Water volume: dehydration
Water, as a key component of life, is a pivotal constituent of the human body. It is a principal factor in metabolism and thermoregulation, plays an essential role in metabolism, and acts as a solution medium, a reactant, and a reaction product of metabolism . In addition, it is a lubricant and a shock absorber. Over half of the mass of the human body in adults is constituted of water (about 60%). This ratio is high in infants (75–80%), toddlers, and children (75–65%), reaches lower percentages in adolescents (60–65%), and may fall to a nadir of 40% in aged humans. In a human of average weight and height, water volume is distributed in the extracellular (40%) and the intracellular (60%) water compartments .
Hydration status is regulated by homeostatic mechanisms residing in the brain, the cardiovascular system, and the kidneys. A homeostatic balance is maintained by the amount of water uptake, the proportion of water included in food, and the water that is produced during metabolism vs. the water consumed or excreted . The primary mechanism of water homeostasis lies in the brain. When water balance is disrupted, the osmotic pressure of the extracellular fluid compartment (ECF) increases. By activation of hypothalamic osmoreceptors, antidiuretic hormone (ADH) is released from the posterior pituitary gland. Both the increased ECF osmotic pressure and ADH elicit the feeling of thirst, while ADH acts on the kidneys to increase water reabsorption even before thirst is elicited. Thirst is often blunted in elderly subjects, who are at risk of having an insufficient water intake in conditions of elevated temperature and humidity.
Both deficient and excessive water intakes are counterbalanced by subtle hormonal changes (renin-angiotensin-aldosterone system—RAAS—ADH, and atrial natriuretic peptide—ANP) that contribute to buffering the deleterious effects of these abnormal conditions [19, 20]. The kidneys are the main sites and regulators of water losses, their unique property being the ability to modify the osmotic pressure of urine within a large range in response to minute changes in plasma osmotic pressure. Aldosterone stimulates sodium and water reabsorption from the gut and the salivary and sweat glands in exchange for potassium. It further stimulates the secretion of potassium into the tubular lumen, thereby upregulating epithelial sodium channels, in the collecting duct and the colon, increasing apical membrane permeability for sodium and thus absorption .
Induction of the HPA axis during stress interacts with the activated RAAS to sensitize subsequent behavioral and autonomic responses to hydromineral imbalance; however, central angiotensinergic circuits activated by subsequent exposure to a psychogenic stressor may also be primed for heightened stimulation [22, 23]. Real threats to water homeostasis and perceived threats derived from psychogenic stress activate the RAAS. Blood-borne angiotensin-II (Ang-II) stimulates angiotensin type 1 receptors (AT1) expressed on neurons residing in circumventricular organs (CVOs). These neurons have direct connections to hypothalamic and limbic nuclei controlling physiologic and behavioral responses to systemic and psychogenic stressors. In addition, AT1 receptors are present on neurons within the confines of the blood-brain barrier and their expression is regulated by the hydration state and stress exposure. These AT1 receptors most likely bind brain-derived Ang-II and influence the function of neurons mediating hydromineral balance and cardiovascular function, as well as affect and mood . Several studies have also demonstrated that aldosterone concentrations are higher in depressed subjects than in healthy controls, eliciting more prominently the aforementioned responses [25, 26].
The RAAS occasionally fails to maintain water homeostasis, resulting in dehydration. Apart from water losses, dehydration may also result from shifts in water compartment redistribution; these water shifts are exaggerated by the actions of cortisol [27, 28]. ANP increases glomerular filtration rate and the sodium filtration fraction, reduces cardiac output, and inhibits both renin secretion and the aldosterone response to angiotensin . As mentioned above, during stress, water tends to shift from the intracellular to the extracellular water compartment to maintain homeostasis of blood pressure and plasma volume. Non-osmotic release of ADH activates the sympathetic nervous system and the RAAS. Moreover, the sympathetic nervous system is involved in the non-osmotic release of ADH (carotid and aortic baroreceptors) and in the activation of RAAS primarily through renal beta-adrenergic receptors .
All in all, in terms of physiology, stress is equal to dehydration for the average human, whether this is due to behavioral changes or to physiologic mechanisms (Fig. 1).
Muscle mass: myosteatosis and sarcopenia
Skeletal muscle is a key organ exhibiting plasticity by adapting its mass to environmental cues, while it affects pathways of carbohydrate, lipid, and protein turnover. Skeletal muscle, the target of numerous hormones, is itself a secretory organ of cytokines and other polypeptides, termed myokines. These myokines have autocrine, paracrine, and endocrine actions and are involved in inflammatory processes. The health of the skeletal muscle is largely dependent on the optimal function of its mitochondria. Muscle mass functionality also depends on the turnover of contractible muscle fibers. Therefore, the health of skeletal muscle mass depends on the production and degradation of protein fibers, a delicate and dynamic balance. Another important aspect of skeletal muscle physiology is its dense vasculature. Muscle contraction depends on an active consumption of energy substrates, provided by an extensive net of muscle microcirculation .
The endomysium, perimysium, and epimysium of skeletal muscles, formed of layers of extracellular matrix, provide essential structural and mechanical support to contractile proteins. For proper function, the skeletal muscle requires adequate elasticity and protein contractility and relies heavily on sufficient cell-matrix interactions. A compound system of collagen, non-fibrillar collagens, proteoglycans, matricellular proteins, matrix metalloproteinases, adhesion receptors, and signaling molecules maintain the physical structure for force transmission within motor units, entrench cellular structures, such as capillaries, and motor neurons, and enable essential sarcolemma-matrix adhesion processes and molecular signaling. Recent proteomic studies confirm that the extracellular matrix readily influences the integrity of the muscles and their cellular functions. Thus, changes in the organization of the extracellular matrix play a crucial role during muscle protein regeneration following injury, extensive neuromuscular activity, or pathologic insults.
Exercise training, which is perceived as a stress event by the human organism, causes elevations of the circulating concentrations of catecholamines and cortisol. Catecholamines stimulate local production of IGF-I and IGF-II by the skeletal muscle. Activation of beta-adrenergic receptors increases intracellular cAMP levels and activates protein kinase A (PKA), which may also stimulate the AKT pathway and the transcription factor CREB, a pathway that should be investigated in contracting muscle. The increase in skeletal muscle glucose uptake during exercise results from a coordinated increase in rates of higher capillary perfusion, surface membrane glucose transport, and intracellular substrate flux through glycolysis. During exercise, skeletal muscle satellite cells are activated, these constituting a distinct muscle precursor cell subtype responsible for postnatal adaptation, growth, and repair. To conclude, since the balance between protein production and degradation is very delicate, every factor affecting this cascade may influence the health of skeletal muscle, contributing to disease [32, 33].
Classic proinflammatory cytokine release, such as that of IL-6, in response to exercise seems to exert pleiotropic effects in skeletal muscle by increasing glucose uptake and fatty acid oxidation locally. Simultaneously, hepatic glucose output and fatty acid release from adipose tissue are stimulated to provide energy substrates for the exercising muscle. Other proinflammatory cytokines may act as anabolic factors in skeletal muscles .
Paradoxically, muscle-originating IL-6, i.e., a myokine, increases during exercise training and provides important autocrine and paracrine benefits by regulating energy metabolism. In persistent inflammatory conditions, such as those experienced during chronic stress, IL-6 secretion and action are coupled with increased muscle wasting, very often acting in combination with cortisol and other molecules to promote atrophy. The direct action of IL-6 as a regulator of atrophy has not as yet been definitively corroborated by experimental findings [35,36,37]. Hyperactivation of the HPA axis associated with hypercortisolemia and subclinical systemic inflammation disrupts the metabolism of muscle mass. Chronic stress and the stress hormones also affect skeletal muscle mitochondrial functions, rendering significant numbers of mitochondria inactive, resulting in their inability to cover their metabolic needs [38,39,40,41]. Hypercortisolemia, on the other hand, induces accumulation of fat within the muscle as well as a dramatic decrease of skeletal muscle mass called, respectively, myosteatosis and sarcopenia .
Thus, chronic stress and associated hypercortisolism together with systematic low-grade inflammation negatively impact on muscle mass, resulting in mitochondrial dysfunction. This dysfunction, in the form of either dysregulated exchange between mitochondria and endoplasmic reticulum  or reduced mitochondrial biogenesis and quality control , may lead to sarcopenia, myosteatosis, osteosarcopenic obesity, and, ultimately, cardiometabolic diseases (Fig. 2) .
Fat mass: obesity and non-alcoholic fatty liver disease
Fat mass, also known as adipose tissue, acts like a thermal insulator and as an energy deposit in the form of triacylglycerols. Adipose tissue is also an active endocrine organ synthesizing and releasing adipokines, i.e., fat-derived cytokines, complement components, growth factors, extracellular matrix proteins, and vasoactive agents. There are three types of adipose tissue, white, beige, and brown. A stem cell type of preadipocytes grows into mature adipocytes according to the energy needs of the human organism.
White adipose tissue includes the subcutaneous abdominal, visceral, retroperitoneal, inguinal, and gonadal fat depots. In contrast to white adipocytes that play a role in energy storage, brown and beige fat cells display energy-dissipating capacity and generation of heat in the process of thermogenesis. Brown adipose tissue contains a large quantity of mitochondria with laminar cristae. It is abundant in neonates and, because of its biological function of thermogenesis, is critical at this age. Thermogenesis is possible because of the presence of uncoupling protein-1 (UCP1), a mitochondrial protein that induces heat production by uncoupling respiration from ATP synthesis .
Positron tomography studies have revealed that adults have active brown fat in their neck, supraclavicular fat, mediastinum, and paravertebral and suprarenal region [46, 47]. The presence of brown-like cells within adipose tissue is termed beige fat. Beige adipocytes, which appear to originate from endothelial and perivascular cells within white adipose tissue, have a unique gene signature, different from that of white and brown adipocytes. Under normal conditions, beige adipose tissue expresses low levels of UCP1, but upon β-adrenergic stimulation induced by exposure to cold or by exercise, beige adipocytes exhibit thermogenic properties .
When hyperplasia or hypertrophy of adipose tissue occurs, obesity begins. Obesity is merely part of the phenotype of a “diseasome” that is not restricted by age, body weight, or BMI [8, 49,50,51,52]. Thus, individually, BMI cannot be solely attributed to excess of fat or skeletal muscle masses . Body phenotypes with relatively normal BMI may exist with accompanying increased fat mass, and/or visceral obesity, that cannot be defined by BMI calculations. Frequently, there are nonlinear relations between structure and function and the various component masses of living organisms. Allometric scaling of body mass provides a theory-based method for predictions of mass-related biological characteristics . Thus, in “lean” obese subjects (with a lean BMI), there is a relatively high visceral fat content and low skeletal muscle mass .
Obesity is associated with adipose tissue dysfunction leading to the development of several pathologies, including carbohydrate intolerance, insulin resistance, type 2 diabetes mellitus, dyslipidemia, non-alcoholic fatty liver, or hypertension [55, 56]. The mechanisms underlying the development of obesity and its associated comorbidities include hypertrophy and hyperplasia of primarily visceral adipocytes, adipose tissue inflammation, impaired extracellular matrix remodeling, and fibrosis, together with altered secretion of adipokines [11, 57, 58]. Chronically stressful conditions cause hypertrophy and hyperplasia of the adipocytes, alter the secretion of adipokines, and cause attraction and activation of stromal fat immune cells [59,60,61]. More specifically, glucocorticoids cause insulin resistance and have a stimulatory effect on the maturation of both omental, subcutaneous abdominal, and other preadipocytes [62, 63]. Glucocorticoid-induced insulin resistance is dependent on 11β-HSD1, the enzyme that converts cortisone into cortisol and results in the critical activation of JNK signaling in adipocytes [64, 65]. Hyperactivation of the HPA axis not only affects adipose tissue directly but also causes changes in eating behavior [2, 66, 67]. When perceived or real chronic stressors are present, eating control is lost due to the hedonic reward of eating as a counter-maladaptation to the dysphoria of stress [66, 68].
Non-alcoholic fatty liver disease (NAFLD), which is characterized by the accumulation of large droplets of triglyceride within hepatocytes in the absence of chronic alcohol consumption, is a leading cause of hepatic dysfunction worldwide. NAFLD represents a wide spectrum of diseases, ranging from simple steatosis to steatosis with inflammation to cirrhosis. Although simple hepatic steatosis is a slowly developing asymptomatic disease, the next stage, non-alcoholic steatohepatitis (NASH), is more likely to cause progressive cirrhosis and hepatocellular carcinoma, resulting in increased mortality . It seems that chronic stress is directly linked to NAFLD and chronic inflammation in visceral fat . Under normal dietary conditions, chronic stress induces noticeable hepatic oxidative stress and inflammation without causing manifest hepatocellular injury. Irrefutably, chronic stress leads to a chronic inflammatory state, including high concentrations of inflammatory cytokines, such as TNF-α and IL-6, both in the systemic and, mainly, in the hepatic circulation, causing NAFLD .
In summary, chronic stress provides a conducive environment for increased inflammation and reactive oxygen species (ROS) generation and hence oxidative stress (OS) in adipose tissue, dysregulating UCP1 expression and activation in both white and brown adipocytes, ultimately promoting lipotoxicity (Fig. 3) [42, 43, 72].
Bone mass: osteopenia and osteoporosis
Bone tissue consists of osteocytes, osteoblasts, osteoclasts, stem cells, and lining cells. Osteocytes represent the most abundant cell type of bone. They are formed by the incorporation of osteoblasts into the bone matrix. Osteocytes remain in contact with each other and with cells on the bone surface via gap junction-coupled cell processes passing through the matrix through small channels, the canaliculi, which connect the cell body-containing lacunae with each other and with the external environment. Οsteoblasts and osteoclasts participate in bone remodeling, a highly crucial function of the bones. In bone remodeling, osteoclasts dissolve/resorb old bone tissue and osteoblasts produce osteocytes, actively renewing bone tissue. Bone tissue participates in numerous functions: it maintains blood pH levels, acts as calcium and phosphate storage, provides protection of vital organs and support for muscles, organs, and soft tissues, helps with leverage and movement, and, lastly, participates indirectly in the formation of blood cells in the bone marrow interspersed within the spongy bones .
Bone quality (bone turnover, geometry, and microarchitecture), accomplished via bone remodeling, plays a major role in bone health. This balance between bone resorption and bone formation, a homeostatic function, is responsible for proper bone architecture and thus for its function. Recently, a large number of studies have demonstrated that bone tissue participates actively in most metabolic pathways. Indeed, bone metabolism has been implicated in energy homeostasis through uncarboxylated osteocalcin, a hormonal product of osteoblasts, suggesting a connection between osteocalcin and insulin signaling through bone remodeling. Leptin, a classic adiponectin, is connected to bone remodeling. Thus, circulating leptin acts on bone cells directly to increase bone formation; however, because it stimulates the sympathetic system, it may inhibit bone formation through increased catecholamine effects [74, 75].
Many studies have linked bone health to reproductive function and immunity. Gonadal sex steroids contribute to maintaining peak bone density until menopause, including during the transient changes in skeletal mineral content associated with pregnancy and lactation. At menopause, decreased gonadal sex steroid production normally leads to rapid bone loss. The most rapid bone loss, due to decreased estrogen concentrations, occurs within the first post-menopausal decade, while age-related bone loss occurs at a slower pace during later life. Age-related bone loss in women is caused by ongoing gonadal sex steroid deficiency and, also, by vitamin D deficiency and secondary hyperparathyroidism .
Additional studies have found that there is intimate interplay between the immune system and bone metabolism. Among the cells of the immune system that regulate bone turnover and the responsiveness of bone cells to calciotropic hormones are bone marrow T lymphocytes . T cells secrete osteoclastogenic cytokines, such as RANKL and TNF-α, as well as factors that stimulate bone formation, one of which is Wnt10b . A significant study demonstrated that the metabolic syndrome and atherosclerosis are linked, since oxidized lipids decrease bone mass by increasing anti-osteoblastogenic inflammatory cytokines and decreasing pro-osteoblastogenic Wnt ligands .
Stress-related inflammation markers have proven to be efficient in predicting change in bone mineral density, i.e., either osteopenia or osteoporosis . In depression, a prototype disease of stress system imbalance, it has been shown that biological factors include the inflammatory-mood pathway, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, metabolic dysfunction, and serotonin’s direct and indirect effects on bone cells causing osteopenia and/or osteoporosis. The pathophysiology lies within the vicious cycle of constant subclinical inflammation, increased proinflammatory cytokines, and disruption of bone remodeling balance . Other molecules, such as IGFBP1 and FGF21, are implicated in bone remodeling. These molecules derive from the liver, though recently they were also characterized as bone hepatokines . IGFBP1, an FGF21-induced pro-osteoclastogenic liver hormone functioning through integrin β1 receptor in the osteoclast lineage, is stimulated by glucocorticoids and promotes excessive bone resorption .
To conclude, stress prevents bone remodeling directly via chronic hypercortisolemia and indirectly via the activated inflammasome (Fig. 4).