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Oxidation and Inflammation in the Immune and Nervous Systems, a Link Between Aging and Anxiety

  • Mónica De la FuenteEmail author
Living reference work entry

Abstract

Anxiety and aging are two related situations. Thus, adult individuals with anxiety show premature aging, and anxiety symptoms or disorders are relatively common in older subjects. According to the oxidation-inflammation theory of aging, chronic oxidative stress and inflammatory stress situations (with higher levels of oxidant and inflammatory compounds and lower antioxidant and anti-inflammatory defenses) are the basis of the age-related impairment of the functions of organisms. This principally affects the homeostatic systems; the nervous, endocrine, and immune systems; as well as their bidirectional communication. The age-related alteration in homeostasis and the resulting increase of morbidity and mortality could thus be explained. This theory also suggests that the immune system, due to its property of producing oxidants and inflammatory compounds to carry out its work, if not well regulated, could be involved in the rate of aging of each individual in the context of neuroimmune communication. It has been observed that an oxidative-inflammatory situation occurs in subjects with anxiety, which contributes to immunosenescence and a shorter life span, As an example of this, there are several models of premature aging in mice, in which those animals with a poor response to stress and consequently high levels of anxiety, show an oxidative and inflammatory stress in their immune cells and brain as well as in other tissues. These animals show premature immunosenescence and a shorter life expectancy than the corresponding counterparts of the same age. In conclusion, oxidation and inflammation, two related processes, could be the link between immunosenescence, aging, and anxiety.

Keywords

Oxidative stress Inflammatory stress Oxi-inflamm-aging Anxiety Aging Neuroendocrine immune axis Premature aging 

Introduction

The maintenance of health or the appearance of diseases may be explained in the context of the communication between the regulatory systems: the nervous, endocrine, and immune systems. This bidirectional neuroendocrine-immune communication is so important for life that it has been evolutionary conserved. The responses of organisms, facing the changes that constantly occur, need to be maintained in a delicate and dynamic balance. Although the term most used to describe this balance is “homeostasis,” due to nothing being static in life, the terms “homeodynamic” should be employed. Therefore, in this chapter when the word “homeostasis” appears, it is being referred to as a dynamic balance. Thus, the maintenance of health depends on this appropriate dynamic balance in all physiological responses. In this context, oxidation and inflammation, which are two related processes, are essential for many functions of the organism, when these processes occur within determined limits. An excess or lack of oxidants, inflammatory compounds, and antioxidant or anti-inflammatory defenses represents an imbalance that could have pathological consequences.

With aging all the physiological systems are impaired, but especially the systems charged with the maintenance of homeostasis and, consequently, more morbidity and mortality occurs. The basis of this deterioration seems to be the age-related increase of oxidative and inflammatory stresses together with the decreased capacity of compensating the corresponding damage. These stresses also underlie the alterations of the nervous system in anxiety disorders, appearing more frequently in aged subjects and representing a premature or accelerated aging state in the individuals that experience them. Thus, oxidation and inflammation constitute a link between anxiety and aging, the immune system playing a relevant role in both processes. The participants in these processes are numerous, and more and more new mechanisms are being discovered. However, this chapter will only cover some of the principal and better known molecules involved in the oxidation and inflammation state as well as their relationships and effects on aging and anxiety.

Neuroimmunoendocrine Communication

Currently, there is abundant work that confirms the existence of bidirectional communication between the regulatory systems, which is mediated by cytokines, hormones, and neurotransmitters through the presence of the corresponding receptors on the cells of the three systems. Moreover, immune, nervous, and endocrine products coexist in lymphoid, neural, and endocrine tissues; the cells of these three systems being capable of the synthesis of all the types of mediators. Thus, cytokines, which are mainly produced by immune cells, but also synthetized by nerve cells, are able to reach neurons and to regulate important brain activities including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, as well as neural circuitry of mood among other functions. In addition, neurotransmitters and hormones, produced by nerve and endocrine cells, but also by leukocytes, modify immune cell functions. This shows the complexity of the regulation of the organism, establishing both long and local circuits. Presently a psychoneuroimmunoendocrine system is generally accepted. This allows the preservation of homeostasis and therefore of health (Verburg-van Kemenade et al. 2016). The scientific confirmation of the communication between these systems has permitted the understanding of why situations of depression, emotional stress, or anxiety are accompanied by a greater vulnerability to infections, cancers, or autoimmune diseases, agreeing with the concept that the immune system is affected. By contrast, pleasant emotions help to maintain a good immune function. In addition, any influence exerted on the immune system will have an effect on the nervous and endocrine systems and vice versa.

Stress, which has been defined as “the nonspecific response of the body to any demand,” forms part of life since all organisms are submitted continuously to “stressors” (all stimuli able to induce stress response). If individuals respond adequately to stressors they are healthy, but the failure of adaptation to life stress represents disease. The concept of stress is only understandable in the framework of “psychoneuroimmunology.” Thus, psychological stressor stimuli can induce modifications in the central nervous system (CNS) and in the sympathetic nervous system (SNS), as well as in the neuroendocrine system, more specifically in the hypothalamic-pituitary-adrenal (HPA) axis. The activation of both SNS and HPA axes leads to the secretion of neurotransmitters and hormones such as noradrenaline, and catecholamines and glucocorticoids (GCs), respectively, which play an important role organizing the stress response by binding to their receptors in brain and peripheral tissues. These neurotransmitters and hormones can act as modifiers of immune functions. Stress-related immune changes are very different not only depending on the type, frequency, or intensity of stressors but also on the characteristics of each individual (personality, life experiences, social situation, controllability, and perception of the situation, among others), all which cause a very high inter-individual variability in responses.

The Basis of Oxidative Stress: Oxidants and Antioxidants

The imbalance between pro-oxidants and antioxidants leads to an accumulation of oxidative damage in macromolecules, resulting in a loss of cell functions. Free radicals (small molecules that contain one or more unpaired electrons, which make them highly reactive because they act as capturers of electrons) are relevant oxidants. The superoxide anion \( \left({\mathrm{O}}_2^{\bullet -}\right) \), the first radical produced from oxygen, can generate the hydroxyl (OH) radical, which although it has a very short half-life, indiscriminately oxidizes the nearby molecules, generating other radicals such as the peroxyl (ROO) and the alkoxyl (RO) radicals. The \( {\mathrm{O}}_2^{\bullet -} \) can interact with other molecules to generate reactive oxygen species (ROS), molecules that do not follow the strict definition of free radicals, but produce them, either directly or mainly through enzyme or metal catalyzed processes. Thus, \( {\mathrm{O}}_2^{\bullet -} \) can produce hydrogen peroxide (H2O2), which is relatively stable compared to other ROS. Moreover, like other oxidants, it also plays an important role in contributing to cellular oxidative damage as well as being able to lead to the generation of other ROS as well as RNS (reactive nitrogen species) through various chemical reactions.

With regard to the free radicals derived from nitrogen, the nitric oxide (NO) molecule and the peroxinitrite (ONOO•) radical are the most important RNS. Thus, NO is an abundant RNS which acts as a relevant signaling molecule in a large variety of physiological processes, including the regulation of blood pressure, neurotransmission, and immune response; NO also has the peculiarity that is soluble in aqueous and lipid media and rapidly diffuses through the cytoplasm and plasma membranes, and when combined with the \( {\mathrm{O}}_2^{\bullet -} \), produces significant amounts of ONOO•,. a potent oxidizing agent that can cause DNA and lipid peroxidation (revised in Vida et al. 2014).

Cellular Sources of ROS and RNS Production

In mammalian species, ROS and RNS are physiologically produced within cells through several mechanisms or pathways. These species are generated in large part from cellular respiration and other metabolic processes, in which several organelles (mitochondria, peroxisomes, etc.) and enzymes (i.e., xanthine oxidase, nitric oxide synthetase, citochromes P450, cyclooxygenase, lypoxigenase, NADPH-oxidase complex, etc.) participate.

Although about 95–98% of ROS are produced in mitochondria respiratory chain complexes (mtROS), other enzymes implicated in other metabolic processes also contribute to the cytosolic pool of ROS. Some enzymes, such as those of mitochondria, do not show as a major property the generation of ROS during their catalytic activity. This is the case, for example, of cytochrome P-450, cycloxygenase, or lypooxygenase, among others. Nevertheless, a soluble cytosolic enzyme such as xanthine/xanthine oxidase (XO) can generate the superoxide anion and H2O2 as a primary intermediate in its role of reducing oxygen. Another enzyme constituting a typical ROS generating system is NADP-oxidase (Nox), which is a family of enzymes present in all the multicellular organisms that generate ROS as the primary species during the catalytic metabolism of oxygen. NADPH oxidase is a multienzyme complex in which NADP is the electron donor for all the five Nox isoforms identified, each of which is based on a distinct catalytic subunit (Nox 1–5). Their various components are assembled in the plasma membrane in functionally active Nox or during activation, transferring electrons from NADPH to oxygen producing \( {\mathrm{O}}_2^{-\bullet } \) and H2O3. Nox2 is formed in the membrane of immune cells and Nox 4 in mitochondria.

Immune cells, especially phagocytic cells, are another major source of oxidants. Phagocytes attack and eradicate pathogens using a mixture of oxidants, such as \( {\mathrm{O}}_2^{-\bullet } \), H2O2, or NO. This innate immune mechanism principally involves the “respiratory burst,” which is carried out when these cells are stimulated in response to appropriate stimuli. This process is mediated by Nox2, a complex that acts from the membranes of phagosomes. This enzyme, relatively well known for its role in innate immunity, also participates in adaptive responses. In part, the cytotoxic effects of these ROS relate to their ability to react with products of other microbicidal systems in these cells, such as hypochlorous acid, produced by the enzymes myeloperoxidase, and NO, generated by inducible nitric oxide synthase (iNOS). In addition, it has been described that non-phagocytic cells such as fibroblasts, endothelial cells, vascular smooth muscle cells, and other cells also possess superoxide-producing enzymes analogous to the phagocyte NADPH-oxidase complex, but in these cells, the low amounts of ROS produced may function as second messengers to influence redox-sensitive signal transduction pathways.

Finally, another source of free radical production is the environment. Thus, ROS are commonly produced by a series of environmental factors, such as ultraviolet and infrared radiation, pollution, chemicals and drugs, or nutrition, among other things.

Antioxidant Defense Mechanisms

All organisms using oxygen generate antioxidant defenses to protect cell components against oxidative damage. They constitute integrated antioxidant defense mechanisms, which act depending on the nature of oxidants present in the systems, as well as the activities and amounts of the antioxidants and their cooperative/synergistic interactions. They are usually effective in blocking harmful effects of ROS and RNS. Endogenous antioxidant defenses include a network of compartmentalized antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR), among others, which distributed within the cytoplasm and in various organelles, work in a complex series of integrated reactions to convert ROS to more stable molecules, such as water and oxygen. Thus, SOD, both the cytosolic (copper/zinc) (SOD1 and SOD3) and the mitochondrial (manganese) (SOD2) isoenzymes, which are considered to be the first line of defense against oxidative insult, convert the \( {\mathrm{O}}_2^{\bullet -} \) into H2O2 and oxygen and suppress the scavenging of NO by superoxide. CAT, which is primarily found in peroxisomes, but is also located less abundantly in mitochondria, is the most reactive enzyme in the majority of the tissues converting toxic H2O2 to water. GPx, which is a family of eight enzymes found in both cytosol and mitochondria, represents one of the major H2O2 scavenger enzymes. Together with its substrate glutathione (GSH), they form a formidable defense against hydrogen and lipid peroxides. Besides the primary antioxidant enzymes, a large number of secondary enzymes act in concert with small molecular-weight antioxidants to form redox cycles that provide necessary cofactors for primary antioxidant enzyme functions. Although endogenous antioxidant enzymes are considered to be a primary defense that prevents biological macromolecules from oxidative damage, they are incomplete without other endogenous small non-enzymatic compounds, such as GSH and thioredoxin. In fact, the glutathione and thioredoxin systems have been implicated in the regulation of cellular redox and in many signaling mechanisms, controlling processes such as DNA synthesis, cell proliferation, and apoptosis, among others. Coenzyme Q or ubiquinone is also an essential antioxidant, particularly abundant in membranes of mitochondria. Exogenous antioxidant compounds, such as vitamins E and C, carotenoids, polyphenols, and trace metals (i.e., selenium, zinc), with diet being their main source, have also to be considered. These endogenous and exogenous non-enzymatic antioxidants can function as direct scavengers of ROS and act interactively (e.g., synergistically) to maintain or re-establish redox homeostasis. Thus, all these antioxidant systems are necessary for sustaining life by their ability to both maintain a delicate intracellular redox balance and decrease or prevent cellular damage caused by excess of ROS. Nevertheless, how such complex antioxidant systems react with oxidants and achieve the required specificity and sensitivity for proper antioxidation is still incompletely understood (Vida et al. 2014; Ma 2014).

Are Oxidants and Antioxidants Harmful or Beneficial?

ROS and RNS are continuously generated by the normal metabolism of cells and they are either beneficial or damaging depending on their concentration. At high concentrations, when the overproduction of ROS and RNS is higher than the efficiency of the antioxidant system, alteration occurs in the equilibrium of pro-oxidant versus antioxidant reactions. This leads to an “oxidative stress” situation, in which ROS and RNS have harmful effects, because they react readily with cellular macromolecules, such as lipids, proteins, carbohydrates, and nucleic acids, causing oxidative damage, and often inducing irreversible functional alterations or even their complete destruction. Thus, an overproduction of ROS and RNS can contribute to the development of many diseases, such as cancer, atherosclerosis, hypertension, or neurological disorders, among others. Nevertheless, at low/moderate concentrations, ROS and RNS are needed to maintain biological homeostasis acting as second messengers in intracellular signaling cascades including gene regulation, signal transduction pathways that mediate cellular functions and being essential for physiological processes and survival. Even, a certain amount of oxidative stress can represent “hormesis,” since at the molecular level, to cope with conditions of stress such as an oxidative stress, organisms have developed a wide range of sophisticated stress response mechanisms, which act at the cellular or organelle-specific level, initiating a series of events for maintenance, repair, adaptation, remodeling, and survival (Rattan 2014). An example of this fact is the case of the immune cells, which need to produce ROS, as well as other oxidant and inflammatory compounds, in order to perform their defensive functions, including the destruction of pathogens and tumor cells, the lymphoproliferative capacity, and the regulation of biosynthesis of antibodies and cytokines. For this reason, if there is an increase of antioxidant compounds such as could occur in the case of a very high ingestion of antioxidant supplements, an imbalance can appear with a low amount of oxidants and their functions are not carried out. Thus a “reductive stress” is as bad as an oxidative stress. Therefore, a perfect dynamic balance between oxidants and antioxidants is essential for the correct functioning of our organism. When this balance is lost by an excess of oxidants or a decrease of antioxidants, a high oxidative stress appears causing disease and aging.

Inflammation and Its Relation to Oxidative Stress

Inflammation is an evolutionary-conserved protective mechanism employed by the organism in which several molecules and cells, especially the immune cells, react to and neutralize foreign damaging agents (endogenous and exogenous antigens) or other stimuli in order to restore the cells to their normal state or replace destroyed tissues. Thus, inflammation is an essential protective part of the response of the organism to infections and injuries, so being necessary for survival. Nevertheless, inflammation has to be controlled in space and time since if inflammatory stimuli persist over time, increase the response, or do not stop, a situation of chronic inflammation occurs, favoring the susceptibility to disease. Similarly to the case of oxidation, a certain amount of inflammatory stress is necessary, especially for immune response, but an excess is noxious and underlies practically all diseases. Consequently, the balance between pro-and anti-inflammatory signals regulates inflammatory response, leading to either restoration of health or the development and progression of disease (Vassileva and Piquette-Miller 2014).

Inflammation is always a parallel result of oxidation; these two processes being interrelated and concatenated. In an inflammatory response, there is immune cell infiltration that can lead to cellular damage due to ROS/RNS overproduction, which can also recruit other inflammatory cells leading to additional ROS/RNS production and amplify the cellular damage. Thus, although in response to this, the antioxidant systems eliminate the excess of free radicals and activate genes involved in oxidative damage repair of molecules; if the inflammation is chronic the rate of ROS leads to depletion of cellular antioxidants, resulting in an induction of recurrent molecular damage. Moreover, the generation of ROS and RNS also leads to signaling cascades that trigger the production of proinflammatory cytokines and chemokines, which in turn also induce ROS and RNS production and the impairment of antioxidant systems, leading to a situation of oxidative stress. It is currently accepted that over production of oxidant compounds can induce an inflammatory response, since oxidants can act as inflammatory mediators (Vida et al. 2014). All this has been observed, but the cause–effect relationship between oxidation and inflammation seems to be more complicated than previously thought, and the nature of the potential interactions of the multiple molecular pathways involved in both processes in modulating cellular damage and dysfunction, remains unclear.

Collateral oxidative and inflammatory damage is inseparable from the immune response, especially that carried out by innate cells, underscoring the necessity of regulatory mechanisms that modulate ROS and inflammatory compound production. When the immune cells function, they produce inflammation. When this is generated without the presence of pathogens, it is denominated “sterile inflammation” and the mechanisms involved in this and in infectious inflammation, although not being exactly the same, share many characteristics (Behnia et al. 2016). In the cells involved in innate immunity, phagocytes (the most typical being monocytes/macrophages and neutrophils, as well as dendritic cells) have to be considered, but also innate lymphoid cells (ILCs). These ILCs are a family of innate immune cells, which are categorized into three groups (ILC1, ILC2, and ILC3) on the basis of the transcription factors that direct their functions and the cytokines they produce, which have diverse roles in host defense, tissue repair, and inflammation. They can regulate adaptive immune response establishing complex crosstalk with elements of this immunity and those of the microenvironment to orchestrate immune homeostasis. Thus, the role of ILCs is complementary rather than a duplicate of adaptive immune system function. These cells play a central role in sensing danger signals in the body and modify immune response on the basis of this information (Almeida and Belz 2016).

Several pathways by which the oxidative damage produced by ROS/RNS promotes chronic inflammation have recently been described. In this context, the molecules denominated “pattern recognition receptors(PRR), which are receptors of “pathogen-associated molecular pattern(PAMPs) molecules, as well as of “damage-associated molecular pattern(DAMPs) molecules, present in cells and especially in those of innate immunity, should be mentioned. To these PRRs belong the ubiquitous family of Toll-like receptors (TLRs) and the cytoplasmic Nod-like receptors (NLR), which are involved in the innate response to eradicate invading pathogens or cell damage caused by injury. Moreover, the activation of TLRs and NLRs by PAMPs or DAMPs is involved in the global stimulation of the innate response through oxidation and inflammation. The list of PAMP and DAMP compounds is very large. LPS is a typical example of a PAMP, activating cells through TLR (TLR4) and NLR. Although the stimulation through TLR has been more studied, the mechanism by which LPS is sensed in the cytosol of host cells has only recently been proposed. This is carried out through a system of “outer membrane vesicles” (OMVs) (Broz 2016). As examples of DAMPs, it is possible to mention oxidized low-density lipoprotein, cholesterol crystals, heat shock proteins (Hsp), and ROS among others. Thus, it has been observed that high levels of HSPs or post-translationally modified molecules, such as oxidized proteins, as well as an increased ROS production, can activate the TLR2 and TLR8 pathways. These will proceed to initiate an inflammatory response by activation and release of proinflammatory cytokines, such as interleukine (IL)-1 and tumor necrosis factor (TNF) families. In this increase of inflammation, the activation of inflammasomes is involved. These inflammosomes are cytosolic multiprotein complexes, which are assembled and activated as a consequence of the triggering of NLRs, promoting proinflammatory caspases, particularly caspase-1. This leads to the processing and secretion of the proinflammatory cytokines such as those of the IL-1 and TNF families mentioned above. Among the different inflammasome complexes, the pyrin domain containing 3 (NLRP3) is one of the most implicated in the release of proinflammatory cytokines. This NLRP3 inflammosome is directly activated by the presence of sustained amounts of ROS, which contribute in this way to inflammation (Goldberg and Dixit 2015; Shrivastava et al. 2016). Therefore, TLRs and the NLRP3 constitute PAMP and DAMP specific receptors, which link oxidative damage to chronic inflammation, since they activate a proinflammatory phenotype inducing the release of the corresponding cytokines, which up-regulate the formation of ROS/RNS in immune cells and the consequent oxidative stress response. In turn, this overproduction of ROS/RNS can cause oxidative damage to biomolecules impairing their cellular functions and creating a circular loop of TLRs and NLRP3 activation. Thus, inappropriate regulation of inflammasomes, via altered innate immune cell functions, and elevated levels of DAMPs, can contribute to the establishment of chronic low-grade inflammation (Kapetanovic et al. 2015).

Another link between oxidative stress and inflammation is the accumulation of oxidized high molecular weight aggregates, which include carbonylated advanced lipoxidation end (ALE) products, advanced glycation end (AGE) products, and malondyaldehyde (MDA) modified proteins, which are indicators of cellular stress responses. For instance, new results suggest that MDA can promote lymphocyte activation via induction of inflammatory pathways, such as inflammatory cytokines, which would induce an oxidative stress situation. Moreover, other studies have shown that both endogenous AGEs production and accumulation have an adverse effect on tissues because they induce ROS production, increasing oxidative stress and stimulating the synthesis and release of proinflammatory cytokines (Luévano-Contreras et al. 2013).

The crosstalk between different enzymatic sources of oxidative stress should also be considered in the oxidation-inflammation connection. Thus, in leukocytes, especially in phagocytic cells, Nox activation has been observed in response to mtROS formation (Kröller-Schön et al. 2014). Current studies provide evidence that mitochondria can modulate innate immunity and systemic inflammatory response and could consequently promote inflammation. Moreover, mitochondria as well as their classical role as regulators of cellular metabolism through production of ATP for energy homeostasis present other mechanisms for the control of cellular and tissue functions. These are carried out through complex mitochondrial-nuclear communications and the extracellular release of mitochondrial components that can act as signaling molecules. In fact, it has been observed that fragments of DNA of mitochondria (mtDNA) produced by ROS can escape from this organelle and are also present in DNA of the nucleus (nDNA), leading to a change of nuclear information (Caro et al. 2010).

Recently, a relevant factor in the link and control of oxidation and inflammation has been proposed. This is the “negative regulator of ROS” (NRROS), which is a protein that represents a crucial mechanism that modulates ROS production by phagocytes during an inflammatory response, and thus regulating the levels of oxidation and inflammation, controlling invading pathogens while minimizing unwanted collateral tissue damage. This protein is located in the endoplasmic reticulum, where it directly interacts with nascent Nox2 facilitating its degradation and impeding Nox 2 trafficking to the phagosome membrane (Noubade et al. 2014). Thus, NRROS dampens ROS production by restricting Nox2 availability and “cools-off” inflammation (Bonini and Malik 2014). In situations with inflammatory signals, for example, the presence of LPS as a consequence of infections, these signals repress NRROS expression in phagocytes, allowing the activation of Nox2 and the consequent increase of ROS to kill pathogens.

With respect to the mediators mentioned in the link between oxidation and inflammation, a question arises: How can the cell-cell communication be carried out in inflammation and oxidation? Besides the role of cytokines in this communication, the relevance of the extracellular vesicles (EVs) has recently been observed. These EVs, both exosomes and microvesicles, represent an important mode of intercellular communication, through which membrane and cytosolic proteins, lipids, and RNA can be transferred between cells. Moreover, EVs are a ubiquitous mechanism for transferring information between cells but also between organisms across all three life Kingdoms. Thus, EVs transport molecules from pathogens to hosts and between parasites and cells in an individual, playing an important role in the healthy or diseased state of the organism, especially in many diseases in which immune cells are involved. For example, cells subjected to oxidative stress secrete EVs, which act as an oxidative stress-induced endogenous danger signal that underlies the pervasive role of TLR inflammatory situations (Turpin et al. 2016; Schorey and Harding 2016).

In summary, oxidation and inflammation are related processes that can cause cell damage, but nevertheless, oxidant and inflammatory compounds are necessary for many functions of the organism. Because of this, the basis of the maintenance of health is the appropriate balance between oxidant and antioxidants as well as between inflammatory and anti-inflammatory compounds.

Oxidative and Inflammatory Stress in Aging: OXI-INFLAMM-Aging

One of the most accepted theories for explaining how the aging process occurs is the theory of free-radicals proposed by Harman in 1957, which has been further developed by several researchers (revised in De la Fuente and Miquel 2009). This theory proposes that aging is the consequence of the accumulation of damage by deleterious oxidation in biomolecules caused by the high reactivity of the free radicals produced in cells as a result of the necessary use of oxygen. Since oxygen is mainly used in respiration to support the life-maintaining metabolic processes, the mitochondria, and more concretely their DNA (mtDNA), are probably the first target of this oxidation, the fixed post-mitotic cells that cannot fully regenerate these organelles being where the aging process starts. Thus, the capacity of mitochondria to generate free radicals near mtDNA is considered one of the most relevant mechanisms of aging. Moreover, the age-associated damage to mitochondria, probably due to changes in the activity of key components of the respiratory chain and depletion of their wide array of antioxidants and detoxifying enzymes, show these organelles as important regulators of longevity. In fact, it has been described that in long-lived species, the rate of mtROS production is lower than those with short lives. Thus, a direct correlation between mtROS production and lifespan has been established (Barja 2013). With aging, there is an increase of mtDNA fragments accumulated inside nDNA, which cause damage. This fact has been suggested as another mechanism contributing to aging (Caro et al. 2010; Cheng and Ivessa 2012). In spite of all the information published supporting the free radical theory of aging, several authors have proposed that it does not provide a complete explanation of the aging process (Liochev 2015; Sanz 2016). In fact, in the last few years more attention has been given to the idea of “inflammaging,” which was suggested by Franceschi et al. (2000) and focuses on the chronic, low-grade inflammatory state that appears with increasing age.

As also mentioned previously, an increased number of observations in the last decades have shown that redox signaling is essential in physiological homeostasis and that the alterations in this are observed in aging (Forman 2016). Thus, the functions of our organism are based on a perfect balance between the levels of oxidant, antioxidant, inflammatory, and anti-inflammatory compounds, and it is the loss of this balance, which leads to the oxidative and inflammatory stress, underlying cell injury, diseases, and aging. Since chronic oxidative stress and inflammation are closely related and both processes seem to be linked to aging and contribute to the physiopathology of age-related diseases, the theory of oxidation-inflammation of aging was proposed (De la Fuente and Miquel 2009). This theory suggested that the age-related changes are associated with a chronic oxidative ad inflammatory stress, which can damage all cells of an organism, but especially those of the regulatory systems, affecting their functions, and thereby increasing morbidity and mortality. Moreover, this theory, in which the idea of an “oxi-inflamm-aging” was suggested, also proposed the involvement of immune cells in the rate of aging. The immune cells, due to their need to generate oxidant and inflammatory compounds in order to carry out their functions, could lose their redox regulation capacity. This is the basis of immunosenescence and of the age-related chronic oxidative and inflammatory stress of the organism, and consequently of the rate of aging. In this regulatory failure, the excess activation of the transcription factor NF-kB seems to be involved (De la Fuente and Miquel 2009; Arranz et al. 2010). In fact, the NF-kB has been shown as the transcription factor most associated with aging, being a molecular culprit of the inflamm-aging process. NF-kB is activated by a variety of external and internal signals, like those involved in inflammatory response and oxidative stress. Moreover, NF-kB transcriptionally regulates hundreds of genes involved in the activation of inflammation and oxidative stress. Thus, several mechanisms that suppress the activation of NF-kB and repress the appearance of a proinflammatory phenotype impact health and lifespan (Salminen et al. 2011). In the immune cells, NF-kB is very relevant in the redox and inflammatory states of these cells. Thus, leukocytes with very high expression of NF-kB showed impaired function and the individuals with these cells die prematurely, whereas when the expression was low, similar to that in leukocytes from adults, the cells functioned appropriately and the subject reached high longevity (Arranz et al. 2010). In this context, we have detected that individuals, whose immune cells present an oxidative stress and a deteriorated function, have a shorter life span. On the contrary, human centenarians and extremely long-lived mice show a good redox state and function in their leukocytes (De la Fuente 2014).

Among other mechanisms involved in aging in the context of oxidation-inflammation is the incapacity of autophagy to completely remove damaged cellular structures, which results in the progressive accumulation of garbage, including cytosolic protein aggregates, defective mitochondria, and lipofuscin. Autophagy or “self eating,” a cytoplasmic pathway for removal of damaged organelles, is relevant in aging and in the control of inflammation. Thus, autophagic degradation of mitochondria seems strongly related to aging and lifespan, and defective autophagy can lead to inflammation and aging (Knuppertz and Osiewacz 2016; Netea-Maier et al. 2016). Lipofuscin, an intralysosomal polymeric substance primarily composed of cross-linked lipid and protein residues due to oxidative processes (Brunk and Teman 2002), increases with aging. In fact, lipofuscin is among the best markers of aging at cellular level and its degree of accumulation is related to mitochondrial damage and oxidative stress (Reeg and Grune 2015). Recent results have shown that there is an age-related lipofuscin increase in the immune cells, especially in phagocytes, which is not present in leukocytes from long-lived mice (Vida et al. 2017).

A possible sequence of facts that occurs with aging would be that the mitochondrial dysfunction and the consequent oxidative stress situation promote lipofuscinogenesis, poor autophagy, progressive oxidative stress, decreased ATP production, and the collapse of cellular machinery (Terman et al. 2010). Moreover, oxidation increases NF-kB signaling and the potentiation of NLRP3 inflammasomes and thus, the age-related proinflammatory phenotype (Salminen et al. 2012).

Age-Related Changes in the Psychoneuroimmunoendocrine System

With aging, many functions of the three regulatory systems involved in homeostasis, i.e., the nervous, endocrine, and immune systems are affected as well as there being an impairment of the communication between those systems. Although this subject has been treated in other chapters of this book, in the present chapter a brief description of several age-related changes in the homeostatic systems and their communication will be commented for a better understanding of the relationship between aging and anxiety.

With respect to age-related change in the nervous system, a progressive loss of its functions is evident. This can be shown, for example, in aspects such as sensation, cognition, memory, and motor activity. The neurobiology of aging has been one of the most rapidly expanding areas of scientific endeavor over the past two decades. There is evidence indicating that normal aging is accompanied by some alterations in the neurotransmission systems of humans and other mammals. In this regard, there are studies in rodents showing an age-related decline in the neurochemical parameters, such as a decrease in the levels of neurotransmitters as well as in the activities of the enzymes involved in their synthesis. The hippocampus, a structure in the CNS equipped with a high degree of flexibility and adaptation due to its neurogenesis capacity, is clearly affected with aging. This age-related decrease of neurogenesis explains the learning and cognitive impairment in aged subjects (Ojo et al. 2015). Moreover, hippocampus neurogenesis may be involved in the regulation of stress-related disorders.

In the endocrine system, several changes accompany healthy aging; these include, for example, the decrease of growth hormone/insulin-like factor-1 axis (somatopause) and of sexual hormones, namely, estradiol (menopause), testosterone (andropause), and dehydroepiandrosterone (adrenopause). Moreover, the age-related disturbances of the HPA axis are responsible for decreasing stress adaptability in old subjects, this being, at least in part, the cause of their health impairment.

During aging, almost every component of the immune system undergoes striking re-structuring, leading to changes that may include enhanced as well as diminished functions which is known as immunosenescence, resulting in the impairment of both innate and adaptive immunity. This contributes to the increased susceptibility to infections, cancer, autoimmune diseases, as well as many other age-related illnesses. In fact, several functions of immune cells are good markers of health, rate of aging (biological age), and longevity. In this sense, the chemotaxis and phagocytosis of phagocytes, the migration and proliferative response to mitogens of lymphocytes, as well as the NK cytotoxicity against tumor cells, functions that decrease with aging, have been proposed as markers of the rate of aging and longevity (Martínez de Toda et al. 2016a). The cytokine network is also affected by aging, and this can contribute to the decline of immune functions. The age-related changes in the immune cell subpopulations are another aspect to consider in immunosenescence.

In aging, it is difficult to determine if the deterioration of the nervous, endocrine, and immune systems occurs simultaneously or starts in one of them and then affects the others. However, many age-related changes happen in the communication between the homeostatic systems, which suffer impairment. This idea was the basis of another theory of aging, which proposed these changes in the neuroimmunoendoerine communication as a probable cause of physiological senescence. Although this theory of aging, as the majority of them, is focused on something that happens with aging but not on its cause, it pointed out the relevance of the altered neuroendocrine-immune communication in the aging process. Several studies on the in vitro response of immune cells to a wide range of concentrations of several neurotransmitters showed how these responses changed depending on the age of the subject. This demonstrated that although the levels of neurotransmitters that contact the immune cells are maintained with age, the response of these cells would be different. Moreover, sympathetic innervation, as well as the concentration of noradrenaline (NA), decreases in spleen and lymph nodes with age. Although the expression of beta-receptors on the immune cells increases during old age, as a compensatory mechanism, higher concentrations of NA are needed for stimulation of the phagocytic function of peritoneal macrophages. The defective response of immune cells to neurotransmitters could contribute to the processes of immunosenescence and concretely in the case of catecholamines and their catabolites explain the inadequate response to stress that occurs with aging. In addition, the age-related impairment of the immune system could affect the functions of the other regulatory systems such as CNS through increased oxidative and inflammatory stress. The immune system and the CNS appear to be especially vulnerable to the age-related effects of oxidative stress and inflammation (De la Fuente et al. 2011). This will be covered later.

Factors that Could Be Involved in the Contradictory Results Obtained in the Studies on Age-Related Changes of the Regulatory Systems

Although everybody agrees that the regulatory systems change with aging and that these alterations represent the impairment of their functions, there are many contradictory results. This fact can be due to several reasons, some of which have been mentioned in the case of the immune system in previous publications (De la Fuente et al. 2011), but they can also be applied to the results in the nervous and endocrine systems. Thus, the age of subjects studied (chronological and biological age), the species and strains analyzed, the location of the cells, the gender differences, the time of day or season in which the functions are studied (the circadian and seasonal rhythms), the different designs and methods used in the determination of a function, are factors to be considered. In addition, many researchers are considering the peculiar characteristics of each subject, something previously not taken into account.

Possible new factors appear in this scientific field, for example, the microbiota of each individual. This is a subject that has been considered in another chapter of this book and will be briefly mentioned. Microbiota, especially the trillions of microorganisms that colonize for example the intestine, have coevolved over hundreds of millions of years with metazoan hosts in a symbiotic relationship. These microorganisms, the majority of which are bacteria, permit the maintenance of host health allowing adequate gut functions, protecting against colonization by exogenous pathogens and regulating immune and nervous system functions. Although this is a field that has been poorly studied in the context of aging, it is known that the age-related changes in microbiota (Bischoff 2016) could be the basis of the impairment function of immune and nerve cells. Moreover, microbiota can regulate the oxidation-inflammation state, not only through the regulation that they practice on immune and nervous system functions but also due to the fact that many microorganisms show antioxidant and anti-inflammatory properties (Shen et al. 2011; Woo et al. 2014). For this reason, they may modulate depression and anxiety states (Bercik et al. 2011) as well as the rate of aging and longevity (Biagi et al. 2013).

Age-Related Changes in the Redox State and Inflammation of the Immune System

Many studies have reported age-related increased oxidative and inflammatory stress in leukocytes from mice and from peripheral blood of humans, these cells being especially sensitive to oxidative damage. Consequently, in leukocytes of aged individuals, in addition to the increase of ROS and proinflammatory compounds as well as the decrease of the antioxidant and anti-inflammatory defenses, oxidative damage to lipids and DNA (higher levels of MDA and 8-hydroxy-2′-deoxyguanosine, 8-OHdG, respectively) appears. Moreover, these oxidized molecules and others, initiate the secretion of inflammatory cytokines, which promotes the activation of a “vicious circle” of oxidative and inflammatory mechanisms. Thus, the above mentioned changes that occur with age in the function of the immune cells could be closely linked, at least in great part, to the age-related chronic oxidative stress and the low-grade of inflammation to which they are exposed during the course of time (De la Fuente and Miquel 2009). In this context, several mechanisms can be mentioned. It is known there is an age-related decline in the proteolytic activity of the proteasome, in its ability to clear damaged proteins, with the further accumulation of these oxidized molecules, which are involved in immunosenescence. Intracellular misfolded protein aggregates, as well as carbonylated, AGE products, Hsps, and MDA modified proteins, all indicators of cell oxidative stress increase during aging and inflammatory conditions (diabetes, atherosclerosis) (Das et al. 2007: Martinez de Toda and De la Fuente 2015), Moreover, this accumulation of oxidized high molecular weight aggregates is associated to increased cellular apoptosis, immune cells from aged individuals being more vulnerable to this process than cells from young subjects (Cannizzo et al. 2011). Indeed, accumulation of proteins modified with AGE has been shown to induce apoptotic cell death in peripheral T cells (Hung et al. 2010), providing another link between oxidative stress and a decreased lymphocyte pool, a hallmark of immunosenescence. Another kind of cellular death, necroptosis, should be also considered (Pasparakis and Vandenabeele 2015). Those AGE products may also transform naive T cells into proinflammatory cells and decrease suppressive function of Treg (Han et al. 2014). Moreover, the receptors, for AGE (RAGE) expressed in immune cells, when AGE or DAMPs link with them, increase NF-kB signaling and thus the production of oxidant and inflammatory compounds. Therefore, the AGE/RAGE axis is a good therapeutic target in age-related inflammatory situations (Ramasamy et al. 2016).

Recently, we have proposed that with aging a vicious circle between oxidative and inflammatory stress with persistent viral infections, tissue injuries, and immunosenescence could be established (Bauer and De la Fuente 2016). With the advance of age a sterile inflammatory response followed by a chronic inflammation occur as the consequence of the increase in tissue injuries and the repair mechanisms for restoring their integrity, in which immune cells are involved. In this sterile inflammation, DAMPs are mediators of the immune response to tissue damage either in absence or presence of infections, constituting the so-called signal 0 s. These DAMPs provide signaling through TLRs and NLRP3, activating inflammation. Moreover, DAMPs also activate immune cells and their signaling pathway mediators such as NF-kB and NADPH-oxidase, as well as increase ROS production. Interestingly, ROS, which are considered a type of DAMP, act as signal-transducing molecules that upregulate proinflammatory cytokine production via TLRs and inflammasome-dependent pathways. Moreover, PAMPs derived from microorganisms, after the recognition by innate immune cells, also constitute “signal 0 s” that, similarly to DAMPs, trigger oxidative and inflammatory responses. In this context, the immune mechanisms generated against noxious stimuli such as infections and tissue injury, acting as defenses against “danger” or “damage,” may result in the development of a vicious circle when these stimuli persist and cannot be eliminated or cleared. This could occur during aging, since the impairment of immune cell function allow the maintenance of the noxious stimuli. As a consequence of this, many diseases appear and the rate of aging is increased. The DAMPs hypothesis of aging is currently being more accepted (Huang et al. 2015: Bauer and De la Fuente 2016). One type of DAMPs such as Hsp, concretely Hsp70, shows age-related changes specific for mitotic or postmitotic tissues and its basal levels in very old animals are similar to those in adults (Martínez de Toda et al. 2016b). In summary, the dysregulation inflammasome activation, via altered innate immune cell functions and the elevated levels of DAMPs, could be involved in the establishment of chronic inflammation and the acceleration of aging (Goldberg and Dixit 2015; Kapetanovic et al. 2015).

The Role of the Immune Cells in Oxi-Inflamm-Aging

As mentioned above, it seems evident that leukocytes can play a fundamental role in the aging process, as the consequence of the fact that the immune cells produce oxidant and inflammatory compounds in high amounts. If during aging adaptive immunity declines, innate immunity, in several aspects, seems to be activated, inducing a pro-oxidative and proinflammatory profile. Therefore, it has been proposed that the cells of innate immunity, especially phagocytes, are the most implicated in the rate of aging of the organism (De la Fuente 2014). In fact, these innate immune cells are involved in the majority of the pathways previously mentioned, which increase the age-related oxidation and inflammation. Moreover, the phagocytic cells, which have been found with different denominations in all animals, including invertebrates (which do not have lymphocytes), could be used by nature to control the life span of each individual (De la Fuente and Miquel 2009).

With respect to the source of ROS in the immune cells, those produced by mitochondria and especially those generated by Nox family should be considered. Although this family has been largely overlooked in aging theories, it has now been suggested as being involved. This ROS production through the Nox is implicated in the defense against microorganisms, but it also acts as a second messenger and activates relevant signaling pathways, in the regulation of the immune response, especially when ROS are produced in lower amounts. In addition, it has been suggested that there is an age-related increase of the production of ROS via Nox2 and Nox4, two activities upregulated with aging, in the phagocytic cells (De la Fuente et al. 2011). This increased oxidation affects other cells and may explain the role of immune cells in the rate of aging of all animals. Thus, although T cells express very low levels of Nox2, this enzyme well characterized in the innate response, also plays an important role regulating many functions of adaptive immunity such as Treg, TCR signaling, or cell death by cytotoxic T cells, among others. Mitochondria in lymphocytes, which are more abundant than in phagocytic cells, seem to show a relevant role in T-cell activation and function. Consequently, the loss of regulated levels of mitochondrial ROS loads to their aberrant development and activity. Thus, in animals with lymphocytes, in which an age-related destruction of the mitochondria appears, these ROS could contribute to the deterioration of the function of these immune cells. A crosstalk between mitochondria and Nox through ROS has been established. Thus, the mtROS triggering Nox over activate the phagocytic cells (Kröller-Schön et al. 2014). Therefore, the idea that the aging process starts in the mitochondria from fixed differentiated cells (De la Fuente and Miquel 2009) can be maintained, as well as the role of ROS produced through Nox in phagocytic cells is relevant in the control of the rate of aging in all animals. Moreover, recently it has been proposed that phagosomal Nox mediates mitochondrial respiratory-chain adaptations in macrophages, which contributes to antibacterial host defense (Garaude et al. 2016).

In addition, it is also necessary to consider the memory capacity of the innate immune cells. Although classically innate immune system cells have been considered to be nonspecific and devoid of memory, it now appears that they can be trained following exposure to microbes and other products and that this may confer a form of memory. Moreover, these cells can be reprogrammed through epigenetic modifications following exposure to pathogens or their products, resulting in heightened responses following a second stimulation. Unlike the antigen-specific memory of the adaptive immune system, the second stimulation does not have to be with the same pathogen or antigen. Certain pathogen or pathogen-derived molecules can prime immune cells, especially macrophages, to secrete more proinflammatory and less anti-inflammatory cytokines (Hamon and Quintin 2016; Fulop et al. 2016). This idea could explain the apparent contradiction between inflammaging and immunosenescence, since the age-related adaptation/remodeling process leads on the one hand to increased inflammation response and on the other to decreased immune response, this being controlled by the innate immune system (Fulop et al. 2016).

Age-Related Changes in the Redox State and Inflammation of the Nervous System

Although neuroinflammation is a major determinant of neural function and disease progression during aging, oxidative stress is also being currently considered in the age-related changes of the CNS (Chiurchiù et al. 2016). The CNS is particularly sensitive to oxidative stress due to many reasons including its high rate of oxygen consumption, resulting in a high ROS production, and the relative abundance of lipids, especially polyunsaturated fatty acids (PUFAs) in membrane, which are highly susceptible to lipid peroxidation by free radical attack. With aging, neurons are especially vulnerable to the long-term effects of continuous exposure to endogenous ROS, showing the negative impact of oxidative stress on molecules, mitochondria, and cell functions. In relation to the antioxidant mechanism, several studies have evaluated the age-related changes in the expression and/or activities of numerous antioxidant systems in brain from both humans and rodents. While some of them have showed an age-dependent decrease in activity and/or expression, others have shown the opposite pattern or no change, depending on the area of brain and animal model analyzed. In fact, these changes in antioxidant enzyme activity are markedly variable depending on some of the factors above mentioned (sex, region of brain, and even on the animal model or analytic techniques employed). In general, there is a decline in the normal antioxidant defenses, which increases the vulnerability of the brain to the deleterious effect of oxidative damage. The increases in antioxidant activities, which have been observed in patients with neurodegenerative diseases, such as Alzheimer’s disease or Parkinson’s disease, were higher in those regions which showed higher lipid peroxidation, seeming to indicate a compensatory mechanism in response to high oxidative stress. Furthermore, it is important to note that oxidative stress influences different regions of the brain at different rates and in different ways (reviewed by Vida et al. 2014).

There are age-related changes in membrane fatty acid composition in neurons, including an increase in unsaturated fatty acids, which makes them better targets for reaction with oxidizing agents. Thus, lipid peroxidation in the brain generates a broad range of compounds such as MDA and 4-hydroxy-2-nonenal (HNE), which increase in cells of different areas of the brain (temporal cortex, hippocampus, and cerebellum) in old experimental animals and humans. The high levels of MDA and HNE contribute to gene induction and cytotoxicity, damaging molecules such as proteins, which are inactivated, as occurs in the case of GPx, and showing neurotoxic actions. In fact, increased levels of protein carbonyls have been found in the hippocampus, as well as in the frontal and occipital cortex of aged humans and rodents, which have been associated with an age-related memory impairment. The DNA also suffers relevant oxidative damaged in neurons, the brain of aged subjects containing higher levels of 8-OHdG in nDNA and especially in mtDNA.

In addition, oxidative stress in the brain, through the interaction among several types of cell, including immune cells, glial cells, and neurons, increases the production of proinflammatory cytokines (i.e., TNF-α, 1 L-1β) and even more ROS and RNS, resulting in neuroinflammation. This process is considered an innate immune response in the CNS against several kinds of stimuli such as pathogens, injury molecules, or chronic mild stress. Neuroinflammation is mediated by the above mentioned PRRs, especially by NLRP inflammasomes, and it has an important role in the etiology of several brain diseases, general metabolic disorders, and brain aging (Singhal et al. 2014). Thus, neuroinflammation is an integral component of neurodegenerative processes, and in this context, DAMPs are nexus between both neuroinflammation and neurodegeneration (Thundyil and Lim 2015).

In the brain, a certain amount of inflammation is necessary, since proinflammatory cytokines such as IL-I and TNF families at constitutive levels are required for normal physiological functions such as learning, memory, and cognition, but the excess of inflammation, which could be denominated as neuroinflammation, is dangerous (Estes and McAllister 2014). In fact, CNS has an ongoing protective inflammatory mechanism, which involves many different immune cells, but this can fail with aging causing neurological disorders, in this context, microglia, as the resident immune cells of the brain provide constant support to neurons in healthy brain. These cells, being the first that react upon any stress signal, are beneficial and useful maintaining CNS homeostasis (Lourbopoulos et al. 2015). Thus, in the case of cellular damage, these cells, which constitutively express surface receptors (such as complement, chemokine and cytokine receptors among others), respond promptly by inducing a protective immune response, which consists of an upregulation of several neurotrophic factors and inflammatory molecules, in order to resolve potential pathogenic conditions. It has been recently proposed that neuroinflammation is mainly sustained by activated microglia exhibiting the Ml phenotype (Ward et al. 2015). With aging, microglia, as well as neurons, becomes dysfunctional, contributing to age-related oxidative damage and chronic inflammation in the brain, which promotes a prolonged activation of microglia and increases susceptibility to neurodegeneration. In fact, activated microglia mediate neurotoxicity by triggering a release of a wide array of neurotoxic products, such as ROS and RNS, these being the most abundant source of free radicals in the brain. Nevertheless, microglial cells have efficient antioxidant defenses, but the elevated and prolonged generation of ROS and RNS can exhaust the reserves of antioxidants, contributing to chronic oxidative damage and the consequent neuronal cell death. In fact, the age-related increase in the release of proinflammatory cytokines and decrease of anti-inflammatory compounds by microglia, especially in the hippocampus and cerebral cortex, are involved in the cognitive deterioration and memory loss associated with aging. Moreover, the chronic low-grade inflammatory state that appears with age primes microglia, which increase ROS production through Nox2 activity, this being the cause of neurotoxicity in several kinds of neurons and of neurodegenerative diseases (Block and Hong 2007). Chronic systemic inflammatory challenges also induce age-dependent microglial responses, which are in line with the impairment of learning and memory, establishing the concept of “microglia aging” (Wu et al. 2016). In addition, the immunosenescence that occurs with age affects the CNS and promotes neuronal dysfunction, especially within susceptible neuronal populations (Deleidi et al. 2015).

As previously mentioned, normal aging is also associated with abnormalities in neuroendocrine responses to stress, in particular as a consequence of altered functions of both HPA and SNS axes, decreasing stress adaptability in old subjects, and therefore, contributing to their deterioration in health.

Control of Oxidation and Inflammation, the Secret of Longevity

It is important to note that several studies support that exceptionally old mice show adult-like steady-state levels of membrane unsaturation and protein oxidative damage in brain, whereas old animals show, in general, increased values when compared to adult and exceptionally old mice (Arranz et al. 2013). All these findings support the idea that lipid peroxidation and accumulation of oxidized proteins contribute to the deterioration of CNS function and support the fact that the differences in fatty acid desaturation-elongation profile in the aging brain can be a mechanism responsible for longevity (Barja 2013).

In the immune system, centenarians and long-lived mice show values of several functions similar to those in the corresponding adult subjects (Martínez de Toda et al. 2016a). Similarly, the levels of oxidative stress in the immune cells are very like those in long-lived individuals and in adults. In general, a lower free radical production and higher antioxidant defenses have been reported in these subjects that reach healthy longevity. Inflammation has also been proposed as the best predictor of successful aging in extreme old age (Arai et al. 2015).

In summary, the maintenance of appropriate redox and inflammatory states allows adequate functions of the CNS and of the immune system, which has been observed in individuals with healthy longevity.

Anxiety and Oxidative-Inflammatory Stress

Anxiety, an emotion characterized by an unpleasant state of inner turmoil, is a normal part of life, when it is considered the response to stressful situations In this context, anxiety has a great adaptive value and for that it has been maintained along the evolutionary process. Anxiety is a complex somatic response involving all physiological systems, especially homeostatic systems and their communication. Nevertheless, the consequences in the organism are different depending on a short-term “state” or a long-term “trait” of anxiety. Thus, when we speak of “anxiety disorders,” we are referring to a group of mental disorders characterized by feelings of anxiety and fear maintained without an identifiable triggering stimulus. The provalence of anxiety in human populations is very high and represents an elevated cost for public health care all over the world (Remes et al. 2016). Moreover, the manifestation of anxiety in numerous psychiatric disorders highlights the importance of studying its underlying biology. Although there are many difficulties to establish a correlation of human psychic disorders in animal models, these have been very useful, and there are many translational studies for human anxiety using rodent models with anxiety-like behavior (Vida et al. 2014).

It is known that anxiety, in a similar way to the response to stress situation, involves an activation of both the HPA and the SNS axes. However, currently, the underlying mechanisms that explain anxiety are still unknown, and they are under continuous study. Most anxiety research has been focused on the alteration of several neurotransmitter systems, such as the gamma-aminobutyric acidergic (GABAergic) and serotoninergic systems, which play important roles in its regulation. Moreover, the alterations in these systems can also modify the functions of the HPA axis, which is crucial for the regulation of stress and anxiety-related responses. More recently, other mechanisms related to oxidative stress and inflammation seem to influence the etiology of normal and pathological anxiety in both humans suffering from anxiety disorder and experimental animals displaying high trail anxiety (Vida et al. 2014; Emhan et al. 2015; Villasana et al. 2016). In this regard, several studies have revealed a possible causal relationship between emotional stress, oxidative stress, and anxiety. The putative role of brain oxidative stress in the genesis of anxiety was firstly observed in rodents, in which the induction of oxidative stress in specific-regions of the brain such as hippocampus, hypothalamus, prefrontal cortex, and amygdala appears in parallel with an anxiogenic behavior. These regions suffer functional and structural atrophic or hyper-trophic changes with anxiety, showing an increased generation of oxidants. Although there are contradictory results since increased, decreased, or unaltered levels of oxidants have been described in relation to anxiety, in general, there is an increase in the levels of oxidants that are observed in the brain of mice and rats submitted to psychological distress. In fact, treatment with antioxidant or treadmill exercise both decreased oxidative stress in those brain regions and prevented anxiety-like behavior of these animals. With respect to the antioxidant mechanisms, a close relationship between genes implicated in antioxidant defenses and anxiety-related phenotypes was shown in several studies. Decreased levels of antioxidants in brain as well as in other locations in rats with an anxiety-like behavior and in humans with a state of trait anxiety have been observed. Thus, an oxidative stress situation in subjects (humans and experimental animals) with anxiety has not only been shown in the nervous system but also at peripheral levels, especially in the immune system (Vida et al. 2014).

In addition, some evidence indicates that there is also a bidirectional relationship between inflammation and anxiety. Thus, subjects with anxiety or animals with experimentally induced anxiety-like behavior show elevated markers of inflammation and were more susceptible to inflammation. Moreover, in situations in which an inflammation is produced, the anxiety-like behavior increases and this inflammation may contribute to an elevated risk of disease in anxious individuals.

The neurobiological mechanisms by which anxiety increases the risk of elevated inflammation remain unclear. However, it has been described that an exacerbated response to a threatening situation over time, which can lead to a chronic stress and anxiety, is accompanied by prolonged activation of threat-related neural circuits and threat-responsive biological systems, such as both HPA and SNS axes, as well as inflammatory response (O’Donovan et al. 2013). Thus, in the stress response, there is an elevation of noradrenaline, catecholamines, and GCs secretion, which might directly affect both basolateral amygdaloid and hypocampal neurons, which have a high concentration of the receptors of these neurotransmitters and hormones. This makes them highly sensitive to the prolonged effects of the activation of the HPA and SNS axes and produce changes that enhance anxiety. Moreover, high levels of GCs and catecholamines in the blood, binding to receptors on immune cells, can initiate intracellular signaling cascades that regulate immune cell gene expression and the release of proinflammatory cytokines. It is important to note that the effects of GCs and catecholamines on the immune system depend on the amount of these hormones released and their receptor expression on immune cells. For this reason, physiological levels of endogenous GCs suppress autoimmune and inflammatory reactions; however, high levels such as those in chronic stress and anxiety situations promote an inflammatory response. Thus, the glucocorticoid receptors (GRs) appear to be downregulated in response to anxiety, limiting the anti-inflammatory effects of GCs. Therefore, higher levels of psychological stress or anxiety, maintained over time, can promote chronic inflammation through structural and functional brain changes, altered sensitivity of immune cell receptors, and the deregulation of the HPA and SNS axes. In fact, there are numerous evidence that supports a link between chronic psychological stress and impaired immune function (Bauer et al. 2013).

In addition, chronic inflammation leads to changes in the brain regions such as amygdala and hippocampus, involved in the development of anxiety. These changes modify the structural and functional activity of the brain, contributing to the modification of neurotransmitter levels, neural plasticity, synapse turnover, and neuronal remodeling and replacement. In general, inflammation decreases the levels of serotonin and dopamine, and increases those of glutamate, which can lead to anxiety. Inflammation also causes microglia cells to release neurotoxic substances that decrease neuroplasticity and lower the numbers of astrocytes, decreasing the ability of the brain to protect itself and recover from neurotoxic damage. Additionally, proinflammatory cytokines and other mediators of inflammation stimulate the HPA axis and the consequent release of GCs. These, although initially, show their anti-inflammatory properties, but if they are produced in high levels or occurs with repeated or chronic stress, lead to an amplification of the inflammatory response, as mentioned above. In consequence, this self-promoting cycle makes it increasingly difficult to return to the normal HPA axis function. Therefore, the bidirectional interactions between peripheral and central inflammatory pathways raise the possibility that inflammatory dysfunction in the brain contributes to the peripheral inflammation and vice versa, in subjects with anxiety or anxiety disorders.

Are Anxiety and Aging Related?

Many psychiatric illnesses are associated with early mortality and with an increased risk of developing physical diseases that are more typically seen in the elderly. In this context, an emerging perspective suggests that anxiety disorders may be associated with premature and accelerated aging. Thus, chronologically, adult individuals with anxiety show premature aging, anxiety being a risk factor for many age-related diseases and for global mortality. As was previously mentioned, psychological stress, which is a feeling of being overwhelmed by the necessity of constant adjustment to a changing environment, can cause anxiety. Moreover, it is important to note that there is a link between the process of aging with both the emotional stress and anxiety, and their molecular consequences. In fact, stress is known to affect the bidirectional communication between homeostatic systems as well as increased production and trafficking of proinflammatory immune cells, especially monocytes, which can reach the brain providing mechanisms that may contribute to prolong anxiety (Reader et al. 2015). In the context of the neuroendocrine-immune network, since all immune cells exhibit receptors for nervous and endocrine system products and many neurotransmitters and hormones modulate immune cell functions, these mediators released after the activation of HPA and SNS in response to stress and anxiety can affect immune cells causing their impairment and immunosenescence. Thus, inadequate response to stress could show a premature immunosenescence with a greater vulnerability to infections, cancers, and autoimmune diseases and the consequent impairment of health and a lower longevity (O’Donovan et al. 2013) resulting in premature aging. In addition, it has also been shown that mice with chronic hyper-reactivity to stress and anxiety show a premature aging of the nervous and immune systems, a higher oxidative stress, and a shorter life span (Vida et al. 2014).

Stress situations affect individuals of all ages, but the older being more affected. In fact, with aging, alterations in the HPA axis and in the SNS appear and they are responsible for decreasing stress adaptability and increasing anxiety in old subjects. Thus, anxiety symptoms or disorders are relatively common in older adult subjects (Blay and Marinho 2012), and brain structural and functional changes that accompany normal aging are more pronounced in subjects with anxiety disorders than in coevals without them. All the molecular changes of brain aging were over-represented in anxious subjects (Pema et al. 2016). There is an overlap between the processes of impaired neurogenesis, neurodegeneration, structural, functional, molecular, and cellular modifications in anxiety disorders and aging. Moreover, in anxiety and aging, a chronic oxidative stress situation and a chronic low-grade systemic inflammation are common manifestations. These oxidation and inflammation states, as mentioned above, are associated with accelerated biological aging and thus, with an increased risk of age-related diseases and premature mortality. This relationship between anxiety and aging is shown in Fig. 1a, b.
Fig. 1

(a) An inappropriate response to stress situations produces changes in the neurochemistry of the brain (1) as well as increasing oxidants (ROS) and proinflammatory mediators (PI) (2), causing cell damage. This deterioration is related to anxiety disorders. As a consequence of the bidirectional communication between nervous and immune systems, these brain mediators reach peripheral immune cells (3) (in the figure represented by the spleen), although other cells of the organism can also be affected. These cells become dysregulated and increase the production of oxidant and inflammatory compounds, which (especially proinflammatory cytokines) reach different cells of the organism, but especially those of the brain, increasing its oxidation-inflammation (4). This fact increases anxiety. Moreover, anxiety is related to premature and accelerated aging. (b) With aging an oxidative and inflammatory stress appears especially in the regulatory systems such as the nervous and the immune systems. In the brain, the damage produced leads to neurodegeneration, which can cause anxiety. In the immune system, this damage causes a deterioration of functions, i.e., immunosencscence. The age-related increase of PAMPs and DAMPs leads to the immune cells, especially those of the innate immunity, to increase the levels of ROS and PI compounds, and consequently immunosenescence. These oxidants and proinflammatory compounds produced in the nervous and immune systems reach the other systems as well as other cells of the organism, increasing oxidation and inflammation and consequently anxiety and immunosenescence, constituting a vicious circle that increases the rate of aging

Model of Mice with Premature Aging and Anxiety

The use of animal models has been suggested as being useful in assessing the relationships between an individual’s diminished ability of managing with stressful situations, anxiety, immunosenescence, chronic oxidative stress and inflammatory stress, accelerated biological age, and shorter longevity (Vida and De la Fuente 2013). In fact, any study on the effects of a determined situation and the longevity of subjects needs to use rodent models with a shorter longevity than humans. In this context, several models of premature aging in mice have been studied and developed during the last few years (De la Fuente and Gimenez-Llort 2010; De la Fuente 2010) In this chapter, only one model, which is especially related to altered stress-related behavior response and anxiety, will be discussed.

This model relies on the differences in performance between mice of the same sex and chronological age when the animals were subjected to a T-maze behavioral test. Thus, the animals exploring the maze slowly showed, at young and adult age, a premature immunosenescence as well as neurochemistry and behavior responses similar to those in chronologically old animals. Moreover, these mice had a lower life span than their counterparts that explored the T maze quicker. For this reason, they were denominated “prematurely aging mice” (PAM) (Viveros et al. 2007). This model can be reproduced in several strains of mice and in both sexes. Using several behavioral tests (the holeboard, the open field, the plus-maze, and the tight rope test), PAM presented less adaptive response to stress, higher levels of emotionality and anxiety, as well as an impaired muscular vigor and coordination when compared to their “non-premature aging mice” (NPAM) counterparts. When, the monoaminergic systems were studied in discrete brain legions (hypothalamus, hippocampus, striatum, frontal cortex, and midbrain), adult PAM (both sexes) showed decreased levels of serotonine, dopamine, and noradrenaline in comparison to NPAM. These neurochemical modifications resemble some of the alterations previously observed in aged animals, and they could explain the altered behavior response and higher levels of emotionality and anxiety of PAM. Moreover, PAM also showed higher neuroinflammation as well as increased baseline corticosterone levels and a blunted stress response when compared to NPAM. This could contribute to the increased anxiety manifested in these animals as well as to premature immunosenescence, showing immune function values more similar to those of older animals. Considering the relevance of an optimal immune function for successful aging, this premature immunosenescence could explain the shorter life span of PAM in comparison to NPAM. Moreover, since it has been demonstrated that the progressive deregulation of immune responses associated with aging may be a result of increased oxidative stress, in immune and other tissues from PAM and NPAM, several oxidants and antioxidants have been studied. The results have revealed that PAM have higher levels of oxidant and proinflammatory compounds, as well as decreased levels of antioxidant defenses in comparison to the NPAM, showing, at adult age, values similar to those in old animals. In summary, all these findings demonstrate that PAM suffer a situation of oxidative and inflammatory stress in their leukocytes and tissues, which is characteristic of mice with an older chronological age, confirming that PAM are biologically older, at the same chronological age, than NPAM (Vida and De la Fuente 2013).

Recently, similar results to those mentioned for PAM have been obtained in mice with a haploinsufficiency of tyrosine hydroxylase, a limiting enzyme of catecholamine synthesis (Garrido et al. 2018).

Conclusions

Aging and anxiety are two situations with a big socioeconomic impact since aging is a process that affects all individuals and currently there is an alarming increase in anxiety disorder patients. Therefore, there is an urgent research need for a better understanding of these states.

Most studies are focused on inflammation as a cause of anxiety and aging, whereas a more limited number are on oxidation. Nevertheless, the involvement in this context of oxidation and inflammation, much related processes, has been hardly studied, especially in the regulatory systems such as the nervous and immune systems, which is the focus of attention of the present chapter. In both anxiety and aging, the first system affected is possibly the nervous system, concretely the CNS, since it is particularly sensitive to oxidative and inflammatory stress due to the reasons previously mentioned. As a consequence of the communication of the nervous system with the immune system, and the characteristics of the latter (mobility of the immune cells, production of oxidants and inflammatory compounds, etc), the leukocytes could be mainly responsible for the general oxidation and inflammation of organisms in both situations. Thus, for example, although other authors think that inflammaging is responsible for the age-related decrease of adaptive and innate responses (Frasca and Blomberg 2016), in this chapter it has been proposed that immune cells, especially those of innate immunity, are principally responsible for the age-related inflammation associated with oxidation, confirming the implication of these cells in oxi-inflamm-aging (De la Fuente and Miquel 2009).

In the aging process, due to the complexity of immune and nervous systems, the age-related changes of both systems as well as their possible roles in this process are only beginning to be understood. Many studies are now describing the critical molecular pathway that underlies the increase in oxidative and inflammatory stress as well as the link between them with age. Although the existence of oxi-inflamm-aging seems to be accepted, the nature of those interactions, mainly in the brain and immune cells, and their key involvement modulating the rate of aging, still remain unclear. Similarly, the molecular mechanisms and the neurobiological pathways underpinning the potential effects of oxidative stress and inflammation on anxiety have not been fully elucidated. Furthermore, in the context of neuroimmune communication, it is important to note that, as with aging, a chronic oxidative stress situation and a chronic low-grade systemic inflammation are common manifestations of emotional stress and anxiety. Thus, the study of new approaches from both genetic and especially nongenetic models of anxiety are important tools in the understanding of all these mechanisms and for obtaining new information regarding specific signaling cascades and pathways involved in the intricate etiology of anxiety.

It is currently shown that the anxiety state in a subject can accelerate his/her rate of aging and consequently decrease his/her health and life span. Moreover, there is an age-related increase of anxiety states. As an example of this, a model of premature aging in mice has been established in our laboratory in which adult animals showing a poor response to stress and high levels of anxiety have an oxidative and inflammatory stress in their immune cells and tissues, as well as a premature immunosenescence and a shorter life expectancy.

If oxidation-inflammation is the first cause of aging and anxiety or is only a consequence of other changes that happen is currently unknown. Nevertheless, it seems clear that the oxidative and inflammatory stresses are involved in the maintenance and development of both states and in their interrelationships (Fig. 1a, b). This is confirmed when the use of several strategies of life style such as the ingestion of diets with appropriate amounts of antioxidants, which also show anti-inflammatory capacity, slow down the aging process and revert the anxiety situation (De la Fuente 2014). In addition, it is accepted that individual physiological states and psychological resources may buffer the negative effects of oxidative and inflammatory stress. These individual differences start in the fetal period and go on throughout the life of each subject, suffering modifications depending on his/her experiences. It is necessary to consider this individuality in order to understand the different consequences of aging and anxiety states as well as the diverse responses to life-style strategies and treatments (Cruces et al. 2014).

Taking this into account, in the future, it will be necessary to perform studies in animal models and humans to elucidate the molecular mechanisms, specific signaling cascades, and neuroimmune biological pathways underpinning the potential effects of oxidative stress and inflammation on aging and age-related diseases, as well as in situations which increase the rate of aging, such as anxiety. Thus, identification of new molecular pathways will allow the development of new therapies and preventative strategies to regulate and decrease the detrimental effects of oxidative stress and inflammation, contributing to the maintenance of the functional capacity of the nervous and immune systems during aging and in anxiety states. For instance, dietary, behavioral, and social interventions could be used as potential means to provide a low-cost and long-term alternative to limit these stresses and thus improve health and decrease anxiety, the rate of aging, and their consequences.

Notes

Acknowledgments

The author thanks Dr. Vida for her help in this manuscript and also expresses her gratitude to Dr. Arranz, Dr. Gimenez-Llort, Dr. Vida, Mr. Garrido, Ms. Ceprian, Ms. Martinez de Toda, and Ms. Cruces for carried out experiments which have allowed us to arrive at some of the ideas expressed in this chapter. This work was supported by several grants (RETICEF: RD12/0043/0018 and PI15/01787) from the ISCIII-FEDER of the European Union.

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Authors and Affiliations

  1. 1.Department of Genetics, Physiology and Microbiology (Animal Physiology), Faculty of Biological SciencesComplutense University of MadridMadridSpain

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