Aging-dependent decrease in the numbers of enteric neurons, interstitial cells of Cajal and expression of connexin43 in various regions of gastrointestinal tract

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Abstract

Aging is a significant risk factor for gastrointestinal dysmotility, but aging-associated differences between different organs and the exact time to start degenerating have remained obscure. Here we evaluated alterations of interstitial cells of Cajal, enteric neurons and connexin43 expression in the stomach, jejunum and colon in 2-, 12-, 16-, 20- and 24-month-old mice, as well as in aged human colon. Interstitial cells of Cajal, cholinergic and nitrergic neurons within the whole digestive tract were reduced over time, but their loss first appeared in stomach, then in intestine, helping to understand that gastric function was first impaired during aging. The decrease of connexin43 expression occurred before interstitial cells of Cajal and neurons loss, suggesting that connexin43 might be the major target influenced during senescence. Furthermore, changes in expressions of pro-inflammatory cytokines (tumour necrosis factor-α, interleukin-1β, interleukin-6) and apoptosis-related proteins (B-cell lymphoma-2, caspase-3) which indicated “inflammaging”, might contribute to the loss of enteric neurons and interstitial cells of Cajal in aged gastrointestinal tract. Our results provide possible therapeutic time window for beneficial intervention for geriatric patients with gastrointestinal motility disorders.

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Most cited references 28

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Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions.

Magnus Simrén, Lena Öhman (2010)

IBS is one of the most common functional gastrointestinal disorders worldwide and is thought to be the result of disturbed neural function along the brain-gut axis. The mechanisms behind this disturbance are not clear, but important roles for low-grade inflammation and immunological alterations in the development of symptoms compatible with IBS have become evident. The development of long-standing gastrointestinal symptoms after infectious gastroenteritis and patients with IBD in remission frequently having functional gastrointestinal symptoms support this hypothesis. An increased innate immune activity in the intestinal mucosa and in blood is found in subpopulations of patients with IBS. Mast cells and monocytes seem to be particularly important. In addition, studies have demonstrated that IBS may be associated with an activated adaptive immune response. Increased epithelial barrier permeability and an abnormal gut flora might lead to increased activation of the intestinal immune system. Functional and anatomical evidence for abnormal neuroimmune interactions has been found in patients with IBS. The link between immune alterations and severity of gastrointestinal symptoms and the positive effect of anti-inflammatory treatments in IBS further highlight the relevance of neuroimmune interactions in this condition.

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Regulation of gastrointestinal motility--insights from smooth muscle biology.

Jeremy K M Sanders, Rachel S Koh, S. Ward … (2012)

Gastrointestinal motility results from coordinated contractions of the tunica muscularis, the muscular layers of the alimentary canal. Throughout most of the gastrointestinal tract, smooth muscles are organized into two layers of circularly or longitudinally oriented muscle bundles. Smooth muscle cells form electrical and mechanical junctions between cells that facilitate coordination of contractions. Excitation-contraction coupling occurs by Ca(2+) entry via ion channels in the plasma membrane, leading to a rise in intracellular Ca(2+). Ca(2+) binding to calmodulin activates myosin light chain kinase; subsequent phosphorylation of myosin initiates cross-bridge cycling. Myosin phosphatase dephosphorylates myosin to relax muscles, and a process known as Ca(2+) sensitization regulates the activity of the phosphatase. Gastrointestinal smooth muscles are 'autonomous' and generate spontaneous electrical activity (slow waves) that does not depend upon input from nerves. Intrinsic pacemaker activity comes from interstitial cells of Cajal, which are electrically coupled to smooth muscle cells. Patterns of contractile activity in gastrointestinal muscles are determined by inputs from enteric motor neurons that innervate smooth muscle cells and interstitial cells. Here we provide an overview of the cells and mechanisms that generate smooth muscle contractile behaviour and gastrointestinal motility.

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Gut peristalsis is governed by a multitude of cooperating mechanisms.

Jan D. Huizinga, Wim Lammers (2008)

Peristaltic motor activity of the gut is an essential activity to sustain life. In each gut organ, a multitude of overlapping mechanisms has developed to acquire the ability of coordinated contractile activity under a variety of circumstances and in response to a variety of stimuli. The presence of several simultaneously operating control systems is a challenge for investigators who focus on the role of one particular control activity since it is often not possible to decipher which control systems are operating or dominant in a particular situation. A crucial advantage of multiple control systems is that gut motility control can withstand injury to one or more of its components. Our efforts to increase understanding of control mechanism are not helped by recent attempts to eliminate proven control systems such as interstitial cells of Cajal (ICC) as pacemaker cells, or intrinsic sensory neurons, nor does it help to view peristalsis as a simple reflex. This review focuses on the role of ICC as slow-wave pacemaker cells and places ICC into the context of other control mechanisms, including control systems intrinsic to smooth muscle cells. It also addresses some areas of controversy related to the origin and propagation of pacemaker activity. The urge to simplify may have its roots in the wish to see the gut as a consequence of a single perfect design experiment whereas in reality the control mechanisms of the gut are the messy result of adaptive changes over millions of years that have created complementary and overlapping control systems. All these systems together reliably perform the task of moving and mixing gut content to provide us with essential nutrients.

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Author and article information

Journal

Journal ID (nlm-ta): Aging (Albany NY)

Journal ID (iso-abbrev): Aging (Albany NY)

Journal ID (publisher-id): Aging

Title: Aging (Albany NY)

Publisher: Impact Journals

ISSN (Electronic): 1945-4589

Publication date Collection: December 2018

Publication date (Electronic): 11 December 2018

Volume: 10

Issue: 12

Pages: 3851-3865

Affiliations

[1 ]Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University , Beijing, 100069, China

[2 ]Beijing Key Laboratory of Cancer Invasion and Metastasis Research , Beijing, 100069, China

[3 ]Cancer Institute of Capital Medical University , Beijing, 100069 , China

Author notes

Correspondence to: Deshan Zhou; email: zhouds08@ 123456ccmu.edu.cn

Article

Publisher ID: 101677

DOI: 10.18632/aging.101677

PMC ID: 6326649

PubMed ID: 30530917

SO-VID: f966a344-84ce-4e1b-b81f-054648fa2528

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Aging-dependent decrease in the numbers of enteric neurons, interstitial cells of Cajal and expression of connexin43 in various regions of gastrointestinal tract

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Most cited references 28

Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions.

Regulation of gastrointestinal motility--insights from smooth muscle biology.

Gut peristalsis is governed by a multitude of cooperating mechanisms.

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