Background Aging is a complex biological process and associated with a progressive decline in functions of most organs including the gastrointestinal (GI) tract. Age‐related GI motor disorders/dysfunctions include esophageal reflux, dysphagia, constipation, fecal incontinence, reduced compliance, and accommodation. Although the incidence and severity of these diseases and conditions increase with age, they are often underestimated due in part to nonspecific and variable symptoms and lack of sufficient medical attention. They negatively affect quality of life and predispose the elderly to other diseases, sarcopenia, and frailty. The mechanisms underlying aging‐associated GI dysfunctions remain unclear, and there is limited data examining the effect of aging on GI motor functions. Many studies on aging‐associated changes to cells within the tunica muscularis including enteric neurons, smooth muscles, and interstitial cells have proposed that cell loss and/or molecular changes may be involved in the pathogenesis of age‐related GI motor disorders/dysfunctions. There is also evidence that the aging contributes to phenotypic changes in innate immune cells, which are physically and functionally linked to other cells in the tunica muscularis and can alter GI (patho) physiology. However, various patterns of changes have been reported, some of which are contradictory, indicating a need for additional work in this area. Purpose Although GI infection due to intestinal bacterial overgrowth, bleeding, and cancers are also important and common problems in the elderly patients, this mini‐review focuses on data obtained from enteric neuromuscular aging research with the goal of better understanding the cellular and molecular mechanisms of enteric neuromuscular aging to enhance future therapy.

Objective: Review the studies that investigate the mechanisms underlying imatinib-resistant gastrointestinal stromal tumors (GIST). Background: GIST are the most common mesenchymal tumors of the gastrointestinal (GI) tract and the most common sarcoma in humans. GIST are thought to be arise from interstitial cells of Cajal (ICC), pacemaker and neuromodulator cells in the GI tract, as well as "fibroblast"-like cells, which are another type of interstitial cells of the gut wall and also known as telocyte or platelet-derived growth factoralpha (PDGFRA)-positive cells. The majority of GIST harbor gain-of-function mutations in either KIT or PDGFRA, and these gain-of-function mutations are mutually exclusive and most often heterozygous.GIST are responsive to the KIT/PDGFRA tyrosine kinase inhibitor (TKI), imatinib, the standard firstline drug for advanced and metastatic GIST. However, imatinib alone does not eradicate GIST despite an initial clinical benefit, and more than 90% of GIST harbor imatinib-resistance. Although second and thirdgeneration TKIs have been developed and are currently in clinical use, they are not curative for refractory and metastatic GIST due to the emergence of clones with drug-resistant mutations. Eradication of drugresistant GIST will cure patients with refractory GIST. Several mechanisms may contribute to refractory GIST. These mechanisms are secondary mutations in KIT and/or PDGFRA, alternative activation of tyrosine kinases, stem cells for GIST and cellular quiescence, a reversible nonproliferating state in which cells retain the ability to reenter cell proliferation. Methods: We review our current optimal treatment approach for managing patients with advanced and refractory GIST. Conclusions: This review explores the novel and potential therapeutic approaches to combat drugresistant GIST.

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Wnt signaling involves multiple pathways that contribute to organ development, cell fate, inflammation, and normal stem cell renewal and maintenance. Although the homeostasis of stem cells in the gastrointestinal (GI) tract highly depends on the Wnt signaling pathway, this regulation is impaired in cancers and in aging. Overactive (uncontrolled) Wnt signaling can induce GI epithelial cancers such as colon and gastric cancer. Overactive Wnt signaling can also contribute to the initiation and progression of gastrointestinal stromal tumor, which is the most common human sarcoma occurring in the walls of the digestive organs, mainly the stomach and small intestine. Wnt expression is positively associated not only with the progression of oncogenesis but also with resistance to chemotherapy and radiotherapy. Of note, recent reports show that decreased Wnt signaling is related to intestinal stem cell aging and that overactivated Wnt signaling leads to gastric pacemaker stem cell aging in tunica muscularis. These findings indicate that Wnt signaling has different crucial aspects of cell fate determination with age in GI tunica mucosa and muscularis. In this review, we summarize the most recent advances in our understanding of Wnt signaling pathways and their role in regulating key aspects during development, carcinogenesis, inflammation, and aging, with the ultimate goal of identifying novel therapies.