The effects of lifestyle factors on physical and cognitive health and its modulation by age and the gut microbiome

Aging is a naturally-occurring process that acts as an shared risk factor for numerous diseases and multi-morbidity. Common age-related diseases include cognitive, physical and metabolic diseases. There is however, significant heterogeneity among older adults of the same chronological age with respect to their health and their biological age. Metabolic pathways involved in energy regulation and immunity are prominent drivers of diversity in biological age and are embedded in an intricate gut-muscle axis. The resulting physiological condition is interlinked with an individual’s behavioral patterns through a feedback loop. These constitute the lifestyle framework of an individual which dictates their overall health and wellbeing. Previous research highlights the importance of prevention of age-related diseases already in middle-aged individuals (Oude Voshaar, Jeuring et al. 2021). 
Ageing is often accompanied by a disbalance of energy metabolism, potentially leading to overweight and metabolic diseases or loss of muscle mass and physical health. Maintaining a healthy balance is therefore crucial for avoiding loss of physical and cognitive function and thereby preserving independence, health and vitality through the aging process. Energy intake is fundamentally related to diet and its nutritional composition, the role of an adequate diet in the prevention and management of metabolic diseases is well known. Contrarily, energy expenditure often relies on exercise as a primary metabolic booster. The well-established link between diet and exercise enables us to manipulate our physiology such as through weight loss and muscle gain. Nevertheless, this relationship is complex and involves numerous physiological systems. The most recent speculation involves the mediating role of gut microbiome due to their ability to ferment foods and producing short-chain fatty acids (SCFA) that regulate host physiology. In the context of healthy aging, understanding the triangle of diet, physical activity and the gut microbiome is fundamental to promote physical and cognitive wellbeing. It is necessary to understand long-term relationships between diet, exercise, the gut microbiome and physical and cognitive decline in order to stimulate healthy ageing (Figure 1).
Dietary choices as well as physical activity can influence the risk for metabolic diseases, physical health and the gut microbiota composition in older adults and is therefore a crucial part of healthy ageing (Van Soest, Hermes et al. 2020). In recent years, plant-based diets, which are mainly based on plant-foods, minimizing or eliminating animal foods, have received increased attention due to their ethical and environmental implications (British Dietary Association 2017). It has been found that plant-based, fiber-rich diets are associated with greater microbial diversity and greater abundance of SCFA producers, however a specific profile associated with a plant-based diet could not be identified yet, due to great variability of diet composition across studies (Tomova, Bukovsky et al. 2019, Trefflich, Jabakhanji et al. 2020). For established dietary patterns, such as vegetarian or Mediterranean diet, a beneficial effect on physical and cognitive decline has been suggested. Via the gut-brain-axis diet can influence these aspects by modulation of the gut microbiome, yet current evidence on this is inconclusive (Ghosh, Rampelli et al. 2020, Van Soest, Hermes et al. 2020). The production of metabolites associated with inflammation could explain the link found between gut microbiota enriched by a Mediterranean diet and reduced physical and cognitive function (Ghosh, Rampelli et al. 2020). 
However, a Mediterranean diet is characterized by high dietary quality with a careful selection of consumed foods, leading to a high intake of polyphenol and antioxidant rich foods, potentially explaining its beneficial effect on health. Additionally, the consumption of animal foods, such as fish, in moderate amounts is encouraged in a Mediterranean Diet. This does not necessarily apply to plant-based diets, as they can vary widely in their composition and thus quality. Previous studies found significantly different effects of plant-based diets of varying composition and quality on metabolic but also mental health outcomes (Satija and Hu 2018, Baden, Kino et al. 2020). It is further unknown whether a fully plant-based diet can have similar positive health effects. On the other hand, previous studies have highlighted the positive effects of dairy and its probiotic properties on bone mineral density and body composition, suggesting it to be a beneficial dietary component especially in an older population prone to muscle loss and osteoporosis (Thorning, Bertram et al. 2017, Ratajczak, Zawada et al. 2021). The importance of a high-quality diet for the management of age-related diseases and weight loss is underpinned by current evidence. Decreasing energy requirements combined with increased needs for micronutrients in older adults pose special dietary challenges, that require further investigation of the optimal dietary composition in older adults (Roberts, Silver et al. 2021). We therefore propose to assess the relationship of diet, specifically plant-based and dairy foods, with the gut microbiome and its interactions with physical and cognitive health outcomes by investigating the influence of plant- and animal-based food groups, a plant-based diet index (Satija, Bhupathiraju et al. 2016) and nutrients. 
Regarding exercise within the realm of physical activity, recommendations encourage individuals to engage in daily 30 minutes of aerobic exercise from three to five days a week (Nelson, Rejeski et al. 2007). Exercise recommendations are substantiated on a wealth of information regarding its benefits promote physical and cognitive wellbeing. Specifically, exercise is a fundamental player in metabolism and energy balance and is split into two main categories: strength and endurance. Strength training is differentially known to boost muscle growth and overall promote muscle health. In aging individuals, light strength training is often recommended due its potential to counteract muscle-degenerating conditions and even lead to significant muscle growth (Guizelini, de Aguiar et al. 2018). Regarding endurance training, there is substantiating evidence pointing towards improved cardiovascular adaptations due to increased oxygenation and improved energy utilization due to mitochondrial biosynthesis (Lundby and Jacobs 2016). These adaptations have also been proved in older adults, hence their inclusion in the recommendations (Müller, Izquierdo et al. 2020). The Dutch health exercise guidelines further recommend adults to engage in resistance exercise at least twice a week (Gezondheidsraad 2017). In addition to promoting physical functionality, exercise also promotes cognitive wellbeing in older adults. Namely, physical activity in older adults improves general cognition as well as memory and motor control. Physical activity is an essential component in both physical and cognitive wellbeing, especially in aging adults, and warrants further research.
As opposed to diet, the effect of exercise on the gut microbiome and henceforth gut-muscle axis in older adults is less researched. Two predominant studies recently investigated the compositional changes in the gut microbiome due to exercise. Zhu et al. suggested that pathogenic bacteria significantly decrease in healthy older individuals after an exercise-based intervention, in addition to overweight and obese older individuals adopting a healthier microbiome profile (Zhu, Jiang et al. 2020). Contrarily, Taniguchi speculated that changes in the gut microbiome due to an intervention are less notable in older adults. The most significant change was the reduction of a specific pathogenic strain, which was correlated to visceral fat loss induced by the intervention (Taniguchi, Tanisawa et al. 2018). The physiological reasons for a decreased evident change in gut microbiome in the older population versus the younger populations may lie behind the gut-muscle axis. It is essential to elucidate the link between physical activity and gut microbiome changes to promote healthy aging.
The ageing population is a major public health challenge of our time, with non-communicable diseases being the main reason for mortality and loss of healthy life years. Previous studies support the notion, that the gut microbiome is subjected to changes over the ageing process, especially among those with impaired health status (An, Wilms et al. 2018). As it has been found that biological age is associated with a decrease in stool biodiversity, we suggest to take in consideration determinants of biological age, for example in form of a metabolic age score and blood metabolites (Maffei, Kim et al. 2017, Akker, Trompet et al. 2020). However, the role of lifestyle, diet and physical activity on alterations to the human gut microbiome, cognitive and physical health as well as their interactions are still unclear. The use of the LifeLines observational cohort study allows us to study the different aspects of plant-based nutrition and the gut-muscle axis by clustering gut metabolic profiles in relation to diverse health parameters in a longitudinal setting. The observed changes due to aging may validate the benefits of physical activity to promote and maintain health in older adults. As effects of lifestyle on the microbiome may mostly be visible long-term, it is sensible to assess these associations in a long-lasting cohort study (Pellanda, Ghosh et al. 2021). The intended research with the database will substantiate the central role of the microbiome in the axis and further promote the need for holistic interventions for older adults. Further research into individuals’ unique microbiome profile will pave the way to tailored and effective interventions and therefore contribute to improve health and quality of life in the older population.