Clarice Luz

The Role of Stress Factors during Aging of the Immune System

This manuscript reviews current evidence suggesting that aging of the immune system (immunosenescence) may be closely related to chronic stress and stress factors. Healthy aging has been associated with emotional distress in parallel to increased cortisol to dehydroepiandrosterone (DHEA) ratio. The impaired DHEA secretion together with the increase of cortisol results in an enhanced exposure of lymphoid cells to deleterious glucocorticoid actions. The lack of appropriated growth hormone signaling during immunosenescence is also discussed. It follows that altered neuroendocrine functions could be underlying several immunosenescence features. Indeed, changes in both innate and adaptive immune responses during aging are also similarly reported during chronic glucocorticoid exposure. In addition, chronically stressed elderly subjects may be particularly at risk of stress‐related pathology because of further alterations in both neuroendocrine and immune systems. The accelerated senescent features induced by chronic stress include higher oxidative stress, reduced telomere length, chronic glucocorticoid exposure, thymic involution, changes in cellular trafficking, reduced cell‐mediated immunity, steroid resistance, and chronic low‐grade inflammation. These senescent features are related to increased morbidity and mortality among chronically stressed elderly people. Overall, these data suggest that chronic stress leads to premature aging of key allostatic systems involved in the adaptation of the organisms to environmental changes. Stress management and psychosocial support may thus promote a better quality of life for elderly people and at the same time reduce hospitalization costs.

Impact of psychological and endocrine factors on cytokine production of healthy elderly people

Human ageing has been associated with immunological changes including blunted T-cell responses and increased production of pro-inflammatory cytokines. Here, we investigated the role of psychological and endocrine factors in the production of pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin (IL)-6) as well as soluble IL-2Ralpha, associated with T-cell activation. Forty-six elderly subjects (60-91 yrs) and 33 young adults (20-40 yrs) were recruited accordingly the SENIEUR protocol. The emotional status was measured by structured clinical interviews. Salivary cortisol levels (9, 12 and 22 h) and serum dehydroepiandrosterone (DHEA) were assessed by radioimmunoassays. The elderly were more stressed, depressed and anxious than the young subjects. Cortisol levels were increased whereas DHEA levels were significantly reduced in the elderly. Both groups showed equivalent production of pro-inflammatory cytokines as well as soluble IL-2Ralpha. Psychological scores were positively correlated to evening cortisol levels and negatively correlated to morning DHEA levels. No relationships were noted between psychological factors and cytokines studied. However, evening cortisol levels were found positively correlated to TNF-alpha and sIL-2Ralpha levels. These data indicate that healthy ageing is associated with significant distress and activation of the hypothalamic-pituitary-adrenal axis. Our data also suggest that there are complex psychoneuroendocrine relationships involved with cytokine production during ageing.

Neuroendocrine and Immunological Correlates of Chronic Stress in ‘Strictly Healthy’ Populations

Background: Chronic stress has been associated with detrimental or maladaptive neuroendocrine and immunological changes. Objectives: We assessed the neuroendocrine and immunological correlates of a realistic chronic stress experienced by strictly healthy caregivers of Alzheimer’s disease patients and age-matched controls. Methods: We screened 330 caregivers and 206 non-caregivers according to the ‘strictly healthy’ conditions established by the SENIEUR protocol. Forty-one strictly healthy caregivers (60.56 ± 16.56 years) and 33 non-stressed controls (60.27 ± 14.11 years) were selected for this study. Salivary cortisol and dehydroepiandrosterone sulfate (DHEAS) were assessed at multiple points by radioimmunoassay. Peripheral T cell proliferation and cellular sensitivity to glucocorticoids (corticosterone and dexamethasone, DEX) were evaluated by colorimetric assays. We also examined the hypothalamic-pituitary-adrenal (HPA) axis response to the administration of a low-dose DEX in vivo. Results: The caregivers were significantly more stressed, anxious and depressed than non-caregivers (all p < 0.0001), in contrast to similar cortisol levels. Caregivers had reduced DHEAS levels (–32%, p < 0.0001), an increased cortisol/DHEAS ratio (39.7%, p < 0.0001) and impaired HPA axis response to DEX intake. Caregivers had a higher T cell proliferation (p < 0.0001) and increased sensitivity to glucocorticoids in vitro (p < 0.01) as compared to non-stressed controls. Conclusions: Our results suggest that the maintenance of health in chronically stressed populations may be associated with both protective and detrimental neuroendocrine and immunological changes.

EVALUATION OF IMMUNE PARAMETERS IN DEPRESSED PATIENTS

The association between depression and altered immunological activities has repeatedly been suggested, but experimental data show contradictory results. In this work, cellular and humoral immunological activities were evaluated in patients presenting major depression, unipolar subtype. Natural killer cell activity (NKCA) was significantly reduced in patients as compared to healthy controls (p < 0.001). However, lymphocyte mitogenic responses and immunoglobulin titers (IgG, IgM, and IgA) were similar for all samples. Hematological, hormonal, and nutritional variables presented normal values in patients and in controls. A familial history of depression was related to lower NKCA and higher phytohemagglutinin responses (p < 0.01). These data suggest possible differential inhibition of cellular immune responses in depressed patients.

Salivary cortisol and dehydroepiandrosterone (DHEA) levels, psychological factors in patients with oral lichen planus.

OBJECTIVE The aim of this study was to determine the salivary levels of dehydroepiandrosterone (DHEA) and cortisol and scores of depression, anxiety and stress in patients with oral lichen planus (OLP). STUDY DESIGN Thirty-one patients with a diagnosis of OLP were selected; they were matched by sex and age with 31 control patients. Symptoms of depression, anxiety and stress were investigated by the instruments Beck Depression Inventory, Beck Anxiety Inventory and Lipps Inventory of Stress Symptoms for Adults, respectively. Saliva was collected in the morning and at night for the determination of DHEA and cortisol levels by radioimmunoassay. RESULTS There was no significant difference between the groups with respect to depression (P=0.832), anxiety (P=0.061) or stress (P=0.611), or with respect to morning and night salivary levels of DHEA (P=0.888, P=0.297) and cortisol (P=0.443, P=0.983). CONCLUSIONS The results suggest an association of OLP with anxiety. However, DHEA and cortisol levels did not differ between groups, which does not support any neuroendocrine aetiology for OLP.

Neuroimmunoendocrine Interactions in Patients with Recurrent Major Depression, Increased Early Life Stress and Long-Standing Posttraumatic Stress Disorder Symptoms

Background: Traumatic events experienced in childhood may lead to psychiatric diseases in adult life, including major depressive disorder (MDD). It remains obscure to what extent early life stress (ELS) is associated with biologically relevant changes in MDD. Objective: We investigated both neuroendocrine and immunological correlates in recurrent MDD with ELS and current posttraumatic stress disorder symptoms. Methods: Thirty-eight female MDD patients with or without childhood trauma and 15 healthy controls took part in this study. Salivary cortisol and dehydroepiandrosterone sulfate (DHEAS) were assessed by radioimmunoassays. Peripheral blood mononuclear cells (PBMCs) were isolated and T cell proliferation and cellular sensitivity to steroids and DHEAS were evaluated by colorimetric assays. Th1/Th2 cytokines were assessed by cytometric bead arrays. Results: MDD patients with or without previous trauma had similarly lower salivary cortisol and DHEAS in parallel with blunted T cell proliferation. PBMCs of depressives were significantly less sensitive to dexamethasone or epinephrine than those of the controls. PBMCs of MDD patients produced significantly lower interleukin (IL)-2, IL-4 and tumor necrosis factor-α levels when compared to healthy controls. Conclusion: We found that a history of ELS did not modify the blunted neuroendocrine and immunological alterations presented by recurrent depressed patients.

Healthy Aging Is Associated with Unaltered Production of Immunoreactive Growth Hormone but Impaired Neuroimmunomodulation

Background: Both endocrine and immune systems are continuously remodeled during aging. Objective: Here, we investigated to what extent adrenal and somatosenescence are associated reciprocal changes in the immune system during strictly healthy aging. Methods: Forty-six elderly subjects and 33 young adults were recruited according to the health criteria of the SENIEUR protocol. Peripheral blood mononuclear cells were isolated and stimulated in vitro with lipopolysaccharide or phytohemagglutinin to assess the production of immunoreactive growth hormone (GH). Peripheral sensitivity to steroids was assessed in vitroby dexamethasone-, cortisol- or dehydroepiandrosterone (DHEA)-induced inhibition of T-cell proliferation. DHEA and GH levels were measured by radioimmunoassays. Results: Healthy elderly had lower salivary DHEA and serum GH levels (somatosenescence). They presented reduced T-cell sensitivity to dexamethasone but similar cellular sensitivities to cortisol and DHEA. Their cells produced similar levels of immunoreactive GH compared to the cells of young adults. Conclusions: These data indicate that healthy aging is associated with adrenal and somatosenescence as well as impaired neuroendocrine immunoregulation at the level of the lymphocyte. In addition, somatosenescence may not be associated with a reciprocal decline in immunoreactive GH.

Salivary dehydroepiandrosterone (DHEA) levels in patients with the complaint of burning mouth: a case-control study

OBJECTIVE This study was conducted to evaluate salivary dehydroepiandrosterone (DHEA) levels, salivary flow rate (SFR), depression, and hopelessness in patients with the complaint of burning mouth (BM). STUDY DESIGN Thirty female patients with BM and 30 age-matched control women without any complaint of burning mouth were enrolled. After anamnesis and oral examination, the salivary flow rate was determined. Depression and hopelessness were evaluated by the application of inventories. Two saliva samples were collected for DHEA analysis. RESULTS Dysgeusia (P = .045) and xerostomia (P = .003) were significantly higher in the BM group. The BM patients showed significantly lower salivary flow rate, both under stimulation (P = .001) and at rest (P < .001). Significant differences between the groups were not found in the depression (P = .416) or hopelessness (P = .597) scores. The BM group revealed significantly lower salivary DHEA levels in the morning samples (P = .003). CONCLUSION Patients with BM exhibit decreased morning salivary DHEA as well as dysgeusia and hyposalivation more frequently than control subjects. Additional investigations are needed to clarify this association.

Psychoneurodendocrine correlates of lymphocyte subsets during healthy ageing.

Ageing has been associated with increased cortisol levels and absolute counts of T lymphocytes with memory phenotype. Although the mechanisms underlying these changes are still unknown, it has been speculated that this could be related to a dysfunction in FAS/CD95 expression in naive or memory cells. In this study, we investigated the role of psychoneuroendocrine variables in regulating CD95 expression on lymphocyte subsets. Forty-six elderly subjects (65-91 years) and 33 young adults (20-40 years) were recruited accordingly the SENIEUR protocol. The psychological status was measured by structured clinical interviews, salivary cortisol was assessed along the day (9, 12 and 22h) and peripheral blood lymphocytes were immunophenotyped. The elderly were more stressed, depressed and anxious than the young subjects. Cortisol levels were increased in the elderly, indicating an activation of the hypothalamic-pituitary-adrenal (HPA) axis. We observed reduced counts of CD45RA+CD95+ cells in the elderly compared to young adults. The elderly subjects also showed a reduced expression of CD3 and CD62L in contrast to increased CD95 expression in CD45RA+ cells. The emotional state was positively correlated with the lymphocyte markers. Our data suggest the healthy ageing is associated with psychoneuroendocrine alterations that may be implicated in the regulation of CD95 expression on peripheral T cells.

Subjective Mild Depressive Symptoms are Associated With Abnormal Diurnal Cycle of Salivary Cortisol in Older Adults

Background: Alterations in cortisol secretion pattern seem to be involved in the associations between aging, depression, and cognitive decline. Objective: The aim of this study was to mainly assess cortisol circadian profile in older adults with subjective depressive symptoms. Methods: Salivary cortisol samples from healthy young (n = 22) and old adults (n = 22), and from older adults who self-reported depressive symptoms in Geriatric Depression Scale (n = 22) were collected at 7 AM, 4 PM, and 10 PM and were analyzed by radioimmunoassay. Results: Older adults with depressive symptoms presented the characteristic cortisol circadian pattern, but they showed higher cortisol levels at 10 PM than healthy young and elderly controls. Conclusions: Our data suggest that mild depressive symptoms could be associated with a cortisol secretion pattern previously described as being predictive of cognitive decline.