Regular physical activity/exercise (PA/PE) has proven to have indisputable and powerful effects on maintaining health, preventing disease, extending the healthspan and lifespan, and may have implications for resilience (Guasch-Ferré et al., 2022; Moore et al., 2016; Piercy & Troiano, 2018; Scully et al., 1998). Although the terms physical activity and exercise are often used interchangeably, PA is considered as any bodily movement that results in energy expenditure. Currently, the COVID-19 pandemic continues to present significant challenges to health and resilience (Torales et al., 2020; Trabelsi et al., 2021). Recent findings show that consistently not meeting PA guidelines during the years preceding the pandemic is a strong risk factor for severe COVID-19 complications, including hospitalisation, admittance to the intensive care unit, and even death (Sallis et al., 2021). The effects of PA on fostering resilience should not be understated, yet significant knowledge and study design gaps remain. As is described in the current Special Issue, the Trans-NIH Resilience Working Group defines resilience as a system's capacity to recover, recover better, adapt, or resist perturbation from a challenge or stressor. Physical activity, as a multidimensional health behaviour that engages a constellation of health-promoting biological pathways, networks, and mechanisms, may facilitate this capacity. From molecular, cellular, and physiological levels of analysis, this brief report elucidates some of the processes and mechanisms involved in association with PA and resilience outcomes in response to physiological, psychosocial, and health-related stressors. Additionally, our study design analysis revealed four critical design features that would be imperative for future investigations to include to be considered a resilience study (see Table 1; Trans-NIH Resilience Working Group, n.d.). First, study designs must include a stressor or a proxy for a stressor to identify the biological responses before and after stressor exposures and their modulation by acute, chronic, or intermittent PA/PE to establish causal associations between PA/PE and resilience outcomes. Second, metrics and measurements should be developed and validated to capture changes that strengthen and empower an individual's psychological, physiological, and molecular capacity to be resilient. Third, there is much heterogeneity in the design and implementation of PA/PE interventions. The field would benefit from identifying the specific components of PA/PE interventions that confer resilience and/or drive molecular/cellular changes that enhance efficacy/effectiveness. Furthermore, future research would benefit by a clear and consistent operationalisation of resilience and subsequent design of studies that clarify the resilience outcomes evoked from a molecular/cellular/physiological level of analysis. These, and other recommendations, are described in detail and could stimulate more harmonious future research to enhance our understanding of PA as a modifiable resilience factor for health promotion and disease prevention. The benefits of PA have been identified at least partially to be mediated by exerkines, a family of signalling moieties including cytokines, nucleic acids, lipids, and metabolites that exert their effects through autocrine, paracrine, and endocrine pathways in response to exercise (Chow et al., 2022). The NIH Common Fund-supported Molecular Transducers of Physical Activity Consortium (MoTrPAC) (Sanford et al., 2020) is a national research initiative designed to discover and characterise the molecular transducers, including exerkines, that mediate the effects of exercise in humans and animal models. MoTrPAC has several design features that could be applied to appropriately investigate resilience, although by itself it cannot be considered a resilience study (see Table 1). In both humans and animals, this initiative collects and analyzes changes across multiple time points in muscle, adipose tissue, and plasma metabolites, which may identify exerkines or a panel of exerkines that mediate the role of PA on health and disease prevention. Future investigations could leverage this panel of exerkines to design studies in which there is a stressor or stressor proxy to clarify PA/PE-induced exerkine changes and corresponding associations with resilience. In skeletal muscle, the stimulation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) results in increased insulin sensitivity, glucose uptake, glycolysis, fatty acid oxidation, and mitochondrial biogenesis, while decreasing energy-consuming processes such as glucose and lipid production to meet energy demands (Spaulding & Yan, 2022). Senile skeletal muscle insulin resistance associated with skeletal muscle dysfunction may be partially prevented and/or treated by PA (Shou et al., 2020). Similarly, one study showed that increased cytoplasmic calcium levels, as occur during muscle contraction, also can directly activate the calcium–calmodulin-dependent protein kinase II (CaMKII) (Rose & Hargreaves, 2003). CaMKII has been associated with increased glucose uptake, glucose transporter protein 4 gene expression, mitochondrial biogenesis, and lipid metabolism (Joseph et al., 2021a, 2021b). However, numerous design elements preclude these studies from being considered resilience investigations (Table 1). Skeletal muscle holds enormous plasticity that responds to its contractile activity, nutritional levels, hypoxia, or DNA damage. Increased PA or heavy work results in a compensatory increase in muscle size (hypertrophy) and strength. The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine threonine protein kinase of the PI3K family. Extensive research has established that mTORC1, an mTOR form of protein complex, plays a central role in muscles of promoting protein, lipid, and nucleotide synthesis required for cell growth (Schiaffino et al., 2021). mTORC1 also facilitates cell growth by promoting a shift in glucose metabolism from oxidative phosphorylation to glycolysis and by suppressing protein catabolism. Deregulated mTOR signalling is implicated in the progression of cancer, diabetes, and ageing processes (Saxton & Sabatini, 2017). The decreased muscle mass in old age is a risk factor for frailty, falls, and fractures. The role of PA in promoting muscle growth is particularly important in enhancing resilience and preventing sarcopenia in the increasing ageing population. Sarcopenia starts developing earlier in life and accelerates after age 50. Nutrition high in proteins and resistance exercises can delay, prevent, and even partially reverse it with a positive impact on the incidence of disability (Cruz-Jentoft, 2019). Although much research has focussed on responses to acute PA/exercise in skeletal muscle, it is important to note that the entire body—that is, all organ systems—are impacted by acute bouts and long-term PA/PE. For instance, the improved cardiac and vascular function associated with habitual patterns of PA contributes to increased aerobic capacity and is protective against risks of cardiovascular disease. Further research is needed in other tissues and organ systems. When properly designed, this research would provide further insights into the molecular mechanisms of how PA stimulates systemic adaptation and enhances resilience. PA increases cellular energy demands, which directly activate exercise responsive signalling molecules such as AMPK. AMPK is considered a primary cellular energy sensor in response to an increase in the ratio of AMP to adenosine triphosphate (ATP) and a key regulator of cellular energy homoeostasis and metabolism (Herzig & Shaw, 2018). In addition, increased energy demand requires an adequate supply of nutrients and an uncorrupted capacity to produce ATP. The effect of ageing on ATP-generating pathways such as hydrolysis of phosphocreatine, oxidative phosphorylation, and anaerobic glycolysis is not entirely understood (Lanza et al., 2005). Because mitochondria are the main source of ATP and its function is impaired in elderly (Fang et al., 2021), the type and amount of exercise in this population needs to be thoroughly evaluated using rigorous study designs. PA/PE induces cellular metabolism and results in systemic adaptation through many metabolic signalling molecules. For example, PA positively affects the expression and/or activity of the evolutionarily conserved nicotinamide adenine dinucleotide (NAD+) dependent lysine deacetylases, sirtuins, in various tissues, resulting in increased mitochondrial biogenesis, oxidative metabolism, and the cellular antioxidant function (Dali-Youcef et al., 2007). The most studied sirtuin, SIRT1, is a transcription factor associated with innumerable physiological processes and is often referred to as a master metabolic regulator. SIRT1 has been demonstrated to promote DNA stability and regulate many critical cellular and endocrine functions that are essential for resilience, including protecting the organism from oxidative stress, enhancing cellular resilience, and decreasing metabolic abnormalities, therefore reducing cardiovascular diseases, cancer, neurodegenerative diseases, and ageing processes (Grootaert & Bennett, 2022; Pinches et al., 2022; Schug & Li, 2011). These PA-induced responses, such as the synchronously decreased energy-consuming and increased energy supply and increased cellular metabolism described above, compel the body to change to meet biological challenges. Regular PA enables and increases the body's ability to adapt to physical demands; induces positive physiological, psychological, and mental progresses; and results in whole-body systemic adaptation. Consequently, it protects the body against the effects of stressful events and enhances the overall resilience. The systemic adaptation process is mediated through many metabolic and molecular signalling molecules. Yet, we understand little of their identities and the responsible mechanisms. Their discovery would be essential to better understand the PA-induced adaptation processes and whether they can be exploited therapeutically to promote resilience. Another potential aspect of PA in resilience is enhancing autophagy, an intracellular recycling process of long-lived proteins and damaged organelles. Autophagy is known to be one of the crucial cellular functions that sustain cellular homoeostasis and promote longevity. Defective autophagy is associated with a variety of diseases (Klionsky et al., 2021; Wang et al., 2020), and autophagic activity declines naturally with age (Wong et al., 2020). PA enhances acute autophagic activity in multiple tissues, such as skeletal muscle, adipose tissue, heart, and brain (Escobar et al., 2019). It is crucial that during exercise, autophagy clears the proteins and organelles damaged by physical stressors such as hypoxia (Moberg et al., 2022), severe energy deficiency (Martin-Rincon et al., 2019), and ageing (Estébanez et al., 2019; Mejías-Peña et al., 2016) to prevent the buildup of these components and maintain cellular function (Table 1). Moreover, the alterations in AMPK activity, calcium, NAD+, and reactive oxygen species levels during PA also are strong stimulators of the autophagic activity (Escobar et al., 2019). A wealth of evidence indicates that PA has the potential to regulate autophagy through a bidirectional process and reduce the risk of cardiovascular disease caused by either insufficient or excessive autophagy (Wang et al., 2020). Advancement of this knowledge could help us understand further the mechanisms of autophagy activation and give rise to potential means to increase cell survival, resilience, and new therapeutic targets. PA targets ageing through many of the same conserved longevity pathways. Ageing is a natural biological process characterised by a gradual decline in metabolism, loss of normal physiological function, and increased susceptibility to diseases (López-Otín et al., 2013), and thus may be considered a health-related stressor itself. A large body of evidence indicates that ageing and age-related diseases are tightly associated with an imbalance in energy supply and demand (Kennedy et al., 2014). PA is one way to alleviate this imbalance and delay key aspects of ageing by regulating, at least in part, mitochondrial physiology via a network of signalling pathways (e.g., the AMPK, CaMKII, and SIRT1) to enhance respiratory capacity and endurance and restore the energy homoeostasis. Reductions in mitochondrial quality and increased production of ATP and aerobic respiration rate are thought to decrease cardiorespiratory fitness (CRF) (Seo et al., 2016)—a known risk factor for cardiovascular disease and premature mortality. In an appropriately designed resilience study (Table 1), short-term, high-intensity interval training improved CRF in community-dwelling older adults (Sian et al., 2022). Additional robustly designed investigations are needed and could provide therapeutic tools for preventing or defying ageing. Physical activity lowers the risk of numerous cancers (Moore et al., 2016), yet its explicit association with cancer-related resilience is less clear. An emerging body of evidence with strong resilience study designs (Table 1) suggests that PA can reduce the risk of colorectal cancer through gut microbiota by relieving constipation—a condition that can pose a significant amount of stress (Mancabelli et al., 2017; Roberts et al., 2003). A combination of PA with lactobacillus supplementation may help alleviate infrequent bowel movements in the elderly (Aoyagi et al., 2019). Studies in human and animal models have shown that exercise-induced changes in hormonal level, inflammation, and immune cell function (natural killer and T cells) play a central modulatory function in reducing tumourigenesis (Pedersen et al., 2016). It is conceivable that lifelong engagement in PA/PE would reveal differential effects on health in different individuals. It may also guide optimal prescriptions of exercise as an overall ageing-related disease prevention strategies. A growing body of evidence suggests that PA/PE promotes central nervous system health and prevents neurodegenerative disease (Pedrinolla et al., 2017). A well-designed study provided causal evidence of associations between PA and resilience outcomes as a function of microglial homoeostasis in humans (Casaletto et al., 2022). Participants underwent actigraphy monitoring and a series of cognitive tests during life. At autopsy, a comprehensive neuropathological evaluation with brain tissue quantified microglial markers. Physical activity-related resistance to cognitive decline was highest in those with the greatest amount of neurodegenerative-related microglial activation, suggesting that PA engages a resistance mechanism in those at greatest risk. Another study extends these findings, revealing that older adults with high tau neural protein concentrations who engaged in medium to high levels of PA exhibited a slower rate of cognitive decline over a 3-year period (Desai et al., 2021), although the relevance and definition of resilience in this study could have been made clearer (Table 1). Overall, the current understanding of the molecular mechanisms evoked by PA shows that PA/PE induces numerous metabolic and cellular adaptations such as altered gene transcription and translation, epigenetic modifications, increased muscle oxidative capacity and mass, and improved cardiovascular and respiratory function over time. These examples of molecular and cellular adaptations occur in many vital tissues and organs, such as heart, vasculature, brain, adipose tissue, liver, gut, and the immune system (Febbraio, 2017; Gao & Galis, 2021; McGee & Hargreaves, 2020). Yet, the molecular underpinnings of PA/PE-induced whole-body adaptations and the variability in PA-induced resilience outcomes remain poorly understood. The MoTrPAC initiative and its infrastructure should make significant contributions to the existing literature concerning on the molecular processes underlying PA/PE-induced benefits and adaptations (Lavin et al., 2022; Sanford et al., 2020). Yet, individual differences in exercise response, as well as the optimal regime for each individual to support and sustain health and resilience remains unclear. In addition, not all individuals are able to equitably benefit from exercise due, in part, to physical disabilities or barriers in the lived environment, such as inaccessibility to sidewalks and hiking trails or unsafe neighbourhoods. As MoTrPAC and other future studies continue to establish a comprehensive map of the molecular networks and gene expressions evoked during PA, these biological substrates could be leveraged in future studies designed to prevent or resist injury, accelerate healing and recovery, and facilitate the development of personalised predictive models to guide training and treatment of enhancing resilience in people with different ability levels. In summary, the potential associations between PA/PE and resilience could reveal new therapeutic approaches and/or targets to enhance the body's ability to recover, adapt, and thrive in response to challenges and guide the prevention and treatment of a wide range of acute and chronic conditions. Nevertheless, the scientific appreciation of the molecular outcomes of PA and their associations with resilience remains in nascent stages. Significant effort should be devoted to the careful design of studies seeking to elucidate the biological mechanisms evoked by PA and its association with resilience outcomes as defined in this Special Issue. It is only then that we can equitably implement successes from PA/PE-resilience trials into more applicable, achievable, and precise interventions to reduce the incidence and prevalence of chronic diseases and enhance resilience, successful ageing, and optimised health for all. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Institutes of Health (NIH) or the U.S. Department of Health and Human Services. The authors have no conflicts of interest to disclose related to this manuscript. Data sharing is not applicable to this article as no new data were created or analysed in this study.
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