Ulcerative colitis is a disease of accelerated colon aging: evidence from telomere attrition and DNA damage.
OBJECTIVE
Telomere shortening is implicated in cancer and aging and might link these 2 biologic events. We explored this hypothesis in ulcerative colitis (UC), a chronic inflammatory disease that predisposes to colorectal cancer and in which shorter telomeres have been associated with chromosomal instability and tumor progression.


METHODS
Telomere length was measured by quantitative polymerase chain reaction in colonocytes and leukocytes of 2 different sets of UC patients and compared with normal controls across a wide range of ages. For a subset of patients, telomere length was measured in epithelium and stroma of right and left colon biopsy specimens. A third set of biopsy specimens was analyzed for phosphorylation of histone H2AX (gammaH2AX), a DNA damage signal, by immunofluorescence and for telomere length by quantitative fluorescence in situ hybridization. Relationships between telomere length, gammaH2AX intensity, age, disease duration, and age of disease onset were explored.


RESULTS
Colonocyte telomeres shorten with age almost twice as rapidly in UC patients as in normal controls. This extensive shortening occurs within approximately 8 years of disease duration. Leukocyte telomeres are slightly shorter in UC patients than in controls, but telomeres of colon stromal cells are unaffected. gammaH2AX intensity is higher in colonocytes of UC patients than in controls and is not dependent on age or telomere length.


CONCLUSIONS
Colonocytes of UC patients show premature shortening of telomeres, which might explain the increased and earlier risk of cancer in this disease. Shorter leukocyte telomeres and increased gammaH2AX in colonocytes might reflect oxidative damage secondary to inflammation.
Risques
Rosa Ana
RA
Department of Pathology, University of Washington, Seattle, Washington, USA.
Lai
Lisa A
LA
Brentnall
Teresa A
TA
Li
Lin
L
Feng
Ziding
Z
Gallaher
Jasmine
J
Mandelson
Margaret T
MT
Potter
John D
JD
Bronner
Mary P
MP
Rabinovitch
Peter S
PS
D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003093:Colitis, Ulcerative / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003430:Cross-Sectional Studies; D004249:DNA Damage; D005260:Female; D005455:Fluorescent Antibody Technique; D006657:Histones / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007413:Intestinal Mucosa / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D015854:Up-Regulation
C468783:H2AX protein, human; D006657:Histones