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• Research Paper Volume 10, Issue 12 pp 3851-3865

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

  Relevance score: 18.313309

  Tingyi Sun, Dandan Li, Shilong Hu, Li Huang, Haimei Sun, Shu Yang, Bo Wu, Fengqing Ji, Deshan Zhou

  Keywords: aging, gastrointestinal motility, interstitial cells of Cajal, enteric nervous system, connexin43

  Published in Aging on December 11, 2018

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  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.

  

  Slower intestinal transit during aging in mice. The ink propulsion distance was illustrated in different age groups (A). The length of small intestine was extended (B) while in vivo intestinal propulsion rate was reduced (C) during aging. Statistical analysis was performed using one-way analysis of variance and data were represented as mean ± SD, statistical significance is: ### P < 0.001 compared with 2-mo-old group; ** P < 0.01, *** P < 0.001 compared with previous group; n=8 mice per group.

  
  
  

  

  Influence of aging on ICCs in the mouse GI tract. The c-kit immunoreactivity (red) showed ICCs network in the whole-mount preparation. The sparseness of cellular network in stomach (A), jejunum (B) and colon (C) appeared at 16, 20 and 24 mo, respectively. In high magnification of 2-mo-old stomach (D), c-kit(+) cells with round or oval cell bodies (left figure, arrows) and cell processes (right figure) including primary (arrow), secondary (arrowhead) and tertiary processes (double arrow) were clearly seen by c-kit immunofluorescence staining. Statistical analysis showed that ICCs density decreased over time from 16 mo in stomach, 20 mo in jejunum and 24 mo in colon (E). Expressions of c-kit protein in 2-, 12-, 16-, 20- and 24-mo-old mice in different organs of GI tract were examined by western blotting (F-H). Densitometric analysis of protein expressions normalized to β-actin and the downtrend of c-kit expression was coincident with ICC-density in all three organs. Statistical analysis was performed using one-way analysis of variance and data were represented as mean ± SD, statistical significance is: (E) ## P < 0.01, ### P < 0.001 compared with previous stomach group; * P < 0.05, *** P < 0.001 compared with previous jejunum group; ††† P < 0.001 compared with previous colon group; (F-H) ## P < 0.01, ### P < 0.001 compared with 2-mo-old group; ** P < 0.01, *** P < 0.001 compared with previous group; n=5 mice per group. Abbreviation: Sto, stomach; Jej, jejunum; Co, colon.

  
  
  

  

  Decrease in ChAT(+) neurons in the MP of mouse GI tract with aging. ChAT immunoreactivity (green) was shown in ganglia and nerve fibers. ChAT-positive area per field gradually decreased from 16 mo in stomach (A), 20 mo in jejunum (B) as well as 20 mo in colon (C), respectively. Diminished immunoreactive area density (D) and the decline in expression of ChAT protein (E-G) were observed in aging mice consistent with morphological results. Densitometric analysis of protein expressions normalized to β-actin. Statistical analysis was performed using one-way analysis of variance and data were represented as mean ± SD, statistical significance is: (D) # P < 0.05, ### P < 0.001 compared with previous stomach group; * P < 0.05, ** P < 0.01 compared with previous jejunum group; ††† P < 0.001 compared with previous colon group; (E-G) ## P < 0.01, ### P < 0.001 compared with 2-mo-old group; ** P < 0.01, *** P < 0.001 compared with previous group; n=5 mice per group. Abbreviation: Sto, stomach; Jej, jejunum; Co, colon.

  
  
  

  

  Age-related reduction in nitrergic neurons in the MP of mouse GI tract. Whole-mount preparations stained with NADPH-d histochemistry showed the variations in number of nitrergic neurons in stomach (A), jejunum (B) and colon (C) which appeared at 16, 20 and 20 mo, respectively. In higher magnification of 2-mo-old stomach (D), more typical NOS(+) neurons were oval in shape and intensely stained, with unstained nuclei. Some lighter cell bodies of NOS(+) neurons (left and right figures, arrows) were also seen which suggested that the activity of NOS were lower. Few cells with vaguely remained cellular outlines (right figure, arrowhead) shown in ganglia were confirmed to be other types of neurons. Statistical analysis showed that the decrease of NOS(+) neuronal numbers was started from 16 mo in stomach, 20 mo in jejunum and colon (E). Western blotting indicated that the trend of nNOS expression was coincident with the number of NOS(+) neurons in all three organs (F-H), and densitometric analysis of protein expressions normalized to β-actin. Statistical analysis was performed using one-way analysis of variance and data were represented as mean ± SD, statistical significance is: (E) # P < 0.05, ## P < 0.01 compared with previous stomach group; *** P < 0.001 compared with previous jejunum group; ††† P < 0.001 compared with previous colon group; (F-H) # P < 0.05, ### P < 0.001 compared with 2-mo-old group; * P < 0.05, ** P < 0.01, *** P < 0.001 compared with previous group; n=5 mice per group. Abbreviation: Sto, stomach; Jej, jejunum; Co, colon.

  
  
  

  

  Diminished enteric neurons in the colon of old mice. PGP9.5 recognized perikarya and nerve fibers within MP, and PGP9.5-positive area per field in 20-mo-old mice were significantly declined compared with 2- and 16-mo-old mice (A-B). The reduction in protein expression of PGP9.5 (C) and HuC/D (D) was observed in aging mice consistent with morphological results. Densitometric analysis of protein expressions normalized to α-Tubulin. Statistical analysis was performed using one-way analysis of variance and data were represented as mean ± SD, statistical significance is: (B-D) ## P < 0.01, ### P < 0.001 compared with 2-mo-old group; ** P < 0.01, *** P < 0.001 compared with 16-mo-old group; n=5 mice per group. Abbreviation: Co, colon.

  
  
  

  

  The decrease of Cx43 protein expression in the mouse GI tract with aging. Expressions of Cx43 within GI longitudinal muscle layer of 2-, 12-, 16-, 20- and 24-mo-old mice were examined by western blotting, and the decline in Cx43 expression was seen from 16 mo in all three organs (A-C). The densitometric analysis of protein expressions normalized to β-actin. Confocal images (D) of double immunofluorescence labelling for Cx43 (green) and c-kit (red) displayed that Cx43-puncta distributed throughout MP of colon, and some co-localized with ICCs (arrows), and in 16- and 24-mo-old mice, Cx43-puncta per field was significantly sparse compared with 2-mo-old mice, prior to the reduction in c-kit-positive area in 24-mo-old mice (D-F). Statistical analysis was performed using one-way analysis of variance and data were represented as mean ± SD, statistical significance is: ### P < 0.001 compared with 2-mo-old group; * P < 0.05, *** P < 0.001 compared with previous group; n=5 mice per group. Abbreviation: Sto, stomach; Jej, jejunum; Co, colon.

  
  
  

  

  The decrease in protein expressions of c-kit, ChAT, nNOS and Cx43 in the colon of elderly humans. Expressions of c-kit, ChAT, nNOS and Cx43 proteins in colonic muscle layers detached from youth and older adults were examined by western blotting (n=4 per group), and similar reduction was observed (A-B). The densitometric analysis of protein expressions normalized to β-actin. Statistical analysis was performed using Student’s t-test and data were represented as mean ± SD, statistical significance is: ** P < 0.01, *** P < 0.001 compared with young group.

  
  
  

  

  Inflammation and apoptosis in the muscle layer from aged colon. Both aged mice (A) and old people (B) exhibited elevated mRNA expression levels of classic pro-inflammatory cytokines including TNF-α, IL-1β and IL-6 compared with those from young. GAPDH was used as internal control. Reduced expression of Bcl-2 (C) and a rise in expression of cleaved caspase-3 (D) were revealed by western blot analysis. The densitometric analysis of protein expressions normalized to β-actin. Statistical analysis was performed using Student’s t-test and data were represented as mean ± SD, statistical significance is: * P < 0.05, ** P < 0.01, *** P < 0.001 compared with young group; n=5 mice or 4 human samples per group.