The Aged Intestine: Performance and Rejuvenation

Abstract

Owing to the growing elderly population, age-related problems are gaining increasing attention from the scientific community. With senescence, the intestine undergoes a spectrum of changes and infirmities that are likely the causes of overall aging. Therefore, identification of the aged intestine and the search for novel strategies to rescue it, are required. Although progress has been made in research on some components of the aged intestine, such as intestinal stem cells, the comprehensive understanding of intestinal aging is still limited, and this restricts the in-depth search for efficient strategies. In this concise review, we discuss several aspects of intestinal aging. More emphasis is placed on the appraisal of current and potential strategies to alleviate intestinal aging, as well as future targets to rejuvenate the aged intestine.

Keywords: aging; bile acids; intestinal microbiota; intestine; short-chain fatty acids.

Figure 1.

The Age-related Changes in the Intestine. During senescence, the intestine gains changes in terms of the intestinal microbiota, immune system, intestinal stem cells, epithelial functions, and the enteric nervous system. These changes in the aged intestine are responsible for many overall age-related diseases, such as the brain, heart, bone, and endocrine system. The Geroscience perspective that makes it more comprehensive to understand anti-aging mechanisms, would enlighten us on the development of strategies to rejuvenate the aged intestine.

Figure 2.

The Factor Network Contributing to the Intestinal Stem Cell Aging. An intracellular and extracellular network contributes to the senescence of ISCs, including telomere dysfunction, DNA damage response, DNA mutation, mitochondrial dysfunction, oxidation stress, autophagy dysregulation, and senescence-associated secretory phenotype. Several cellular signaling pathways are also involved, such as the Wnt and mTOR pathways. ATM/R, protein kinases ATR and ATM; AKT, protein kinase B; mTOR, mammalian target of rapamycin; ROS, reactive oxygen species; PGC1α, peroxisome proliferator activated receptor-γ co-activator 1-α.

Figure 3.

An integral view on the anti-aging effect of metformin in the intestine. Four main changes take place in the aging intestine, including the intestinal microbiota, immune system, ISCs, and epithelial functions. Metformin exerts its integral effects to mitigate age-related changes in the intestine. ?Metformin alters bacterial metabolism to improve the production of beneficial metabolites, as well as to interfere with folate metabolism, which leads to a changed microbial composition. ?The anti-inflammatory effect of metformin is mediated by the regulation of mitochondrial gene expression, activation of AMPK, and inhibition of P38. ?Through attenuating the age-related specific AKT overexpression, metformin relieves DNA damage and ISC hyperplasia in the midgut of Drosophila, favoring homeostasis of ISCs. ?Tight junctions and mucus produced by goblet cells are both important components in the maintenance of the intestinal barrier. The inhibition of JNK signaling and Wnt signaling by metformin contributes to the expression of tight junction proteins and the differentiation of ISCs to goblet cells, which, accompanied by a metformin-induced increase in Muc2 expression, reinforces the intestinal barrier. AMPK, adenosine 5’-monophosphate-activated protein kinase; DSS, dextran sulfate sodium; AKT (PKB), protein kinase B; TOR, target of rapamycin; ISC, intestinal stem cell; EB, enteroblast; JNK, c-Jun N-terminal kinase.