Ulcerative Colitis Is a Disease of Accelerated Colon Aging: Evidence From Telomere Attrition and DNA Damage

doi:10.1053/j.gastro.2008.04.008

Gastroenterology

Volume 135, Issue 2, August 2008, Pages 410-418

https://doi.org/10.1053/j.gastro.2008.04.008 Get rights and content

Background & Aims: 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 (γH2AX), a DNA damage signal, by immunofluorescence and for telomere length by quantitative fluorescence in situ hybridization. Relationships between telomere length, γH2AX 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. γH2AX 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 γH2AX in colonocytes might reflect oxidative damage secondary to inflammation.

Section snippets

Patients and Samples

Three different sets of UC patients and normal colon controls were analyzed (Table 1). The first set included fresh frozen biopsy specimens from 79 normal colon controls (ages, 2–79 years) and 85 UC patients (ages, 14–79 years) and was analyzed for telomere length using quantitative polymerase chain reaction (Q-PCR). The second set included leukocyte DNA from 45 normal controls (ages, 33–79 years) and 102 UC patients (ages, 31–80 years) and was analyzed for telomere length using Q-PCR. UC

Accelerated Telomere Shortening in the Colon of UC Patients

The relationships between telomere length and age in normal control and UC colonocytes are shown in Figure 1. We previously reported the association between Q-PCR measured telomere length and age in a subset of 47 normal colons.²⁰ In that set, however, only 4 cases were younger than 40 years old. To explore colonocyte telomere dynamics more broadly in younger patients, we have added 32 additional individuals, most of them between 2 and 40 years of age. Figure 1A shows the expected decrease of

Discussion

We have demonstrated an accelerated shortening of colonocyte telomere length with age in UC patients compared with normal controls. On average, by age 33 years, UC patients have acquired very short colonocyte telomeres, comparable with that reached in normal individuals by age 60 years. Moreover, this rapid attrition occurs within the first 8 years of the disease, although patients with late-onset disease have short colonocytes telomeres irrespective of disease duration. These findings have a

References (44)

M.Z. Levy et al.
Telomere end-replication problem and cell aging
J Mol Biol
(1992)
T. von Zglinicki
Oxidative stress shortens telomeres
Trends Biochem Sci
(2002)
J.M. Sedivy
Telomeres limit cancer growth by inducing senescence: long-sought in vivo evidence obtained
Cancer Cell
(2007)
K. Takubo et al.
Telomere lengths are characteristic in each human individual
Exp Gerontol
(2002)
U. Herbig et al.
Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a)
Mol Cell
(2004)
M. Rutter et al.
Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis
Gastroenterology
(2004)
M.A. Blasco et al.
Telomere shortening and tumor formation by mouse cells lacking telomerase RNA
Cell
(1997)
T.A. Brentnall et al.
Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis
Gastroenterology
(1994)
E.E. Furth et al.
Induction of the tumor-suppressor p16(INK4a) within regenerative epithelial crypts in ulcerative colitis
Neoplasia
(2006)
A. Cottliar et al.
High frequencies of telomeric associations, chromosome aberrations, and sister chromatid exchanges in ulcerative colitis
Am J Gastroenterol
(2000)

B. Usselmann et al.

Deficiency of colonic telomerase in ulcerative colitis

Am J Gastroenterol

(2001)

R. Chen et al.

DNA fingerprinting abnormalities can distinguish ulcerative colitis patients with dysplasia and cancer from those who are dysplasia/cancer-free

Am J Pathol

(2003)

R.S. Maser et al.

Connecting chromosomes, crisis, and cancer

Science

(2002)

A. Aviv

Telomeres and human somatic fitness

J Gerontol A Biol Sci Med Sci

(2006)

T. von Zglinicki et al.

Telomeres as biomarkers for ageing and age-related diseases

Curr Mol Med

(2005)

R.A. DePinho

The age of cancer

Nature

(2000)

M.A. Blasco

Telomeres and human disease: ageing, cancer and beyond

Nat Rev Genet

(2005)

F. d'Adda di Fagagna et al.

A DNA damage checkpoint response in telomere-initiated senescence

Nature

(2003)

L.B. Schultz et al.

p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks

J Cell Biol

(2000)

T. von Zglinicki et al.

Human cell senescence as a DNA damage response

Mech Ageing Dev

(2005)

J.A. Eaden et al.

The risk of colorectal cancer in ulcerative colitis: a meta-analysis

Gut

(2001)

R.A. Risques et al.

Cancer surveillance in inflammatory bowel disease: new molecular approaches

Curr Opin Gastroenterol

(2006)

Cited by (148)

Chronic low-dose deltamethrin exposure induces colon injury and aggravates DSS-induced colitis via promoting cellular senescence
2024, Ecotoxicology and Environmental Safety
Deltamethrin (DLM) is a commonly used insecticide, which is harmful to many organs. Here, we explored the effects of chronic low-dose DLM residues on colon tissue and its potential mechanism.
The mice were given long-term low-dose DLM by intragastric administration, and the body weights and disease activity index (DAI) scores of the mice were regularly recorded. The colon tissues were then collected for hematoxylin-eosin, immunofluorescence and immunohistochemistry staining. Besides, the RNA sequencing was performed to explore the potential mechanism.
Our results showed that long-term exposure to low-dose DLM could cause inflammation in mice colon tissue, manifested as weight loss, increased DAI score, increased apoptosis of colonic epithelial cells, and increased infiltration of inflammatory cells. However, we observed that after long-term exposure to DLM and withdrawal for a period of time, although apoptosis was restored, the recovery of colon inflammation was not ideal. Subsequently, we performed RNA sequencing and found that long-term DLM exposure could lead to the senescence of some cells in mice colon tissue. The results of staining of cellular senescence markers in colon tissue showed that the level of cellular senescence in the DLM group was significantly increased, and the p53 signalling related to senescence was also significantly activated, indicating that cellular senescence played a key role in DLM-induced colitis. We further treated mice with quercetin (QUE) after long-term DLM exposure, and found that QUE could indeed alleviate DLM-induced colitis. In addition, we observed that long-term accumulation of DLM could aggravate DSS-induced colitis in mice, and QUE treatment could reverse this scenario.
Continuous intake of DLM caused chronic colitis in mice, and the inflammation persisted even after discontinuation of DLM intake. This was attributed to the induction of cellular senescence in colon tissue. Treatment with QUE alleviated DLM-induced colitis by reducing cellular senescence. Long-term DLM exposure also aggravated DSS-induced colitis, which could be mitigated by QUE treatment.
Telomeres as hotspots for innate immunity and inflammation
2024, DNA Repair
Aging is marked by the gradual accumulation of deleterious changes that disrupt organ function, creating an altered physiological state that is permissive for the onset of prevalent human diseases. While the exact mechanisms governing aging remain a subject of ongoing research, there are several cellular and molecular hallmarks that contribute to this biological process. This review focuses on two factors, namely telomere dysfunction and inflammation, which have emerged as crucial contributors to the aging process. We aim to discuss the mechanistic connections between these two distinct hallmarks and provide compelling evidence highlighting the loss of telomere protection as a driver of pro-inflammatory states associated with aging. By reevaluating the interplay between telomeres, innate immunity, and inflammation, we present novel perspectives on the etiology of aging and its associated diseases.
Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia
2024, Genes and Diseases
CDC42 controls intestinal epithelial (IEC) stem cell (IESC) division. How aberrant CDC42 initiates intestinal inflammation or neoplasia is unclear. We utilized models of inflammatory bowel diseases (IBD), colorectal cancer, aging, and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and neoplasia. Intestinal specimens were collected to determine the levels of CDC42 in IBD or colorectal cancer. Cdc42 floxed mice were crossed with Villin-Cre, Villin-CreER^T2 and/or Lgr5-eGFP-IRES-CreER^T2, or Bmi1-CreER^T2 mice to generate Cdc42 deficient mice. Irradiation, colitis, aging, and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation, IESC/progenitor regenerative capacity, and IEC repair. Our studies revealed that increased CDC42 in colorectal cancer correlated with lower survival; in contrast, lower levels of CDC42 were found in the inflamed IBD colon. Colonic Cdc42 depletion significantly reduced Lgr5⁺ IESCs, increased progenitors' hyperplasia, and induced mucosal inflammation, which led to crypt dysplasia. Colonic Cdc42 depletion markedly enhanced irradiation- or chemical-induced colitis. Depletion or inhibition of Cdc42 reduced colonic Lgr5⁺ IESC regeneration. In conclusion, depletion of Cdc42 reduces the IESC regeneration and IEC repair, leading to prolonged mucosal inflammation. Constitutive monogenic loss of Cdc42 induces mucosal inflammation, which could result in intestinal neoplasia in the context of aging.
Frailty and pre-frailty with long-term risk of elderly-onset inflammatory bowel disease: A large-scale prospective cohort study
2023, Annals of Epidemiology
To investigate the prospective association of frailty status with the long-term risk of elderly-onset IBD in a large prospective cohort.
Participants free of IBD and cancer at enrollment from the UK Biobank cohort were included. Baseline pre-frail and frail status was measured by Fried phenotype including weight loss, exhaustion, low grip strength, low physical activity and slow walking pace, defined as meeting one or two criteria and meeting three or more criteria. Primary outcome was elderly-onset IBD, including elderly-onset ulcerative colitis (UC) and Crohn’s disease (CD). Multivariable Cox regression was conducted to examine the related associations.
Overall, 417,253 participants (aged 56.18 ± 8.09 years) were included. Of whom, 19,243 (4.6 %) and 188,219 (45.1 %) were considered frail and pre-frail, respectively. During a median of 12.4 years follow-up, 1503 elderly-onset IBD cases (1001 UC, 413 CD, and 89 IBD-Unclassified) were identified. Compared with non-frail, individuals with frail (HR=1.40, 95 %CI: 1.13–1.73) and pre-frail (HR=1.15, 1.03–1.28) showed significantly higher risk of elderly-onset IBD after multivariable adjustment (P_trend<0.001). The positive association was more evident regarding risk of elderly-onset CD (HR=2.16, 1.49–3.13 for frail; HR=1.49,1.20–1.85 for pre-frail; P_trend<0.001). Sensitivity analyses and subgroup analyses according to age, gender and body mass index (BMI) demonstrated similar results.
Frailty and pre-frailty are associated with increased risk of elderly-onset IBD, particularly elderly-onset CD.
A new face of old cells: An overview about the role of senescence and telomeres in inflammatory bowel diseases
2023, Ageing Research Reviews
Cellular senescence is a pivotal factor contributing to aging and the pathophysiology of age-related diseases. Despite the presence of inflammation and abnormal immune system function in both inflammatory bowel diseases (IBD) and senescence, the relationship between the two remains largely unexplored. Therefore, our study aimed to investigate the intricate connection between cellular senescence, telomeres, and IBD. The review highlights the presence of senescence markers, particularly p16 and p21, in IBD patients, suggesting their potential association with disease progression and mucosal inflammation. We emphasize the critical role of macrophages in eliminating senescent cells and how disturbance in effective clearance may contribute to persistent senescence and inflammation in IBD. Additionally, we shed light on the involvement of telomeres in IBD, as their dysfunction impairs enterocyte function and disrupts colonic barrier integrity, potentially exacerbating the pathogenesis of the disease. Targeting senescence and telomere dysfunctions holds promise for the development of innovative therapeutic approaches to mitigate intestinal inflammation and alleviate symptoms in IBD patients. By unraveling the precise role of senescence in IBD, we can pave the way for the discovery of novel therapeutic interventions that effectively address the underlying mechanisms of intestinal inflammation, offering hope for improved management and treatment of IBD patients.
The regulatory feedback of inflammatory signaling and telomere/telomerase complex dysfunction in chronic inflammatory diseases
2023, Experimental Gerontology
Inflammation is believed to play a role in the progression of numerous human diseases. Research has shown that inflammation and telomeres are involved in a feedback regulatory loop: inflammation increases the rate of telomere attrition, leading to telomere dysfunction, while telomere components also participate in regulating the inflammatory response. However, the specific mechanism behind this feedback loop between inflammatory signaling and telomere/telomerase complex dysfunction has yet to be fully understood. This review presents the latest findings on this topic, with a particular focus on the detailed regulation and molecular mechanisms involved in the progression of aging, various chronic inflammatory diseases, cancers, and different stressors. Several feedback loops between inflammatory signaling and telomere/telomerase complex dysfunction, including NF-κB-TERT feedback, NF-κB-RAP1 feedback, NF-κB-TERC feedback, STAT3-TERT feedback, and p38 MAPK-shelterin complex-related gene feedback, are summarized. Understanding the latest discoveries of this feedback regulatory loop can help identify novel potential drug targets for the suppression of various inflammation-associated diseases.

View all citing articles on Scopus

: Supported by NIH grants P20 CA103728, R01 CA068124, and P30 AG13280 and the Crohn's and Colitis Foundation of America.

: Conflicts of interest: No conflicts of interest exist.

View full text

Clinical–Alimentary TractUlcerative Colitis Is a Disease of Accelerated Colon Aging: Evidence From Telomere Attrition and DNA Damage

Section snippets

Patients and Samples

Accelerated Telomere Shortening in the Colon of UC Patients

Discussion

J Mol Biol

Trends Biochem Sci

Cancer Cell

Exp Gerontol

Mol Cell

Gastroenterology

Cell

Gastroenterology

Neoplasia

Am J Gastroenterol

Am J Gastroenterol

Am J Pathol

Connecting chromosomes, crisis, and cancer

Science

Telomeres and human somatic fitness

J Gerontol A Biol Sci Med Sci

Telomeres as biomarkers for ageing and age-related diseases

Curr Mol Med

The age of cancer

Nature

Telomeres and human disease: ageing, cancer and beyond

Nat Rev Genet

A DNA damage checkpoint response in telomere-initiated senescence

Nature

p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks

J Cell Biol

Human cell senescence as a DNA damage response

Mech Ageing Dev

The risk of colorectal cancer in ulcerative colitis: a meta-analysis

Gut

Cancer surveillance in inflammatory bowel disease: new molecular approaches

Curr Opin Gastroenterol

Clinical–Alimentary Tract
Ulcerative Colitis Is a Disease of Accelerated Colon Aging: Evidence From Telomere Attrition and DNA Damage