Somatotrope GHRH/GH/IGF-1 axis at the crossroads between immunosenescence and frailty.

Immunosenescence, characterized by complex modifications of immunity with age, could be related to frailty syndrome in elderly individuals, leading to an inadequate response to minimal aggression. Functional decline (i.e., the loss of ability to perform activities of daily living) is related to frailty and decreased physiological reserves and is a frequent outcome of hospitalization in older patients. Links between immunosenescence and frailty have been explored and 20 immunological parameters, including insulin-like growth factor-1 (IGF-1), thymopoeisis, and telomere length, were shown to be affected in elderly patients with functional decline. A strong relationship between IGF-1 and thymic ouput was evidenced. IGF-1, a mediator of growth hormone (GH), was subsequently shown to induce interleukin-7 secretion in cultured primary human thymic epithelial cells. We are exploring the stress hypothesis in which an acute stressor is used as the discriminator of frailty susceptibility. GH can counteract the deleterious immunosuppressive effects of stress-induced steroids. Under nonstress conditions, the immunosenescent system preserves physiological responses, while under stress conditions, the combination of immunosenescence and a defect in the somatotrope axis might lead to functional decline.

Expression of the growth hormone/insulin-like growth factor axis during Balb/c thymus ontogeny and effects of growth hormone upon ex vivo T cell differentiation.

AIMS: We address the question of the expression and the role of the growth hormone/insulin-like growth factor (GH/IGF) axis in the thymus. METHODS: Using RT-qPCR, the expression profile of various components of the somatotrope GH/IGF axis was measured in different thymic cell types and during thymus embryogenesis in Balb/c mice. The effect of GH on T cell differentiation was explored via thymic organotypic culture. RESULTS: Transcription of Gh, Igf1, Igf2 and their related receptors predominantly occurred in thymic epithelial cells (TEC), while a low level of Gh and Igf1r transcription was also evidenced in thymic T cells (thymocytes). Gh, Ghr, Ins2, Igf1, Igf2, and Igfr1 displayed distinct expression profiles depending on the developmental stage. The protein concentrations of IGF-1 and IGF-2 were in accordance with the profile of their gene expression. In fetal thymus organ cultures (FTOC) derived from Balb/c mice, treatment with exogenous GH resulted in a significant increase of double negative CD4-CD8- T cells and CD4+ T cells, together with a decrease in double positive CD4+CD8+ T cells. These changes were inhibited by concomitant treatment with GH and the GH receptor (GHR) antagonist pegvisomant. However, GH treatment also induced a significant decrease in FTOC Gh, Ghr and Igf1 expression. CONCLUSION: These data show that the thymotropic properties of the somatotrope GH/IGF-1 axis involve an interaction between exogenous GH and GHR expressed by TEC. Since thymic IGF-1 is not increased by GH treatment, the effects of GH upon T cell differentiation could implicate a different local growth factor or cytokine.

The role of the thymus in the integrated evolution of the recombinase-dependent adaptive immune response and the neuroendocrine system.

Before being able to react against infectious non-self-antigens, the immune system has to be educated in recognition and tolerance of neuroendocrine self-proteins. This sophisticated educational process takes place only in the thymus. The development of an autoimmune response directed to neuroendocrine glands has been shown to result from a thymus dysfunction in programming immunological self-tolerance to neuroendocrine-related antigens. This thymus dysfunction leads to a breakdown of immune homeostasis with an enrichment of 'forbidden' self-reactive T cells and a deficiency in self-antigen-specific natural regulatory T cells in the peripheral T lymphocyte repertoire. A large number of neuroendocrine self-antigens are expressed by the thymic epithelium, under the control of the autoimmune regulator (AIRE) gene/protein in the medulla. Based on the close homology and cross-tolerance between thymic type 1 diabetes-related self-antigens and peripheral antigens targeted in ß-cells by autoimmunity, a novel type of vaccination is currently developed for the prevention and cure of type 1 diabetes. If this approach were found to be effective in reprogramming immunological tolerance that is absent or broken in this disease, it could pave the way for the design of negative/tolerogenic self-vaccines against other endocrine and organ-specific autoimmune disorders.

Transcriptomic biomarkers of the response of hospitalized geriatric patients admitted with heart failure. Comparison to hospitalized geriatric patients with infectious diseases or hip fracture.

The abundance of a preselection of transcripts involved in inflammation, immunosenescence and stress response was compared between PBMC of healthy aged donors and aged patients in acute phase of heart failure and at recovery. This study identified 22 transcripts differentially abundant in acute phase of heart failure versus healthy aged subjects. Transcripts involved in inflammation and oxidative stress were more abundant. Those associated with T-cell functions were less abundant. The results were compared to two other major acute geriatric issues: infectious diseases and hip fracture. In acute phase, compared to healthy aged subjects, the abundance of 15/22 transcripts was also altered in both geriatric infectious diseases and hip fracture. Many variations had not vanished at the recovery phase. The abundance of CD28, CD69, LCK, HMOX1, TNFRSF1A transcripts, known to be altered in healthy aged versus healthy young subjects, was further affected in acute phase of the three geriatric diseases considered. The transcript levels of BCL2, CASP8, CCL5, DDIT3, EGR3, IL10RB, IL1R2, SERPINB2 and TIMP1 were affected in all three pathological conditions compared to healthy aged, but not versus healthy young subjects. In conclusion, this work provides critical targets for therapeutic research on geriatric heart failure, infectious diseases and hip fracture.

Serum IL-6 and IGF-1 improve clinical prediction of functional decline after hospitalization in older patients.

BACKGROUND AND AIMS: Although inflammatory and hormonal markers have been associated with further functional adverse outcomes in community- dwelling seniors, these markers have not been studied from this perspective in acutely ill older patients. This prospective study was designed to determine whether biological markers can improve the predictive value of a clinical screening tool to assess the risk of functional decline in hospitalized older patients. METHODS: Patients aged 75 years and over admitted for hip fracture, acute heart failure or infection (n=118) were recruited. The clinical screening tool SHERPA was filled in on admission, with concomitant measurement of interleukin-6 (IL-6), insulin-like growth factor 1 (IGF-1), C-reactive protein (CRP), white blood cells, urea, albumin, pre-albumin and total cholesterol. Functional decline was defined as a decrease of one point in the activities of daily living scale between pre-admission and 3-month post-discharge status. We compared the discrimination calibration of SHERPA vs SHERPA+, a logistic regression model including SHERPA and selected biomarkers. RESULTS: Three months after discharge, functional decline had occurred in 46 patients. IL-6 and IGF-1 were selected, since their levels were significantly different between decliners and non-decliners, and were included in the new logistic regression model SHERPA+. Areas under the ROC curve [95% CI] for functional decline prediction were 0.73 [0.63-0.81] for SHERPA vs 0.79 [0.69-0.86] for SHERPA+ (p=0.14). However, SHERPA+ was better calibrated, as the average predicted risk of functional decline within subgroups matched the proportion which actually underwent functional decline (Brier score=0.185). Since functional decline was higher in patients with hip fracture, the SHERPA+ model was challenged by including the diagnosis. Only SHERPA, IGF-1 and diagnosis were significantly associated with functional decline. CONCLUSIONS: Selected biological markers may marginally improve the clinical prediction of post-discharge functional decline in hospitalized patients, and may allow to stratify them appropriately. The predictive value of these biomarkers is not fully independent of disease status. Further studies are needed to confirm these results in a cohort representative of older patients admitted through the emergency department.

Differentially abundant transcripts in PBMC of hospitalized geriatric patients with hip fracture compared to healthy aged controls.

The abundance of a selection of transcript species involved in inflammation, immunosenescence and stress response was compared between PBMC of 35 geriatric patients with hip fracture in acute phase (days 2-4 after hospitalization) or convalescence phase (days 7-10) and 28 healthy aged controls. Twenty-nine differentially abundant transcripts were identified in acute phase versus healthy ageing. Twelve of these transcripts remained differentially abundant in convalescence phase, and 22 were similarly differentially abundant in acute phase of geriatric infectious diseases. Seven of these 22 transcripts were previously identified as differentially abundant in PBMC of healthy aged versus healthy young controls, with further alteration for CD28, CD69, LCK, CTSD, HMOX1, and TNFRSF1A in acute phase after geriatric hip fracture and infectious diseases. The next question is whether these alterations are common to other geriatric diseases and/or preexist before the clinical onset of the diseases.

Transcriptomic biomarkers of the response of hospitalized geriatric patients with infectious diseases.

BACKGROUND: Infectious diseases are significant causes of morbidity and mortality among elderly populations. However, the relationship between oxidative stress, immune function and inflammatory response in acute phase of the infectious disease is poorly understood. RESULTS: Herein the abundance of a selection of 148 transcripts involved in immunosenescence and stress response was compared in total RNA of PBMC of 28 healthy aged probands and 39 aged patients in acute phase of infectious disease (day 2-4 after hospitalization) or in convalescence phase (day 7-10). This study provides a list of 24 differentially abundant transcript species in the acute phase versus healthy aged. For instance, transcripts associated with inflammatory and anti-inflammatory reactions (TNFRSF1A, IL1R1, IL1R2, IL10RB) and with oxidative stress (HMOX1, GPX1, SOD2, PRDX6) were more abundant while those associated with T-cell functions (CD28, CD69, LCK) were less abundant in acute phase. The abundance of seven of these transcripts (CD28, CD69, LCK, CTSD, HMOX1, TNFRSF1A and PRDX6) was already known to be altered in healthy aged probands compared to healthy young ones and was further affected in aged patients in acute phase, compromising an efficient response. CONCLUSION: This work provides insights of the state of acute phase response to infections in elderly patients and could explain further the lack of appropriate response in the elderly compared to younger persons.

Transcriptomic biomarkers of human ageing in peripheral blood mononuclear cell total RNA.

Age-related changes of gene expression contribute to the physiological alteration observed with human ageing. Herein, the abundance of a selection of 148 transcripts involved in immunosenescence and stress response was compared in total RNA of PBMC of healthy young to middle-age probands (35.0 +/- 6.5 year old) and healthy old probands (82.5 +/- 6.8 year old). This study provides a list of 16 differentially abundant transcripts species in the healthy old probands. Thus, these changes of abundance can be considered as easily accessible biomarkers of ageing. Some of these differential abundances like CD28, CD69, LCK (decreased abundance in old subjects), CD86, Cathepsin D, H and S (increased abundance in old subjects) might explain biochemical and cytochemical changes observed at the protein level in the immune system and thus might correspond to regulatory processes affecting the ageing process. Indeed these changes reflect the low-grade pro-inflammatory status observed in old persons and suggest a hypo-responsiveness of T-cells together with an increase in antigen presentation potential. In addition, among the differentially abundant transcripts were transcripts involved in the oxidative stress response HMOX1 and HSPA6 mRNAs were found as more abundant in PBMC from elderly subjects.

Impact of growth hormone (GH) deficiency and GH replacement upon thymus function in adult patients.

BACKGROUND: Despite age-related adipose involution, T cell generation in the thymus (thymopoiesis) is maintained beyond puberty in adults. In rodents, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and GH secretagogues reverse age-related changes in thymus cytoarchitecture and increase thymopoiesis. GH administration also enhances thymic mass and function in HIV-infected patients. Until now, thymic function has not been investigated in adult GH deficiency (AGHD). The objective of this clinical study was to evaluate thymic function in AGHD, as well as the repercussion upon thymopoiesis of GH treatment for restoration of GH/IGF-1 physiological levels. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-two patients with documented AGHD were enrolled in this study. The following parameters were measured: plasma IGF-1 concentrations, signal-joint T-cell receptor excision circle (sjTREC) frequency, and sj/beta TREC ratio. Analyses were performed at three time points: firstly on GH treatment at maintenance dose, secondly one month after GH withdrawal, and thirdly one month after GH resumption. After 1-month interruption of GH treatment, both plasma IGF-1 concentrations and sjTREC frequency were decreased (p<0.001). Decreases in IGF-1 and sjTREC levels were correlated (r = 0.61, p<0.01). There was also a decrease in intrathymic T cell proliferation as indicated by the reduced sj/beta TREC ratio (p<0.01). One month after reintroduction of GH treatment, IGF-1 concentration and sjTREC frequency regained a level equivalent to the one before GH withdrawal. The sj/beta TREC ratio also increased with GH resumption, but did not return to the level measured before GH withdrawal. CONCLUSIONS: In patients with AGHD under GH treatment, GH withdrawal decreases thymic T cell output, as well as intrathymic T cell proliferation. These parameters of thymus function are completely or partially restored one month after GH resumption. These data indicate that the functional integrity of the somatotrope GH/IGF-1 axis is important for the maintenance of a normal thymus function in human adults. TRIAL REGISTRATION: ClinicalTrials.gov NTC00601419.