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. 2013 Sep;68(9):1045-56.
doi: 10.1093/gerona/glt106. Epub 2013 Jul 20.

Age-associated remodeling of the intestinal epithelial barrier

Lee Tran  1 , Beverley Greenwood-Van Meerveld
Affiliations

Age-associated remodeling of the intestinal epithelial barrier

Lee Tran et al. J Gerontol A Biol Sci Med Sci. 2013 Sep.

Abstract

Disorders of the gastrointestinal tract are common in the elderly people; however, the precise trait(s) of aging that contribute to the vulnerability of the gastrointestinal tract are poorly understood. Recent evidence suggests that patients with gastrointestinal disorders have increased intestinal permeability. Here, we address the hypothesis that disruption of the intestinal barrier is associated with aging. Our results demonstrated that permeability was significantly higher in colonic biopsies collected from old baboons compared with young baboons. Additionally, colonic tissue from the older animals had decreased zonula occluden-1, occludin, and junctional adhesion molecule-A tight junction protein expression and increased claudin-2 expression. Upregulation of miR-29a and inflammatory cytokines IFN-γ, IL-6, and IL-1β was also found in colonic biopsies from old baboons relative to young baboons. These results show for the first time that a pivotal contributing factor to geriatric vulnerability to gastrointestinal dysfunction may be increased colonic permeability via age-associated remodeling of intestinal epithelial tight junction proteins.

Keywords: Aging; Cytokines; MicroRNA; Permeability; Tight junctions.

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Figures

Figure 1.
Figure 1.
Hematoxylin and eosin staining revealed no histological differences between colonic biopsies from young and old baboons (A). Review by a pathologist blind to the study confirmed that there was no evidence of increased fibrosis, crypt atrophy, or acute inflammation in the aged samples when compared with the young samples. Quantification of myeloperoxidase (MPO) activity within the colonic biopsies showed no difference between young or old baboons (B). Statistical significance was *p > .05 by Student’s unpaired t test.
Figure 2.
Figure 2.
Aging increases colonic permeability. A reduction in transepithelial electrical resistance (TEER; A) and an increase in horseradish peroxidase (HRP) flux (B) was apparent in biopsies from old baboons compared with young baboons. Statistical significance was *p < .05 by Student’s unpaired t test.
Figure 3.
Figure 3.
Aging restructures colonic epithelial tight junctions. Confocal micrographs of cross-sections imaged from colonic biopsies are shown for young (left) and old (middle) baboons in addition to a quantification of the fluorescent optical densities of the micrographs (right). Overall, there was a significant decrease in zonula occluden-1 (ZO-1; A), occludin (B), and junctional adhesion molecule (JAM)-A immunofluorescence (C). Although there was a trend toward increased claudin-2 expression, the change was not statistically significant (D). Statistical significance was *p < .05 by Student’s unpaired t test.
Figure 4.
Figure 4.
Aging alters expression of tight junctions. Western blot was used to quantify total expression levels of tight junction proteins. Quantification of the optical densities is shown on the left panel with representative blots on the right. Detection by chemiluminescence revealed positive bands for the tight junction proteins zonula occluden-1 (ZO-1) at ~225kDa (A), occludin at ~65kDa (B), junctional adhesion molecule (JAM)-A at ~36kDa (C), and claudin-2 at ~22kDa (D). Glyceraldehyde 3-phosphate dehydrogenase (~36kDa) was used to normalize ZO-1, occludin, and claudin-2 optical densities, and β-actin (~42kDa) was used to normalize JAM-A. There was a significant decrease in ZO-1, occludin, and JAM-A expression in contrast to a significant increase in claudin-2 protein expression. Statistical significance is *p < .05 by Student’s unpaired t test.
Figure 5.
Figure 5.
MicroRNA and glutamine synthase expression in colonic biopsies. With age there was a significant increase in miR-29a but not miR-122a or miR-212 expression within the colonic biopsies (A). There was no significant difference in GLUL expression in the same samples (B). Statistical significance was *p < .05 by Student’s unpaired t test.
Figure 6.
Figure 6.
From the cytokine panel, there was a significant increase in IFN-γ, IL-6, and IL-1β expression in aged colonic tissue compared with young colonic tissue. There was also a trend toward increased IL-12 production that was not statistically significant. Statistical significance was *p < .05 by Student’s unpaired t test.
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