Aging of the mammalian gastrointestinal tract: A complex organ system

Age

Volumn 36, Issue 3, 2014, Pages 1019-1032

  Saffrey, M Jill ^a  

^a OPEN UNIVERSITY   (United Kingdom)

Author keywords

Diet; Enteric nervous system; Interstitial cells; Intestinal immune system; Intestinal smooth muscle; Microbiota; Mucosal epithelium; Stem cells

Indexed keywords

AGING; ANIMAL; CELL AGING; CELL COMMUNICATION; CELL POPULATION; CELL TYPE; CENTRAL NERVOUS SYSTEM; DIGESTION; ENDOCRINE SYSTEM; GASTROINTESTINAL ABSORPTION; GASTROINTESTINAL DISEASE; GASTROINTESTINAL SECRETION; GASTROINTESTINAL TRACT; GASTROINTESTINAL TRACT FUNCTION; GLIA CELL; HUMAN; IMMUNE SYSTEM; INTESTINE BLOOD FLOW; INTESTINE CELL; INTESTINE EPITHELIUM; INTESTINE FLORA; INTESTINE INNERVATION; INTESTINE MUCOSA; INTESTINE MUSCLE; MAMMAL; MORBIDITY; MYENTERIC NEURON; NERVE CELL; NERVE CELL DEGENERATION; NERVE FIBER; NEURAL CREST CELL; NEURAL STEM CELL; NONHUMAN; PHENOTYPE; PHYSIOLOGY; PROGENY; REVIEW; SENESCENCE; SIGNAL TRANSDUCTION; SMOOTH MUSCLE FIBER; STOMACH EPITHELIUM; SUBMUCOSAL NEURON;

AGING; ANIMALS; ENTERIC NERVOUS SYSTEM; GASTROINTESTINAL TRACT; HUMANS; PHYSIOLOGY;

EID: 84905367737     PISSN: 01619152     EISSN: 15744647     Source Type: Journal    
DOI: 10.1007/s11357-013-9603-2     Document Type: Review

References (108)

1. Abalo R, Jose Rivera A, Vera G, Isabel Martin M (2005) Ileal myenteric plexus in aged guinea-pigs: loss of structure and calretinin-immunoreactive neurones. Neurogastroenterol Motil 17:123-132 (Pubitemid 40204020)
2. Abalo R, Vera G, Rivera AJ, Martin MI (2007) Age-related changes in the gastrointestinal tract: a functional and immunohistochemical study in guinea-pig ileum. Life Sci 80:2436-2445 (Pubitemid 46818293)
3. Bernard CE, Gibbons SJ, Gomez-Pinilla PJ, Lurken MS, Schmalz PF, Roeder JL, Linden D, Cima RR, Dozois EJ, Larson DW, Camilleri M, Zinsmeister AR, Pozo MJ, Hicks GA, Farrugia G (2009) Effect of age on the enteric nervous system of the human colon. Neurogastroenterol Motil 21:e746-e746
4. Biagi E, Candela M, Fairweather-Tait S, Franceschi C, Brigidi P (2012) Aging of the human metaorganism: the microbial counterpart. Age (Dordr) 34:247-267
5. Bitar KN (2003) Aging and neural control of the GI tract: aging and gastrointestinal smooth muscle: from signal transduction to contractile proteins. Am J Physiol Gastrointest Liver Physiol 284:G1-G7
6. Bitar KN (2005) Aging and Gi smooth muscle fecal incontinence: is bioengineering an option. Exp Gerontol 40:643-649
7. Bitar KN, Patil SB (2004) Aging and gastrointestinal smooth muscle. Mech Ageing Dev 125:907-910 (Pubitemid 39572628)
8. Buczacki SJ, Zecchini HI, Nicholson AM, Russell R, Vermeulen L, Kemp R, Winton DJ (2013) Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 495:65-69
9. Camilleri M, Cowen T, Koch TR (2008) Enteric neurodegeneration in ageing. Neurogastroenterol Motil 20:185-196 (Pubitemid 351197400)
10. Chatoor DR, Taylor SJ, Cohen CR, Emmanuel AV (2007) Faecal incontinence. Br J Surg 94:134-144 (Pubitemid 46340391)
11. Chen YM, Zhang JS, Duan XL (2003) Changes of microvascular architecture, ultrastructure and permeability of rat jejunal villi at different ages. World J Gastroenterol 9(4):795-799
12. Ciccocioppo R, Di Sabatino A, Luinetti O, Rossi M, Cifone MG, Corazza GR (2002) Small bowel enterocyte apoptosis and proliferation are increased in the elderly. Gerontology 48:204-208 (Pubitemid 34621616)
13. Claesson MJ, Jeffery IB, Conde S, Power SE, O'Connor EM, Cusack S, Harris HM, Coakley M, Lakshminarayanan B, O'Sullivan O, Fitzgerald GF, Deane J, O'Connor M, Harnedy N, O'Connor K, O'Mahony D, van Sinderen D, Wallace M, Brennan L, Stanton C, Marchesi JR, Fitzgerald AP, Shanahan F, Hill C, Ross RP, O'Toole PW (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488:178-184
14. Clevers H (2013) Stem cells: a unifying theory for the crypt. Nature 495:53-54
15. Clevers HC, Bevins CL (2013) Paneth cells: maestros of the small intestinal crypts. Annu Rev Physiol 75:289-311
16. Corns RA, Hidaka H, Santer RM (2002) Neurocalcin-alpha immunoreactivity in the enteric nervous system of young and aged rats. Cell Calcium 31:53-58 (Pubitemid 34552444)
17. Cowen T, Johnson RJR, Soubeyre V, Santer RM (2000) Restricted diet rescues rat enteric motor neurones from age related cell death. Gut 47:653-660
18. Cryan JF, O'Mahony SM (2011) The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterol Motil 23:187-192
19. da Silva Porto G, Bertaglia Pereira JN, Tiburcio VG, Stabille SR, Garcia de Faria H, de Melo Germano R, de Britto Mari R (2012) Effect of caloric restriction on myenteric neuroplasticity in the rat duodenum during aging. Auton Neurosci Basic Clin 168:43-47
20. Drozdowski L, Thomson AB (2006) Aging and the intestine. World J Gastroenterol: WJG 12:7578-7584 (Pubitemid 46040567)
21. Duncan SH, Flint HJ (2013) Probiotics and prebiotics and health in ageing populations. Maturitas 75:44-50
22. El-Salhy M, Sandstrom O (1999) How age changes the content of neuroendocrine peptides in the murine gastrointestinal tract. Gerontology 45:17-22 (Pubitemid 29007981)
23. El-Salhy M, Sandstrom O, Holmlund F (1999) Age-induced changes in the enteric nervous system in the mouse. Mech Ageing Dev 107:93-103 (Pubitemid 29113076)
24. Feher E, Penzes L (1987) Density of substance P, vasoactive intestinal polypeptide and somatostatin-containing nerve fibers in the ageing small intestine of the rats. Gerontology 33:341-348 (Pubitemid 18038682)
25. Firth M, Prather CM (2002) Gastrointestinal motility problems in the elderly patient. Gastroenterology 122:1688-1700 (Pubitemid 34533562)
26. Forsythe P, Kunze WA (2013) Voices from within: gut microbes and the CNS. Cell Mol Life Sci: CMLS 70:55-69
27. Fujihashi K, McGhee JR (2004) Mucosal immunity and tolerance in the elderly. Mech Ageing Dev 125:889-898 (Pubitemid 39572626)
28. Furness JB (2006) The enteric nervous system. Blackwell, Oxford
29. Furness JB (2012) The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol 9:286-294
30. Gabella G (1989) Fall in the number of myenteric neurons in aging guinea pigs. Gastroenterology 96:1487-1493
31. Gaboriau-Routhiau V, Lecuyer E, Cerf-Bensussan N (2011) Role of microbiota in postnatal maturation of intestinal T-cell responses. Curr Opin Gastroenterol 27:502-508
32. Gallagher P, O'Mahony D (2009) Constipation in old age. Best Pract Res Clin Gastroenterol 23:875-887
33. Gamage PPK, Ranson RN, Patel BA, Yeoman MS, Saffrey MJ (2013) Myenteric neuron numbers are maintained in aging mouse distal colon. Neurogastroenterol Motil 25(7):e495-505
34. Garrett WS, Gordon JI, Glimcher LH (2010) Homeostasis and inflammation in the intestine. Cell 140:859-870
35. Gershon MD (2011) Behind an enteric neuron theremay lie a glial cell. J Clin Invest 121:3386-3389
36. Gomez-Pinilla PJ, Gibbons SJ, Sarr MG, Kendrick ML, Shen KR, Cima RR, Dozois EJ, Larson DW, Ordog T, Pozo MJ, Farrugia G (2011) Changes in interstitial cells of cajal with age in the human stomach and colon. Neurogastroenterol Motil 23:36-44
37. Greaves LC, Barron MJ, Campbell-Shiel G, Kirkwood TB, Turnbull DM (2011) Differences in the accumulation of mitochondrial defects with age in mice and humans. Mech Ageing Dev 132:588-591
38. Greaves LC, Barron MJ, Plusa S, Kirkwood TB, Mathers JC, Taylor RW, Turnbull DM (2010) Defects in multiple complexes of the respiratory chain are present in ageing human colonic crypts. Exp Gerontol 45:573-579
39. Greaves LC, Preston SL, Tadrous PJ, Taylor RW, Barron MJ, Oukrif D, Leedham SJ, Deheragoda M, Sasieni P, Novelli MR, Jankowski JA, Turnbull DM, Wright NA, McDonald SA (2006) Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission. Proc Natl Acad Sci U S A 103:714-719 (Pubitemid 43153091)
40. Hoyle CH, Saffrey MJ (2012) Effects of aging on cholinergic neuromuscular transmission in isolated small intestine of ad libitum fed and calorically-restricted rats. Neurogastroenterol Motil 24:586-592
41. Johnson RJ, Schemann M, Santer RM, Cowen T (1998) The effects of age on the overall population and on subpopulations of myenteric neurons in the rat small intestine. J Anat 192(Pt 4):479-488 (Pubitemid 28379249)
42. Joseph NM, He S, Quintana E, Kim YG, Nunez G, Morrison SJ (2011) Enteric glia are multipotent in culture but primarily form glia in the adult rodent gut. J Clin Invest 121:3398-3411
43. Jurk D, Wang C, Miwa S, Maddick M, Korolchuk V, Tsolou A, Gonos ES, Thrasivoulou C, Jill Saffrey MJ, Cameron K, von Zglinicki T (2012) Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11:996-1004
44. Kapur RP (2013) Counting neurons is not as easy as 'one-two, three'. Neurogastroenterology and Motility (in press)
45. Kirkwood TB (2004) Intrinsic ageing of gut epithelial stem cells. Mech Ageing Dev 125:911-915
46. Kobayashi A, Donaldson DS, Erridge C, Kanaya T, Williams IR, Ohno H, Mahajan A, Mabbott NA (2013) The functional maturation of M cells is dramatically reduced in the Peyer's patches of aged mice. Mucosal Immunology (in press)
47. Korsak K, Dolatshad NF, Silva AT, Saffrey MJ (2012a) Ageing of enteric neurons: oxidative stress, neurotrophic factors and antioxidant enzymes. Chem Cent J 6:80
48. Korsak K, Silva AT, Saffrey MJ (2012b) Differing effects of NT-3 and GDNF on dissociated enteric ganglion cells exposed to hydrogen peroxide in vitro. Neurosci Lett 517:102-106
49. Kruger GM, Mosher JT, Bixby S, Joseph N, Iwashita T, Morrison SJ (2002) Neural crest stem cells persist in the adult gut but undergo changes in self-renewal, neuronal subtype potential, and factor responsiveness. Neuron 35:657-669 (Pubitemid 35223026)
50. Laranjeira C, Sandgren K, Kessaris N, Richardson W, Potocnik A, Vanden Berghe P, Pachnis V (2011) Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury. J Clin Invest 121:3412-3424
51. Lee MF, Russell RM, Montgomery RK, Krasinski SD (1997) Total intestinal lactase and sucrase activities are reduced in aged rats. J Nutr 127:1382-1387 (Pubitemid 27284008)
52. Li, H.J., Ray, S.K., Singh, N.K., Johnston, B., Leiter, A.B., 2011. Basic helix-loop-helix transcription factors and enteroendocrine cell differentiation. Diabetes, Obesity & Metabolism 13 Suppl 1, 5-12.
53. Lobachevsky PN, Radford IR (2006) Intestinal crypt properties fit a model that incorporates replicative ageing and deep and proximate stem cells. Cell Prolif 39:379-402 (Pubitemid 44427327)
54. Lopes GS, Ferreira AT, Oshiro ME, Vladimirova I, Jurkiewicz NH, Jurkiewicz A, Smaili SS (2006) Aging-related changes of intracellular Ca2+ stores and contractile response of intestinal smooth muscle. Exp Gerontol 41:55-62 (Pubitemid 43031368)
55. Lopes GS, Mora OA, Cerri P, Faria FP, Jurkiewicz NH, Jurkiewicz A, Smaili SS (2004) Mitochondrial alterations and apoptosis in smooth muscle from aged rats. Biochim Biophys Acta 1658:187-194 (Pubitemid 39278482)
56. Mabbott NA, Donaldson DS, Ohno H, Williams IR, Mahajan A (2013) Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol 6(4):666-677
57. Makivuokko H, Tiihonen K, Tynkkynen S, Paulin L, Rautonen N (2010) The effect of age and non-steroidal anti-inflammatory drugs on human intestinal microbiota composition. Br J Nutr 103:227-234
58. Maloum F, Allaire JM, Gagne-Sansfacon J, Roy E, Belleville K, Sarret P, Morisset J, Carrier JC, Mishina Y, Kaestner KH, Perreault N (2011) Epithelial BMP signaling is required for proper specification of epithelial cell lineages and gastric endocrine cells. Am J Physiol Gastrointest Liver Physiol 300:G1065-G1079
59. Martin K, Kirkwood TB, Potten CS (1998) Age changes in stem cells of murine small intestinal crypts. Exp Cell Res 241:316-323 (Pubitemid 28366557)
60. Matsumoto M, Ishige A, Yazawa Y, Kondo M, Muramatsu K, Watanabe K (2012) Promotion of intestinal peristalsis by Bifidobacterium spp. capable of hydrolysing sennosides in mice. PloS One 7:e31700
61. May CL, Kaestner KH (2010) Gut endocrine cell development. Mol Cell Endocrinol 323:70-75
62. McVey Neufeld KA, Mao YK, Bienenstock J, Foster JA, Kunze WA (2013) The microbiome is essential for normal gut intrinsic primary afferent neuron excitability in the mouse. Neurogastroenterol Motil: Off J Euro Gastrointest Motil Soc 25:e183-e188
63. Metzger M (2010) Neurogenesis in the enteric nervous system. Archives italiennes de biologie 148:73-83
64. Moretto MM, Lawlor EM, Khan IA (2008) Aging mice exhibit a functional defect in mucosal dendritic cell response against an intracellular pathogen. J Immunol 181:7977-7984
65. Moss C, Dhillo WS, Frost G, Hickson M (2012) Gastrointestinal hormones: the regulation of appetite and the anorexia of ageing. J Human Nutr Diet: Off J British Dietetic Association 25:3-15
66. Nelson G, Wordsworth J, Wang C, Jurk D, Lawless C, Martin-Ruiz C, von Zglinicki T (2012) A senescent cell bystander effect: senescence-induced senescence. Aging Cell 11:345-349
67. Neunlist M, Van Landeghem L, Mahe MM, Derkinderen P, des Varannes SB, Rolli-Derkinderen M (2013) The digestive neuronal-glial-epithelial unit: a new actor in gut health and disease. Nat Rev Gastroenterol Hepatol 10:90-100
68. Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, Pettersson S (2012) Host-gut microbiota metabolic interactions. Science 336:1262-1267
69. Nooteboom M, Johnson R, Taylor RW, Wright NA, Lightowlers RN, Kirkwood TB, Mathers JC, Turnbull DM, Greaves LC (2010) Age-associated mitochondrial DNA mutations lead to small but significant changes in cell proliferation and apoptosis in human colonic crypts. Aging Cell 9:96-99
70. Ogino T, Miura S, Komoto S, Hara Y, Hokari R, Tsuzuki Y, Watanabe C, Koseki S, Nagata H, Hachimura S, Kaminogawa S, Ishii H (2004) Senescence-associated decline of lymphocyte migration in gut-associated lymphoid tissues of rat small intestine. Mech Ageing Dev 125:191-199 (Pubitemid 38317274)
71. Ogra PL (2010) Ageing and its possible impact on mucosal immune responses. Ageing Res Rev 9:101-106
72. Patel B, Patel N, Fidalgo S, Ranson R, Saffery J, Yeoman M (2012) Age-related changes in colonic motility, faecal output and the properties of faecal pellets in the mouse. Neurogastroenterol Motil 24:129
73. Peck CJ, Samsuria SD, Harrington AM, King SK, Hutson JM, Southwell BR (2009) Fall in density, but not number of myenteric neurons and circular muscle nerve fibres in guinea-pig colon with ageing. Neurogastroenterol Motil 21:e1075-e1090
74. Phillips RJ, Powley TL (2001) As the gut ages: timetables for aging of innervation vary by organ in the Fischer 344 rat. J Comp Neurol 434:358-377 (Pubitemid 32402140)
75. Phillips RJ, Powley TL (2007) Innervation of the gastrointestinal tract: patterns of aging. Autonomic Neuroscience: Basic & Clinical 136:1-19 (Pubitemid 47385391)
76. Phillips RJ, Kieffer EJ, Powley TL (2003) Aging of the myenteric plexus: neuronal loss is specific to cholinergic neurons. Auton Neurosci 106:69-83 (Pubitemid 36870909)
77. Phillips RJ, Kieffer EJ, Powley TL (2004) Loss of glia and neurons in the myenteric plexus of the aged Fischer 344 rat. Anat Embryol 209:19-30 (Pubitemid 40064369)
78. Phillips RJ, Pairitz JC, Powley TL (2007) Age-related neuronal loss in the submucosal plexus of the colon of Fischer 344 rats. Neurobiol Aging 28(2007):1124-1137 (Pubitemid 46635916)
79. Phillips RJ, Walter GC, Ringer BE, Higgs KM, Powley TL (2009) Alpha-synuclein immunopositive aggregates in the myenteric plexus of the aging Fischer 344 rat. Exp Neurol 220:109-119
80. Radford IR, Lobachevsky PN (2006) An enteroendocrine cell-based model for a quiescent intestinal stem cell niche. Cell Prolif 39:403-414 (Pubitemid 44427328)
81. Rhee SH, Pothoulakis C, Mayer EA (2009) Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol 6:306-314
82. Ruhl A (2005) Glial cells in the gut. Neurogastroenterol Motil 17(6):777-790
83. Saffrey MJ (2013) Cellular changes in the enteric nervous system during ageing. Dev Biol 382:344-355
84. Salles N (2009) Is stomach spontaneously ageing? Pathophysiology of the ageing stomach. Best Pract Res Clin Gastroenterol 23:805-819
85. Sam AH, Troke RC, Tan TM, Bewick GA (2012) The role of the gut/brain axis in modulating food intake. Neuropharmacology 63:46-56
86. Sanders KM, Hwang SJ, Ward SM (2010) Neuroeffector apparatus in gastrointestinal smooth muscle organs. J Physiol 588:4621-4639
87. Sandstrom O, El-Salhy M (1999a) Ageing and endocrine cells of human duodenum. Mech Ageing Dev 108:39-48 (Pubitemid 29210238)
88. Sandstrom O, El-Salhy M (1999b) Human rectal endocrine cells and aging. Mech Ageing Dev 108:219-226 (Pubitemid 29240627)
89. Sandstrom O, El-Salhy M (2000) Duodenal endocrine cells in mice with particular regard to age-induced changes. Hist Histopathol 15:347-353 (Pubitemid 30218827)
90. Sandstrom O, Mahdavi J, El-Salhy M (1998) Effect of ageing on colonic endocrine cell population in mouse. Gerontology 44:324-330 (Pubitemid 28517493)
91. Santer RM, Baker DM (1988) Enteric neuron numbers and sizes in Auerbach's plexus in the small and large intestine of adult and aged rats. J Auton Nerv Syst 25:59-67 (Pubitemid 19020868)
92. Santiago AF, Alves AC, Oliveira RP, Fernandes RM, Paula-Silva J, Assis FA, Carvalho CR, Weiner HL, Faria AM (2011) Aging correlates with reduction in regulatory-type cytokines and T cells in the gut mucosa. Immunobiology 216:1085-1093
93. Savidge TC, Sofroniew MV, Neunlist M (2007) Starring roles for astroglia in barrier pathologies of gut and brain. Lab Invest J Techn Methods Pathol 87:731-736 (Pubitemid 47077264)
94. Schmucker DL, Owen RL, Outenreath R, Thoreux K (2003) Basis for the age-related decline in intestinal mucosal immunity. Clin Dev Immunol 10:167-172 (Pubitemid 38089408)
95. Schmucker DL, Thoreux K, Owen RL (2001) Aging impairs intestinal immunity. Mech Ageing Dev 122:1397-1411 (Pubitemid 32721923)
96. Smits GJ, Lefebvre RA (1996) Influence of aging on gastric emptying of liquids, small intestine transit, and fecal output in rats. Exp Gerontol 31:589-596 (Pubitemid 26315002)
97. Somara S, Bashllari D, Gilmont RR, Bitar KN (2011) Real-time dynamic movement of caveolin-1 during smooth muscle contraction of human colon and aged rat colon transfected with caveolin-1 cDNA. Am J Physiol Gastroint Liver Physiol 300:G1022-G1032
98. Somara S, Gilmont RR, Martens JR, Bitar KN (2007) Ectopic expression of caveolin-1 restores physiological contractile response of aged colonic smooth muscle. Am J Physiol Gastroint Liver Physiol 293:G240-G249 (Pubitemid 47105175)
99. Stevens TK, Soffer EE, Palmer RM (2003) Fecal incontinence in elderly patients: common, treatable, yet often undiagnosed. Cleve Clin J Med 70:441-448 (Pubitemid 36621495)
100. Taylor RW, Barron MJ, Borthwick GM, Gospel A, Chinnery PF, Samuels DC, Taylor GA, Plusa SM, Needham SJ, Greaves LC, Kirkwood TBL, Turnbull DM (2003) Mitochondrial DNA mutations in human colonic crypt stem cells. J Clin Investig 112:1351-1360 (Pubitemid 38057689)
101. Thomson AB (2009) Small intestinal disorders in the elderly. Best Pract Res Clin Gastroenterol 23:861-874
102. Thrasivoulou C, Soubeyre V, Ridha H, Giuliani D, Giaroni C, Michael GJ, Saffrey MJ, Cowen T (2006) Reactive oxygen species, dietary restriction and neurotrophic factors in age-related loss of myenteric neurons. Aging Cell 5:247-257 (Pubitemid 43805614)
103. Tiihonen K, Ouwehand AC, Rautonen N (2010) Human intestinal microbiota and healthy ageing. Ageing Res Rev 9:107-116
104. Van Ginneken C, Schafer KH, Van Dam D, Huygelen V, De Deyn PP (2011) Morphological changes in the enteric nervous system of aging and APP23 transgenic mice. Brain Res 1378:43-53
105. Wang C, Jurk D, Maddick M, Nelson G, Martin-Ruiz C, von Zglinicki T (2009) DNA damage response and cellular senescence in tissues of aging mice. Aging Cell 8:311-323
106. Wang C, Houghton MJ, Gamage PPKM, Collins HE, Patel BA, Yeoman MS, Ranson RN, Saffrey MJ (2013) Changes in the innervation of themouse internal anal sphincter during aging. Neurogastroenterol Motil 25(7):e469-477
107. Williams AM, Probert CS, Stepankova R, Tlaskalova-Hogenova H, Phillips A, Bland PW (2006) Effects of microflora on the neonatal development of gut mucosal T cells and myeloid cells in the mouse. Immunology 119:470-478 (Pubitemid 44722209)
108. Xiong Z, Sperelakis N, Noffsinger A, Fenoglio-Preiser C (1993) Changes in calcium channel current densities in rat colonic smooth muscle cells during development and aging. Am J Physiol 265:C617-C625 Research Council