ABSTRACT
OBJECTIVES: Human age-dependent telomere attrition and telomere shortening are associated with several age-associated diseases and poorer overall survival. The aim of this study was to determine longitudinal leucocyte telomere length dynamics and identify factors associated with temporal changes in telomere length. DESIGN AND METHODS: Leucocyte telomere length was measured by quantitative polymerase chain reaction in 8074 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, an ongoing community-based prospective cohort study initiated in 1997. Follow-up data were available at two time-points up to 2007. Leucocyte telomere length was measured, on between one and three separate occasions, in a total of 16 783 DNA samples. Multilevel growth models were created to identify the factors that influence leucocyte telomere dynamics. RESULTS: We observed an average attrition rate of 0.47 ± 0.16 relative telomere length units (RTLUs) per year in the study population aged 48 (range 39-60) years at baseline. Annual telomere attrition rate increased with age (P < 0.001) and was faster on average in men than in women (P for interaction 0.043). The major independent factors determining telomere attrition rate were active smoking (approximately tripled the loss of RTLU per year, P < 0.0001) and multiple traits of the metabolic syndrome (waist-hip ratio, P = 0.007; blood glucose level, P = 0.045, and HDL cholesterol level, P < 0.001). CONCLUSIONS: Smoking and variables linked to the metabolic syndrome are modifiable lifestyle factors that accelerate telomere attrition in humans. The higher rate of cellular ageing may mediate the link between smoking and the metabolic syndrome to an increased risk of several age-associated diseases.
Subject(s)
Cellular Senescence/genetics , Smoking/adverse effects , Telomere Shortening , Adult , Body Mass Index , Female , Humans , Leukocytes , Male , Metabolic Syndrome/genetics , Middle Aged , Smoking/genetics , Smoking/mortality , Telomere/genetics , Telomere Shortening/geneticsABSTRACT
Aim of this explorative study was to determine the prognostic value of protein expression of the DNA damage repair enzymes ERCC1, hRad51, and BRCA1 for tumour response and survival of non-small-cell lung cancer patients treated with chemotherapy. Patients with either a short or long overall survival were selected from a randomized phase III trial comparing cisplatin-gemcitabine and epirubicin-gemcitabine. Tumour biopsies were assessed for differences in immunohistochemical staining using antibodies against ERCC1, hRad51, and BRCA1. A total of 33 patients were included. A positive nuclear staining for ERCC1, hRad51, and BRCA1 was observed in 44, 12, and 90% of biopsies, respectively. In large cell carcinoma nuclear hRad51 staining was absent. In five biopsies stained for hRad51 an unexpected membrane-like staining was observed; these biopsies showed no nuclear staining. DNA damage repair protein expressions were not significantly different in responders versus non-responders, or in patients with a short or long overall survival. In conclusion, immunohistochemical staining of ERCC1, hRad51, and BRCA1, in tumour biopsies from non-small-cell lung cancer patients was not predictive for tumour response and survival after chemotherapy.
