Studies of genetic determinants of muscle mass/strength have revealed different risk phenotypes for sarcopaenia [23][24][25]; however, an under-researched but relevant field is the relationship between nutritional habits and variants in genes that affect appetite and dietary preferences. PANINI will address this through comprehensively studying the interplay between genetic background, diet and sarcopenic/frail phenotype. Genetic analysis will stratify participants for their response to physical and nutritional interventions across PANINI. Next-generation sequencing (on a sub-sample) will integrate these results with the genetic characterizations in NU-AGE; candidate genomic variants will be evaluated on a larger mixed gender cohort. Metabolic network modelling will be used to study changes in energy metabolism associated with ageing. Model predictions will be validated with molecular data from a select number of participants in the PANINI data set. The main projects in PANINI and their key methodologies and outcome variables are summarised in Table 1. Publications as they arise will be open access and linked from the PANINI website http:// www.birmingham.ac.uk/panini. The PANINI toolkit and shared data set PANINI will recommend a key set of gold standard nutrition and physical activity measures in ageing as a standardised toolkit, and make this widely available outside the PANINI consortium to encourage standardised measurement. Through the toolkit, we will bring together all of the PANINI projects to contribute to the development of a shared database for analysis of various ageing profiles across the range of older adult populations. Our data management plan (available on the PANINI website) is that this standardisation will result in a unique shared data set from which ageing profiles across countries, settings, frailty, and independence status could be determined and compared focusing particularly on nutritional status, physical activity, and physical function, as well as comparing relative change across the interventions in the network. The main components of the toolkit are: socio-demographics; anthropometrics (including body composition where possible); comorbidities and medication use; typical health behaviours including water intake; nutritional assessment questionnaire (and food frequency questionnaires or food/diet diaries where possible); physical activity via questionnaires (and accelerometry where possible); physical function via the short physical performance battery (SPPB); frailty through hand-grip strength, balance, and walking speed; falls efficacy and activities of daily living scales; brief cognitive assessment; and depression assessment. We will also link, where possible, with matching data from existing European cohorts on ageing. For example, through the beneficiaries of the network and their existing links, we will collaborate to examine existing nutritional and physical function data in the Birmingham Hip Fracture, EMPOWER, MUMC+, COGA, ERMA, Grey Power 1 and 2, NU-AGE, ProMo, and Bronovo studies, with appropriate permissions. The PANINI shared data set will be made an open access resource at the conclusion of the project enabling the PANINI consortium and collaborators to answer research questions regarding physical activity and nutritional status impacts on healthy/unhealthy ageing. Researchers or networks wishing to become affiliated with the PANINI network for collaboration and/or data contributions to the shared data set should contact the Principal Investigator (PI)-Professor A. C. Whittaker.

PANINI training
To understand the impact of age-related changes upon normal body processes such as nutritional intake, and exercise capacity, and to relate this to overall effects on physical and mental well-being, a multidisciplinary approach is required. PANINI is providing multidisciplinary PhD training and secondments (summarised in Table 2) across an inter-sectoral network of eight leading academic and non-academic research institutions across Europe (six universities, one research enterprise, and one SME, as detailed in Table 1). Our partners: six private sector companies (Danone Nutricia Research; HUR Ltd.; HURLabs; Move it or Lose it; Scriptoria; and Blueberry Training); one large healthcare partner (University Hospitals Birmingham NHS Foundation Trust); two ageing charities (Age UK and UNIEKBO); and one Joint Research Council, who contribute to training, supervision, and dissemination, providing an innovative and inter-sectoral environment to produce maximum impact of PANINI's research. We are keen to open up the PANINI training network to other research and training networks; our main activities, open to (a limited number of) external participants, are detailed in Table 2; so please contact the PI if interested. It is also our plan to develop a CPD distance learning course from the materials developed and delivered during the PANINI project, after its completion, to increase training resources and build research capacity in multidisciplinary ageing research.

Outreach, dissemination, and impact
PANINI's approach to dissemination, impact, and innovation is to co-create our strategy with our stakeholders, holding public engagement events annually. These will allow us to refine our research methodology and dissemination approaches to meet stakeholder needs and expectations. Researchers will engage the public via annual individual or small group interactive activities such as science association events, older adults' societies, articles in older adults' newsletters, pod/vodcasts, and the media in a widely accessible manner. Further, an initial PANINI public engagement event is planned for midway through the project, where the ESRs will engage older adults with key messages and demonstrations from their projects. A final larger scale public engagement event is planned for the end of the network. Older adults and representatives from charities, industry, and the health sector with an interest in ageing research will be invited to attend these events. Midway through the project, it is our intention to present PANINI symposia at relevant interdisciplinary conferences with a focus on ageing, presenting the goals of the network and initial findings from the individual ESR projects and their collaborative work. Towards the end of the project, with key stakeholders, e.g., ageing charities, health professionals, and policy makers, we will refine a set of physical activity and nutritional intake recommendations for older adults of different frailty and dependency statuses which will be integrated with the knowledge gained regarding nutritional intake and physical function across the network. This will be integrated into a policy document for healthy ageing and discussed with representatives of health policy-making bodies at national (e.g., Public Health England) and European levels (e.g., EIP-AHA and DG-SANCO). These activities are summarised in Table 2; our dissemination plan is available on the PANINI website. In conclusion, a key target of PANINI is to develop a cohort of the next-generation researchers able to communicate healthy ageing research across disciplinary boundaries and value the benefits of the cross fertilisation of ideas and problem solving across the emerging interdisciplinary areas essential for integrative 'whole person' physical activity and nutrition research. Key impact will be through the anticipated widely disseminated significant advances in understanding the central processes that contribute to healthy ageing and the factors and mechanisms underpinning successful interventions. Key outputs will be a PANINI toolkit of recommended measures; a shared data set used to interrogate health and well-being in ageing across a range of older populations as predicted by the toolkit and a co-created health policy statement. Further, the training resources will also be made widely available in order as a resource to develop research capacity in physical activity and nutrition in ageing.