Exercise, specifically aerobic and combined with resistance training, have been recognized as a potential intervention to modulate inflammatory profile in humans ^[1][2][3][80,81,82], with a particular emphasis in older adults, in reversing or attenuate immunosenescence in aging ^[4][5][6][83,84,85], as well as reducing the development of chronic diseases ^[7][86].

During exercise, skeletal muscle functions as an endocrine organ, secreting several myokines such as IL-6, IL-7, and IL-15. In addition to the pleotropic effects mentioned above, IL-6 can stimulate cortisol released by the adrenal glands, acting as a second anti-inflammatory signal and improving glucose uptake through the stimulation of AMPK signaling ^[8][87]. IL-6 is conventionally used as marker of inflammation and several studies evaluating the impact of exercise in their inflammatory profile report the significant reduction in IL-6 levels after different periods of intervention. A study on females with metabolic syndrome found that a 12 week-long aerobic exercise intervention promotes a decrease in IL-6 ^[9][88]. The role of IL-6 in the framework of exercise as an anti-inflammatory therapy for cancer cachexia is also very significant (reviewed in ^[7][86]).

A study conducted by Chen et al. ^[10][89] performed an evaluation of the differentially expressed genes (DEGs) in a group of 24 sedentary middle-aged men with different basal levels of IL-6 that undertook a 24 week-long physical activity program. The analysis of DEGs, followed by functional enrichment analysis and protein–protein interactions, showed that C-C motif chemokine receptor 7 (CCR7) and hemoglobin subunit delta (HBD) genes were induced by myocyte enhancer factor 2A (MEF2A), arising as key regulatory factors modulated by exercise ^[10][89]. The authors conclude that inflammation-related genes such as CCR7, HBD, and interferon-gamma (IFN-γ) might serve vital roles in reducing inflammation by exercise and might prevent the risk of chronic diseases in sedentary individuals ^[10][89].

IFN-γ is a cytokine with a relevant role in several aspects of both adaptive and innate immunity. Firstly, it is most recognized for its pro-inflammatory properties but has been also recognized for its pleiotropic functions such as induction and maintenance of regulatory T cells, induction of tolerogenic dendritic cell characteristics, and immunosuppressive tumor environment. These properties place IFN-γ among the major endogenous immune regulators, contributing to both immunity and tolerance in several stages of the immune response ^[11][12][90,91]. Svajger et al. (2021) demonstrated that IFN-γ can exert important tolerogenic effects on dendritic cells, in in vitro assays, through a strong upregulation of programmed death-ligand 1 (PD-L1), an inhibitory molecule ^[11][90].

Shaw et al. (2020) observed that exercise in acute hyperketonemia appears to amplify the initiation of the pro-inflammatory T-cell-related IFN-γ response, with an increased IFN-γ mRNA expression during and following prolonged, strenuous exercise ^[13][92]. Hasanli et al. (2020) evaluated the impact of physical or psychological stress on the IFN-γ levels in male Sprague Dawley rats submitted to exercise activity, psychological stress, or the combination of exercise and psychological stress. The study showed that the different interventions did not modulate significantly the levels of IFN-γ either immediately after exercise or after 72 h, despite fluctuations in cytokine values, with a tendency to decrease immediately after exercise and increase 72 h later ^[14][93]. Vijayaraghava (2017) conducted an experimental study with the application of different grades of exercise and evaluated the impact on IFN-γ plasma levels, in individuals of different ages and body mass index (BMI) values. The levels of plasma IFN-γ were significantly modulated by moderate exercise, with a significant increase in plasma levels after a bout of moderated exercise, and the highest values were found after 1 month of moderate exercise. On the contrary, after a bout of strenuous exercise, plasma levels reduced in comparison with baseline values. The study results also showed that regular physical activity confers protection against excessive inflammation in spite of higher age or BMI, with respect to IFN-γ levels ^[15][94]. Conversely, Farinha et al. evaluated the impact of 12 weeks of aerobic exercise and observed a decrease in IL-1β, TNF-α, IL-6, and IFN-γ in women with metabolic syndrome ^[9][88].

Therefore, exercise has an emerging potential to improve immune system performance and reduce the risk of low-grade inflammation from childhood to old age ^{[9][16][17][18][19][20]}[88,95,96,97,98,99]. A systematic review conducted by Bautmans et al. (2021) revealed significant anti-inflammatory effects of exercise in the elderly—namely, in reducing circulating levels of CRP, IL-6, and TNF-alpha and also that the performed exercise interventions seem suitable to apply and safe for older patients, without inducing an exacerbation of inflammation following exercise ^[21][100].

Desynchronization of circadian clocks induced by modern lifestyle could predispose to inflammation and metabolic impairment and increase the risk of chronic diseases ^[22][23][101,102]. A relevant aspect is the connection of exercise with circadian rhythm physiology. Several studies point that exercise can modulate circadian rhythm, acting as a circadian time cue and changing the phase of a molecular clock in peripheral tissues. In addition to studies on animal models, studies on humans have revealed that endurance and resistance exercises stimulate the expression of clock genes ^[24][25][26][103,104,105]. Several studies explain the effect of exercise on core molecular clock genes, through the influence in exercise-responsive genes—AMPK, HIF-1α, and PGC1α. Increased activity of AMPK changes Per and Cry stability, modulating clock genes expression ^[24][26][27][103,105,106].

A recent study by Souza Teixeira et al. shows an improvement in the anti-inflammatory profile, with a lifelong physical exercise related to clock genes expression in effector-memory CD4+ T cells in master athletes. Master athletes presented different peripheral and cellular inflammatory responses after acute exercise, compared with untrained individuals, with higher levels of IL-8, IL-10, IL-12p70, and IL-17A and augmented expression of Cry1, REV-ERBα, and TBX21 ^[28][107].

Clock genes are involved in inflammatory response through the activation of NF-κB transcription and activation of pro-inflammatory cytokines ^[28][29][107,108]. CLOCK can upregulate NF-κB-mediated transcription in the absence of BMAL1; therefore, BMAL1 may have an anti-inflammatory role ^[30][54]. Tylutka et al. concluded that physical activity sustained throughout life could lead to rejuvenation of the immune system by increasing the percentage of naïve T lymphocytes or by decreasing the inverse CD4/CD8 ratio ^[29][108]. Taking into account the available data, growing evidence supports the vision that exercise may counteract immunosenescence and improve the immune system. Exercise-induced changes in immunosenescence-related markers of immune cells were reviewed by Mathot et al., supporting the effect of long-term exercise on senescent T-lymphocytes and the increase in dendritic cells after exercise in older adults. The data also suggest a significant influence of the type and intensity of exercise on immunosenescence-related markers, mainly in older adults, highlighting the greater impact of aerobic exercise and resistance exercise protocols with lower loads and a greater number of repetitions (2 sets of 30 consecutive repetitions at 40% of 1RM) ^[6][28][85,107].

The skeletal muscle system has its own clock gene expression and can be stimulated by physical activity. Acute aerobic and resistance exercise increases the expression of skeletal muscle clock genes in humans ^[31][109]. An acute session of aerobic exercise (70 min at 70% VO2max) increased the expression of the BMAL1 gene by 1.6 times 4 h after exercise, and to 3.5 times 8 h after exercise, in trained men ^[31][109]. Likewise, an active session of isotonic knee extension resistance, including both concentric and eccentric phases (10 sets of 8 repetitions at 80% of 1RM) increased the expression of the BMAL1 gene by approximately 1.2 times, assessed 6 h after exercise in untrained healthy men ^[32][110], as well as positively regulating the clock genes Cry1 and Per2 by exercise, compared with control without exercise.

Four weeks of low-intensity resistance exercises resulted in a significant change in the expression of clock genes in the skeletal muscle of mice ^[33][111], supporting the fact that exercise can be an external stimulus for skeletal muscle rhythm. Skeletal muscle BMAL1 and Per2 gene expression significantly increased after a 12-week exercise intervention in elderly with obesity and prediabetes ^[34][112] Furthermore, skeletal muscle BMAL1 gene expression may improve insulin sensitivity. Interestingly, Clock- and BMAL1 gene mutant mice exhibit approximately 30% reductions in maximum muscle strength and 40% in mitochondrial volume ^[35][12]. Although with the absence of the CLOCK gene, the animals’ ability to adapt to 8 weeks of endurance exercise was not impaired ^[36][113].

Thus, the practice of physical exercise seems to modulate the interrupted skeletal muscle clock, contributing to improvements in the metabolic health of the entire body. These data have broad implications in the context of clinical practice, suggesting the importance of exercise, and, more specifically, the interaction of exercise and muscle, as a therapeutic strategy to help readjust body molecular clocks.

The cardiovascular system is influenced to a great extent by chronobiologic rhythms that are determined by the CNS and peripheral clocks, determining short- (minutes and hours) and long-term (months and years) functional fluctuations. The peripheral clocks are within each cardiovascular cell and are crucial in the modulation of aspects such as endothelial function, vasodilation and resistance, blood pressure, hormone dynamics, body temperature, heart rate, etc. ^[37][114].

The effects of physical exercise on the cardiovascular system have been widely described, which include improvements in endothelial function, relaxation of the arterial wall and vasodilation, lower blood pressure and impedance, lower heart rate, improved heart-to-vascular coupling, and overall greater cardiovascular efficiency ^[38][115]. Even though acute exercise induces an increase in systolic blood pressure and heart rate, the intensification in shear stress that encompasses physical activity stimulates the release of NO by the endothelial cells, thus promoting vasodilation and improved blood supply to the working muscles ^[39][40][41][116,117,118]. The post-exercise phase depicts lower blood pressure and heart rate, in line with a positive modulation of the autonomic nervous system, with a change in the sympathetic/parasympathetic balance toward a higher influence of the parasympathetic axis ^[41][118]. The positive modulation of the cardiovascular system provided by physical exercise has also important long-term effects, mostly due to its beneficial impact on the endothelium and overall arterial structure, able to shift the trajectories of arterial aging toward a more beneficial one and therefore preventing the occurrence of early vascular aging ^[42][43][119,120]. Physical exercise thus provides a valuable tool to prevent biological aging and contribute to better cardiovascular health and lesser incidence of major cardiovascular events. Furthermore, physical exercise has been shown to modulate the circadian clocks to a similar extent as that produced by photic light cues ^[44][121], thus adding to its regulatory effect on the cardiovascular system. Physical exercise, particularly aerobic training, also produces important neuroendocrine changes, including, but not limited to, decreased cortisol and increased melatonin production during the night, contributing to a more effective sleep ^[45][46][47][122,123,124].

The adjustments of circadian rhythmicity produced by exercise have been shown to occur, even for low-intensity endurance exercise ^[33][111], and seem to be independent of the time of day the individual performs the exercise ^[48][125], although optimal diurnal exercise periods can be adjusted according to the individual chronotype ^[49][126]. According to previous research, individuals can be categorized into three distinct chronotype groups: early circadian chronotype, intermediate circadian chronotype, and late circadian chronotype ^[50][127]. Individuals in the early circadian chronotype group appear to have a greater disposition to early (morning) physical exercise, while those in the late circadian chronotype prefer to exercise during the late evening. The matching of exercise periodicity with individual chronotype could thus be an enhancement factor for skeletal muscle performance and circadian clock adjustments, producing better cardiovascular protection and improved sleep quality ^[51][128].