The Role of Physical Activity in Physical and Mental Health

Physical activity (PA) is any activity in which we use muscle force to produce movement, leading to an energy expenditure above the basal metabolic rate. Engaging large muscle groups results in higher energy expenditure and has a greater effect on the musculoskeletal, respiratory, and cardiovascular systems. Motor activity is a broader concept, representing the total amount of motor actions a person performs daily such as drawing, writing, or brushing teeth. Motor culture refers to the arsenal of sports-related motor habits, skills, and associated motor abilities. It is important to distinguish between physical activity and physical exercise, as these terms are often used interchangeably. Exercise is a subcategory of physical activity in which movement is planned and structured with the goal of improving or maintaining physical fitness [1]. Physical exercise consists of three key components: strength, aerobic efficiency, and stability (endurance). When engaging in physical activity, it is necessary to work on improving all three of these components. Physical activity is generally considered in two aspects: basic physical activity and health-enhancing physical activity. Basic physical activity includes all low-intensity daily activities such as standing, slow walking, or carrying light objects. Individuals whose physical activity is limited to these types of activities are categorized as physically inactive or sedentary. It is well known that 77% of the U.S. population lacks sufficient physical activity in their daily routine [2]. Any form of physical activity that benefits health without causing harm is termed health-enhancing physical activity. This may include sports, but they are not a mandatory component. Certain professions, such as construction or agriculture, involve physical activity sufficient to achieve health benefits. The volume of physical activity is determined by three factors: frequency, intensity, and duration. Frequency is measured over a period (e.g., once per week), while duration and intensity depend on individual capabilities. Peak aerobic fitness, measured as VO2 max, is the most reliable indicator of physical fitness and longevity [3]. VO2 max represents the maximum rate at which an individual can utilize oxygen. It is measured when a person performs physical exertion at their upper limit. The more oxygen the body can use, the higher the VO2 max. At rest, approximately 300 mL of oxygen per minute is required to generate enough ATP. During physical activity, this need increases to 3000 mL/min or more. The more trained an individual is, the more oxygen they can utilize for ATP production, making them more functional and resilient. This parameter is crucial not only for athletes but also for overall longevity. Studies show that poor cardiorespiratory fitness carries a relative risk of mortality comparable to that of established cardiovascular risk factors. Numerous studies have found that individuals who engage in regular exercise live up to a decade longer than those with a sedentary lifestyle [4]. The benefits of any amount of physical activity, even minimal, increase with greater engagement.

The functions of skeletal muscles include generating movement, maintaining body posture, regulating body temperature, and stabilizing joints. Skeletal muscle is also an endocrine organ [5]. Under different physiological conditions, the skeletal muscle secretome (the myokines secreted by muscles with autocrine, endocrine, and paracrine functions) contains subgroups of 654 different proteins, as well as lipids, amino acids, metabolites, and small RNAs. The secretome is released from skeletal muscle cells into the interstitium of the skeletal muscles or into the bloodstream, where it can be detected at measurable plasma concentrations. The secreted proteins often have endocrine effects [6]. The skeletal muscle secretome is influenced by physical exercise. Williams and colleagues studied biopsy samples from the vastus lateralis muscle of eight sedentary 23-year-old Caucasian men. Biopsies were taken before and after a six-week endurance exercise training program. The exercise regimen consisted of pedaling on a cycle ergometer for one hour, five days a week, over six weeks ("The skeletal muscle-specific proteome," The Human Protein Atlas). Out of 13,108 genes expressed in muscles, 641 genes were activated following endurance training, while the expression of 176 genes was suppressed. Of the 817 genes whose expression changed, 531 were identified as part of the skeletal muscle secretome. Since many of the genes regulated by exercise were found to be associated with the secretome, this suggests that a significant portion of the effects of exercise is endocrine rather than metabolic. The main pathways influenced by secreted exercise-regulated proteins are related to cardiac, cognitive, renal, and platelet functions [7]. A ten-year study of approximately 4,500 individuals over the age of fifty found that those with low muscle mass had up to a 50% higher mortality risk compared to the control group [8]. Further analysis revealed that muscle strength, rather than muscle mass, was the more significant factor. In terms of mortality risk, muscle strength was found to be more important than cardiorespiratory fitness [9]. At the biochemical level, physical exercise stimulates the production of endogenous cytokines from muscles, which send signals to immune cells, promoting muscle growth and bone health [10]. Exercise also induces the production of brain-derived neurotrophic factor (BDNF), which enhances hippocampal function and, consequently, memory abilities. Additionally, exercise helps maintain healthy blood vessels and improves brain trophic support [11].

Coaches in sports use five intensity levels to structure athletes' training programs. For example, Zone 1 can be described as a walk in the park, while Zone 5 is a sprint. Zone 2 involves movement at a pace slow enough to maintain a conversation but fast enough to make it somewhat strained essentially between light and moderate intensity. Muscle mass begins to decline as early as the age of 30, along with a decrease in muscle contraction power (force × velocity). This occurs because the most significant change in aging muscles is muscle fiber atrophy. Endurance training in Zone 2, combined with resistance exercises, can help prevent the atrophy of slow-twitch muscle fibers.

Some of the main characteristics of aging include decreased cardiorespiratory capacity, joint degeneration, loss of strength and muscle mass, reduced bone density, and impaired balance. Both physical activity levels and muscle mass decline sharply after around the age of 65, with the process becoming even more pronounced after 75. By the age of 80, a person has lost approximately 8 kg of muscle mass compared to their peak muscle mass in early adulthood [12]. However, individuals who maintain higher levels of physical activity experience a smaller muscle mass loss around 3–4 kg. Therefore, the less we move due to weakness, the weaker we become due to a lack of movement. Muscle atrophy and sarcopenia increase the risk of falls [13]. Approximately 800,000 older adults are hospitalized each year due to fall-related injuries. Physical exercise in all its forms is the most effective strategy against sarcopenia. However, exercise requires much more effort, consistency, and knowledge than taking any medication. The more effort we invest now, the greater the benefits we will reap in the future. At the same time, a study conducted on 12 healthy volunteers with an average age of 67 found that after just ten days of bed rest (which is roughly the duration a person might experience during a severe illness), participants lost 3.3 kg of muscle mass [14]. Bone mass is also lost simultaneously. Training eccentric strength (e.g., lowering the arms after lifting weights, descending a hill while carrying a backpack) helps with spatial awareness and balance control. Stability refers to the subconscious ability to manage, slow down, and stop force. Stability prevents older adults from falling when stepping off a high curb or getting off a bus. When stability is lacking, joints especially weight-bearing ones absorb the impact, increasing the risk of injury. Stability training begins with breathing. Deep, steady breathing activates the parasympathetic nervous system and is essential for both stability and movement.

When attempting to address chronic diseases individually, we must not forget that they are interconnected and largely preventable through a common preventive approach. Epigenetic modification through physical activity is a strategy applicable to all chronic diseases. The steps we take to improve our metabolic health and prevent type 2 diabetes also reduce the risk of cardiovascular disease, cancer, and Alzheimer’s disease. The explanation for this lies in the fact that some of the 100 miRNAs, which have been found to be modulated in response to exercise, are involved in the pathogenesis of cancer [15], metabolic, and cardiovascular diseases [16]. Some physical exercises reduce the risk of all chronic diseases, while others help maintain the physical and cognitive resilience that centenarians inherit through their genes.

A study by Gomarasca (2022) shows that moderate-intensity aerobic exercise in older women reduces the expression of IL-1β, IL-6, and TNF-α at the inflammasome level [17]. Physical exercise regulates genes responsible for inflammatory and anti-inflammatory responses, with epigenetics playing a key role in this process [18].

The health benefits of physical activity can be summarized as follows:

• Reduces cardiovascular risk;
• Lowers the risk of diabetes;
• Decreases the risk of obesity and metabolic syndrome;
• Reduces the risk of malignant diseases;
• Lowers the risk of premature death;
• Supports the increase of muscle mass and strength;
• Protects against osteoporosis and fractures;
• Decreases the risk of falls;
• Improves functional capacity in degenerative joint diseases;
• Reduces stress, anxiety, and depression;
• Enhances self-esteem and quality of life, regardless of age;
• Improves cognitive function;
• Enhances sleep quality;
• Strengthens immune defense.

Physical Activity and Epigenetic Changes in the Joint – Mechanism of Action

The effects of exercise on joint health vary depending on the type, frequency, and intensity of physical activity. Numerous studies indicate that moderate exercise slows the progression and alleviates the symptoms of osteoarthritis (OA), while excessive physical exercise has adverse effects on the joints [19]. A meta-analysis of 29 randomized controlled trials (RCTs) involving four types of physical activities demonstrated that moderate exercise can positively influence cartilage composition in animals [19]. Moderate physical exercise can prevent or mitigate the impact of multiple risk factors associated with OA pathogenesis through various potential mechanisms, including inflammation, autophagy, aging, programmed chondrocyte death, and cytokine signaling. Moderate exercise can also prevent and suppress low-grade focal inflammation contributing to joint structure degeneration. Moreover, moderate exercise can increase the expression levels of IL-4 and IL-10, which induce M2 macrophage differentiation and activation associated with an anti-inflammatory response [20].

The recommended parameters for moderate aerobic exercise in patients with OA have been summarized according to guidelines provided by the American College of Sports Medicine [21]. The recommended exercise duration is generally 30–60 minutes per day, 3–5 times per week. Most studies report beneficial effects after four weeks of exercise, with further improvements observed by the eighth week [22]. A six-week duration has consistently been recognized as a turning point for distinguishing between short-term and long-term exercise effects.

Following the classification and description of OA progression mentioned above

Many protective cytokines regulated by exercise can reduce the risk of developing osteoarthritis (OA) and slow its progression. The expression of bone morphogenetic protein (BMP), a growth factor considered essential for maintaining the morphology and function of articular cartilage and subchondral bone, is regulated by mechanical stress [23]. BMP can effectively reduce cartilage degeneration by inducing the chondrogenic differentiation of stem cells and extracellular matrix (ECM) synthesis. Iijima (2018) reported that moderate exercise increases BMP expression in chondrocytes from the superficial cartilage zones, thereby preventing cartilage degeneration, osteophyte formation, and subchondral bone sclerosis [22]. Transforming growth factor-beta (TGF-β) and platelet-derived growth factors (PDGF) are involved in chondrocyte differentiation and maturation and play an important role in cartilage protection. Research findings suggest that exercise regulates TGF-β production, potentially reducing the risk of OA.

Exercise reverses the degenerative phenotype primarily by protecting the extracellular matrix (ECM) and preventing catabolism. There is substantial evidence that moderate exercise can reduce the production of matrix metalloproteinases (MMPs) and ADAMTS while contributing to the restoration of aggrecan and type II collagen levels in cartilage [24]. Moderate treadmill exercise regulates the osteogenic potential of mesenchymal stem cells (MSCs) while inhibiting their differentiation into adipocytes [25]. Additionally, experimental results indicate that long-term moderate-intensity exercise reduces bone resorption by regulating the balance between osteoblasts and osteoclasts [26]. This series of therapeutic effects based on chondrocyte function, ECM quality, and bone metabolism is essential for restoring the properties and structural integrity of articular cartilage and bone.

Physical exercise, especially long-term exercise, is one such factor that has also been proven to influence DNA methylation and chromatin modifications. A summary of 25 reports published between 2012 and 2019 highlights the role of epigenetic mechanisms in skeletal muscle responses to exercise. Physical activity induces gene regulation in muscles, with the average loop distance between associated enhancers and promoters of muscle genes being 239,000 nucleotide bases [27]. Endurance training alters the expression of these genes through epigenetic DNA methylation or demethylation at CpG sites. In another study by Biferali B (2019), twenty-three sedentary individuals with an average age of 27 years performed single-leg endurance exercises for three months, while the other leg served as an untrained control [28]. The training involved knee flexion and extension exercises for 45 minutes per session, four times a week. Biopsies of the m. vastus lateralis were taken from both legs before the training period and 24 hours after the last training session. The endurance-trained leg exhibited significant changes in DNA methylation at 4,919 sites across the genome compared to the untrained leg. Transcriptomic analysis using RNA sequencing identified 4,076 differentially expressed genes. The transcriptionally regulated genes were associated with DNA methylation changes. Increased methylation was primarily linked to genes involved in muscle remodeling and glucose metabolism, while decreased methylation was associated with genes involved in inflammatory and immune processes as well as transcriptional regulation [29]. No long-term adverse health effects of intensive exercise have been reported in the literature. Training status is an important adaptive factor.

Another mechanism of exercise-induced long-term changes in gene expression is through histone acetylation or deacetylation. The altered long-term expression of hundreds of muscle genes after training also includes genes encoding proteins with endocrine functions secreted into systemic circulation. In a study by Lindholm ME (2014), six sedentary Caucasian men, around 23 years old, provided m. vastus lateralis biopsies before enrolling in an exercise program [30]. The program consisted of six weeks of 60-minute stationary cycling sessions, five days per week. Four days after completing the exercise program, biopsies were taken again. The results showed epigenetically altered gene expression, with 641 genes upregulated and 176 genes downregulated due to histone tail acetylation and deacetylation.

Critically short telomeres induce cellular aging in vascular smooth muscle cells [31], a process that can also be regulated through physical activity. Regular aerobic exercise may serve as a bridge to maintaining telomere length [32] via a telomerase-mediated process. According to Recchioni (2017), incorporating daily endurance or strength training alters several miRNAs isolated from blood plasma and various tissues [33]. It is also important to note that certain miRNAs can be used as biomarkers for cardiorespiratory fitness [34]. The relationship between DNA methylation patterns, telomere length, and aerobic training has been elucidated [35]. Different exercise regimens can influence telomere length and improve human health and lifespan [36]. Although diet, genetic predisposition, and a healthy lifestyle impact DNA methylation and telomere length, the findings from the studies mentioned above indicate that regular physical activity and fitness are the primary factors controlling structural DNA modifications. In fact, telomere length is positively correlated with cardiorespiratory fitness, training level (sedentary, active, moderately trained, or elite athlete), and training intensity but is shorter in overtrained athletes [37]. The telomere shortening process is slow, so studying the effect of training on telomere length requires long-term research.

Resistance training includes all types of exercises that induce muscle contraction against external resistance, increasing muscle strength, tone, mass, and endurance. While numerous studies have examined the relationship between aerobic training and telomere length, few have investigated the link between resistance and endurance training and DNA damage or telomeres. According to Seaborne (2018), skeletal muscle DNA is vulnerable to DNA methylation changes induced by a single bout of resistance exercise, and this effect is maintained for 22 weeks after the training session [38]. Moreover, 12 weeks of moderate-intensity resistance training improve muscle oxidative capacity, prevent damage, and promote myofibril regeneration, making it suitable for patients with mitochondrial diseases [39]. Franzke (2014) analyzed the effect of six months of strength training at varying intensities, combined or not with a dietary strategy based on protein and vitamin supplementation. The effect of these workouts was studied on DNA strand breaks in older (around 65 years old) and very old (around 98 years old) participants. They found an increased rate of DNA damage in all groups, which aligns with previous studies. Chronic exercise is an effective and accessible method contributing to telomere maintenance, DNA methylation levels, and inflammation control. Aerobic and endurance training appear to be the most effective for preserving telomere length compared to anaerobic-based workouts. Moderate-intensity resistance training may also be beneficial for maintaining telomere length in older adults. Since telomeres naturally shorten with age, long-term studies will be necessary to assess the significant effects of physical exercise on telomere dynamics.

Pietrangelo T (2015) observed increased expression of miR-1, miR-133b, and miR-206, along with reduced O₂ consumption and increased intracellular calcium concentrations, after 12 days of low-to-moderate-intensity mountain walking training in healthy subjects [40]. The research team linked the elevated levels of these miRNAs to mitochondrial apoptosis inhibition and muscle regeneration as an adaptive response. Another study found that alternating low-intensity interval walking (at 40% of peak aerobic capacity) with moderate-intensity walking (at 70% of peak aerobic capacity) in older men led to hypermethylation of the ASC gene. This hypermethylation in its promoter region was associated with reduced levels of IL-1β and IL-18, which are involved in the pathogenesis of type 2 diabetes, rheumatoid arthritis, osteoarthritis, and atherosclerosis. Therefore, moderate physical activity may help reduce the risk of diseases related to systemic inflammation and aging.

The evidence presented so far indicates that regular physical exercise can prevent accelerated biological aging and maintain physical and mental performance through epigenetic reprogramming. Regular exercise induces changes in gene expression and methylation of specific genes. For example, shortly after endurance training, lower mRNA expression of TLR4 and CD14 is observed [41], along with higher methylation levels of an apoptosis-related protein that mediates the inflammatory cytokines IL-1β and IL-18. Physical exercise alters gene expression as cells adapt to the metabolic changes during training. Occasional aerobic exercise can also change the DNA methylation profile [42], but if the exercises are not regular, the epigenetic adaptations will regress.

Personalized Physical Activity Programs Tailored to the Individual Needs and Characteristics of the Patient.

There is no one-size-fits-all solution or universal physical activity program applicable to everyone. What matters more is the awareness of individuals and the personal feedback between doctor and patient, where individual regimens are modified according to the patient's condition. The debate over whether strength exercises or cardio training is more beneficial is endless and irrelevant. The best approach is the one that fits the specific needs of the individual. Physical activity regimes should be individually dosed: from daily activities such as walking 2-3 km, opening jars, climbing several flights of stairs, lifting weights from the floor, to more targeted workouts. Healthy mitochondria play an important role not only for muscles but also in maintaining the health of the brain and other vital organs. To keep mitochondria in optimal condition, long-duration, steady endurance training in Zone 2 intensity is required. This helps in the effective use of fats as an energy source, as fatty acids can only be metabolized by mitochondria. Zone 2 training is important for non-professional athletes for two reasons. First, it builds an endurance base regardless of the type of physical activity. Second, it plays a key role in preventing chronic diseases by improving the function of our mitochondria. When we train in Zone 2, the primary work is performed by type 1 muscle fibers (red, slow to respond to electrical stimulation), which are rich in mitochondria and fatigue-resistant. When the intensity increases, type 2 (white, fast-contracting) muscle fibers are activated. These fibers have more powerful and stronger contractions but are less efficient and fatigue more quickly. Intense physical exercise leads to their hypertrophy and increased lactate production, which turns into lactic acid, causing the familiar muscle soreness 2–3 days after physical exertion. The efficiency of our mitochondria determines the speed at which the body clears lactate, which is related to improved endurance. If after training we feel "muscle soreness," it means we have exceeded Zone 2.

Another effect of training in Zone 2 is that it increases cerebral blood flow and stimulates the production of brain-derived neurotrophic factor. This has a neuroprotective effect, which explains the benefits of training in Alzheimer's disease and other neurodegenerative conditions.

What is the ideal amount of exercise for patients with OA? All previous studies show that any physical activity is better than no physical activity. A study of over 1,500 adults with early-stage OA in the lower limb joints found that even 1 hour of physical activity per week increases the likelihood that the disease will not progress over the next 4 years. An analysis of 280 studies concluded that training programs lasting 3–6 months lead to moderate improvements in pain and physical function, but these benefits depend on the exercise volume or adherence to the program. These data provide flexibility for clinicians when prescribing physical activity for patients with knee and hip OA. Current guidelines recommend that older adults engage in approximately 150 minutes of moderate physical activity per week, but for patients with chronic pain, this may seem difficult to achieve. An alternative way to track activity is by the number of steps taken. While 10,000 steps is a popular target, even fewer steps can bring health benefits. A study of nearly 1,800 participants with knee OA found that each additional 1,000 steps per day reduced the risk of developing functional limitations by 16%-18% over 2 years. According to the researchers, 6,000 steps per day is the key threshold that best predicts the likelihood of maintaining functionality. This target of 6,000 steps daily could be a practical and motivating encouragement for people with chronic pain [43].

The American College of Sports Medicine recommends that adults (18–65 years old) incorporate not only moderate-intensity aerobic exercises (≥ 30 min daily, ≥ 5 days a week for a total of ≥ 150 min per week) but also strength training for all major muscle groups [44]. To maximize the benefits, programs should account for key variables such as the type of exercise, intensity, duration, frequency, progression, and rest according to the individual preferences and needs of each subject [45]. The design of training programs should begin with an assessment of the individual’s initial fitness level, taking into consideration the patient’s medical history and clinical symptoms. The use of wearable sensor technologies would allow for remote monitoring of patients with OA. These types of devices can record joint movements, activity levels, and other indicators. Clinicians can provide real-time feedback and offer useful information to patients by analyzing the collected data, allowing for proactive management and intervention. Sensors provide an accessible and practical alternative for remote monitoring of patient movement. Through them, large quantities of real-time data can be gathered and analyzed, enabling timely decision-making, advice, and guidance from a distance, and encouraging patient collaboration.

Understanding the health benefits of optimal physical activity regimes enables healthcare providers to promote an active lifestyle among our contemporaries. In the long term, such an approach can have a sustainable and significant impact on public health.

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