Background&Aims&Methods: Telomere shortening and senescence are hallmarks of human aging. To study the effect of telomere shortening on the aggressive and protective gastroduodenal secretions, murine duodenal HCO3- and gastric HCl secretion were measured in vitro. Results: In mTERC-/-mice, forskolin-stimulated HCO3- secretion was reduced by 43%, compared with age-matched wt mice with long telomere reserves (P<0.0001). In contrast, forskolin-stimulated gastric acid secretion was not significantly altered (P>0.05). Duodenal mucosa of mTERC-/- showed villous atrophy, whereas gastric mucosal histology was not altered. p21 is a downstream effector of senescence signaling resulting in cell cycle arrest. In order to investigate whether the defect in HCO3- secretion in mTERC -/-mice was due to p21 dependent senescence induced by telomere shortening, we analyzed duodenal mucosal HCO3- secretion in late generation mTERC-/- p21-/- double knockout mice. In mTERC-/- p21-/- mice duodenal atrophy as well as forskolin-stimulated duodenal HCO3- secretion was rescued (P>0.05). Conclusion: Telomere shortening and senescence has a differential effect on gastroduodenal ion transport functions, resulting in an imbalance between aggressive and protective secretions and thus predisposing to duodenal ulcer formation.