ReviewThe impact of ageing on the intestinal epithelial barrier and immune system
Introduction
Ageing is an ill-defined process involving changes in various body systems which converts a mature, fit person into an increasingly infirm one. With the passage of time, individuals show a lower degree of adaptation with consequent increase in mortality, due to increased incidence of cancer and infectious disease [1], [2], as well as a decline of mental health, wellbeing and cognitive abilities [3], [4], [5]. Advancements in science and medicine, and improved living standards have led to an increase of the ageing population in Western societies. For example, latest figures show that 10 million people in the United Kingdom are over 65 years old, estimating that there will be 5½ million more elderly people in 20 years’ time, with that number nearly doubling to around 19 million by 2050 [6]. This predicted increased life expectancy of the population has significant social and economic consequences. However, new research suggests that extending life span while reducing the prevalence of comorbities is a realistic goal, and that developing strategies to delay ageing can produce significant economic benefit, in excess of $7 trillion over a period of 50 years [7]. These data provide a compelling argument to increase our understanding of the ageing process, in order to improve the quality of life of an ever increasing segment of the population worldwide, and alleviate the economic burden associated to it.
One of the most important effects of the ageing process is a significant decline of the efficacy of both the adaptive and innate immune systems [8], [9]; in particular, ageing has a profound influence on the intestinal immune system, and it would appear that age-associated alterations arise in the mucosal immune system of the GI-tract earlier than in systemic immune compartments [10]. Although our knowledge of the age-related changes of the systemic immune system has improved over the past few years, our understanding of the mechanisms of mucosal immunosenescence of the intestine is still largely incomplete. The aim of this review is to summarise the age-associated changes affecting the different stages of the gut immune response, from the early events occurring at the mucosal interface mediated by various components of the epithelial barrier, to the generation of antigen-specific immune responses.
Section snippets
Introduction to the intestinal immune system
It is generally accepted that the GI tract represents the largest immunologic organ in terms of numbers of lymphocytes and at any given time, the gut-associated lymphoid tissue (GALT) can accommodate nearly 70% of the total lymphocytes in the body [11]. Although this figure has been questioned by estimating the real number of lymphocytes in the gut to be closer to 5–20% of all lymphocytes [12], it is without doubt that the intestinal immune system copes daily with an antigen load that surpasses
The intestinal epithelium in ageing
Although the main task of the epithelium overlying mucosal surfaces of the intestinal tract is the provision of an effective barrier to the vast majority of macromolecules and microorganisms present in the intestinal lumen, it has become evident in the past few years that the epithelial layer is much more than a mere physical barrier. Indeed, intestinal epithelial cells (IECs) engage in a dynamic cross-talk with the intestinal immune system [22], [23] that helps to achieve the task of
Interaction between the gut epithelium and the microbiota
Accommodating the vast microbiota is possibly the biggest challenge facing the intestinal epithelium. This is not a passive process, since it involves various host defence mechanisms which have evolved to regulate the composition of the microbiota, and to protect against infection and colonisation by pathogenic or opportunistic microbes. The primary mediators of this activity are various anti-microbial peptides (AMPs) that are secreted by IECs [38], [39] and the mucus that coats the epithelium
Crossing the epithelial barrier
Antigen sampling across the FAE of the PPs via M cells is a critical step in enabling the immune system to monitor the luminal contents allowing for an appropriate course of action. M cells are specialised epithelial cells strategically located in the FAE overlying the PPs originally described by Owen and Jones [62], and are key in the transcytosis of microorganisms and macromolecules to the underlying immune system. Initially, conflicting results were reported whereby the intestinal uptake of
Antigen-presentation
Antigen transported across the epithelial barrier to the inductive sites of the intestinal immune system is then dealt with by APCs. DCs are crucial for the presentation of antigen to immunocompetent B and T cells, and have a key role in the induction of peripheral tolerance [14]. T cell priming by DCs appears to be compromised in aged mice. Aged mice showed a suboptimal T cell priming to Encephalitozoon cuniculi that could be improved by using MLN–DCs from young animals to stimulate aged T
Conclusions
Older people suffer from a decline in immune system function, which in the gut affects their ability to tolerate ingested nutrients or resident microbiota, response to infections and is often compounded by malnutrition and dehydration. All these factors contribute greatly to the increased morbidity and mortality rates within older populations. Compared with immunosenescence of systemic immunity, age-associated changes in the intestinal immune system (summary in Table 1) are less well understood
Acknowledgments
Work in our laboratory is supported by the Biotechnology and Biological Sciences Research Council (BBSRC) Institute Strategic Programme BB/J004529/1: The Gut Health and Food Safety ISP.
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