Proliferating cell nuclear antigen expression is increased in small bowel epithelium in the elderly

Corazza, Gino Roberto; Ginaldi, Lia; Quaglione, Gina Rosaria; Ponzielli, F; Vecchio, Luigi Del; Biagi, Federico; Quaglino, D

doi:10.1016/s0047-6374(98)00044-x

Cited by 39 publications

(23 citation statements)

References 23 publications

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“…Although the fusion and branching of the villi were previously observed in the small intestine of PolgD257A mice at 10 mo of age (21), they were not prominent features in our 7-mo-old PolgD257A mice. However, the increased length and width of the villi in these mice are consistent with similar observations made in aged humans (11,50) and rodents (18,27). Increased villus surface area could be a compensatory response for the reduction of absorptive capacity of enterocytes stemming from an aging-associated hyperproliferation of precursor cells (17).…”

Section: G920 Disruption Of Stem-progenitor Cell Cycle By Polgd257asupporting

confidence: 87%

“…1H) than those of WT mice. These data show that the PolgD257A mutation affects the gross morphology of the small intestines mimicking the changes in dimension found in the small intestine in aged humans (11,50).…”

Section: Small Intestine Morphometricssupporting

confidence: 55%

“…In humans, a compensatory increase in cell proliferation in the small intestines has been observed in the aging population correlating with increased size of the small intestine villi and crypt compartments (11,50). Similarly, in aging rodents, increases in length and width of villi and crypt dimensions have been reported (18,27).…”

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confidence: 96%

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Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption

Fox

Magness

Kujoth

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Changes in intestinal absorption of nutrients are important aspects of the aging process. To address this issue, we investigated the impact of accelerated mitochondrial DNA mutations on the stem/progenitor cells in the crypts of Lieberkühn in mice homozygous for a mitochondrial DNA polymerase gamma mutation, Polg D257A, that exhibit accelerated aging phenotype. As early as 3–7 mo of age, the small intestine was significantly enlarged in the PolgD257A mice. The crypts of the PolgD257A mice contained 20% more cells than those of their wild-type littermates and exhibited a 10-fold increase in cellular apoptosis primarily in the stem/progenitor cell zones. Actively dividing cells were proportionally increased, yet a significantly smaller proportion of cells was in the S phase of the cell cycle. Stem cell-derived organoids from PolgD257A mice failed to develop fully in culture and exhibited fewer crypt units, indicating an impact of the mutation on the intestinal epithelial stem/progenitor cell maintenance. In addition, epithelial cell migration along the crypt-villus axis was slowed and less organized, and the ATP content in the villi was significantly reduced. On a high-fat, high-carbohydrate diet, PolgD257A mice showed significantly restricted absorption of excess lipids accompanied by an increase in fecal steatocrits. We conclude that the PolgD257A mutation causes cell cycle dysregulation in the crypts leading to the age-associated changes in the morphology of the small intestine and contributes to the restricted absorption of dietary lipids.

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Section: G920 Disruption Of Stem-progenitor Cell Cycle By Polgd257asupporting

confidence: 87%

Section: Small Intestine Morphometricssupporting

confidence: 55%

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Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption

Fox

Magness

Kujoth

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Careful morphometric studies agree that ageing in humans is not associated with a reduction in the extent of the absorptive area [1,2]. This preservation of normal morphology seems to be due to an increased enterocyte turnover and to an expansion of the proliferative zone of small intestinal mucosa [3].…”

Section: Introductionmentioning

confidence: 88%

Small Bowel Enterocyte Apoptosis and Proliferation Are Increased in the Elderly

Ciccocioppo¹,

Sabatino

Luinetti

et al. 2002

Gerontology

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Background: It is known that in the elderly the small bowel does not reveal structural and functional deteriorations in normal conditions, whereas the absorptive function is impaired in stress conditions. Objective: The balance between enterocyte apoptosis and proliferation being responsible for the maintenance of tissue size, mucosal morphology and function in the gastrointestinal tract, the aim of our study was to evaluate the rates of enterocyte apoptosis and proliferation in the duodenal mucosa of aged human beings in comparison to adults. Methods: For this purpose, the terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine triphosphate nick end labelling (TUNEL) technique and immunohistochemistry for MIB-1 detection were applied on histological sections of endoscopic duodenal biopsy specimens obtained from 12 healthy elderly subjects (mean age 77.6 years; M/F 7/5) and 12 healthy adult subjects (mean age 37.7 years; M/F 8/4). Counts were performed, at a constant magnification (×200), by computer-aided analysis and the results expressed as median percentages of positive enterocytes. Results: The results showed a significant increase in enterocyte apoptosis in the elderly (15.3 vs. 2.1% in the adults, p < 0.001) which was positively correlated (r_s = 0.65, p < 0.05) with a significant increase in enterocyte proliferation (37.7 vs. 15.8% in the adults, p < 0.0001). Conclusions: These data suggest that the maintenance of mucosal architecture throughout the process of aging is due to either a hyperproliferative state or an exaggerated apoptosis with a consequent cellular immaturity, which may impair the absorptive function observed in stress conditions.

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“…Studies on duodenal morphology have reported a high incidence of pathologic lesions in the duodenum in the older population, which may reflect the high percentage of H. pylori-infected persons in the studied cohorts (32). A more recent study found normal villus length in the distal duodenum of elderly individuals but a strong increase in the cells that stained positive for proliferating cell nuclear antigen, suggesting that the percentage of undifferentiated enterocytes in the duodenum may increase with age and absorptive capacity decrease (11). However, the sample size was small.…”

Section: Discussionmentioning

confidence: 86%

Telomere shortening is associated with reduced duodenal HCO₃⁻secretory but normal gastric acid secretory capacity in aging mice

Tuo

Riederer

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Tuo B, Ju Z, Riederer B, Engelhardt R, Manns MP, Rudolph KL, Seidler U. Telomere shortening is associated with reduced duodenal HCO 3 Ϫ secretory but normal gastric acid secretory capacity in aging mice. Am J Physiol Gastrointest Liver Physiol 303: G1312-G1321, 2012. First published September 27, 2012; doi:10.1152/ajpgi.00035.2012.-The incidence of duodenal ulcer, especially Helicobacter pylori-negative duodenal ulcer, strongly increases with age. In humans, telomere length shortening is considered to be one critical factor in cellular senescence and organ survival. In this study, we compared basal and stimulated gastric acid and duodenal HCO 3 Ϫ secretory rates in aged late-generation (G3) telomerase-deficient (mTERC Ϫ/Ϫ ) mice, which are characterized by severe telomere dysfunction due to the inability to elongate telomeres during cell division. We found that basal and forskolinstimulated HCO 3 Ϫ secretion and short-circuit current (Isc) in isolated duodenal mucosa of G3 mTERC Ϫ/Ϫ mice were markedly reduced compared with age-matched wild-type mice. In contrast, basal and forskolin-stimulated acid secretory rates in isolated G3 mTERC Ϫ/Ϫ gastric mucosa were not significantly altered. Correspondingly, duodenal mucosa of G3 mTERC Ϫ/Ϫ mice showed slimming and shortening of villi, whereas gastric mucosal histology was not significantly altered. However, the ratios of cystic fibrosis transmembrane conductance regulator (CFTR) and solute-linked carrier 26 gene family (Slc26a6) mRNA expression in relation to cytokeratin-18 were not altered in duodenal mucosa. The further knockout of p21, which is a downstream effector of telomere shortening-induced senescence, rescued villus atrophy of duodenal mucosa, and basal and forskolinstimulated duodenal HCO 3 Ϫ secretion and Isc in mTERC Ϫ/Ϫ p21 Ϫ/Ϫ double-knockout mice were not different from wild-type controls. In conclusion, genetic ablation of telomerase resulted in p21-dependent duodenal mucosal atrophy and reduced duodenal HCO 3 Ϫ secretory capacity, whereas gastric morphology and acid secretory function were preserved. This suggests that telomere shortening during aging may result in an imbalance between aggressive and protective secretions against duodenal mucosa and thus predispose to ulcer formation. telomere shortening; gastric acid secretion; duodenal HCO 3 Ϫ secretion; duodenal ulcer; aging PEPTIC ULCER, ESPECIALLY DUODENAL ulcer, is a common disease.

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Proliferating cell nuclear antigen expression is increased in small bowel epithelium in the elderly

Cited by 39 publications

References 23 publications

Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption

Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption

Small Bowel Enterocyte Apoptosis and Proliferation Are Increased in the Elderly

Telomere shortening is associated with reduced duodenal HCO₃⁻secretory but normal gastric acid secretory capacity in aging mice

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Proliferating cell nuclear antigen expression is increased in small bowel epithelium in the elderly

Cited by 39 publications

References 23 publications

Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption

Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption

Small Bowel Enterocyte Apoptosis and Proliferation Are Increased in the Elderly

Telomere shortening is associated with reduced duodenal HCO3−secretory but normal gastric acid secretory capacity in aging mice

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Telomere shortening is associated with reduced duodenal HCO₃⁻secretory but normal gastric acid secretory capacity in aging mice