PhysAgeNet Deliverable D2.2 Scientific literature status, requirements and roadmap for the development of standards and utilisation of biomarkers, behavioural markers and environmental factors with open data

CA20104 – Network on evidence-based physical activity in old age (PhysAgeNet) Deliverable D2.2 D2.2 Scientific literature status, requirements and roadmap for the development of standards and utilisation of biomarkers, behavioural markers and environmental factors with open data RCO 1 Compile the literature on biological and behavioural markers, and environmental factors Contributors Working Group 2 Erja Portegijs (WG2 leader), Carl-Philipp Jansen (WG2 co-leader), Oron Levin (WG2 core group), Maryam Ziaei (WG2 subgroup leader), Ivan Bautmans (WG2 subgroup leader), Wouter Vints (WG2 review leader), Veerle Knoop (WG2 review leader), David Beckwée (WG2 review leader) Participants in the expert discussions and review groups have all contributed to these results This publication is based upon work from COST Action PhysAgeNet, CA20104, supported by COST (European Cooperation in Science and Technology). COST (European Cooperation in Science and Technology) is a funding agency for research and innovation networks. Our Actions help connect research initiatives across Europe and enables scientists to grow their ideas by sharing them with their peers. This boosts their research, career and innovation. 1 Table of Content 1. Introduction ........................................................................................................................................ 2 2. Results ................................................................................................................................................. 3 2.1. INTRINSIC CAPACITY ................................................................................................................ 3 2.1.1. LOCOMOTOR AND VITALITY CAPACITY AND FUNCTION ............................................. 3 2.1.2. COGNITIVE CAPACITY AND FUNCTION ............................................................................ 6 2.1.3. PSYCHOLOGICAL FACTORS ................................................................................................ 7 2.2. EXTERNAL FACTORS ...................................................................................................................... 9 2.2.1. ENVIRONMENTAL FACTORS .................................................................................................. 9 3. Roadmap to compile and condense ............................................................................................ 10 4. References ........................................................................................................................................ 11 2 1. INTRODUCTION Author: Erja Portegijs Healthy Ageing is highlighted by the Unites Nations’ “Decade of Healthy Ageing” and emphasizes the growing importance of addressing the challenges associated with ageing populations. Physical activity in old age is important for maintenance of health and function, and the prevention of chronic conditions. In addition, health benefits of physical activity interventions are widely reported using a wide variety of measures. However, there is no consensus on specific concepts and measures to be used for assessing intervention outcomes. The success of interventions, however, also depends on its implementation and uptake by the target group. Research is typically conducted in well-controlled settings and with a bias towards participants with better function and higher activity. When implementing physical activity interventions in real-life settings, various factors affect the uptake of the intervention, adherence to the protocol, and sustained participation. Thus, research on physical activity interventions should assess not only outcomes, but also other factors functioning as moderators or mediators of the interventions. This requires a holistic focus, encompassing not only more traditional physical or biological biomarkers, but also behavioral and environmental markers. Technology and digital tools are increasingly used to support physical activity interventions. Compared with traditional rehabilitation, technologies such as serious games can use vivid video and pictures and may become more attractive, acceptable, and more effective as a higher diversity of tasks can be trained. Furthermore, these technologies can provide timely feedback, continuous monitoring, and outcome assessment, as such informing the instructor for personalized adaptations. However, such technology-assisted interventions may require additional skills and understanding from older participants (Kim & Xie 2017), posing additional barriers and selection bias. To advance the measurement and monitoring of (technology-assisted) physical activity intervention outcomes as well as factors related to their uptake and maintenance in old age, the PhysAgeNet COST action network brought together researchers from different European universities. Technology-assisted interventions provide a timely context. However, they are not always suitable when studying novel and less researched measurement and monitoring parameters. Therefore, on a cases by case basis, literature reviews are based on physical activity interventions, or technology-assisted physical activity interventions. Experts discuss and clarify biological and behavioral biomarkers and environmental factors comprehensively and decided upon the most relevant context. Jointly the results of WG2 will establish requirements and a roadmap for future monitoring of interventions. Regular expert discussions were conducted in 2022 and are still ongoing. It was decided to depart from the pre-existing terminology of biological and behavioral biomarkers and environmental factors and to capture and tie together these and other relevant concepts holistically in a theoretical framework. Experts together decided to use the Healthy Ageing framework developed by the WHO (2015). The concept of "healthy ageing" focuses on maintaining functional ability and overall well-being in older age, rather than solely focusing on disease management. The framework is typically applied in the context of mapping the aging process. However, the PhysAgeNet WG2 intends to use it in the context of physical 3 activity intervention. The framework identifies intrinsic and extrinsic factors and linked functional domains (figure 1). Furthermore, subdomains are listed and specified. Considering the broad range of parameters to be considered for a holistic framework, it was decided to split into three expert groups, with further subdivisions when relevant, discussing the following topics: • Vitality and locomotor ability and function • Cognitive ability and function • Psychological factors • Environmental factors The following section 2 describes the work and progress in each group and section 3 describes how this contributes to the development of the set of requirements and roadmap for assessing (technology-assisted) physical activity interventions. 2. RESULTS 2.1. INTRINSIC CAPACITY 2.1.1. LOCOMOTOR AND VITALITY CAPACITY AND FUNCTION Author: Veerle Knoop (Ivan Bautmans) Locomotor and vitality capacity are two domains of intrinsic capacity and have recently been redefined by an expert taskforce initiated by the WHO. A new WHO working definition of vitality capacity (VC) has been proposed by 20 international experts in an expert meeting, defining VC as "a physiological state (due to normal accelerated biological ageing processes) resulting from the interaction between multiple physiological systems, reflected in (the level of) energy and metabolism, neuromuscular function, and immune and stress response functions of the body" (Bautmans et al., 2022). Locomotor capacity on the other hand is defined by the WHO taskforce as “a state (static or dynamic over time) of the musculoskeletal system that encompasses endurance, balance, muscle strength, muscle function, muscle power and a joint function of the body” (Veronese et al., 2022). Early identification and monitoring of changes in intrinsic capacity is key to better prevention and health management. However, no current consensus exists on the metrics for systematic quantification or monitoring of locomotor and vitality capacity in the context of intrinsic capacity. Methodology to identify domains and biomarkers for vitality and locomotor capacity Since May 2022 monthly (virtual) meetings have been organized to identify biomarkers for intrinsic capacity (vitality & locomotor) and functional ability affecting the uptake or maintenance of the intervention or factors indicating mechanisms of change. As a first step different domains for vitality and locomotor capacity were proposed by the experts, they were divided into outcomes, moderators and mechanisms. As a next step, different biomarkers for each domain were identified. These next biomarkers and domains were used subsequently to 4 conduct a systematic review on measures that can be recommended for routine monitoring of vitality and locomotor capacity. A large set of biomarkers were evaluated and grouped by the experts involved (see table 1, step 1). All the biomarkers were coded according to the experts into outcomes, moderators and mechanisms. As a next step, biomarkers appointed as outcomes will be evaluated according to the following criteria: feasible to quantify biomarkers or proxy biomarkers; useful and informative for monitoring (sufficient sensitivity to change with intervention) and implementable (e.g., in dedicated population surveys on ageing or multipurpose surveys). Table 1. Steps to identify biomarkers for vitality & locomotor capacity Stepwise identification of biomarkers for vitality and locomotor capacity Vitality Domain Biomarkers Energy & metabolism Self-perceived fatigue (moderator) Muscle fatigability (outcome) Malnutrition (moderator) Body composition (moderator) Fibre typing (moderator) Circulating biomarkers of metabolism (mechanism) Neuromuscular strength Knee extensor strength (outcome) Knee flexor strength (outcome) Handgrip strength (moderator) Respiratory Muscle strength (outcome) Voluntary muscle activation (moderator) Muscle contractibility (mechanism) Muscle stiffness (mechanism) Muscle power (mechanism) Immune & stress response Inflammatory biomarkers (mechanism) Immune symptoms (moderator) O2 Saturation (outcome) Autonomic function (outcome) Hormonal levels (mechanism) Locomotor Muscle power Stair climbing test (outcome) Chair stand test (outcome) Cycling test (outcome) Vertical jump (outcome) Joint function Flexibility (outcome) Range of Motion (outcome) Sit and reach test (outcome) Upper back stretch (outcome) Hip flexion (outcome) Hip external rotation (outcome) Spinal mobility (outcome) Functional reach (outcome) Muscle strength 1 RM test (outcome) Isokinetic device(outcome) Electrical stimulation (outcome) 5 Rate or Torque development (outcome) Balance Berg Balance scale (outcome) Functional reach test (outcome) Centre or pressure signals (outcome) Endurance Gait speed (outcome) 2min walk test (outcome) PA levels (outcome) Functional ability Normal gait speed (outcome) 2-minutes walk test (outcome) Physical activity questionnaires (outcome) Activity of Daily living questionnaires (outcome) To ensure sufficient manpower to carry out the review work it was decided to firstly focus on two topics and to conduct umbrella reviews specified below: • Review 1: “Measurement properties of instruments to measure lower limb functional ability and balance after technology-assisted physical activity interventions in community-dwelling older adults: an umbrella review of systematic reviews and metaanalysis of randomized clinical trials” (Review # 1, leaders Ivan Bautmans and Veerle Knoop). Since a large overlap between functional ability and balance we decided to combine both domains and perform an umbrella review to identify available instruments suitable for measuring lower-limb functional ability in communitydwelling older adults and b) to critically review the measurement properties of the identified instruments. Many different physical technology-assisted interventions have been proposed to improve functional ability and balance in older adults. However, it is not clear yet which instruments for functional ability and balance are key to measure effects of technology assisted physical interventions. In this umbrella review, we will compile the existing literature on lower limb functional ability and balance measurements used after technology assisted interventions. For this the instruments are needed to have good psychometric properties and should be a distinct attribute for measuring lower limb functional ability and balance. We will indicate any missing pieces in the current state of research, which will help researchers to prioritize functional ability and balance factors that are relevant to better understand and interpret intervention effects. The PROSPERO protocol has been submitted and the selection process has been started. We expect to condense the list of variables for measuring functional ability and balance and propose variables that can be used in the Cost action framework. • Review 2: “The effect of physical interventions on inflammatory markers (Il-6, IL10, CRP, TNF-alpha), an umbrella review of systematic reviews and meta-analyses” (Review # 2, leader Ivan Bautmans). Based on a recent published systematic review we found that the inflammatory markers CRP, IL-6, TNF-a and IL-10 (anti) inflammatory marker were most responsive to exercise (Bautmans et al., 2021). However, we would like to confirm this in an umbrella review and to look only at evidence for CRP, IL-6, TNF-a and IL-10 based on already published systematic reviews and meta-analysis. Aging-related alterations of the immune system involve a chronic low-grade inflammation called “inflammageing”, characterized by increases in the levels of pro-inflammatory molecules, which impair the maintenance of immunological homeostasis. Different modalities of exercise interventions have been proposed to reduce inflammageing in 6 older adults. This umbrella review will focus on gathering evidence on the possible modification of circulating levels of inflammatory molecules, particularly C-reactive protein (CRP), tumour necrosis factor alpha (TNF-α), interleukin 6 (IL6), and interleukin10 (IL10), by exercise interventions in community-dwelling populations of older adults. Therefore, the review question to be addressed is: Are circulating concentrations of CRP, TNFα, IL6 or IL10 (O) in older adults (aged 60 and over) (P) influenced by exercise interventions (I)? The PROSPERO protocol has been submitted and the selection process has been started. We expect to condense the list of variables for measuring functional ability and balance and propose variables that can be used in the Cost action framework. 2.1.2. COGNITIVE CAPACITY AND FUNCTION Authors: Maryam Ziaei, Oron Levin (Wouter Vints) Towards identifying biomarkers for brain and cognitive health. Our subgroup aims to identify biomarkers from cognitive and neural domains to better understand how and why exercise impacts cognitive functions and which areas show the most significant effects. Thorough literature review is carried out to delineate the factors that contribute to this relationship and reported in several papers. The review papers will provide valuable insights into the factors that contribute to brain and cognitive health. These factors will serve as the basis for developing targeted strategies and guidelines to improve cognitive and brain health. Our goal is to deliver tangible outcomes that will have a significant impact on cognitive and brain health. Methodology to identify biomarkers for cognitive capacity and function We conduct three literature searches for publications reporting the effects of physical activity (PA) on different sets if of biological markers related to cognitive function (1 and 2) and on functional markers of brain and cognitive function (3). • Circulating factors released into the blood stream from muscle tissue that are either expected or known to (in)directly affect the central nervous system through exercise (Review # 1, leader Wouter Vints). This review is planned to be a living systematic review. A list of relevant muscle-derived biological markers (i.e. myokines) with relevance for exercise-induced cognitive changes will be extracted from this review paper, which will be updated on a regular basis for a period of five years after publication of the first version of the review. The specific review questions are: (1) which specific cognitive components are associated with exercise-induced myokine level changes; (2) which of the studied myokines in exercise-cognition studies in older adults significantly increases or decreases with exercise; (3) to what extent does the pooled effect size of the exercise effect on myokine levels in exercise-cognition studies depend on exercise characteristics (i.e., type of exercise, intensity of exercise intervention duration, frequency of exercise, session length); (4) which of the studied myokines can be considered a mediator of cognition; and (5) whether specific myokines affect specific cognitive components. A Cochrane proposal of the living systematic review has been submitted and a protocol paper is in progress. 7 • Brain and muscle metabolites that can be quantified in-vivo with magnetic resonance spectroscopy (MRS) and that are known to be markers of neurodegeneration, neurogenesis, brain/muscle tissue composition, age-related co-morbidities, or muscle/brain metabolic status (Review # 2, leader Oron Levin). This review is planned as scoping review with an overarching aim to highlight the role of MRS as a feasible method for assessing the effects of physical exercise on muscle and brain metabolism. The specific review questions are: (1) what MRS methods are used in research or clinical settings for quantification of brain and muscle metabolites and which biomarkers can be quantified reliably with those methods; (2) what MRS neurometabolites and biochemical properties could be significant and possibly useful biomarkers for quantification of exercise-induced outcomes in brain and muscle tissue; (3) what MRS measurements are considered most valid biomarkers for exercise-induced changes in brain and muscle health in the general aging population; (4)what MRS biomarkers can be used as predictors for beneficial or detrimental exercise on cognition, mobility, mental health or quality of life in the aging population; (5) is there a sufficient body of experimental data coming from MRS studies to guide evidence-based recommendations on exercise duration and intensity for preserving/improving brain and muscle health in aging. Based on the findings a set of MRS biomarkers that can be serve as markers of exercise-induced beneficial/detrimental effects on brain and muscle health will be extracted. Since use of MRS for exploring exercise-induced effects on brain health in aging is relatively new, the review will also discuss methodological limitations, research gaps and propose directions for further research. The scoping review protocol has been registered and a protocol paper is in progress. • Cognitive functions are executive function and multi-tasking or speed of processing. A literature review reporting the effects of physical activity (PA) on functional parameters of cognitive function will be conducted with a focus on brain structure and functional biomarkers (Review # 3, leader Maryam Ziaei). A scoping review protocol for preregistration is in progress and will be submitted by the end of April. 2.1.3. PSYCHOLOGICAL FACTORS Author: David Beckwée No single intervention strategy, or package of strategies was found to be effective across all persons, conditions, and settings. Effects of physical activity (PA) interventions to improve older adults’ health for example depend on intervention duration and adherence. Adherence to intervention protocols is defined by the World Health Organisation (WHO, 2003) as the ‘extent to which a person’s behaviour corresponds with agreed recommendations from a healthcare provider’, that is, adherence translates as the degree to which the target intensity and volume of a physical exercises are achieved and sustained over time (Hawley-Hague et al. 2016). Patients often encounter multiple barriers that impede their ability to adhere to intervention plans optimally, which are at least partly rooted in the participant’s psychological determinants and behavior (Collado-Mateo et al. 2021). The issue of how to motivate patients to continue exercising following supervised PA interventions holds significant relevance in clinical practice. Technologies may increase exercise uptake and long-term adherence as they can overcome many perceived barriers to exercise. However, when using technology, users’ adherence to the 8 technology (in addition to the intervention) is a distinct construct that needs to be considered (Payne et al. 2021). Technological interventions are often plagued by rapidly declining retention rates (Chen et al. 2015). In addition, existing commercially available health technologies are limitedly grounded in behavioral theory and tested for their efficacy (Payne et al. 2021), the rapid pace of new technology development makes it increasingly difficult for researchers to develop, pilot-test, and evaluate interventions before such technologies become outdated or obsolete (Baker et al. 2014, Pagota et al. 2015). Methodology to identify psychological concepts and variables The aim of this subgroup is to conduct a scoping review to identify psychological and motivational factors that contribute to older people’s adherence when they use technology to support the physical activity intervention. “Psychological and motivational factors of older people’s adherence to technology-supported physical activity interventions. A Scoping Review.” (Review # 1, leaders David Beckwée and Erja Portegijs). The methods used to identify articles about physical activity in older adults will be reviewed for evidence of the interaction between adherence and (psychological or motivational) measures. Based on multiple expert discussions, the following structure and definitions were developed to guide the work: • Standardized measures of a particular psychological variable of the older participant Psychological capability is defined as the capacity to engage in the necessary thought processes such as comprehension and reasoning. Motivational determinants are defined as reflective processes (involving evaluations and plans) and automatic processes (involving emotions and impulses that arise from associative learning and/or innate dispositions). o Examples of psychological capabilities: Thinking Skills, Critical Thinking, Mental Processes/Competencies, Reflection, Analysis, Reasoning o Examples of motivational determinants: Implementation Plans, Attitudes, Emotions, Goals, Intention • Outcomes related to adherence of the older participant. At least one outcome should relate to user’s adherence to the physical intervention and/or adherence to the technology. Adherence to the physical intervention reflects the dose-response relationship of physical interventions and can be expressed within the FITT dimensions (Frequency, Intensity, Time and Type of exercises). Adherence to the technology reflects the fact that the technology itself can be a determining factor in intervention effects. • Examples of adherence to the physical intervention: The ratio of the number of sessions that were carried out versus the number of planned sessions, and the ratio of the [total ‘training load’ x duration] versus [prescribed total training load x duration] (Compliance) • Examples of adherence to the technology: number of logins, number of days of technology use, time spent on the platform, number of lessons or modules accessed or finished, number of elements accessed or used • Description of the physical interventions. Exercise and PA have many dimensions and vary in frequency, intensity, type, duration, materials, provider, delivery, location, dosage, tailoring, and compliance. Therefore, relevant information on the physical interventions, as recommended by the ‘Consensus on Exercise Reporting Template (CERT)’ (Slade et al. 2016), will also be extracted. • Functional measures. Whenever PA/exercise practice is linked to the use of technology, it is not sufficient to promote the effects of the technologies without an accompanying