Intestinal aging-related immune dysfunction: mechanisms and interventions

Abstract

Intestinal immunosenescence, a hallmark of organismal aging, has emerged as a critical biological process impacting the health of elderly individuals. This review systematically examines the core mechanisms underlying intestinal immunosenescence, including immune cell dysfunction, imbalances in immune-microbiota interactions, and impaired barrier function. We analyze its associations with infectious diseases, chronic inflammation, and neurodegenerative disorders, summarizing recent advances in dietary interventions, microecological therapy, and other emerging strategies. By integrating cutting-edge technologies, we prospect the development of precision interventions aimed at delaying intestinal immunosenescence, thereby providing a theoretical basis for improving the healthspan of the aging population.

1. Introduction

The intestine serves as the largest immune organ in the human body, harboring approximately 70%–80% of immune cells and constituting the first line of defense against pathogens [1,2]. Its unique immune architecture includes Peyer’s patches (PPs), intraepithelial lymphocytes (IELs), lamina propria lymphoid tissues, lymphoid follicles and mesenteric lymph nodes (MLNs), which form a multilayered defense system that plays a key role in maintaining immune balance [3].

Intestinal immunity exhibits dual functions. On the one hand, it recognizes pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs) to activate innate immune responses and eliminate invading microbes [4–6]. On the other hand, it develops immune tolerance to the commensal microbiota by regulating immune cell subsets such as T cells and innate lymphoid cells (ILCs) [7,8], thus maintaining the host-microbiota symbiotic relationship. Disruption of this dynamic balance is closely related to various diseases, and the decline in gut immune function during aging further exacerbates this imbalance.

Immunosenescence refers to the gradual decline in immune system structure and function with aging, ultimately leading to poor vaccination efficacy, persistent low-grade inflammation, increased infection susceptibility, and age-related disease onset [9–11]. In the intestinal microenvironment, aging exerts detrimental effects on the mucosal immune system by impacting immune cells, cytokines, and signaling pathways, thereby disrupting the intestinal immune barrier and leading to immune dysfunction. This disruption can subsequently trigger a variety of immune-related diseases. In addition to the immune barrier, the intestinal barrier also comprises biochemical, physical, and biological barriers, which collectively coordinate the transport of ions and nutrients, immune regulation, and the intricate balance of gut microbiota diversity [12]. In the aging process, the expression of tight junction proteins decreases, and the mucus layer thins, leading to increased intestinal permeability [13,14]. This destruction of the physical barrier alters the microenvironment of bacterial growth, thereby affecting the composition and function of the gut microbiota [15,16]. In addition, aging-induced changes in the gut microbiota can also compromise the integrity of the intestinal mucosa and gut homeostasis, subsequently leading to diminished immune responsiveness and regulatory capacity and an inability to effectively counteract various exogenous insults [17]. The decline in immune system function, in turn, also impacts the gut microbiota, resulting in a sustained decline in immunity [18].