Due to several advances in medicine over the past 200 years, allied to improvements in nutrition, sanitation, housing and working conditions, human life expectancy increased dramatically across the globe. However, this increased life expectancy has not been accompanied by a comparable increase in healthspan (considered here as the period of life free from age-associated disease). As a result of living longer, a greater proportion of us will develop age-related chronic diseases (e.g. cardiovascular disease, dementia, type 2 diabetes, sarcopenia), with several lifestyle, social and psychological factors influencing the trajectory of disease development and severity (Shiels et al., 2019). Notably an estimated two-thirds of people over 65 years of age suffer from two or more of these age-related diseases, referred to as the multi-morbidities of ageing (Figueira et al., 2016). It is well established in both model and non-organisms that a range of environmental, pharmacological and genetic interventions can extend lifespan and preserve physiological function and homeostasis in old age (Gems & Partridge, 2013; Green et al., 2022). A large and growing body of evidence also establishes that physical exercise is a powerful practice that can target and decrease many of the mechanisms that drive cellular ageing (Carapeto & Aguayo-Mazzucato, 2021; Chen et al., 2021; Garatachea et al., 2015). Experimental models of lifelong exercise establish protection against pro-ageing inflammatory processes, multiple types of cancer (Nilsson et al., 2019) and signs of frailty associated with ageing (Garcia-Valles et al., 2013). Importantly, it seems that even leisure time physical activity adopted as a practice during mid-life is associated with longer life expectancy (Moore et al., 2012). In this special issue of The Journal of Physiology we are delighted to showcase a range of topical reviews and research articles that followed an online symposium, ‘Can exercise prevent the age-related decline in adaptive homeostasis? Evidence across organisms and tissues’, organised by The Physiological Society on 12 October 2021. This issue is truly multidisciplinary and translational, addressing important questions about healthspan using molecular, cellular and tissue level approaches, in model organisms and in humans. The authors discuss how ageing deleteriously impacts multiple physiological processes and pathways, and how we can use exercise and other interventions to mitigate this age-related dyshomeostasis. In the following pages we summarise highlights from each of these papers. In the first paper from this special issue, ‘Drugs, clocks and exercise in ageing: hype and hope, fact and fiction’, Furrer and Handschin discuss pharmacological interventions that show promise in modulating the ageing process and are potentially able to improve late-life health and wellbeing (Furrer & Handschin, 2023). Critically, these authors help to separate fact from fiction for a topic that can be confusing for both experts and non-experts and has, at times, been susceptible to hyperbole and sensationalism. They then compare these pharmacological interventions to non-pharmacological interventions, most notably exercise and general activity. This is an incredibly timely and comprehensive review that then goes on to discuss barriers in the development of anti-ageing pharmacologics and how we may overcome these barriers to design realistic and effective novel intervention strategies to improve late-life health in humans. In the paper ‘Exercise-induced modulation of neuroinflammation in ageing’, Barad, Augusto and Kelly discuss age-related disequilibrium within the central nervous system (CNS) and the critical role that inter-organ communication may play in CNS dysfunction, particularly highlighting the role of immune cells (Barad et al., 2023). They assess the evidence showing that endurance exercise can induce adaptive benefits to neuroimmune communications that can help ameliorate homeostatic challenges caused by immunological stresses or ageing. The authors highlight the relevance of glial cells in CNS function and how cellular metabolic programming within different immune cells may increase resilience to age-related dyshomeostasis following exercise. They then explore potential experimental avenues to better understand the mechanistic processes underlying how exercise impacts glial cell function. Finally, the authors discuss a topic of growing concern amongst the scientific community, namely the limitations in the disproportionate use of male animals in fundamental biology research. In their paper ‘The time is now: regular exercise maintains vascular health in ageing women’, Tamariz-Ellermann and colleagues consider the critical role that oestrogen plays in maintaining cardiovascular health in females and how the menopause is associated with a profound decline in cardiovascular health (Tamariz-Ellemann et al., 2023). The authors explore the wealth of evidence demonstrating that regular exercise can help maintain cardiovascular health in women, with positive effects that appear to be strongly associated with exercise-induced activation of the oestrogen-related receptor-α. Timing, as ever, seems important and while initiating exercise around the time of menopause appears be more effective at preserving cardiovascular health than initiating exercise later on, the message is clear, that physical activity at any stage across the life-course is likely to reap multi-systemic benefits. The authors finish with a note of caution, that because countries differ significantly in participation and adherence to regular physical activity programmes, there should not be a ‘one size fits all’ approach when comparing vascular changes following physical activity across different demographics. In the research article ‘Fasting for 20 h does not affect exercise-induced increases in circulating BDNF in humans’, Gibbons and colleagues examine whether brain-derived neurotrophic factor (BDNF) underlies the common neuroprotective benefits observed in ageing rodents and humans following intermittent fasting and exercise (Gibbons et al., 2023). The authors suggest that cerebral metabolic flexibility (switching from glucose to ketone bodies/lactate as a fuel source) induced by these interventions helps maintain brain metabolic function when glucose is limited, but also initiates several signalling pathways critical in maintaining neuronal and synaptic plasticity and function, such as inducing BDNF, thereby helping to maintain cognitive function with ageing. Circulating BDNF (serum-, platelet- and plasma-derived) and cerebral blood flow (duplex ultrasound) was quantified in 12 healthy human participants (6 male, 6 female), employing a cross-over design following (1) 20 h of fasting, (2) light prolonged exercise, (3) short duration, intense exercise, and (4) combined fasting and intense exercise. Surprisingly, fasting did not elevate BDNF levels despite a nine-fold increase in ketone body delivery to the brain. Both light and intense exercise, irrespective of whether the participant was fed or fasted, increased BDNF levels, with the increase being much more pronounced following high intensity cycling. The authors suggest that periodic bouts of intense exercise may be one feasible avenue to boost BDNF production and potentially slow age-related cognitive decline in humans, although as the authors imply, more research is required to better understand the mechanistic underpinnings. For a discussion of Gibbons and colleagues’ study, including notes on potential clinical implications, see the Journal Club article by Decker (2023). The idea that white adipose tissue (WAT) acts only as a relatively inert lipid store has been confined to history, and it is now well established that WAT is a highly plastic tissue that elicits pleiotropic effects on metabolism and health. Vasamsetti and colleagues review the role of visceral adipose tissue (VAT) in cardiovascular health and pathology (Vasamsetti et al., 2023) in their paper ‘Regulation of cardiovascular health and disease by visceral adipose tissue-derived metabolic hormones’. Specifically, the authors focus on bioactive adipokines, such as adiponectin and omentin, synthesized and secreted by VAT into the general circulation and acting on metabolic tissues such as liver and muscle. Some of these adipokines are anti-inflammatory, eliciting beneficial cardiovascular effects associated with an increase in endothelial nitric oxide synthase production, while others such as leptin and resistin can be pro-inflammatory and lead to endothelial dysfunction. The authors discuss how levels of these adipokines change across the life-course and the influence of these changes on metabolic parameters including inflammation, insulin resistance, lipid profiles and cardiovascular dysfunction. The authors finish by highlighting that there are significant knowledge gaps in the actual role of these cytokines in age-related health. In particular, they emphasize the current difficulties in developing effective therapeutic approaches in patients that differ in BMI or that suffer comorbidities such as metabolic syndrome and type 2 diabetes, and consequently present with very different cytokine profiles. While we have known for over 100 years that reduced food intake (caloric restriction) extends lifespan and delays age-related dysfunction, more recently it has become clear that modulating both macronutrients and micronutrients can similarly affect lifespan and health. In a tour de force, Flores, Lamming and colleagues reduced by 67% each of the essential amino acids histidine, lysine, methionine, phenylalanine, threonine and tryptophan individually in the diet of male and female C57BL/6J mice, and examined metabolic health and ageing (Flores et al., 2023). They showed that a 12-week exposure to diets low in threonine, phenylalanine and histidine all decreased adiposity and increased energy expenditure relative to chow fed controls, but that diets low in methionine, lysine or tryptophan had no effect. The authors then went on to show that restricting dietary histidine in mice fed an obesogenic diet also reduced adiposity, elevated energy expenditure and improved a number of metabolic health parameters. Indeed, total body fat in the low histidine diet mice was similar to that of chow fed controls, despite being maintained on an obesogenic diet for a number of weeks. Improvement in glycaemic control, enhanced glucose uptake and reduced hepatic steatosis were also observed in these animals, effects that do not appear to be fibroblast growth factor 21-dependent. The authors also investigated the impact of reduced dietary histidine on lifespan when initiated at 16 month of age in both male and female C57BL/6N mice. No effect of reduced dietary histidine was observed on either frailty or lifespan in either sex but adiposity was reduced in males. Finally, the authors show conservation of these findings in humans, showing a significant positive correlation between dietary histidine and BMI in both males and females. Consequently, this work suggests that modulating dietary histidine may be a new opportunity worth exploring to help combat the global obesity epidemic. It will also be interesting to see if life-long dietary histidine restriction under chow/obesogenic diets can extend lifespan and extend healthspan. For a Journal Club style discussion of this manuscript by Flores and colleagues, please enjoy the paper by Apolinário, Carneiro and Macêdo (Apolinario et al., 2023). Mitochondrial dysfunction and disruptions in protein homeostasis are two well-established drivers of cellular ageing, both likely contributing to musculoskeletal decline with advancing age. In a pre-clinical trial using a unique model of primary osteoarthritis with progressively impaired mobility, Musci and colleagues tested the effects of an oral phytochemical compound for targeting skeletal muscle mitochondrial function and mechanisms contributing to proteostasis (Musci et al., 2023). Treatment with this compound, called PB125, improved several aspects of locomotor muscle mitochondrial respiration. Specifically, the authors observed an increase in electron transfer system capacity, an attenuation of the age-related decline in both coupled and uncoupled mitochondrial respiration in both males and females treated with the dietary supplement. Additionally, the decline in muscle protein synthesis observed in this model with progression of musculoskeletal decline was attenuated in the PB125 treated animals. Treatment-related improvements in these drivers of cellular ageing were also accompanied by maintenance of voluntary mobility. As the authors point out, it will be exciting to identify if this safe dietary supplement, already available for use in humans, improves other important aspects of muscle function and mobility with advancing age including strength, gait and balance. Rahman, Hian-Cheong and Thoms, the authors of a Journal Club article focused on Musci and colleagues’ work, also raise the important point of identifying whether interventions like PB125 help prevent the loss of type II myofibres, a characteristic of muscle ageing in humans (Rahman et al., 2023). It is well-established that exercise alters production of skeletal muscle metabolites and that changes in the muscle metabolome likely play an important role in mediating health benefits. However, there is some evidence to suggest that advancing age alters the beneficial metabolic adaptations enjoyed in youth. In the article ‘Exercise and aging impact kynurenine/tryptophan pathway and acylcarnitine metabolite pools in skeletal muscle of older adults’, Hinkley and colleagues do a deep dive into the human muscle metabolome, testing the hypothesis that the muscle metabolome response to acute exercise is blunted in healthy older adults compared to younger adults (Hinkley et al., 2023). The authors carried our metabolite profiling and phenotyping of muscle biopsies obtained from young active, older active and older sedentary participants prior to and following an acute bout of endurance exercise. They report novel muscle metabolite signatures, some of which involve kynurenine/tryptophan pathway metabolites and acylcarnitines. Muscle kynurenine/tryptophan metabolites were impacted by both age and physical activity, with greater kynurenine in muscle from older humans, and elevations in downstream metabolites kynurenic acid and NAD+ in samples from active participants regardless of age. Acylcarnitines are thought to reflect impaired metabolic health when present in higher concentrations in circulation. Here, acylcarnitines were elevated in exercise-trained muscle of both young and older adults, a finding that the authors posit suggests that muscle may act as a metabolic sink to reduce circulating acylcarnitines. An important take-home message from this study is that the exercise-induced response of a variety of muscle metabolite pools, including acylcarnitine and ketone bodies, was similar among the groups studied here, suggesting that the metabolic benefits of exercise can be achieved in both young older humans. We are grateful to the speakers in our online symposium, who showed great patience to stay with us during significant delays encountered during the pandemic. We thank all the contributors to this special issue, who we believe have produced a seminal collection of papers around the exciting, important and timely topics of ageing, exercise, health and cellular homeostasis. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors declare no competing interests. K.L.H. and C.S. both contributed to the conception of the work, drafted and revised the work. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. No funding was received for this work. We are grateful to The Physiological Society for all their help and support in helping to bring the symposium and the special issue to fruition including Caitlin Oates, Events and Marketing Officer; Sally Howells, Managing Editor; Diana Jones, Peer Review Manager; and the peer reviewers of all of the manuscripts included in this issue.
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