The Roles of Psychological Stress, Physical Activity, and Dietary Modifications on Cardiovascular Health Implications
Summary and Keywords
Psychological stress disorders, such as depression and chronic anxiety contribute to increased risk of cardiovascular disease and mortality. Acute psychological and physical stress exacerbate the activity of sympathetic-adrenal-medullary system, resulting in the elevation of cardiovascular responses (i.e., heart rate and blood pressure), along with augmented inflammation and oxidative stress as major causes of endothelial and metabolic dysfunction. The potential health benefits of regular physical activity mitigate excessive inflammation and oxidative stress. Along with physical exercise, complementary interventions, such as dietary modification are needed to enhance exercise effectiveness in improving these outcomes. Specifically, dietary modification reduces sympathetic nervous system activity, improve mitochondrial redox function, and minimize oxidative stress as well as chronic inflammation.
The programmed “fight or flight” response to stressful stimuli is an evolutionally conserved mechanism that enables a system to return to and maintain homeostasis (Selye, 1936). As hunter–gatherers, our early human ancestors faced persistent threats of starvation, predators, and illness, and relied upon the robust fight or flight response for survival. To the contrary, the progression to modern, sedentary civilizations accompanied by social status and the demands of occupational productivity have shifted the source of stress from predominately physical to psychological in nature (Boyce & Ellis, 2005), and the stress response necessary for survival early in human evolution may be detrimental in today’s societal structure (Boyce & Ellis, 2005). Nonetheless, the compounded effects of psychological stressors are an integrated part of daily life (Cohen & Janicki-Deverts, 2012), and as the cumulative effects of psychological perturbations exceeds an individual’s perceived ability to adapt, the resulting physiological sequelae can drive disease (Kozela et al., 2016; Singh & Siahpush, 2014).
The psychological stress response occurs through a bidirectional communication route between the brain and body and is mediated by the integrated coordination of the autonomic nervous system in combination with the endocrine and immune systems (McEwen, 1998; Wohleb, McKim, Sheridan, & Godbout, 2015). While homeostasis represents a narrow range of biological operation (i.e., pH or body temperature), the term “allostasis” refers to a functional range that changes based on an individual’s physical and psychological state to maintain stability (i.e., heart rate and blood pressure) (Sterling & Eyer, 1988). Allostatic responses to an acute stressor are similar to those proposed by Selye (1936), and involve activation of the sympatho-adrenal medullary (SAM) system to facilitate the rapid release of catecholamines (epinephrine [EPI] and norepinephrine [NOR]) primarily from the adrenal medulla and nerve endings, respectively (Flatmark, 2000). Catecholamines further activate the hypothalamic-pituitary adrenal (HPA) axis, mediating the release of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) from the paraventricular nucleus of the hypothalamus. In turn, CRH and AVP active the pituitary gland to release adrenocorticotrophic hormones (ACTH), which subsequently stimulates the release of glucocorticoids (cortisol) from the adrenal cortex (Herman & Cullinan, 1997). Upon cessation of a respective stressor, the allostatic response is inactivated and levels of EPI, NOR, and cortisol return to a baseline “operating range” (McEwen, 2000), but as the magnitude or frequency of a particular stressor or collection of stressors increase over time, allostasis may not fully inactivate (McEwen, 1998). As a result of the repetitive challenge to an allostatic state, dysregulated exposure to catecholamines and cortisol leads to allosteric load and the manifestation of symptoms associated with cardiovascular disease (CVD) development and pathology (Licht et al., 2010; McEwen & Stellar, 1993). Given that CVD is a leading cause of death in the world (Lozano et al., 2013), an increased understanding of the involved mechanisms, and the time course in which they occur, will provide insight into potential therapies aimed at ameliorating CVD.
CVD, cardiovascular disease; EPI, epinephrine; NOR, norepinephrine
Traditionally, studies investigating the mechanisms that link psychological stress to CVD have focused on the transient response of the SAM system and the HPA axis. However, unlike cortisol, stress-induced EPI and NOR reactivity is not habitualized in response to repeated stress exposures (Schommer, Hellhammer, & Kirschbaum, 2003), and augmented responses predict long-term mortality from CVD (Carroll et al., 2012). In addition, Licht and colleagues (2010) have demonstrated that indices of CVD are closely associated with dysregulated concentrations of EPI and NOR from chronic sympathetic nervous system (SNS) activation and decreased parasympathetic activity (PNS), but not changes in the HPA axis. The regulated release of EPI and NOR is important in facilitating appropriate cardiovascular functions, such as heart rate and blood pressure, and the reactivity of these responses vary depending upon an individual’s perception of the psychological stressor. Similarly, individuals with elevated levels of psychological stress at rest, such as those who are depressed or present with high levels of anxiety, exhibit an exacerbated physiological stress response compared to low-stress controls (Weinstein et al., 2010), suggesting that an additive effect of psychological stress may result.
Although transient changes in catecholamines alone are insufficient to fully explain the causal link observed between psychological stress and CVD, EPI and NOR released following psychological stress initiate the activation of intracellular inflammatory pathways in leukocytes, eliciting profound immunological responses characterized by the release of pro-inflammatory cytokines into the periphery (Bierhaus et al., 2003; Goebel, Mills, Irwin, & Ziegler, 2000; Weinstein et al., 2010). Importantly, excessive production of EPI and NOR can also promote the expression of oxidative stress to overcome the antioxidant defense capacity (Graziano et al., 2014), thereby contributing to the potential for CVD development (Blankenberg et al., 2003) (see Figure 1). Thus, the potential health benefits of regular physical activity on the mitigation of excessive inflammation and oxidative stress is important in understanding the benefits of physical activity in regard to stress and CVD. Along with physical exercise, complementary interventions, such as dietary modification can also enhance positive inflammatory and oxidative responses.
Inflammatory Reactivity to Acute Psychological Stress
Laboratory experiments designed to mimic acute psychological stress in a controlled setting demonstrate that cellular gene expression, signaling the process of protein synthesis, and plasma concentration of the pro-inflammatory cytokines (immune cells that promote systemic inflammation) interleukin (IL)-1β, IL-6, and, to a less extent, tumor necrosis factor alpha (TNF-α) are transiently increased in a manner dependent upon current stress status and how an individual perceives the intensity of the stressor (Brydon et al., 2005; Steptoe, Hamer, & Chida, 2007; Weinstein et al., 2010; Yamakawa et al., 2009). Steptoe and colleagues (2007) highlights three potential factors that may explain the heightened concentration of pro-inflammatory cytokines: reductions in plasma volume, increased number of leukocytes (white blood cells), and a redistribution of leukocyte subsets, and finally, increased synthesis of inflammatory proteins due to activation of the intracellular signaling cascade. While the two former factors are well described and reviewed by Steptoe et al. (2007), the dynamics of the psychoneuroimmunological system and the interactions of dysregulated catecholamine concentrations on immune function may underscore the deleterious effects of acute and chronic psychological stress on health and disease.
Pro-Inflammatory Signaling in Response to Psychological Stress
Among leukocytes, monocytes are considered to be the predominant cell source responsible for the production of pro-inflammatory cytokines in response to cellular activation (Wright, Ramos, Tobias, Ulevitch, & Mathison, 1990) and psychological stress (Brydon et al., 2005) (see Figure 2). Monocytes exhibit a cellular phenotype specific to the environmental milieu within the periphery from which they derive (Bories et al., 2012), and following psychological stress, activated monocytes are recruited to the vascular endothelium and differentiate into resident macrophages. More worrisome may be that the stress-induced mobilization of monocytes to the vascular bed enhances the progression of psychological stress disorders and CVD, as discussed in a variety of studies (Gu, Tang, & Yang, 2012; Wohleb, McKim, Sheridan, & Godbout, 2015). Thus, investigating the function of monocytes may provide insight into the mechanisms involved with tissue-derived pathology (Bories et al., 2012).
Monocytes express a pattern recognition receptor referred to as Toll-like receptor 4 (TLR4), which is a key trans-membrane receptor that classically recognizes the lipid portion of the gram-negative bacteria lipopolysaccharide (LPS) (Pålsson‐McDermott & O’Neill, 2004). Prior to TLR4 activation, LPS is bound by LPS-binding protein (LBP), a liver-derived acute-phase protein observed in plasma (Schumann et al., 1990). This high-affinity complex facilitates the formation of a ternary complex with CD14 (cluster of differentiation) (Hailman et al., 1994). CD14 is expressed in high concentrations of monocytes and serves as a vital intermediate step enabling the presentation of LPS to the myeloid differentiation factor 2 (MD-2) and TLR4 on the cell surface (Akashi et al., 2003). Finally, two LPS/MD-2/TLR4 complexes interact to form a TLR4 homodimer, resulting in the activation of the intracellular inflammatory cascade that contributes to the phosphorylation of the protein inhibitor of κB (IκBα) (DiDonato, Hayakawa, Rothwarf, Zandi, & Karin, 1997; Mercurio et al., 1997; Park et al., 2009; Shimazu et al., 1999). Phosphorylated IκBα disassociates from the nuclear factor (NF)-κB transcription factor and is targeted for degradation in the cytoplasm (Baeuerle & Baltimore, 1988a, 1988b; Henkel et al., 1993). Meanwhile, NF-κB translocates into the nucleus to initiate the transcription of numerous pro-inflammatory genes, and is identified as the primary transcription factor involved in the psychological stress-induced activation of monocytes and pro-inflammatory signaling (Bierhaus et al., 2003; Wolf, Rohleder, Bierhaus, Nawroth, & Kirschbaum, 2009).
Studies utilizing LPS-induced production of pro-inflammatory cytokines to examine how the sensitivity of immune responses are altered in response to acute psychological stress have yielded inconsistent results. Gaab and colleagues (2005) have reported that the production of IL-6 and TNF-α decreases in individuals with chronic fatigue syndrome and increases in a control group following administration of the Trier Social Stress Test. To the contrary, Maes and colleagues (1998) have demonstrated that LPS-induced production of IL-6, TNF-α, and the pro-inflammatory cytokine interferon gamma (IFNγ) increase prior to participating in a university examination compared to an unstressed period between examinations. Researchers further stratified the study participants into high and low-stress responders. As a result, the group exhibiting the greatest levels of perceived stress produced the highest levels of pro-inflammatory cytokines and the lowest production levels of the anti-inflammatory cytokines IL-4 and IL-10 compared to the low-stress groups, implying that elevated perceptions of stress prime immune cells toward a hyper-responsive pro-inflammatory state. Furthermore, Huang et al. (2015) have reported that elevated concentrations of LBP are associated with greater production levels of LPS-induced IL-6 in obese compared to normal-weight individuals following completion of the Stroop Color-Word and mental arithmetic tasks. Obesity is a chronic, low-grade inflammatory condition, and circulating immune cells that are primed toward a pro-inflammatory phenotype during obesity at baseline also appear to be hyper-responsive following psychological stress. This posit is further corroborated by Wolf and colleagues (2009), who demonstrated that resting levels of LPS-induced IL-6 are positively associated with stress-induced NF-κB activation.
Cellular stimulation with the catecholamines EPI and NOR interact with LPS-induced inflammatory signaling and converge at NF-κB to regulate gene transcription. EPI and NOR primarily stimulate β2-adrenergic receptors (ADR) and α1a-ADR, which are G-couple protein receptors (GCPR). The β2-ADR interacts with Gs proteins to increase adenylate cyclase activity, which in turn increases cyclic adenosine monophosphate (cAMP), and subsequently, protein kinase A (PKA). cAMP-PKA inhibits IκBα degradation and NF-κB nuclear translocation, and thus, inhibits LPS-induced pro-inflammatory signaling (Dimitrov et al., 2013; Farmer & Pugin, 2000; Hong et al., 2015; Parry & Mackman, 1997). Conversely, α1-ADRs interact with Gq proteins to activate phospholipase C (PLC). PLC increases both inositol triphosphate (IP3) and diacylglycerol (DAG), and while IP3 increases intracellular Ca2+, DAG stimulation of protein kinase C augments NF-κB transcriptional activity through mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) signaling (Grisanti et al., 2011; van der Voort, Kavelaars, van de Pol, & Heijnen, 2000).
Recent findings suggest that monocyte activation with EPI and associated β2-ADR agonists inhibit pro-inflammatory signaling (Dimitrov et al., 2013; Hong et al., 2015). In addition to reduced levels of LPS-induced IL-6 and TNF-α, β2-ADR agonists also down-regulate the expression of TLR4/CD14 complex and adhesion molecules on the cell surface of monocytes. This indicates that β2-ADR-mediated signaling reduces cell sensitivity to inflammatory stimuli and aids in the regulation of monocyte trafficking and migration to the vascular endothelium (Kizaki et al., 2008; Wang, Xu, Zhang, & He, 2009). To prevent over activation, β2-ADR signaling also employs a negative feedback loop that is increased in response to psychological stress and associated with the stress-induced EPI response (Crabb et al., 2016). However, in chronically stressed individuals, the responsiveness of β2-ADR is blunted, and associated with numerous indices of CVD, including elevated resting blood pressure and heart rates, body mass index (BMI), triglycerides, fasting glucose, and total and low density cholesterol levels (Euteneuer, Mills, Rief, Ziegler, & Dimsdale, 2012; Hong et al., 2015). Furthermore, the cellular sensitivity of β2-ADR responsiveness is decreased in a manner dependent upon systemic concentrations of pro-inflammatory cytokines (Hong, Dimitrov, Pruitt, Shaikh, & Beg, 2014), suggesting that the desensitization of β2-ADR signaling contributes to greater cellular production of pro-inflammatory cytokines.
Similarly, expression levels of G protein-coupled receptor kinase 2 (GRK-2), which is involved in the desensitization of the β2-ADR, are increased and associated with EPI in response to acute psychological stress (Crabb et al., 2016). In addition, Patial, Luo, Porter, Benovic, and Parameswaran (2010) has reported that GRK-2 increases IκBα phosphorylation in response to TNF-α stimulation of macrophages, thus resulting in the enhanced translocation of NF-κB into the nucleus. Therefore, GRK-2 may increase as a mechanism that facilitates an unimpaired pro-inflammatory response following psychological stress. However, while it is currently unknown whether or not the impaired anti-inflammatory response to β2-ADR stimulation reflects receptor sensitivity or altered function of the intracellular pathway, these findings suggest that dysregulated EPI responses augment the progression of CVD risk factors (Hong et al., 2015).
Bierhaus and colleagues (2003) has demonstrated that stress-induced EPI and NOR responses are associated with NF-κB activation in isolated human leukocytes. However, whereas physiologically relevant concentrations of EPI have no effect on NF-κB activation in monocytes, stimulation with concentrations of NOR consistent with those observed in plasma following acute psychological stress transiently increases NF-κB expression levels (Bierhaus et al., 2003). In addition, these responses were attenuated in the presence of α1-ADR antagonists, and β2-ARD agonists, suggesting that the stress-induced pro-inflammatory response is primarily mediated by NOR activation of the α1-ADR and the anti-inflammatory capacity of β2-ADR sensitivity.
In contrast to β2-ADR expression, α1-ADR expression is low to undetectable in monocytes of healthy individuals under basal conditions (van der Voort et al., 1999). However, α1-ADR expression is induced in human monocytes following LPS stimulation (Heijnen, van der Voort, van de Pol, & Kavelaars, 2002; van der Voort, Kavelaars et al., 2000), and in individuals with chronic inflammatory conditions (Heijnen et al., 1996; van der Voort, Heijnen, Wulffraat, Kuis, & Kavelaars, 2000). Likewise, similar results are observed in vascular endothelial cells (Heijnen et al., 2002). There are three subtypes of α1-ADR, a, b, and d, and while stimulation of monocytes with IL-1β and TNF-α increase α1a-ADR expression, the expression of the α1b- and α1d-ADR subtypes are decreased in a dose-dependent manner (Heijnen et al., 2002). These findings imply that elevated concentrations of NOR exhibited in high stress individuals, coupled with the desensitized β2-ADR and the elevated expression of the α1a-ADR in response to pro-inflammation, further enhances the progression of chronic low-grade pro-inflammation and stresses the allosteric load that is involved with CVD pathogenesis.
Impact of Physical Activity on Cardiovascular Reactivity and Inflammatory Responses to Psychological Stress
Much like psychological stress, acute exercise elicits cardiovascular responses characterized by increased concentrations of catecholamines, immune cell activation, and cardiovascular reactivity (Goebel et al., 2000). However, while the physiological responsiveness to mental stress is considered an adverse response linked to CVD, exercise is paradoxically considered to be beneficial to cardiovascular health (Hamer, 2012), potentially by conferring an anti-inflammatory response. More specifically, acute exercise reduces TLR4 surface expression on CD14+ monocytes (Lancaster et al., 2005), while contracting skeletal muscle elicits a robust increase in IL-6, which is believed to mediate an anti-inflammatory response by facilitating an increase in IL-10 and decreasing TNF-α production (Petersen & Pedersen, 2006). Brownley and colleagues (2003) have reported that a single bout of submaximal aerobic exercise attenuates the psychological stress-induced heart rate and blood pressure responses, lowers the concentrations of EPI and NOR in plasma, and increases the sensitivity of β2-ADRs. Although the effects of acute aerobic exercise on the psychological stress response has only been examined in heathy individuals and have not yet been extended into individuals with varying levels of baseline stress, these findings suggest that a single bout of aerobic exercise downregulates the cardiovascular responsiveness to psychological stress and alters cellular signaling pathways in a manner that supports anti-inflammatory signaling, and thus, support the “cross-stress adaptation” hypothesis that indicates that the benefits of physical activity modifies the physiological response to psychological stress (Sothmann et al., 1996).
Research on the impact of physical activity on psychological health has increased over the past decade. For example, Roshanaei-Moghaddam, Katon, and Russo (2009) reported that depressive symptoms predict sedentary behavior, and recently, Edwards and Loprinzi (2016) have reported that increased levels of anxiety are observable in as little as one week from the onset of sedentary behavior. Fortunately, anxiety levels induced by sedentary behavior are reduced below baseline levels upon resuming physical activity for one week (Edwards & Loprinzi, 2016). Although the mechanisms linking psychological stress and physical activity have not been fully clarified, these findings suggest that symptoms related to psychological stress can be positively altered rapidly and maintained through habitual physical activity.
Regular participation in physical activity, especially aerobic exercise that increases cardiorespiratory fitness levels (VO2max), lowers an individual’s perception of a stressor, reduces symptoms of depression, and enhanced feelings of well-being (Hamer, Molloy, de Oliveira, & Demakakos, 2009; Poole et al., 2011; Rod, Grønbaek, Schnohr, Prescott, & Kristensen, 2009). In addition, physical activation and elevated VO2max are associated with reduction of sympathetic tone, resulting in reductions in resting heart rates and blood pressure at rest, and in response to acute psychological stress, increased physical fitness is associated with an attenuated cardiovascular response and lower catecholamine and inflammatory reactivity (Hong, Farag, Nelesen, Ziegler, & Mills, 2004; Forcier et al., 2006; Hamer & Steptoe, 2007; Nabkasorn et al., 2006; Rimmele et al., 2007). Other studies indicate leukocyte trafficking (immune cells migrating to and from peripheral tissues indicating a decrease in activity) is decreased in physically active individuals (Hong et al., 2004, 2005), and that enhanced parasympathetic tone with increased fitness levels may also facilitate anti-inflammatory responses by suppressing pro-inflammatory cytokine production in response to pro-inflammatory stimuli (Borovikova et al., 2000; Bruchfeld et al., 2010; Rosas-Ballina et al., 2009). Furthermore, Hong and colleagues (2014) report that β2-ADR sensitivity to receptor agonists is increased in physically active individuals, and predicts an elevated anti-inflammatory responses upon activation. These findings imply that physical activity increases the intracellular signaling mechanisms that are more closely associated with the anti-inflammation pathway, and thus, is associated with the reduced risk of CVD (Kodama et al., 2009; Kullo, Khaleghi, & Hensrud, 2007).
Recent studies have sought to further examine the effectiveness of aerobic exercise training intervention in previously sedentary individuals as a nonpharmacological approach to therapeutically reducing the cardiovascular burden of psychological stress. Early studies report that moderate intensity aerobic exercise intervention lasting 8 to 12 weeks does not alter cardiovascular reactivity to psychological stress (Alex et al., 2013; Lindgren et al., 2013; Ray & Carter, 2010; Sloan et al., 2011). Conversely, Costin and colleagues (2013) report that 5 weeks of rigorous physical activity (2.5 hours per day, 5 days per week) reduces cardiac reactivity to psychological stress, and thus, suggesting the possibility that adverse cardiovascular effects to psychological stress can be reversed with short-term aerobic exercise intervention. In addition, the observations reported by Costin et al. (2013) highlight the importance of physical activity in young adults who may be faced with numerous stressors and a reduced ability to cope (Evans & Kim, 2013). However, results from this study with young adults cannot be assumed to transfer to adult populations. Given this limitation, longer intervention periods utilizing various aerobic exercise protocols may be more relevant in today’s society. A study by von Haaren and colleagues (2016) has recently indicated that 20 weeks of supervised aerobic exercise at moderate intensity reduces the effects of psychological stress on the autonomic nervous system exhibited by enhanced parasympathetic tone, and suggests that long-term aerobic exercise is sufficient to attenuate adverse physiological responses to psychological stress. However, no studies have fully investigated the effects of aerobic exercise intervention on the acute psychological stress-induced inflammatory response and the mechanisms associated with intracellular signaling and gene activation. Therefore, there are ample research opportunities to delineate the complexities involved in the therapeutic effects of physical activity on mechanisms of psychological stress, and the potential interactions with the PNI system.
Cellular Redox in Relation to Oxidative Stress and Cardiovascular/Metabolic Disease
Oxidative stress is associated with the progression of several chronic diseases including Asperger syndrome (Parellada et al., 2012), cancer (Gao et al., 2016), Parkinson’s disease (Bolner, Micciolo, Bosello, & Nordera, 2015), heart disease, atherosclerosis (Bonnefont-Rousselot, 2016), chronic fatigue (Gonthier & Favrat, 2015), depression (Hirose et al., 2016), and Alzheimer’s (Bermejo et al., 2008). In addition, some studies have linked chronic stress to metabolic dysfunction such as type 2 diabetes (Shallcross et al., 2015). This may be at least partially related to the finding that excessive glucocorticoid secretion (which can be a result of psychological high stress) can cause dysfunction of pancreatic beta cells (Beaudry & Riddell, 2012). Such effects can increase risk for developing insulin resistance and cause more pronounced effects on individuals with type 2 diabetes. Further, individuals working in high stress occupations (i.e., firefighters and military personnel) experience significant exposure to psychological and physiological stress and therefore demonstrate excessive activation of the SAM and HPA axes, which can facilitate the progression of CVD (Huang, Webb, Evans et al., 2010). To illustrate this relationship of occupation stress and CVD, the prevalence of death among firefighters as attributed to CVD has increased to 46.5% (Kahn, Woods, & Rae, 2015) which may be related to the exacerbated responses from SAM and HPA axis noted with firefighting events (Huang, Webb, Garten et al., 2010; Webb et al., 2011, 2010). In addition, since oxidative stress and chronic inflammation may facilitate the progression of CVD, individuals suffering from chronic diseases should seek to incorporate dietary and exercise interventions to optimize functioning of the redox environment (oxidation-reduction reactions) and mitigate oxidative stress and inflammation. Acute oxidative stress is highly beneficial for cellular functioning since ROS can trigger favorable mitochondrial adaptations. However, chronic oxidative stress can cause severe cardiometabolic dysfunction, which causes a domino effect for individuals suffering from chronic diseases including obesity, Parkinson’s, depression, etc.
Ground state oxygen (O2; more stable electron configuration) is heavily utilized during normal metabolism and exercise for its role in cellular oxidative phosphorylation. However, this diradical is not as reactive as other reactive oxygen species (ROS) such as superoxide (O2−), hydrogen peroxide (H2O2), and the hydroxyl radical (OH−). This is likely due to the parallel spin that is maintained by both unpaired valence electrons. Increased stress on the mitochondria (due to intense aerobic exercise, chronic stress, or elevated caloric intake) can result in the formation of ROS (Huang et al., 2015) which can challenge the redox environment. Overall cellular and metabolic function depends largely on the mitochondrial redox environment, especially since mitochondrial oxygen leakage is a main source of oxidative stress (Jastroch, Divakaruni, Mookerjee, Treberg, & Brand, 2010). Excessive production of pro-oxidant ROS can damage cellular proteins, disrupt the redox environment, down-regulate antioxidant status, and promote vascular inflammation, which can increase risk for metabolic dysfunction as well as CVD. The latter mainly occurs as a result of the combined effect of LDL oxidation (induced by ROS) as well as chronic inflammation (which can also contribute to additional oxidative stress). Endogenous antioxidants such as superoxide dismutase, glutathione, and catalase are important in neutralizing these pro-oxidant molecules to promote vascular and metabolic health. Antioxidant status can be improved via dietary intervention (e.g., increased consumption of fruits and vegetables) (Teixeira, Mill, Pereira, & Molina, 2016); however, exercise can also act as a potent stimulus to endogenous antioxidants (Wiecek et al., 2016).
One of the major benefits associated with exercise training is an increase in endogenous antioxidant status that coincides with improved redox function of the mitochrondria and may facilitate improved vascular function and reduced risk for CVD (X. Li et al., 2016). This may be due to increased activity of several signaling proteins that are associated with mitochondrial biogenesis including peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1-α), which (as a result of exercise), can be activated by the de-acetylation and phosphorylation by sirtuin-1 (SIRT1) and AMP-activated protein kinase (AMPK) respectively (Cantó & Auwerx, 2009). Increased activation of PGC1-α is a potent stimulator to mitochondrial biogenesis that increases oxidative characteristics of skeletal muscle, which is increasingly important for individuals that suffer from chronic inflammation and oxidative stress such as obese and diabetic populations. Hence, improving the oxidative capacity of skeletal muscle is not only a benefit for athletic populations, but the implications for metabolic and cardiovascular health are significant since this adaptation can reverse metabolic dysfunction seen in individuals that are chronically exposed to oxidative stress. Exercise is a potent stimulus to AMPK, which can trigger phosphorylation of PGC1-α likely due to the energy imbalance (i.e., changes in AMP/ATP ratios) that favor AMPK production. Elevated AMPK activity is a favorable effect for obese individuals especially due to the role that it plays in glucose and lipid metabolism (Hardie, 2007; Ojuka, Nolte, & Holloszy, 2000; Zhou et al., 2001). Interestingly, dietary modification can also have a strong effect on this pathway (Cantó & Auwerx, 2009). Given the significance of oxidative stress and inflammation in relation to CVD progression, the dietary modifications discussed in this article will address those performed in attempt to modulate these factors.
Individuals suffering from chronic diseases such as Parkinson’s and Alzheimer’s demonstrate increased oxidative stress (Luca, Luca, & Calandra, 2015; Yan, Wang, & Zhu, 2013). Considering the aforementioned, this could be related to the finding that PGC1-α activity is reduced in individuals with Alzheimer’s disease (Qin et al., 2009; Zheng et al., 2010). A recent review article by Sweeney and Song (2016) illustrates a relationship between elevated oxidative stress and decreased PGC1-α activity that can have an adverse effect on cognitive function. While PGC1-α promotes mitochondrial biogenesis that supports the mitochondrial redox environment as well as normal metabolism (St-Pierre et al., 2006), it is also important to note that inhibited PGC1-α activity has an adverse effect on brain neurons via mitochondrial dysfunction (St-Pierre et al., 2006; Weydt et al., 2006). PGC1-α also triggers endogenous antioxidants such as superoxide dismutase and glutathione peroxidase (St-Pierre et al., 2006). Therefore, impaired expression can further increase oxidative stress susceptibility and potentially contribute to greater risk for dysfunction. These reports suggest a paradigm for individuals suffering from chronic stress to incorporate exercise and dietary interventions to improve PGC1-α activity to improve skeletal muscle, metabolic, and neurological function.
Chronic inflammation is another factor that is strongly associated with oxidative stress and cardiometabolic dysfunction (Deng, Lyon, Bergin, Caligiuri, & Hsueh, 2016; Wang et al., 2015). Obese individuals, as well as individuals suffering from neurological dysfunction demonstrate elevated production of circulating cytokines, which is also associated with impaired cardiometabolic health. Adipose tissue (especially visceral adipose tissue) secretes cytokines that promote dyslipidemia, CVD, and insulin resistance (Ouchi, 2016). These cytokines can promote macrophage foam cell accumulation and contribute to atherogenesis (Tedgui & Mallat, 2006). Exercise is a mechanism of activation for SIRT1 activity that is beneficial for regulating glucose and lipids, in addition to preventing atherogenesis by attenuating vascular foam cell accumulation (Li, Ni, Guo, & Li, 2016). In terms of dietary strategies to reduce inflammation, CR has been shown to acutely reduce cytokine production (Ershler et al., 1993) as well as increase SIRT1 activity (Kitada & Koya, 2013) which may contribute to improved longevity and cardiometabolic health.
To illustrate the importance of dietary habits on cardiometabolic health, it is important to note that poor dietary habits are the largest predictors of death and disease (Mozaffarian, 2016). Dietary routines have a direct effect on serum LDL cholesterol and triglycerides, as well as blood pressure, glucose homeostasis, oxidative stress, and inflammation (Schmid et al., 2015). In terms of general dietary recommendations, traditional low-fat, high carbohydrate diets are likely not optimal for maintaining cardiometabolic health. Rather, a diet that is lower in sodium, carbohydrates, and higher in vegetable fats is likely more beneficial for these health-related parameters. Specific foods that should generally be limited include refined grains, starches and added sugars, processed meats, sugar-sweetened beverages and foods high in sodium (Mozaffarian, 2016). Foods to be generally promoted (by more than one serving per day) include fruits, nuts, seeds, vegetables, legumes, whole grains, fish, dairy products, and vegetable oils (Mozaffarian, 2016). These specific recommendations are merely guidelines designed to improve health-related parameters associated with the pathogenesis of CVD, obesity, and diabetes. Further, there is little evidence to date to suggest that significant reductions of the ingestion of selected nutrients such as fat and sodium has any direct effect on reducing prevalence of cardiometabolic disease (Chowdhury et al., 2014; Howard et al., 2006; Micha & Mozaffarian, 2010; Tinker et al., 2008).
Excessive caloric intake (specifically high fat feeding) is potentially problematic since this will contribute to increased risk of weight gain but also can increase mitochondrial stress and cause mitochondrial oxygen leakage, thus contributing to excessive ROS generation and acute oxidative stress (Fisher-Wellman & Bloomer, 2010), which is associated with the progression of obesity and insulin resistance (Cheng et al., 2011). In addition, high fat feedings have been shown to increase the expression of genes (SRC-3 and GCN5), which can inhibit SIRT1 activity and subsequently result in the increased acetylation and deactivation of PGC1-α (Coste et al., 2008). This can have an adverse effect on oxidative metabolism, which can further increase risk for metabolic and cardiovascular dysfunction among high stress occupations, in addition to individuals suffering from chronic diseases. However, careful consideration is required to accurately interpret such acute trials. It is important to note that adverse acute responses may not always translate to detrimental chronic dysfunction.
In addition to inducing acute postprandial oxidative stress, high fat diets have a greater likelihood of inducing postprandial elevations in inflammatory markers including TNF-α, IL-6 and C-reactive protein (CRP) (Aljada et al., 2004; Nappo et al., 2002; Tsai, Li, Lin, Chao, & Chen, 2004). Postprandial metabolic responses to meals of various composition is now being considered an important response that may facilitate endothelial health and risk for atherosclerosis (Nappo et al., 2002). One important finding is that this response appears to be dose dependent (i.e., affected by caloric density) such that elevations in insulin, glucose, triglycerides, and cytokines tend to be greater in energy dense meals in both obese men and normal-weight men (Schwander et al., 2014). Some evidence suggests that tomatoes and orange juice may have the ability to reduce postprandial inflammation (Burton‐Freeman, Talbot, Park, Krishnankutty, & Edirisinghe, 2012; Ghanim et al., 2010); however further research is needed to confirm the cardiometabolic effects of chronic consumption of such foods. However, it is important to consider whether or not acute effects are likely to induce chronic responses. An example is that acute exercise can cause oxidative stress (Berdichevsky, Guarente, & Bose, 2010) while chronic exercise can increase endogenous antioxidants (Huang et al., 2015). This is significant since ROS can trigger favorable physiological adaptations. Individuals seeking to reduce lipid intake to reduce caloric consumption should be advised to avoid increasing the ingestion of excessive carbohydrates, especially refined carbohydrates. Diets that are high in carbohydrates are associated with the progression of dyslipidemia (Welsh et al., 2010), obesity (Ludwig, 2000), insulin resistance (Dekker, Su, Baker, Rutledge, & Adeli, 2010) and CVD (Vasdev, Longerich, & Gill, 2004).
Increasing skeletal muscle oxidative capacity can promote healthy redox balance to modulate the aforementioned cardiovascular and metabolic dysfunction. In terms of dietary modification, several methodological approaches have been investigated with reports of caloric restriction (CR) being highly common and well supported. Moderate CR (i.e., roughly 10% below ad libitum caloric intake) has the ability to induce similar cellular adaptations compared to those occurring in response to exercise training. CR also has been shown to promote longevity (Corbi, Conti, Scapagnini, Filippelli, & Ferrara, 2012); reduce oxidative stress (Ungvari, Parrado-Fernandez, Csiszar, & De Cabo, 2008); increase NO bioavailability (Raitakari et al., 2004); and improve blood lipids, which can reduce risk for atherosclerosis (Ross et al., 2000; Verdery & Walford, 1998). CR may also be effective at reversing beta cell dysfunction (i.e., improving glucose/insulin sensitivity) supported by one study in obese mice (Gao, Yan, Zhao, Tao, & Zhou, 2015). Fasting and CR may also increase PGC1-α activity, which is likely the result of elevated SIRT1 activity, and allows for favorable adaptations regarding energy regulation, endocrine responses, and stress responses (Ungvari, Parrado-Fernandez, Csiszar, & De Cabo, 2008). SIRT1 also contributes to elevations in eNOS expression in endothelial cells, which can contribute to improved cardiovascular function (Ungvari et al., 2007).
Research recently suggests that CR may specifically act to improve longevity of the cardiovascular system by delaying the progression of atherosclerosis (Bales & Kraus, 2013). While the majority of trials showing benefits of caloric restriction in improving longevity have been conducted in animals (Bodkin, Alexander, Ortmeyer, Johnson, & Hansen, 2003; Heilbronn & Ravussin, 2003; Lane et al., 1995), some benefits in humans have also been suggested (Redman & Ravussin, 2011). The benefits achieved with this dietary modification are likely attributed to reduced ROS generation (Turturro, Hass, & Hart, 1998; Ungvari et al., 2008) and the hormesis hypothesis (Turturro, Hass, & Hart, 1998). It is important to note that the CR has been shown to reduce inflammation (González, Tobia, Ebersole, & Novak, 2012), and improve blood lipids (Fontana, Meyer, Klein, & Holloszy, 2004), hypertension (Blumenthal et al., 2010), and insulin resistance (Henry & Gumbiner, 1991; Ichihara, Shima, Nonaka, & Tarui, 1975). All of these factors have a strong association between individuals that suffer from chronic oxidative stress and inflammation such as obese populations and individuals with type 2 diabetes. Future research should examine the effects of caloric restriction in such populations.
It is important to investigate the effects of chronic dietary modification before speculating chronic effects of acute responses. Ketogenic diets (i.e., chronic high fat diets) were originally introduced as a beneficial treatment for epileptic seizures (Lambrechts et al., 2017). A ketogenic diet is one that comprises of roughly 70–75% fat, 20–25% protein, and 5–10% carbohydrates. It appears as though there may be some evidence to support future research in the area of ketogenic diets in relation to cardiometabolic health. Ketogenic diets induce similar adaptations compared to what is seen with caloric restriction, which may include activation of AMPK and SIRT1 to subsequently activate PGC1-α (Paoli, Bianco, Damiani, & Bosco, 2014). This process has beneficial effects on glucose homeostasis and insulin sensitivity (Paoli et al., 2014). These findings have direct implications for individuals with type 2 diabetes, but it is also important to note that impaired mitochondrial function plays a role in the pathogenesis of neurological disease such as Alzheimer’s (Paoli et al., 2014). Further, some literature supports ketogenic diets in relation to not only the improvement of mitochondrial redox function but also that it may be a safe and effective treatment for individuals suffering from epilepsy and mitochondrial complex defects (Kang, Lee, & Kim, 2013; Kang, Lee, Kim, Lee, & Slama, 2007).
Ketogenic diets have also been shown to improve body composition without having an adverse effect on physical performance (Paoli et al., 2012). Improvements in body composition may facilitate cardiometabolic benefits. Further, literature also shows that this dietary modification may be effective at increasing antioxidant status and preventing oxidative stress in healthy females (Nazarewicz, Ziolkowski, Vaccaro, & Ghafourifar, 2007) as well as high school Taekwondo athletes (Rhyu, Cho, & Roh, 2014). However, the lack of sufficient human trials in relation to longitudinal ketogenic diet interventions warrant further investigation pertaining to the potential effects on cognitive function and cardiometabolic health.
Collectively, it appears as though an energy deficit has the potential to induce favorable changes on mitochondria since both caloric restriction and exercise increases AMP/ATP ratios (Cantó & Auwerx, 2009). These responses are likely highly beneficial for individuals chronically exposed to high amounts of physiological and psychological stress especially since chronic stress exposure coincides with oxidative stress and chronic inflammation (Black & Garbutt, 2002). Both of these physiological parameters are associated with chronic disease and can be improved with dietary modification including moderate caloric restriction (Ungvari et al., 2008). Without appropriate lifestyle modification, chronic oxidative stress and inflammation could cause a domino effect in someone who already has an increased likelihood of cellular dysfunction. Specific sources of cellular dysfunction that could be the result of chronic stress include pancreatic beta cells (Ichihara, Shima, Nonaka, & Tarui, 1975) and endothelial cells. Given the available literature, it is imperative that such populations engage in both exercise and dietary interventions to improve metabolic and cardiovascular function.
The literature shows distinct cardiovascular and metabolic benefits associated with regular physical activity and dietary interventions including the involvement of select micronutrients, or moderate caloric restriction. Specifically, regular exercise and dietary modification reduces sympathetic nervous system activity, improves mitochondrial redox function, and minimizes oxidative stress as well as chronic inflammation. While the majority of the studies conducted have been small scale and relatively short term, the implication for future research in relation to cardiometabolic and cognitive health is significant, especially for individuals suffering from chronic stress or disease.
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