title: Aging is associated with increased proliferation and decreased apoptosis in the colonic mucosa.
abstract: Although the incidence of colon cancer increases with advancing age, reasons for this increase are not fully understood. Earlier studies have demonstrated that in Fischer-344 rats, aging is associated with increased crypt cell production in the colon, an event considered to be central to the initiation of carcinogenesis. Apoptosis also plays a critical role in the development and progression of colon cancer. Therefore, we have examined the age-related changes in proliferation and apoptosis in the colonic mucosa of 4-5, 12-14, and 22-24 month-old Fischer-344 rats. We have observed that proliferative activity in the colon, as assessed by proliferating cell nuclear antigen immunoreactivity, is higher (50-80%) in 12-14 and 22-24 month-old rats than in their 4-6 month-old counterparts. In contrast, the number of apoptotic cells, (as determined by TdT-mediated dUTP nick-end labeling assay) in the colonic mucosa of 12-14 and 22-24 month-old rats are considerably lower (50-60%) than in 4-6 month-old animals. These changes are accompanied by a concomitant reduction (75%) in pro-apoptotic Bak and stimulation (200%) of anti-apoptotic Bcl-xL levels. Since activation of caspases is associated with initiation and maintenance of apoptosis, we also analyzed the levels of pro and active forms of caspase-3, 8 and 9. The levels of active forms of caspase-3, 8 and 9 are found to be considerably (60-80%) lower in the colonic mucosa of 22-24 month-old rats, compared to their younger counterparts. This is accompanied by decreased cleavage of poly(ADP-ribose) polymerase, a substrate for caspases. In conclusion, our data show that aging enhances proliferation, but attenuates apoptosis in the colonic mucosa. These changes may partly be responsible for the age-related rise in colorectal cancer.
authors.affiliation: Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Xiao
authors.forename: L
authors.initials: L
authors.lastname: Moragoda
authors.forename: R
authors.initials: R
authors.lastname: Jaszewski
authors.forename: J A
authors.initials: JA
authors.lastname: Hatfield
authors.forename: S E
authors.initials: SE
authors.lastname: Fligiel
authors.forename: A P
authors.initials: AP
authors.lastname: Majumdar
mesh_terms: D000375:Aging / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D003106:Colon / Q000166:cytology* / Q000378:metabolism; D003856:Deoxyuracil Nucleotides; D020287:In Situ Nick-End Labeling; D007413:Intestinal Mucosa / Q000166:cytology* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
chemical_list: C494774:Bak1 protein, rat; C494813:Bcl2l1 protein, rat; D003856:Deoxyuracil Nucleotides; D008565:Membrane Proteins; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C027078:deoxyuridine triphosphate; D011065:Poly(ADP-ribose) Polymerases; C505410:Casp3 protein, rat; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases