Changes in peripheral blood lymphocyte subsets in elderly subjects are associated with an impaired function of the hypothalamic–pituitary–adrenal axis

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Abstract

A growing body of evidence indicates that ageing brings a progressive disruption in the immune and endocrine systems. However, very few reports have correlated the changes in the immune system with the endocrine function in the elderly. The aim of the present study was to investigate the changes occurring in the peripheral blood lymphocyte subpopulations with age and correlate them with the hypothalamic–pituitary–adrenal (HPA) function. We determined the peripheral blood lymphocyte phenotype and the T cell receptor usage by flow cytometry analysis. The HPA function was evaluated by the basal serum levels of adrenal steroids and the response to stimulation with a low-dose ACTH. In the elderly, we observed a decrease of major T subsets together with an increase of NK cells and activated T cells. With regard to the HPA function, the most significant decline was found in dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEAS). A close correlation between immune changes with ageing and DHEA response to ACTH stimulation was found. The present study showed an inverse correlation of lymphocyte changes with the plasma levels of steroids, especially DHEA and its metabolite, DHEAS. This association was not found for other steroids and points for the possibility of using DHEA to correct the immunological decline associated with ageing.

Introduction

Ageing is accompanied by a number of quantitative and qualitative changes in the immune response which are grouped by the term of immunosenescence (Pawelec and Solana, 1997). As a consequence, elderly individuals show an increased susceptibility to neoplasias, infectious diseases and autoimmune processes (Castle, 2000). Most of the immune changes during the ageing process have been extensively studied in mice (Mountz et al., 2001). Recently, many reports have addressed this issue in humans by different approaches. Some of them have described immunophenotypical changes in peripheral blood lymphocyte subsets detected by flow cytometry, such as an increase in CD3+CD7− cells, a decrease of naive and an increase of memory T cells, an expansion of CD28− T cells or an increase of NK cells (Malinowski and Rapaport, 1995, Fagnoni et al., 1996, Ginaldi et al., 2001). Other studies have reported a functional impairment of lymphocytes in ageing: thymic involution, impaired lymphocyte proliferative responses, increased susceptibility of T cells to apoptosis, impairment in type 2 cytokine production and abnormal NK function (Mackall and Gress, 1997, Aggarwal and Gupta, 1998, Sakata-Kaneko et al., 2000, Bruunsgaard et al., 2000, Solana and Mariani, 2000).

The immune system is not the only one that suffers from senescence. The endocrine system also undergoes important changes during ageing. Endocrinosenescence carries a substantial decline in the hormone levels of at least three endocrine axes: hypothalamic–pituitary–gonadal, hypothalamic–pituitary–adrenal (HPA) and growth hormone-insulin-like growth factor I (Roshan et al., 1999). Among them, the HPA axis is the one that best integrates the neuroendocrine and immune system. The HPA axis undergoes a number of age-related changes that can play a possible role in the occurrence of several age-associated pathological conditions (Ferrari et al., 2001).

Despite the evidence indicating a close communication between the neuroendocrine and immune systems, there have been quite few reports in this field (Straub et al., 1998). Specifically, it has not been investigated if the changes in peripheral blood lymphocyte subsets are related to the impaired HPA axis. Thus, the aim of the present study was to investigate the changes occurring in the peripheral blood lymphocyte subpopulations in the elderly and to correlate them with the serum hormone levels of the HPA axis and with the adrenal reserve measured through the response of those hormones to low-dose ACTH.

Section snippets

Subjects and samples

Following informed consent, 34 healthy young donors (14 male and 20 female; mean age: 24.8±3.1 years; range: 20.1–30.4) and 23 healthy aged volunteers (nine male and 14 female; mean age: 73.0±8.0 years, range: 60.4–94.3) were included in the study. All the subjects were in healthy condition, according to accurate clinical investigations and to hematological and biochemical parameters. None of the donors was taking drugs that could affect the immune system or had a prior history of neoplasia,

Peripheral blood lymphocyte subpopulations

Peripheral blood T lymphocytes (CD3+) levels were lower in aged compared with young subjects. This decrease could be attributed to both major types of CD4+ and CD8+ T lymphocytes (Table 2). Elderly donors showed a significant increase in the frequencies of NK cells (CD3−CD16+CD56+) and also T cells with a killer phenotype (CD3+CD16+CD56+). In this regard, although T cells expressing the CD57 NK cell marker represent minor subpopulations of peripheral blood T cells, they were also increased

Discussion

The results of the present study showed changes of all circulating lymphocyte subsets with age that confirmed previous reports. A decrease of major T subsets together with an increase of NK cells and activated T cells were the major findings observed. However, the most novel finding was that many of those modifications that are known to characterise the immunosenescence process were clearly correlated with the decay of androgen steroids of the HPA axis with age. Although correlation does not

Acknowledgements

This work was partially supported by grants from the ‘Fundación Marqués de Valdecilla’ (1998 and 2000) and FIS (FIS98/0846), Spain. We are very grateful to Bárbara Garcı́a for English revision of the manuscript.

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