Trends in intestinal aging: From underlying mechanisms to therapeutic strategies

Abstract

Intestinal aging is central to systemic aging, characterized by a progressive decline in intestinal structure and function. The core mechanisms involve dysregulation of epithelial cell renewal and gut microbiota dysbiosis. In addition to previous results in model organisms like Drosophila melanogaster, recent studies have shown that in mammalian models, aging causes increased intestinal permeability and intestinal-derived systemic inflammation, thereby affecting longevity. Therefore, anti-intestinal aging can be an important strategy for reducing frailty and promoting longevity. There are three key gaps remaining in the study of intestinal aging: (1) overemphasis on aging-related diseases rather than the primary aging mechanisms; (2) lack of specific drugs or treatments to prevent or treat intestinal aging; (3) limited aging-specific dysbiosis research. In this review, the basic structures and renewal mechanisms of intestinal epithelium, and mechanisms and potential therapies for intestinal aging are discussed to advance understanding of the causes, consequences, and treatments of age-related intestinal dysfunction.

Keywords: Cross-talk; Intestinal aging; Intestinal epithelial renewal; Intestinal permeability; Intestine-derived systemic inflammation; Mechanism; Stem cell; Therapeutic strategy.

Graphical abstract

Figure 1

Basic structures of intestinal epithelium and molecular mechanism of intestinal stem cells. (A) Structure and cell composition of intestinal epithelium. (B) The regulatory mechanisms of intestinal stem cells in self-repair of intestinal epithelium.

Figure 2

Mechanisms of intestinal aging. (A) Molecular mechanisms of intestinal aging related to stem cells involve regulation of ISC proliferation, differentiation, and repair via pathways such as WNT/β-Catenin and Notch. (B) Inflammatory factor release, immune cell dysfunction (e.g., CD4⁺ T cells), and immune signaling disorders drive intestinal inflammation. (C) Kinase pathways (e.g., AMPK) regulate intestinal cell metabolism and aging. (D) miRNAs are differentially expressed in senescent intestinal cells, modulating cellular function. (E) Intestinal aging is associated with diseases (such as AD and Parkinson's disease) through dysregulation of intestinal flora. (F) Drugs (chemotherapeutic agents/antibiotics/non-steroidal anti-inflammatory drugs (NSAIDs)) induce intestinal aging through oxidative stress, apoptosis, and barrier damage. (G) Gut microbiota dysbiosis-mediated mechanisms in aging.

Figure 3

Therapies that regulate intestinal dysfunction caused by aging.

Figure 4

Mechanisms of Chinese herbal compound prescriptions and natural medicinal agents in treating intestinal senescence. Active ingredients regulate pathways like SIRT1/3/6 and AMPK/mTOR, repair the intestinal barrier (regulate TJ proteins), inhibit inflammatory factors, and balance microecology via SCFA.

Figure 5

Mechanisms of marketed drug therapies for intestinal aging. Marketed drugs (e.g., atorvastatin, metformin, empagliflozin, and senolytics combination) regulate core pathways (e.g., WNT signaling pathway, p-MAPK pathway, mTOR pathway, P65 NF-κB pathway), influence senescence-related factors (e.g., P16, P21), and inflammatory mediators (e.g., SA-β-gal, SASP). In intestinal function regulation, these drugs repair the intestinal barrier (modulate TJ proteins OCLN and ZO1), balance the intestinal microbiota, and leverage SCFA for anti-inflammatory effects while regulating immune cells (e.g., Treg cells, γδ T cells).

Figure 6

Mechanisms of action of probiotics in intestinal aging. Different probiotics act according to their characteristics. Core mechanisms include regulating intestinal microbiota balance, enhancing intestinal barrier function (modulating the expression of TJ proteins and mRNAs), inhibiting inflammation via the TNFα and NF-κB pathways, alleviating oxidative stress, and regulating the intestinal microenvironment through SCFA.

Figure 7

Mechanisms of action of endogenous components in intestinal aging. Endogenous components act on intestinal aging through multidimensional pathways. Core mechanisms include strengthening intestinal barrier function (up-regulating the mRNA and protein expression of OCLN and ZO1), inhibiting inflammation (targeting inflammatory pathways and factors like TLR4/NF-κB and IL1), alleviating oxidative stress (activating the GPX4/SOD2 pathway and reducing ROS levels), and participating in senescence regulation (affecting pathways and key molecules such as SIRT1, P53, and WNT-β-Catenin).

Figure 8

Schematic diagram of intestinal aging mechanisms and treatment strategies.