Myokines as mediators of exercise-induced cognitive changes in older adults: protocol for a comprehensive living systematic review and meta-analysis

BackgroundThe world’s population is aging, but life expectancy has risen more than healthy life expectancy (HALE). With respect to brain and cognition, the prevalence of neurodegenerative disorders increases with age, affecting health and quality of life, and imposing significant healthcare costs. Although the effects of physical exercise on cognition in advanced age have been widely explored, in-depth fundamental knowledge of the underlying mechanisms of the exercise-induced cognitive improvements is lacking. Recent research suggests that myokines, factors released into the blood circulation by contracting skeletal muscle, may play a role in mediating the beneficial effect of exercise on cognition. Our goal in this ongoing (living) review is to continuously map the rapidly accumulating knowledge on pathways between acute or chronic exercise-induced myokines and cognitive domains enhanced by exercise.MethodRandomized controlled studies will be systematically collected at baseline and every 6 months for at least 5 years. Literature search will be performed online in PubMed, EMBASE, PsycINFO, Web of Science, SportDiscus, LILACS, IBECS, CINAHL, SCOPUS, ICTRP, and ClinicalTrials.gov. Risk of bias will be assessed using the Revised Cochrane Risk of Bias tool (ROB 2). A random effects meta-analysis with mediation analysis using meta-analytic structural equation modeling (MASEM) will be performed. The primary research question is to what extent exercise-induced myokines serve as mediators of cognitive function. Secondarily, the pooled effect size of specific exercise characteristics (e.g., mode of exercise) or specific older adults’ populations (e.g., cognitively impaired) on the relationship between exercise, myokines, and cognition will be assessed. The review protocol was registered in PROSPERO (CRD42023416996).DiscussionUnderstanding the triad relationship between exercise, myokines and cognition will expand the knowledge on multiple integrated network systems communicating between skeletal muscles and other organs such as the brain, thus mediating the beneficial effects of exercise on health and performance. It may also have practical implications, e.g., if a certain myokine is found to be a mediator between exercise and cognition, the optimal exercise characteristics for inducing this myokine can be prescribed. The living review is expected to improve our state of knowledge and refine exercise regimes for enhancing cognitive functioning in diverse older adults’ populations.RegistrationSystematic review and meta-analysis protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on the 24th of April 2023 (registration number CRD42023416996)

Jėgos treniravimas ir raumenų-smegenų sąveika: smegenų silpimo pasekmės senėjimo ir nugaros smegenų sužalojimo atvejais.

Cognitive decline is inherent to aging [1]. It can manifest in various ways, including concentration difficulties, disorientation, slower information processing, frequently being unable to recall things, absent-mindedness, or forgetfulness, while the ability to use previously acquired knowledge, skills, and experiences generally remains intact [2]. Depending on individual and environmental factors, cognitive aging will sooner or later lead to a need for assistance [3]. Some major risk factors include educational level, physical inactivity, obesity, type 2 diabetes mellitus, smoking, high blood pressure, alcohol use, brain trauma, depression, air pollution, hearing loss, and social isolation. It is estimated that the prevalence of dementia could be reduced by 40% at the population level by eliminating these risk factors [4]. However, worldwide, the opposite trend is occurring. For example, the prevalence of physical inactivity increased by 5% between 2005 and 2017 [5], type 2 diabetes mellitus increased by 50% between 1990 and 2015 [6], and the prevalence of obesity rose by 300% between 1975 and 2014 [7]. A 2013 research article estimated that by 2025, the current healthcare system would no longer be able to provide necessary care due to the aging population and an increase in individuals living with chronic diseases if no additional efforts are made in prevention [8]. Exercise plays an important role in maintaining good physical and mental health. It has positive effects on nearly every body system, including the brain [9]. An improvement in cognitive functions has been confirmed in an impressive number of studies involving participants of all ages [10][11][12]. Despite this knowledge, which has been around for decades, there remains uncertainty and a lack of consensus on the underlying mechanisms [13]. An interesting finding was made in 2003 by Bente Pedersen’s research group in Denmark. They discovered that the cytokine interleukin-6 (IL-6) was released by muscle cells during contractions, triggering signaling cascades in other organs, and they called it a ‘myokine’ [14]. It later became clear that during exercise, thousands of factors enter the bloodstream from almost all body systems, each with its own local and/or systemic effects. These exercise-related factors were called ‘exerkines’ [15]. Only a limited number of these exerkines are known to have effects on the brain or to be associated with cognitive changes after exercise [16]. The function of most exerkines remains unknown. The primary goal of this dissertation was to gain more knowledge and understanding of the role of exerkines in promoting brain health and cognitive function after exercise in older adults. Research into the role of exerkines, and the mechanism underlying the effect of exercise on cognitive functioning in general, is essential for developing evidence-based exercise programs aimed at preventing age-related cognitive decline. For our intervention studies, we chose resistance training, as more research has been conducted on endurance training up till now, while some researchers argued that myokines might be released to a greater extent after resistance training compared to endurance training [17]. In addition, research was conducted on individuals with spinal cord injuries. In this population, neuromuscular electrical stimulation was chosen as an intervention, as it may release even higher amounts of myokines than resistance training [18][19]. In Part I of this dissertation, a literature review was conducted on the effects of exerkines on neuroplasticity. In the first study (Chapter 1), we detailed the signaling cascades activated by 16 exerkines with known (in)direct effects on long-term synaptic potentiation (LTP) [20]. LTP is a form of neuroplasticity at the level of the synaptic connection between two nerve cells. In these synaptic connections, a chemical reaction occurs that leads to the transmission of a nerve impulse from one nerve cell to the next. To reach the threshold at which a new nerve signal is generated in the following nerve cell, the chemical signal must be sufficiently strong. LTP increases the chemical signal released by the pre-synaptic nerve cell and lowers the threshold for transmitting the signal in the post-synaptic nerve cell [21]. Although the described signaling cascades are based on animal research, they can be seen as an indication of the neurobiological effects of exerkines at the molecular level. Therefore, this knowledge forms an important theoretical background for research into the effects of exerkines. Additionally, we described changes in exerkine levels in circulation after exercise from human studies and in the brain, primarily from animal studies. Overall, we can state that exerkines with neurotrophic or anti-inflammatory effects increased after a single session of exercise (acute exercise) and after exercise over several weeks (chronic exercise). Exerkines with pro-inflammatory effects also increased after acute exercise but decreased after chronic exercise. Thus, sustained exercise appears to have a neurotrophic and antiinflammatory effect, mediated by changes in exerkines. It is important to note that the effect of exercise depended on various influencing factors, such as the type of exercise (resistance training, endurance training, multimodal training, mind-body training, balance exercises, etc.), the intensity and duration of the training, or the volume of the exercise program, as well as weight loss associated with the intervention, age, gender, or comorbidities of the study participants. In a second article (Chapter 2), we described the protocol for a future literature review with meta-analysis [16]. In this review, we aim to systematically map the current state of knowledge regarding the role of myokines in cognitive functioning in older adults and, if possible, conduct an analysis of the mediating role of these myokines on cognitive functioning. We plan to update this article every six months over a minimum of five years post-publication. To be as comprehensive as possible, we developed a list of 1,126 potential myokines derived from various secretome and transcriptome studies on human skeletal muscle. After an initial literature analysis, we included 33 studies in the meta-analysis. The results are currently being analyzed. Part II of this dissertation contains the results of a cross-sectional analysis we conducted to investigate the relationship between baseline exerkine levels and signs of brain aging [22][23]. More specifically, we assessed the levels of inflammatory (interleukin-6, IL-6; kynurenine) and neurotrophic (insulin-like growth factor-1, IGF-1) factors in the blood of older adults and looked for associations with neurometabolic signs of neuroinflammation and neurodegeneration, as well as gray matter atrophy in the brain (Chapter 3). We then analyzed the influence of participants’ personal characteristics on blood factors and markers of brain aging (Chapter 4). Based on previous research, we specifically tested whether age, global cognition, body fat percentage, or characteristics of sarcopenia (muscle strength, muscle volume, and physical performance) in older adults were related to the levels of neurotrophic or inflammatory factors in the blood, total gray matter volume in the brain, and neurometabolic status and gray matter volumes of five selected brain regions [23]. We found the following: Older adults with underweight or obesity had lower total brain volumes. Additionally, lower handgrip strength was associated with lower total brain volumes. Furthermore, older adults with lower handgrip strength had lower levels of N-acetylaspartate in two of the five measured brain regions, the dorsal posterior cingulate cortex and the dorsolateral prefrontal cortex. Lower levels of this neurometabolite may indicate that fewer nerve cells are present per volume, a sign of neurodegeneration. Finally, lower handgrip strength was associated with higher levels of kynurenine in blood serum [23]. Higher kynurenine levels in blood serum were also associated with neurometabolic changes consistent with neuroinflammation and neurodegeneration [22]. This suggests that handgrip strength and kynurenine may potentially serve as proxy measures for assessing brain health [22][23]. Part III of this dissertation presents the results of our intervention studies in older adults. We investigated whether a lower-body resistance training intervention could influence circulating blood factors (IL-6, kynurenine, and IGF-1), neurometabolites related to neurodegeneration and neuroinflammation, subregional gray matter volume in the hippocampus, or cognitive performance in older adults, and whether there were relationships between changes in these outcomes in the intervention group. In the first intervention study (Chapter 5), we compared cognitive changes immediately after a single high-load resistance training session with a control group [24]. Cognition was tested using three computerized cognitive tasks and a balance-cognition dual-task [24]. In the dual-task, participants were asked to maintain balance while standing in tandem Romberg position on a force plate, while simultaneously solving a math problem. In this study, we confirmed that even a single session of resistance training led to immediate improvements in working memory. This acute effect of exercise has been found in other studies and generally lasts for 15-60 minutes. In a second intervention study (results are presented in Chapters 6 and 7), we evaluated the effect of a twelve-week moderate-tohigh-intensity resistance training intervention in seventy older adults with either intact cognitive function or an elevated risk of mild cognitive impairment (MCI) [25][26]. We discovered that older adults at higher risk of MCI had higher kynurenine levels and lower subiculum volumes (a part of the hippocampus) compared to cognitively healthy adults. We observed a non-significant increase in IL-6 levels and in total N-acetylaspartate levels in the hippocampus and a reduction in age-related decline of the gray matter volume of the dentate gyrus of the hippocampus, with a moderate effect size. The findings for hippocampus volume suggested that the intervention group experienced prevention of further volumetric loss rather than improvement. We can speculate that the effects might have been significant if the intervention had lasted longer. It is estimated that an intervention period of at least 6 months is necessary. This will need to be confirmed in future research. Finally, our results showed improvements in the Go/No-go test in the intervention group compared to the control group, but this effect depended on the cognitive status of the older adults and was only significant in those at high risk for MCI. The Go/No-go test is a cognitive inhibition test in which participants must respond as quickly as possible to a ‘Go’ signal, but withhold a response to a ‘No-go’ signal. It is a component of executive functioning. The twelve-week intervention study with older adults took place during the COVID-19 pandemic, which caused additional challenges in recruiting participants and continuing the experiments. Some older participants decided to withdraw from the experiment or had to stop due to illness. It is important to note that an infection with the COVID-19 virus (SARS-CoV-2) may have neurological consequences, which could have potentially affected our results. We had the opportunity to make a unique comparison of pre- and post-COVID-19 structural and neurometabolic brain measurements in three participants (Chapter 8) [27]. In this case series, we discovered neurometabolic changes in the hippocampus that could indicate neuroinflammation immediately after recovery from COVID-19. Finally, our research findings showed increased hippocampus volume in the experimental participants with COVID-19. In contrast with our statement above that hippocampal volume did not change in experimental group, at group level, but rather decreased in controls, this may indicate that on an individual basis some participants did show increases in volume following resistance exercise and this was not influenced by COVID-19. Part IV of this dissertation contains all studies related to individuals with spinal cord injuries. Chapter 9 consists of a literature review, in which we suggested that there is accelerated age-related cognitive decline in this population, likely caused at least in part by a chronic neuroinflammatory response originating from the location of the spinal cord injury [28]. Based on our previous findings and knowledge from older adults, we hypothesized that the anti-inflammatory and neurotrophic effects of exercise could prevent or delay cognitive decline in individuals with spinal cord injuries. However, a systematic review of this topic did not yield any intervention studies evaluating the relationship between exercise and cognition in this population [28]. Therefore, we conducted our first intervention study (Chapter 10) aimed at evaluating the acute effects of muscle training with low- or high-intensity neuromuscular electrical stimulation on lactate levels, IGF-1 levels, and information processing speed [29]. The study had a crossover design. We found that lactate increased significantly after both interventions. Lactate has previously been shown to have positive direct and indirect effects on neuroplastic processes in the brain [30][31]. However, we did not find a significant increase in IGF-1 or significant improvement in information processing speed. Additional findings showed that a longer time since the spinal cord injury was associated with smaller changes in IGF-1 in the low-intensity group, and a higher injury level was associated with smaller improvements in information processing speed. Using this information, we ultimately designed a new intervention study with a chronic (12-week) intervention using neuromuscular electrical stimulation (Chapter 11). This research is currently ongoing at Maastricht University, Netherlands, but the protocol for this study is included in this dissertation [32]. In conclusion, there is neuroscientific evidence for an effect of exerkines on synaptic plasticity in animal studies [1]. This suggests that exerkines may, at least in part, mediate the positive effects of exercise on cognitive functions. Elevated serum kynurenine levels and decreased handgrip strength are potential markers of brain aging in older adults. Older adults should aim for a healthy body fat percentage, as both underweight and obesity were associated with brain volume loss. Both a single session and a twelve-week resistance training intervention have positive effects on executive functioning in older adults, as demonstrated by a working memory task in healthy older adults and a cognitive inhibition task in older adults with high MCI risk, respectively. Increases in IGF-1 in the exercise group and IL-6 in the total group were associated with improvements in working memory. However, these findings need to be confirmed in larger and longer-duration studies. From the final part of this dissertation, we can conclude that individuals with spinal cord injuries experience accelerated cognitive aging, which may be partly caused by chronic neuroinflammation. To date, there are no studies that have examined the effects of exercise on cognitive functions or brain health in this population. We conducted a pilot study where the intervention consisted of a single session of neuromuscular electrical stimulation. We found an increase in lactate but no changes in IGF-1 or cognitive performance on an information processing speed test. Based on all that I have learned during the preparation of this dissertation, I would advise everyone to choose multimodal physical exercise in a motivating and enjoyable setting, so that exercise can be sustained throughout life and help prevent or mitigate cognitive aging