Plasma cytokine profiles in elderly humans

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Abstract

It is known that as we age, immune dysregulation often occurs, leading to failing health, and increased susceptibility to a number of different diseases. In this study we have investigated plasma cytokine profiles in order to identify immune markers of ageing. Plasma samples were obtained from 138 participants of the Swedish longitudinal NONA study (aged 86, 90 and 94 years) and 18 healthy Swedish volunteers (aged between 32 and 59 years). Our results show significantly increased levels of the pro-inflammatory cytokine interleukin-6 (P<0.0001) and soluble intercellular adhesion molecule-1 (P<0.0001) in the elderly group. The anti-inflammatory cytokine interleukin-10 did not alter with age whereas active (naturally processed) transforming growth factor-β levels were significantly (P<0.0001) increased in the elderly group. No difference was observed between males and females. These data suggest that there are measurable changes in cytokine profiles with ageing with increased levels of potentially harmful molecules, which may contribute to immune alterations and declining health in the elderly population.

Introduction

Cytokines are signal molecules with important effects within, but also outside the immune system. It is suggested that cytokines might be involved in immunosenescence (Straub et al., 2000). We have chosen to measure the plasma cytokines interleukin-6 (IL-6), interleukin-10 (IL-10), soluble intercellular adhesion molecule-1 (sICAM-1) and transforming growth factor-β (TGF-β), since these are known to be detectable in this medium, have important regulatory roles in inflammation, and have been suggested to play a role in the ageing process or are associated with diseases of ageing.

IL-6 is a multifunctional, pleiotropic cytokine. IL-6 levels increase after both the menopause and andropause, presumably because of a loss of the regulatory influence of secondary sex steroids such as oestrogen. It has been suggested that these age-related increases in IL-6 account for many of the phenotypic changes seen with advanced age, including decreased lean body mass, osteopenia, low-grade anaemia, decreased serum albumin and cholesterol, and increased inflammatory proteins such as C-Reactive protein and serum amyloid A. Furthermore, this rise in IL-6 has been linked to development of frailty and susceptibility to disease, such as osteoporosis and Alzheimers, in elderly individuals (Ershler and Keller, 2000).

sICAM-1 levels have been shown to increase with age (Miles et al., 2001) and are also significantly associated with several established risk factors for cardiovascular diseases (CVD) (Rohde et al., 1998). Due to this correlation several groups have now suggested that sICAM-1 may be an early marker of atherosclerosis (Ikata et al., 2000, Rohde et al., 1998, Noguchi et al., 1998).

Only one study has investigated serum levels of the anti-inflammatory cytokine IL-10 in the elderly and has found no difference in cytokine levels when compared with younger controls (Peterson et al., 1994). Several studies have however looked at the ex vivo capacity of macrophages from elderly donors to produce IL-10 and found this to be increased (Pawelec et al., 2000, Castle et al., 1999, Sadeghi et al., 1999).

TGF-β is a family of closely related molecules encoded by distinct genes, producing a versatile cytokine, which is secreted in a latent form (McMahon et al., 1996, Saharinen et al., 1999) and activated by proteolysis during processes such as cell growth, differentiation and immune modulation. Five isoforms have been described, of which TGF-β1 is the most studied. A few publications (murine) have suggested that fibroblast and joint fluid levels of TGF-β1 decrease with age, contributing to osteopenia and poor wound healing responses in elderly animals (reviewed by Kudravi and Reed (2000)), while another publication shows increased TGF-β production in senescent fibroblasts (Frippiat et al., 2001). Only two groups have investigated plasma levels of TGF-β in elderly humans and have found no change in this cytokine with gender or age (Young et al., 1999, Peterson et al., 1994).

In the present study, plasma samples were taken from the NONA study, representing an unselected Swedish ageing population. A random sample of 138 individuals was investigated as to the plasma levels of IL-6, sICAM-1, IL-10 and TGF-β1, and compared with younger healthy individuals. The health status of the elderly group was also taken into account using various selection criteria that divided the elderly into healthy, moderately healthy and frail elderly.

Section snippets

Subjects

The NONA study is a longitudinal investigation of an unselected Swedish population-based sample of the oldest old. Blood for the immunological analyses was drawn in 138 individuals aged between 86 and 94 years. The mean age of the sample was 90 years with a total proportion of women of 70%. The sample consists of three sub-groups aged 86, 90 and 94, respectively. Results were compared with 18 healthy Swedish volunteers (staff working in the laboratories at the Ryhov Hospital in Jönköping) aged

Results

Cytokine levels were measured in plasma taken from elderly (Swedish NONA) and middle aged (Swedish NONA control) (Table 1). The pro-inflammatory cytokine IL-6, as well as sICAM-1 were significantly increased (P<0.0001) in the elderly group, the anti-inflammatory cytokine IL-10 showed no change and active TGF-β levels were significantly (P<0.0001) increased in the elderly group. No significant differences were observed between males and females (data not shown).

Discussion

Cytokines are central to immune cell communications, and therefore age-related changes in cytokine profiles will contribute to many of the functional alterations observed in the ageing immune system. In this report we add to the information beginning to emerge on immune ageing. We have shown significantly increased levels of IL-6, sICAM-1 and active TGF-β1 and unaltered levels of IL-10, in individuals from the Swedish NONA population aged 86–94, when compared with middle aged healthy Swedish

Acknowledgements

The NONA study is supported by a grant from the Swedish Social Research Council (SFR) and the Vardal Foundation in Sweden. The NONA Immune Study especially acknowledge the support from the Research Board in the County Council of Jönköping and the Research Council in the Southeast of Sweden (FORSS). We also acknowledge Länsjukhuset Ryhov for provision of laboratory resources for the completion of these studies. This work was performed under the aegis of the European Union Thematic Network on

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