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Glucocorticoids and Dehydroepiandrosterone: A Role in Immunosenescence?

  • Moisés E. BauerEmail author
Living reference work entry

Abstract

This chapter summarizes current evidence suggesting that immunosenescence may be influenced by both psychological stress and stress hormones. The age-related immunological changes are also similarly found during chronic stress, bipolar disease, or chronic glucocorticoid exposure. It follows that endogenous glucocorticoids (cortisol) could be associated to immunosenescence. Previous studies have shown that healthy older adults are emotionally distressed in parallel to increased cortisol/dehydroepiandrosterone (DHEA) ratio. Furthermore, chronic stressed older adults may be particularly at risk of stress-related pathology because of further alterations in glucocorticoid-immune signaling. Although DHEA and its metabolites have been described with immune-enhancing properties, their potential use as hormonal boosters of immunity should be interpreted with caution. The psychoneuroendocrine hypothesis of immunosenescence is presented in which the age-related increase in the cortisol/DHEA ratio is the major determinant of immunological changes observed during aging. Finally, preliminary evidence indicated that stress-management interventions in older adults are capable of attenuating some important features of immunosenescence.

Keywords

Aging Immunosenescence Glucocorticoids Lymphocytes 

Introduction

Aging is a continuous and slow process that compromises the normal functioning of various organs and systems in both qualitative and quantitative terms. A growing body of previous studies has indicated that aging remodels the immune system (immunosenescence), changing its organization and functionality that negatively influence the health of older adults. Immunosenescence has been associated with the etiology and clinical course of most (if not all) age-related diseases, including cardiovascular diseases, osteoporosis, Alzheimer’s disease, diabetes, cancer, autoimmune disorders, infectious diseases, as well as poorer vaccine responses (Licastro et al. 2005; Pera et al. 2015; Aspinall et al. 2007).

The components of the immune system are not aging at the same speed or the same direction (Fulop et al. 2013). The speed of individual’s biological clock depends on the important interaction between genetic inheritance and environment. Key environmental modulators (e.g., early-life stress, negative lifestyles, diet/obesity, repeated infections, etc.) are well known to shape the DNA and modulate gene expression via epigenetic mechanisms during lifetime (epigenetic drift). In addition, the methylation profile observed in CpG DNA sites across different tissues can accurately predict the chronological age (epigenetic clock) (Horvath 2013), and premature senescence (as observed in HIV infection) involves the acceleration of age-related methylation patterns (Rickabaugh et al. 2015). Genetic polymorphisms of immune-related genes (e.g., HLA), genes in the inflammatory network, and regulatory genes have all been implicated with either pathological or successful aging (Ruan et al. 2014). In addition, several extrinsic/intrinsic factors are known to influence the pace of immunosenescence, including stress hormones (glucocorticoids), chronic inflammatory conditions, and persistent viral infections. There is mounting evidence indicating that aging immune system (e.g., thymic involution, reduced naïve T cells, and T-cell proliferation) looks like those observed during chronic stress (Selye 1936; McEwen et al. 1997) or pharmacological treatment with glucocorticoids (GC) (Fauci 1975).

This chapter will summarize data indicating that endocrinosenescence may importantly impinge on the immunosenescence. It has been observed in a decline in growth hormone (GH), sex hormones, and dehydroepiandrosterone (DHEA) with aging. DHEA is the major secretory product of the human adrenal and is synthesized from cholesterol stores. The hormone is uniquely sulfated (DHEAS) before entering the plasma, and this prohormone is converted to DHEA and its metabolites in the peripheral tissues (Canning et al. 2000). Serum DHEA levels decrease by the second decade of life in humans, with approximately 5% of the original level in older adults (Migeon et al. 1957), a process termed the adrenopause and is thought to be due to reduced cellularity in the zona reticularis of the adrenal gland. As DHEAS and DHEA have several immune-enhancing properties (further discussed in this chapter), the lack of these adrenal factors during aging may be also cogent for the immunosenescence. In contrast, there is also evidence suggesting that aging is associated with significant activation of the hypothalamic-pituitary-adrenal (HPA) axis (Deuschle et al. 1997; Ferrari et al. 2004; Bauer et al. 2009), with increased cortisol levels in man. The HPA axis is a major stress-responsive system, and consequently higher cortisol levels are also found during chronic stress or major depression. Cortisol and DHEA secretion follows a circadian pattern with peak levels at waking and nadir at approximately midnight. The HPA axis is pivotal for the homeostasis of the immune system, and its dysregulation has been associated with several immune-mediated diseases. For instance, HPA axis over-activation can affect susceptibility to or severity of infectious disease through the immunosuppressive effect of the glucocorticoids (Kiecolt-Glaser et al. 1996; Vedhara et al. 1999). In contrast, blunted HPA axis responses are associated with enhanced susceptibility to autoimmune inflammatory disease (Sternberg 2002). Of note, older adults are particularly at risk for both infectious and chronic inflammatory diseases. Conversely, chronic inflammatory diseases may be associated with premature aging of the immune system and present several similarities of immunosenescence including shortening of cellular telomeres, decreased T-cell receptor specificities, loss of naïve T cells, and increased production of pro-inflammatory cytokines (Weyand et al. 2014). In addition, patients with RA frequently show an early development of common age-related morbidities, including osteoporosis (Kleyer and Schett 2014), cardiovascular diseases (Goronzy et al. 2010), and cognitive impairment (Petersen et al. 2015). Dysregulation of the HPA axis may indeed contribute to but it is not solely responsible to immunosenescence.

This chapter reviews that immunosenescence may be closely related to both psychological distress and stress hormones. In particular, striking similarities of immunological changes are found during aging, stress exposure, or GC treatment in vivo. The neuroendocrine hypothesis of immunosenescence is reconsidered in which both the psychological distress and increased cortisol/DHEA (C/D) ratio are thought to be major determinants of immunological changes observed during aging. Finally, preliminary evidence may indicate that stress-management interventions in older adults are capable of attenuating some important features of immunosenescence.

Healthy Aging is Associated with Emotional Distress and Increased Glucocorticoid Exposure

Psychological distress may be an important risk factor for immunosenescence. Human aging has been associated with several psychological and behavioral changes, including difficulty to concentrate progressive cognitive impairments and sleep disturbances (Piani et al. 2004; Howieson et al. 2003). Although individually identified, these alterations may be associated with major depression. Indeed, depression is highly prevalent in several age-related chronic degenerative diseases, including cardiovascular diseases, Parkinson’s disease, Alzheimer’s dementia, cancer, and rheumatoid arthritis (Dew et al. 1998). In addition, both aging (Franceschi and Campisi 2014) and major depression (Dowlati et al. 2010) have been associated to increased levels of pro-inflammatory cytokines and could thus contribute for further immunological diseases in the frail older adults.

Mounting evidence has indicated that healthy aging is associated with significant psychological distress (Schnittger et al. 2012; Moreno-Villanueva and Burkle 2015). In particular, strictly healthy older adults (as assessed by the SENIEUR protocol) were significantly more stressed, anxious, and depressed than young adults (Luz et al. 2003; Collaziol et al. 2004). The SENIEUR protocol defines rigorous criteria for selecting healthy individuals in immunogerontological studies (Ligthart et al. 1984). The health conditions are checked accordingly to clinical investigations and to hematological and various biochemical parameters. Based on this protocol, it is possible to select up to 10% of strictly healthy volunteers from older adults. The literature on stress and aging is still debatable, and some studies did not report these changes (Stone et al. 2010; Nolen-Hoeksema and Ahrens 2002). This could be due to sociodemographic methodological issues, since specific clinical interviews are required to assess depression during aging.

In parallel to psychological distress, it was observed that SENIEUR older adults had significantly higher (~45%) salivary cortisol production throughout the day compared to young adults (Luz et al. 2003). Cortisol peaked in the morning and presented a nadir at night, with a regular circadian pattern for both groups. These data further suggest that healthy aging is associated with significant activation of the HPA axis (Deuschle et al. 1997; Heuser et al. 1998; Ferrari et al. 2000, 2004; Halbreich et al. 1984; Van Cauter et al. 1996). It has been also observed flattened diurnal amplitude of ACTH and cortisol levels during aging (Ferrari et al. 2004; Deuschle et al. 1997). Increased cortisol levels are also seen in demented patients (Popp et al. 2015), major depression (Zunszain et al. 2011), or during chronic stress (Stalder et al. 2014; Bauer et al. 2000).

In addition, it was observed that healthy elders had lower DHEA levels (−54%) throughout the day compared to young adults (Luz et al. 2006). Furthermore, older adults also displayed a flat circadian pattern for DHEA secretion. The morphological correlates of the age-related changes of DHEAS/DHEA secretion are progressive atrophy of the zona reticularis of adrenal glands (Ferrari et al. 2001). The lack of appropriate DHEA levels could be another detrimental factor during immunosenescence since this hormone has immune-enhancing properties (as further discussed in this chapter).

The higher cortisol in parallel to lower DHEA levels will consequently lead to higher glucocorticoid exposure and related toxic effects. The assessment of molar concentrations (C/D) is thus more informative than misleading single hormonal assessment and may constitute another way to evaluate the adrenal function (Straub et al. 2000; Ferrari et al. 2001; Butcher and Lord 2004). The C/D ratio may contribute to the effective determination of functional hypercortisolemia. The impaired DHEA secretion, together with the increase of cortisol, results in an enhanced exposure of various bodily systems (including brain and immune system) to the cytotoxic and modulatory effects of GCs. Some brain cells (hippocampus) and lymphocytes are specially targeted by the cortisol because they express higher densities of mineralocorticoid receptors (MRs) and GC receptors (GRs) (McEwen et al. 1997). The peripheral tissues of elders may be thus more vulnerable to the GC actions in a milieu of low protective DHEA levels. The antagonist action of DHEA to cortisol in the brain suggests that measurement of cortisol alone may provide an incomplete estimate of hypercortisolemia.

In our previous study, psychological distress was positively related to salivary cortisol levels and negatively correlated to DHEA levels during aging (Luz et al. 2003). Therefore, it becomes difficult to dissociate these neuroendocrine changes observed in the older adults with those produced by psychological stimuli. It should be also pointed out that endocrinosenescence includes a substantial decline in several hormones, including growth hormone, testosterone, progesterone, and aldosterone – all of which with reported immunomodulatory properties. Thus, the endocrinosenescence may be considered as another risk factor for immunosenescence.

The Glucocorticoid Cascade Hypothesis

Cumulative neural damage produced by life stressors may contribute to increased basal HPA axis function during aging. In this context, peripheral GCs may have an important role in damaging key brain areas involved with regulation of the HPA axis. Evidence for GC involvement in hippocampal aging led to the establishment of the “glucocorticoid cascade hypothesis” (Sapolsky et al. 1986). This hypothesis states that GCs participate in a fed-forward cascade of effects on the brain and body. In this case, progressive damage to the hippocampus, induced by GCs, promotes a progressive elevation of adrenal steroids (i.e., cortisol) and dysregulation (downregulation of GC receptors) of the HPA axis (Sapolsky et al. 1986). The glucocorticoid cascade hypothesis of aging is a prime example of “allostatic load” (McEwen 1998, 2003) since it recognizes a mechanism that gradually wears down a key brain structure, the hippocampus, while the gradually dysregulated HPA axis promotes pathophysiology in tissues and organs throughout out the body. The net results of the age-related hippocampal damage are impairment of episodic, declarative, spatial, and contextual memory and in regulation of autonomic, neuroendocrine, and immune responses. Of note, the effects of glucocorticoids on the hippocampus are reversible.

Sapolsky and colleagues (1986) have also proposed that several age-related pathologies are also observed following excessive glucocorticoid exposure and include muscle atrophy (Salehian and Kejriwal 1999), osteoporosis/hypercalcemia (Tamura et al. 2004), hyperglycemia/hyperlipidemia, atherosclerosis, type II diabetes, and major depression (Lee et al. 2002).

Similarities Between Aging and Chronic Glucocorticoid Exposure

I have now discussed that healthy aging is associated with psychological distress in parallel to increased C/D ratio. This section will provide significant evidence that the immunological changes observed during aging are also similarly found during psychosocial stress or chronic GC exposure.

It seems reasonable to speculate that increased cortisol and lower DHEA may contribute to immunological changes observed during aging. All leukocytes and many cells in lymphoid tissues exhibit receptors for the neuroendocrine products of the HPA and sympathetic-adrenal-medullary axes. Most primary and secondary lymphoid organs show atrophy during aging. Mammal aging is associated with progressive thymic involution (3% per year following adolescence) and consequently reduced export of naïve T cells (CD27+CD28+CD45RA+) (Schwab et al. 1997; Hirokawa and Makinodan 1975). Thymic involution precedes the malfunctioning of the immune system, resulting in a diminished capacity to generate new T cells and to mount an adaptive immune response to new pathogens and vaccines. In addition to aging, chronic GC exposure as observed during psychological distress (Selye 1936) or pharmacological GC treatment (Fauci 1975) also induces atrophy of the thymus, triggering apoptotic death in immature T- and B cell precursors and mature T cells which are exquisitely sensitive to corticosteroids (Sapolsky et al. 2000). Therefore, thymic involution is not an exclusive phenomenon of aging but is also associated with excessive stress hormone exposure and may be driven in part by age-related changes to the HPA axis. Circulating glucocorticoids have several pleiotropic effects on the immune system (Fig. 1), ranging from permissive/stimulatory at low concentrations (or acute stress) to suppressive at high concentrations (or chronic stress) (Dhabhar 2014). These immunological changes that can be subgrouped accordingly to alterations involving cellular trafficking and cell-mediated immunity.
Fig. 1

Pleiotropic effects of glucocorticoids on immune cells and lymphoid tissues. These effects are largely dependent of tissue-specific hormonal concentration (low, high levels) and whether acute or chronic stress is elicited. In general, low glucocorticoid levels are permissive or stimulatory for the immune system, and high levels are immunosuppressive and anti-inflammatory

Changes in Cellular Trafficking

Trafficking or redistribution of peripheral immune cells in the body is of pivotal importance for effective cell-mediated immune responses. Aging is associated with several peripheral enumerative changes in leukocytes, including a decrease of naive (CD45RA+) and an increase of memory (CD45RO+) T cells, an expansion of terminally differentiated CD28- T cells, or increased natural killer (NK) cells (Hannet et al. 1992; Gabriel et al. 1993; Martinez-Taboada et al. 2002; Faria et al. 2008). Of key note, the adaptive immune system (B and T cells) is especially targeted during aging, with several quantitative and functional defects described and importantly associated with impaired immunity (Nikolich-Zugich 2014).

Interestingly, T cells are also targeted in the same direction during psychosocial stress (Dhabhar 2014; Bosch et al. 2009) or after pharmacological treatment with GC (McEwen et al. 1997; Bauer et al. 2002) (see Table 1). Furthermore, circadian variations in T-cell subsets in human blood are differentially regulated via release of cortisol and catecholamines (Dimitrov et al. 2009). Naive T cells show pronounced circadian rhythms with a daytime nadir, whereas terminally differentiated effector CD8+ T-cell counts peak during daytime. Indeed, glucocorticoids are well known to affect T-cell migration, leading to a redistribution of the cells from blood to the bone marrow, accompanied by a concurrent suppression of lymph node homing. These changes are produced by GC-induced upregulation of CXCR4 (involved with homing to bone marrow) and downregulation of CD62L (involved with homing to lymph nodes) (Besedovsky et al. 2014). It has been found that aging, glucocorticoid, or chronic-stress can increase naturally occurring regulatory T cell (Treg, CD4+CD25+FoxP3+) numbers (Hoglund et al. 2006; Navarro et al. 2006; Trzonkowski et al. 2006). In contrast, reduced counts of inducible Tregs have been found to increase during aging (Jagger et al. 2014). Notwithstanding the underlying mechanisms are not completely understood, previous work has observed differences in steroid signaling associated with increased numbers of regulatory T cells. In particular, it has been shown that murine regulatory T cells expressed higher GR levels, were more resistant to GC-induced apoptosis (with high Bcl-2 levels), and expressed high levels of glucocorticoid-induced TNF receptor (GITR) than CD4+CD25- cells (Chen et al. 2004), an important receptor associated with its suppression action. In spite of the several similarities among age- and stress-related immunological alterations, only a few studies have addressed the role of stress factors on human immunosenescence.
Table 1

Changes in cellular trafficking. Direction of arrows indicates increase (Open image in new window), decrease (Open image in new window) or no change (Open image in new window) compared to corresponding control levels. ? = data not available; NK, natural killer; Treg = regulatory T cells (CD4+CD25+FoxP3+); CD3+CD45RA+ (naïve T cells); CD3+CD45RO+ (memory T cells). Based on references (Dhabhar 2014; Fauci 1975; Bauer et al. 2002; McEwen et al. 1997; Hoglund et al. 2006; Navarro et al. 2006; Trzonkowski et al. 2006; Bosch et al. 2009)

A previous study reported the role of psychoneuroendocrine factors in regulating the distribution of peripheral T-cell subsets during healthy aging (Collaziol et al. 2004). The mechanisms underlying the regulation of the peripheral pool of lymphocytes are still largely unknown. It has been speculated that CD95 (APO1/Fas) may be involved in this process through engagement of apoptosis (Potestio et al. 1999). CD95 is a member of tumor necrosis factor (TNF) family, and its ligand (CD95L) is found on activated T cells (Nagata and Golstein 1995). The CD95-CD95L binding seems to play an important role in maintaining the cellular homeostasis of the immune system and may contribute to stress-related changes in cell trafficking (Yin et al. 2000). Confirming previous reports, it was demonstrated that changes in lymphocyte distribution were noted in older adults as demonstrated by a significant drop in naïve T cells associated with higher expression of CD95 in this subset (Collaziol et al. 2004). It has been hypothesized that this change (i.e., increased CD95) may prone CD45RA+ (naïve) T cells for apoptosis and may explain age-related reductions in naïve cells. In addition, the same study reported that healthy older adults were more distressed than younger adults, and stress scores were positively correlated to CD95 expression on CD45RA+ cells.

Glucocorticoid raises may lead to the fluctuations of lymphocyte subsets observed during aging. It has been demonstrated that GC-induced apoptosis on monocytes is at least partially mediated by the expression of both CD95 and CD95L (Schmidt et al. 2001). Another study showed that glucocorticoids may either induce T-cell apoptosis in a CD95-independent manner or protect T cells from CD95-mediated apoptosis (Zipp et al. 2000). Furthermore, there is some evidence that psychological stress may regulate the proportion of peripheral lymphocytes via the expression of CD95. It has been demonstrated that chronic stress may induce lymphocyte apoptosis in mice (Yin et al. 2000) or in man (Oka et al. 1996) via upregulation of CD95. Our results support the concept that age- or stress-related increase in cortisol levels may be preferentially altering the expression of CD95 on CD45RA+ cells. Preliminary data from our laboratory indicate that human CD45RA+CD95+ cells are in fact more sensitive to dexamethasone (DEX) treatment in vitro (unpublished results). There is some data suggesting that human naïve T CD4+ cells are more sensitive to DEX than memory T CD4+ cells (Nijhuis et al. 1995). Overall, our results suggest that there are complex psychoneuroendocrine interactions involved with the regulation of the peripheral pool of lymphocytes. In particular, it was shown that both psychological stress and GCs synergize during aging to produce alterations in T-cell trafficking.

Changes in Cell-Mediated Immunity

Although many components of the immune system show age-related changes, T cells show the most consistent and largest alterations. T cells are of pivotal importance for the generation of cell-mediated immunity. Cell-mediated immunity is a process that requires (1) recognition of antigens, (2) cell activation and proliferation, and (3) effector functions such as cellular cytotoxicity, phagocytosis, and immunoglobulin synthesis. Steps 2 and 3 seem to be particularly impaired during aging. Following antigen recognition, lymphocytes need to divide into several clones in order to mount effective cell-mediated immune responses. Cell division or proliferation can be readily assessed in vitro by stimulating lymphocytes with mitogens. When diseased subjects are excluded, immunosenescence involves impaired humoral responses and blunted T-cell proliferation to mitogens. The latter is one of the most documented age-related change observed during aging (Nikolich-Zugich 2014; Fulop et al. 2013; Murasko et al. 1987). Yet, these changes are not exclusive of aging, and either chronic stress or GC treatment is associated with decrements of T-cell proliferation (Dhabhar 2014; Sapolsky et al. 2000) (see Table 2). Indeed, it has been shown that healthy SENIEUR older adults (>60 years old) were significantly more distressed, had activated HPA axis, and had blunted (−54%) T-cell proliferation compared to young adults (Luz et al. 2006) (Fig. 2). Interestingly, the HPA axis may be implicated with this change since salivary cortisol levels were found negatively correlated to T-cell proliferation.
Fig. 2

Effects of chronic stress on cortisol and T-cell function during aging. Young adults (Y), elderly (E), or stressed elderly (SE) subjects were compared accordingly to area under the curve (AUC) cortisol production (A), T-cell proliferation to phytohemagglutinin (PHA) stimulation (B), or T-cell sensitivity to glucocorticoids in vitro (C). Data summarized from previous work (Bauer et al. 2000; Luz et al. 2002, 2003) and shown as the percentage of change between groups. (Adapted from Bauer (2005))

The effector phases of both innate and acquired immunity are in large part mediated by cytokines. Different subpopulations of CD4+ T cells synthesize specific cytokines and have been designated Th1 (IFN-γ, IL-2) or Th2 (IL-4, IL-10) cells. Th1 cytokines provide help for cell-mediated responses and the IgG2a antibody class switching, whereas Th2 cytokines help B cells and IgA, IgE, and IgG1 antibody class switching. Both human and mouse models have demonstrated that aging is associated with a Th1 to Th2 shift in cytokine production (Nikolich-Zugich 2014). However, this is not an age-specific phenomenon but also seen during chronic stress (Dhabhar 2014) or GC treatment (Galon et al. 2002; Ramirez et al. 1996).

Previous work has suggested that cytokines and hormones could be considered as possible links between endocrinosenescence and immunosenescence (Straub et al. 2000). Indeed, it has long been known that pro-inflammatory cytokines can readily activate the HPA axis during infection in animals (Besedovsky et al. 1977) or after administration in humans (Mastorakos et al. 1993). Other studies have linked the age-related decline in DHEA production to increased serum levels of interleukin (IL)-6 (Daynes et al. 1993; Straub et al. 1998). The relative GC excess resulting from the increased cortisol/DHEA ratio could be associated with accelerated features of low-grade inflammation in older adults, a process known as “inflammaging.” Inflammaging appears to be a common age-related phenomenon and is related to frailty, morbidity, and mortality during aging (Franceschi and Campisi 2014). Indeed, chronic inflammation is involved in the pathogenesis of major age-related diseases, including Alzheimer’s disease, atherosclerosis, diabetes, major depression, sarcopenia, and cancer. However, we do not know exactly how the extent of these changes may be related to alter psychological and HPA axis functions in older adults.

However, a question remains to be answered: how does an anti-inflammatory hormone (GCs) promote low-grade inflammation? First, increased GC levels would lead to increased abdominal fat (as seen during aging or GC treatment) and development of metabolic syndrome. Adipocytes and infiltrating macrophages secrete various adipokines (e.g., leptin, TNF-α, IL-6, IL-18) that reach the circulation and may thus contribute to inflammaging (Ouchi et al. 2011). Second, increased GC levels would promote immune cells more resistant to steroids (discussed in section “Aging Impairs Neuroendocrine-Immunoregulation”). The age-related acquired steroid resistance would render cells poorly responsive to anti-inflammatory actions of endogenous GCs.

Role of DHEA During Immunosenescence

The lack of appropriate DHEAS levels during aging could be another detrimental factor for immunosenescence. This androgen and its metabolites have reported immune-enhancing properties in contrast to the immunosuppressive action of GCs. Indeed, this hormone may be considered as natural antagonist of GCs, and the impaired DHEA secretion, together with the increase of cortisol, results in an enhanced exposure of lymphoid cells to the deleterious GC actions. Therefore, previous studies have evaluated the immunomodulatory DHEA(S) effects in vitro as well as its properties during in vivo supplementation. The immunomodulatory in vitro effects include increased mitogen-stimulated IL-2 production (Daynes et al. 1990; Suzuki et al. 1991), increased rodent or human lymphocyte proliferation (Padgett and Loria 1994), stimulated monocyte-mediated cytotoxicity (McLachlan et al. 1996), diminished TNF-α or IL-6 production (Di Santo et al. 1996; Straub et al. 1998), increased neutrophil superoxide generation (Radford et al. 2010), and enhanced natural killer cell activity (Solerte et al. 1999). Although both T and B cells can be stimulated in vitro by DHEA, they seem to require different hormonal concentrations (Sakakura et al. 2006).

DHEA(S) replacement therapy has yielded significant beneficial effects for healthy elders, including increased well-being, memory performance, bone mineral density, and reduced proinflammatory markers (Buvat 2003). It has been shown that DHEA supplementation significantly increased NK cell counts and activity and decreased IL-6 production and T-cell proliferation of older adults (Casson et al. 1993) while increased IL-2 production by T cells (Hazeldine et al. 2010). These data highlight the potential use of DHEA(S) as antiaging hormone. However, there is lacking information concerning the clinical significance of those findings. Because of its anti-inflammatory properties, the potential benefits of DHEA have been investigated in autoimmune diseases as well as vaccine preparations. It has been shown that DHEA treatment in vivo can significantly ameliorate the severity of experimental autoimmune diseases by suppressing the proliferation of autoreactive T cell, by reducing pro-inflammatory cytokines, and by increasing the numbers and function of CD4+CD25+FOXp3+CD127- regulatory T cells (Treg) (Tan et al. 2009; Auci et al. 2007). However, following encouraging studies demonstrating beneficial effects of DHEA supplementation in murine lupus models, the effect of DHEA on disease activity in lupus patients remains controversial (Sawalha and Kovats 2008). Previous studies have also explored the potential use of DHEA as adjuvant in vaccine preparations. Notwithstanding the clear adjuvant effects of DHEA during immunization to hepatitis B (Araneo et al. 1993) or influenza (Danenberg et al. 1995) in mice, negative effects have been reported following influenza vaccination in older humans (Danenberg et al. 1997; Degelau et al. 1997). We have previously investigated the adjuvant properties of DHEAS during an immunization to Mycobacterium tuberculosis in mice (Ribeiro et al. 2007). Only young mice co-immunized with vaccine and DHEAS showed an early increase in specific IgG levels compared to old mice. However, splenocytes of both young and old mice that received DHEAS showed increased IFN-γ production following priming in vitro with vaccine. These data further highlight the importance of DHEAS as hormonal adjuvant because of the role of this cytokine in the cellular response against mycobacteria. However, these animal data are in contrast to previous studies reporting DHEA(S) with minor (Degelau et al. 1997) or no adjuvant effects (Evans et al. 1996; Ben-Yehuda et al. 1998; Danenberg et al. 1997) during immunization to influenza or tetanus in older adults. Therefore, extrapolation from studies on murine models to the human should be regarded with caution – especially because of lower circulating DHEA(S) levels in rodents.

Aging Impairs Neuroendocrine-Immunoregulation

Most GC effects on the immune system are mediated via intracellular GC receptors (GR; genomic action) (Mcewen et al. 1997). However, high concentration of GCs may also interact with membrane binding sites at the surface of the cells (nongenomic action) (Gold et al. 2001). The presence of these receptors indicates that the immune system is prepared for HPA axis activation and the subsequent elevation in endogenous GCs. However, the functional effect of a stress hormone will depend on the sensitivity of the target tissue for that particular hormone. For instance, the number and activity of specific receptors for these signaling molecules on the target organ will ultimately direct the physiologic effect of the stressor.

The GC sensitivity (a) may vary between different target tissues in the same organism, (b) shows large individual differences, and (c) can be acutely changed in times of acute stress (Rohleder et al. 2003; Hearing et al. 1999). Furthermore and of special interest of this review, (d) GC sensitivity changes during human ontogeny. Kavelaars and colleagues (1996) have shown that cord blood T cells of newborns appear to be extremely sensitive to inhibition of the proliferative response. This high sensitivity of cells to DEX can still be observed in the first 2 weeks after birth. Subsequently, the sensitivity to DEX inhibition of T-cell proliferation gradually decreases. At 1 year of age, the adult response pattern has been acquired. It is interesting that the increased sensitivity of the immune system to GC inhibition occurs at a period in life when the endogenous levels of glucocorticoids are low (Sippell et al. 1978). The increased sensitivity to glucocorticoids may serve as a compensatory mechanism, so that the important regulatory function of glucocorticoids is fully maintained despite low circulating levels.

We have previously investigated the lymphocyte sensitivity to both synthetic (DEX) and natural occurring steroids (cortisol and DHEA) and so examined whether aging was associated with alterations in neuroendocrine-immunoregulation (Luz et al. 2006). It was found that healthy (SENIEUR) elders had a reduced (−19%) in vitro lymphocyte sensitivity to DEX (but not cortisol or DHEA) when compared to young adults. This phenomenon has previously been described during chronic stress (Rohleder et al. 2002; Bauer et al. 2000), major depression (Truckenmiller et al. 2005; Bauer et al. 2002, 2003), or in clinical situations where GCs are administered, including treatment of autoimmune diseases, organ transplantation, and allergies. Aging has been associated with altered cellular sensitivity to GC, as investigated by the cytokine (TNF-α and IL-6) production after psychosocial (acute) stress test (Trier social stress test, TSST) (Rohleder et al. 2002). In particular, monocytes of healthy (non-SENIEUR) older men had a higher sensitivity to DEX treatment in vitro at baseline and showed a reduced sensitivity to this steroid following acute stress exposure (speech coupled to mental arithmetic task). These data suggest that psychological factors may be implicated in regulating peripheral GC sensitivity during healthy aging. Furthermore, a study comparing cross-country differences in stress-induced cortisol secretion revealed that Brazilian elders exhibited higher basal and stress-induced (TSST) cortisol levels compared to the Canadian participants (Souza-Talarico et al. 2014). Therefore, country context may modulate cortisol secretion patterns and could impact the population health.

Altered steroid immunoregulation may have important therapeutic implications in clinical situations where GCs are administered, and clinicians should consider both patient’s age and psychological status in prescribing steroids as anti-inflammatory drugs. A reduced sensitivity to GCs can also be demonstrated at the central level during aging. Indeed, higher cortisol levels in old than in young subjects have been described during some pharmacological challenges, such as the DEX suppression test, the stimulation by human or ovine corticotrophin-releasing hormone or by physostigmine (Raskind et al. 1994; Ferrari et al. 2001). Taken together, these data indicate that both aging and chronic stress are associated with impaired steroid sensitivity and highlight the importance to understand its underlying mechanisms at central or peripheral level.

Potential Mechanisms of Impaired GC Signaling

The mechanisms underlying acquired steroid resistance are poorly understood. It has been observed that increased cortisol levels (hypercortisolemia) would produce lymphocytes partially resistant to the effects of GC treatment in vitro. There is evidence indicating that impaired GC sensitivity could be observed during the chronic treatment with GC treatment (Silva et al. 1994; de Kloet et al. 1998). Various underlying mechanisms may be involved in this steroid resistance (Rohleder et al. 2003). Figure 3 summarizes putative molecular mechanisms that may account for age-related changes in GC sensitivity. There is some evidence that aging is associated with reduced numbers of intracellular GRs (Zovato et al. 1996; Grasso et al. 1997), but changes in GR affinity cannot be ruled out. In addition, altered translocation of GC/GR complex to nucleus and altered activity of transcription factors may also explain acquired GC resistance. Alternatively, it has been shown that a non-ligand binding β-isoform of the human GR (hGRβ) may also be implicated in acquired steroid resistance (Castro et al. 1996). It was hypothesized that the hGRβ probably heterodimerises with ligand-bound hGRα and translocates into the nucleus to act as a dominant negative inhibitor of the classic receptor. However, there is no evidence for age-related changes in expression of GR isoforms. Furthermore, we cannot exclude the participation of mutations in the GR or changes in the GR transduction system (e.g., altered AP-1 and NF-κB expression, heat shock proteins) in promoting tissue sensitivity to glucocorticoids (reviewed in Bronnegard et al. 1996).
Fig. 3

The anti-inflammatory and immunosuppressive actions of glucocorticoids are modulated by changes in cellular sensitivity. Extracellular hormone availability can be determined by (1) differential expression of tissue-dependent expression of 11β-hydroxysteroid dehydrogenases that catalyze the interconversion of active glucocorticoids (cortisol) to inactive forms (cortisone) and vice versa (Zhang et al. 2005) and (2) levels of plasma corticosterone-binding globulin (CBG) which delivers biologically active glucocorticoids (GCs) into peripheral tissues. The anti-inflammatory actions of GCs are mainly produced by the inhibitory action of IkBα on NFkB (a major transcription factor for inflammatory genes). The immunosuppressive actions of GCs are mediated by enhanced secretion of IL-4, IL-10, and IL-13. However, the cellular sensitivity to glucocorticoids can be modulated by several mechanisms, including (3) altered densities of functional membrane or intracellular glucocorticoid receptor (GRα) as well as receptor affinity changes (Pereira et al. 2003), (4) altered expression of heat shock proteins (HSP90 and HSP56) which stabilize GRα and are dissociated following binding of GCs (Picard et al. 1990), (5) altered expression of GRβ which in turn antagonizes GRα (Castro et al. 1996), (6) altered translocation of GR-GC complexes into the nucleus (Matthews et al. 2004), (7) altered expression of several cytokines (Pariante et al. 1999b; Kam et al. 1993), and (8) altered expression of transcription factors AP-1 (Adcock et al. 1995) and NFκB which antagonizes the GRα. Dashed lines represent inhibitory actions on GRα. (Adapted from Bauer (2005))

In addition, there is considerable evidence that cytokines may have a significant impact on GR expression and function. There is some evidence suggesting that local concentrations of cytokines produced during an inflammatory response may produce acquired GR resistance (Pariante et al. 1999a). Of note, the GR resistance in major depression has been associated with increased levels of pro-inflammatory cytokines (TNF-α, IL-1, and IL-6) and acute phase proteins (Maes et al. 1993; Trzonkowski et al. 2004; Schiepers et al. 2005; Carvalho et al. 2014). In addition, a previous study reported that IL-13 (a Th2 cytokine) reduced the GR-binding affinity in peripheral blood mononuclear cells (PBMCs) (Spahn et al. 1996). In conclusion, several molecular and cellular mechanisms may explain the age-related alterations in GC signaling.

The Influence of Chronic Stress on Aging

Superimposing chronic stress during aging might thus accelerate features of immunosenescence. It is well known that chronic exposure to psychological stress is correlated with suppressive immune functions (Reviewed in Glaser and Kiecolt-Glaser 2005; Dhabhar 2014). These associations may be explained by accelerate aging of several lymphoid organs and key immunological functions (Bauer 2008). Stressed elders may thus be at risk for the development of stress-related pathologies because of detrimental additive effects of stress upon the aged immune system.

Is there any elderly population especially at risk for premature immunosenescence? Older caregivers of spouses with dementia represent such model to study the superimposing (and detrimental) effects of chronic psychological stress upon immunosenescence. Caregiving for the first-grade elderly relative with dementia is an exceptionally demanding task associated with increased stress, anxiety, depression, and notably suppressed immune functions (Redinbaugh et al. 1995).

The daily stress experienced by the caregivers of Alzheimer patients may accelerate many age-related changes, particularly on neuroendocrine and immune systems. It has been shown that caregivers of demented patients had a blunted T-cell proliferation in association with increased cortisol levels compared to non-stressed elders (Bauer et al. 2000). In addition, lymphocytes of older caregivers were relatively more resistant to treatment with steroids compared to age-matched controls (non-caregivers). When submitted to stress, the elderly populations present immunological alterations in similar magnitude to the circulating cortisol levels (see Fig. 2). These data may indicate that psychosocial stress and cortisol would lead to premature immunosenescence. Supporting this, psychosocial stress was found significantly correlated to higher oxidative stress, lower telomerase activity, and shorter telomeres, which are all recognized factors of cell senescence and longevity (Epel et al. 2004).

Mounting evidence indicates that caregiving is an important risk factor associated to poor health and quality of life of elderly populations. When compared to non-caregiver subjects, individuals caring to a partner with dementia or stroke report more infectious diseases (Kiecolt-Glaser et al. 1991); they have impaired immunity to vaccines including those to influenza (Kiecolt-Glaser et al. 1996; Vedhara et al. 1999) and pneumococcal pneumonia antigens (Glaser et al. 2000). Older caregivers also had slowed responses of wound healing compared to controls (Kiecolt-Glaser et al. 1995). Other studies also reported that caregivers had an increased risk for developing hypertension (Shaw et al. 1999) and may thus be at higher risk for developing heart disease (Vitaliano et al. 2002). Furthermore, a previous longitudinal study reported that older caregivers had increased mortality rates (63%) when compared to controls (Schulz and Beach 1999). It has been shown that IL-6 (a known inflammatory cytokine) may be implicated with this altered morbidity associated with stress during caregiving (Kiecolt-Glaser et al. 2003). Lower sensitivity to GC seems to provide one potential mechanism through which chronic stress promotes low-grade inflammation. It has been shown that genes underexpressed by family cancer caregivers included glucocorticoid response elements, while genes overexpressed included NF-κB response elements, compared to non-caregiving controls (Miller et al. 2008).

The Psychoneuroendocrine Hypothesis of Immunosenescence

The studies reviewed here support the notion that immunological changes observed during healthy aging may be closely related to both psychological distress and stress hormones. Of note, changes in cellular trafficking as well as cell-mediated immunity observed during aging are similarly found following stress or chronic GC exposure. These changes are mainly produced via engagement of specific intracellular adrenal receptors expressed on peripheral lymphocytes. Based on these data, the neuroendocrine hypothesis of immunosenescence is reconsidered here (see Fig. 4). During aging, cumulative neuronal damage produced by stress-related cortisol action in the brain (hippocampus and hypothalamus) is associated with decreased central sensitivity to cortisol (Sapolsky et al. 1986; Raskind et al. 1994; Ferrari et al. 2001). This will lead to increased cortisol levels (Deuschle et al. 1997; Heuser et al. 1998; Ferrari et al. 2004; Luz et al. 2003; Halbreich et al. 1984; Van Cauter et al. 1996) which in turn may produce more neuronal damage in the brain and promote thymic involution. These effects may be exacerbated by reduced DHEA/DHEAS levels frequently observed during aging. The impaired DHEAS secretion, together with the increase of cortisol, results in an enhanced exposure of various bodily systems (including brain and immune system) to the cytotoxic/immunomodulatory effects of GCs. These tissues are preferentially targeted by cumulative cortisol action because they express the greatest densities of MRs (hippocampus) and GRs (thymus) (McEwen et al. 1997). The critical consequence of thymic involution is reduced output of naïve T cells – a hallmark of immunosenescence. It remains to be investigated, however, why peripheral T cells are preferentially targeted during aging compared to B or NK cells. Differential GRα expression among lymphoid cells may explain these differences. It should be kept in mind this hypothesis is oversimplistic and does not take into account other stress-related mediators (neuropeptides, norepinephrine, GH, etc.) and intrinsic cellular mechanisms of aging, including oxidative stress and telomere shortening.
Fig. 4

The psychoneuroendocrine hypothesis of immunosenescence. During aging, cumulative neuronal damage produced by stress-related cortisol action in the brain (1) (Sapolsky et al. 1986) is associated with decreased central sensitivity to cortisol (2) (Raskind et al. 1994; Ferrari et al. 2001). This specific effect is associated with increased cortisol/DHEA ratio (3) (Ferrari et al. 2004; Luz et al. 2003) which in turn may produce more neuronal damage in the brain and further promote thymic involution (4). The latter may be related to immunosenescence via two ways: (a) indirectly reducing the output of central naïve T cells and (b) directly acting at the level of peripheral lymphoid cells (5) (Luz et al. 2006). (Adapted from Bauer (2005))

Psychosocial Interventions to Reduce Stress and Ameliorate Immunosenescence

Considering that chronic stress could lead to premature aging of the immune system, in addition to its other detrimental effects, it is reasonable to investigate if stress-management interventions can attenuate or reverse some features of immunosenescence. By reducing stress perception and promoting healthy behaviors, stress-management interventions may also promote balance in cortisol/DHEA (C/D) hormones, induce vagal tone, and improve immune responses.

Psychosocial interventions have been proven effective in attenuating stress and improving adrenal hormones during aging (Schulz et al. 2002). For instance, an enrichment program for older adults increased significantly DHEA, testosterone, estradiol, and GH levels (Arnetz et al. 1983). The enrichment or activation program aimed to increase the elders’ social activation, competence, and independence and to counteract social isolation and passivity. A randomized controlled trial showed that older adults who practiced relaxation had reduced antibody titers to latent HSV-1, indicating that a lifestyle intervention resulted in lower levels of antigenic stimulation (Gouin et al. 2008). These data indicate that stress-buffering strategies can lead to an improvement in cellular immune-mediated control of latent viruses.

An important field of interest is the possibility to influence the quality of life through acupuncture. Acupuncture is certainly the most popular intervention of Traditional Chinese Medicine in western countries. We have previously explored the effects of acupuncture on stress-related psychological symptoms and cellular immunity in older adults (Pavao et al. 2010). The acupuncture treatment consisted of six sessions, and the procedures included the insertion of needles at bilateral acupoints (LI4, SP6, and ST36) in healthy young and older adults. Repeated applied acupuncture was able to significantly attenuate psychological distress (−15 to −47%) as well as increased T-cell proliferation (~50%), with greater intensity older adults (Pavao et al. 2010). Notably, the T-cell proliferation of older adults reached similar levels of those found in the young adults. Acupuncture may exert its relaxation effects by influencing neurotransmitter, neurotrophic factors, and hormonal pathways underlying emotional states. More recently, in a randomized controlled study, we have investigated the efficacy of a similar acupuncture intervention to promote the quality of sleep (a common complaint of older adults), modulate neurotrophic factors (i.e., brain-derived neurotrophic factor, BDNF) involved with synaptic plasticity and cognitive functions, and potentially ameliorate immunosenescence-related changes in lymphocyte trafficking (Zuppa et al. 2015). The true procedure as compared to placebo one was highly effective in modulating sleep quality (53%), buffering depression (−48%), and stress (−25%) in healthy older adults. However, neither changes in plasma BDNF nor lymphocyte subsets (T, B, NK, senescent markers) were observed following the intervention. As C/D levels were not investigated in those studies, the underlying mechanisms have, as yet, to be clarified.

Conclusions and Outlook

When age-related diseases are controlled for, healthy aging is associated with changes in allostatic systems (endocrine and immune) that play major roles in the adaptation of organism to outside forces that are threatening the homeostasis of the internal milieu. In particular, healthy aging is associated with significant psychological distress and activation of the HPA axis (increased cortisol and reduced DHEA). Over weeks, months, or years, exposure to increased secretion of stress hormones would result in allostatic load (“wear and tear”) and its pathophysiologic consequences (McEwen 1998). Given the findings that even discrete HPA axis activation may impair cognitive function (Lupien et al. 1994) and induce sleep disturbances (Starkman et al. 1981), conditions frequently associated during aging and psychological or pharmacological strategies attenuating or preventing increased HPA function during aging might be of considerable benefit for the older adults.

Although the mechanisms underlying immunosenescence are still being unraveled, it is becoming increasingly clear that many of the physiologic changes associated with aging are characterized by deficient communication between neuroendocrine and immune systems. Data presented here suggest that aging is associated with reduced lymphocyte sensitivity to GCs. Glucocorticoid-induced acquired resistance may have an important physiological significance of protecting cells from the dangerous effects of prolonged GC-related immunosuppression. However, the significance of this adaptive phenomenon is questionable since T-cell proliferation is still profoundly suppressed during aging. Additionally, altered steroid immunoregulation may have important therapeutic implications in clinical situations where GCs are administered, including treatment of autoimmune diseases, organ transplantation, and allergies. Clinicians should consider both patient’s age and psychological status in prescribing steroids as anti-inflammatory drugs.

The concept of hormesis should be discussed here considering the genetic, hormonal, and lifestyle factors involved in accelerating or buffering immunosenescence. Aging, senescence, and death are the final consequences of impaired homeostasis or failure of homeodynamics (Rattan 2006). The most important component of homeodynamics is represented by the capacity of living systems to deal (cope) with stress. A progressive shrinking of the homeodynamic space (or buffering capacity) is the hallmark of aging and strongly associated with age-related diseases (Rattan 2008). The stress responses in mammals include apoptosis, inflammation, and increased glucocorticoids – that are also associated with healthy aging. The clinical consequences of stress responses can be both harmful and beneficial, depending on the characteristics of the stressor (Calabrese 2008). This phenomenon of biphasic dose response was termed hormesis (Southam and Ehrlich 1943), and it has been described across different disciplines including toxicology, pharmacology, medicine, radiation biology, and gerontology (Calabrese et al. 2012). A good example of stress-induced hormesis is the beneficial effects of moderate exercise (hormetic agent) to increase immunity and lower levels of oxidative stress (Radak et al. 2008). Physical inactivity or overtraining is associated with damaging oxidative stress and blunted immune responses. Furthermore, acute or mild stress is generally associated with enhanced immune functions (Dhabhar 2009), which prepare the organism to better cope with the stressor. In contrast, chronic stress, which is not resolved via coping or adaptation, is considered to be distress, and it has been associated with suppressed immune functions and inflammation (Glaser and Kiecolt-Glaser 2005). These effects are related to GC concentration and to duration of tissue exposure to peripheral GCs. For instance, low cortisol levels produce permissive or stimulatory immune changes, whereas long-term or high cortisol levels are immunosuppressive (Fig. 1). Hormetic stressors (hormetins) can be applied successfully to interventions in aging and can be categorized as physical, nutritional, or psychological hormetins (Rattan 2008). Moderate exercise, hormonal and nutritional supplementation, and psychosocial interventions are good examples of stress-induced hormesis aimed to improve homeodynamic space in aging. Recent studies suggest that lifestyle factors (such as physical activity) and human health may be linked through epigenetic mechanisms such as DNA methylation, histone modifications, and micro-RNAs (Sanchis-Gomar et al. 2012). Therefore, by favoring hormesis, the interventions reviewed here would render epigenetic changes involved with the attenuation of immunosenescence.

Chronic stressed older adults may be particularly at risk of stress-related pathology because of further alterations in GC-immune signaling. Older individuals who experience chronic stress exhibit poorer immune functions, and thus increased disease vulnerability, than their less stressed counterparts. Indeed, chronic stressed older adults are associated with increased morbidity and mortality rates. Therefore, stress management and psychosocial support should promote a better quality of life for the older adults as well as reduce hospitalization costs for the governments. In addition, the maintenance of health status during aging may protect elders from chronic stress exposure. Further studies in systems biology are needed to analyze the role and relationships of health-related behaviors on immunity that might promote better coping with aging and stress exposure.

Notes

Acknowledgments

This study was supported by grants from CNPq and FAPERGS.

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Laboratory of Stress Immunology, School of SciencesPontifical Catholic University of the Rio Grande do SulPorto AlegreBrazil

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