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World J Gastroenterol. Apr 28, 2014; 20(16): 4467-4482
Published online Apr 28, 2014. doi: 10.3748/wjg.v20.i16.4467
Increased susceptibility of aging gastric mucosa to injury: The mechanisms and clinical implications
Andrzej S Tarnawski, Amrita Ahluwalia, Michael K Jones
Andrzej S Tarnawski, Amrita Ahluwalia, Michael K Jones, University of California Irvine and the Veterans Administration Long Beach Healthcare System, 5901 E. 7th Street, Long Beach, CA 90822-5201, United States
Author contributions: Tarnawski AS, Ahluwalia A and Jones M contributed to this paper; Tarnawski AS designed the overall concept and outline of the manuscript; Ahluwalia A and Jones MK contributed to the discussion and design of the manuscript; Tarnawski AS, Ahluwalia A and Jones MK contributed to the writing, editing and revision of the manuscript, illustrations, and review of literature (55%, 30% and 15%, respectively).
Supported by VA Merit Review grant to Tarnawski AS
Correspondence to: Andrzej S Tarnawski, MD, PhD, DSc, University of California Irvine and the Veterans Administration Long Beach Healthcare System, 5901 E. 7th Street (09/151), Long Beach, CA 90822-5201, United States. atarnawski@yahoo.com
Telephone: +1-562-8265437 Fax: +1-714-8464496
Received: January 13, 2014
Revised: January 30, 2014
Accepted: April 1, 2014
Published online: April 28, 2014
Processing time: 105 Days and 22.7 Hours
Abstract

This review updates the current views on aging gastric mucosa and the mechanisms of its increased susceptibility to injury. Experimental and clinical studies indicate that gastric mucosa of aging individuals-“aging gastropathy”-has prominent structural and functional abnormalities vs young gastric mucosa. Some of these abnormalities include a partial atrophy of gastric glands, impaired mucosal defense (reduced bicarbonate and prostaglandin generation, decreased sensory innervation), increased susceptibility to injury by a variety of damaging agents such as ethanol, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), impaired healing of injury and reduced therapeutic efficacy of ulcer-healing drugs. Detailed analysis of the above changes indicates that the following events occur in aging gastric mucosa: reduced mucosal blood flow and impaired oxygen delivery cause hypoxia, which leads to activation of the early growth response-1 (egr-1) transcription factor. Activation of egr-1, in turn, upregulates the dual specificity phosphatase, phosphatase and tensin homologue deleted on chromosome ten (PTEN) resulting in activation of pro-apoptotic caspase-3 and caspase-9 and reduced expression of the anti-apoptosis protein, survivin. The imbalance between pro- and anti-apoptosis mediators results in increased apoptosis and increased susceptibility to injury. This paradigm has human relevance since increased expression of PTEN and reduced expression of survivin were demonstrated in gastric mucosa of aging individuals. Other potential mechanisms operating in aging gastric mucosa include reduced telomerase activity, increase in replicative cellular senescence, and reduced expression of vascular endothelial growth factor and importin-α-a nuclear transport protein essential for transport of transcription factors to nucleus. Aging gastropathy is an important and clinically relevant issue because of: (1) an aging world population due to prolonged life span; (2) older patients have much greater risk of gastroduodenal ulcers and gastrointestinal complications (e.g., NSAIDs-induced gastric injury) than younger patients; and (3) increased susceptibility of aging gastric mucosa to injury can be potentially reduced or reversed pharmacologically.

Keywords: Aging gastric mucosa; Injury; Phosphatase and tensin homologue deleted on chromosome ten-PTEN; Survivin; Apoptosis; Hypoxia

Core tip: This review focuses on aging gastric mucosa and its increased susceptibility to injury. The following events occur in aging gastric mucosa: reduced mucosal blood flow and hypoxia, upregulates PTEN that activates pro-apoptotic caspases and reduces anti-apoptosis protein, survivin. The imbalance between pro- and anti-apoptosis mediators results in increased apoptosis and increased susceptibility to injury. Aging gastropathy is an important and clinically relevant issue because of: (1) an aging world population; (2) older patients have much greater risk of gastroduodenal ulcers and gastrointestinal complications (e.g., non-steroidal anti-inflammatory drugs-induced gastric injury) than younger patients; and (3) increased injury of aging gastric mucosa can be reversed pharmacologically.