Age related microsatellite instability in T cells from healthy individuals

Krichevsky, Spencer; Pawelec, Graham; Gural, Alexander; Effros, Rita B.; Globerson, Amiela; Yehuda, Dina Ben; Yehuda, Arie Ben

doi:10.1016/j.exger.2003.12.016

Cited by 51 publications

(40 citation statements)

References 12 publications

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“…Several studies suggest that the capacity for MMR as judged by MSI or mismatch levels is diminished as a function of ageing possibly due to the loss of key MMR proteins (see, e.g. Annett et al, 2005;Ben Yehuda et al, 2000;Krichevsky et al, 2004;Neri et al, 2005). Although we do not know whether correlations between ageing and loss of MMR reflect a direct role for MMR in preventing ageing or are indirect consequences of the ageing process, these studies raise intriguing possibilities.…”

Section: Mmr and Ageingmentioning

confidence: 90%

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

397

359

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DNA mismatch repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

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Section: Mmr and Ageingmentioning

confidence: 90%

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

397

359

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“…It was already observed that one feature of aging is the appearance of microsatellite instability. Previous studies showed that peripheral blood cells from old donors have an elevated frequency of microsatellite instability that could not be associated with defects in mismatch repair genes (21,22). Additionally, some evidence indicates that telomerase reactivation in cancer cells provides other advantages not related to telomere stabilization, which are involved in increased repair system efficiency (23) and augmented chromosomal stability (24).…”

Section: Discussionmentioning

confidence: 99%

Telomerase inhibition by an siRNA directed against hTERT leads to telomere attrition in HT29 cells

Nascimento

Alves²,

Fiedler³

2006

Oncol Rep

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Abstract. Human telomerase is a ribonucleoprotein complex composed of at least the reverse catalytic transcriptase hTERT and RNA component hTR. The enzyme stabilizes telomere length and thereby contributes to unlimited cell proliferation, i.e. immortality. Reactivation of telomerase activity during carcinogenesis is a common hallmark in most human tumor types. Consequently, telomerase is an attractive molecular target toward which to direct cancer therapeutic agents. RNA interference (RNAi) has been shown to be an effective method for inhibiting the expression of a given gene in human cells by targeting with short duplex RNA (short-interfering RNA or siRNA). Thus, we evaluated the ability of siRNAs to inhibit telomerase activity in the HT29 immortal human colorectal adenocarcinoma cell line as a model for colorectal carcinogenesis. By transient expression of a specific siRNA directed against hTERT, we reduced telomerase activity in the transfected cells. Moreover, telomere lengths were reduced in cells stably expressing this particular RNA sequence, cloned as an shRNA into an eukaryotic expression vector. The cell clone that displayed a telomerasenegative phenotype showed dramatically reduced telomere lengths and stopped proliferation. We observed that the vector was integrated into the cell genome and, despite telomere shortening, cells retained their MSI phenotype. We conclude that we have developed a potent telomerase inhibitor leading to cell death.

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“…Reference range was TSH 0.36-4 mIU/l, FT 4 9-26 pmol/l, T 3 1.1-2.9 nmol/l, anti-TPO !30 IU/ml and anti-TG !40 IU/ml. Positive ThAbs were considered if either anti-TPO or anti-TG or both autoantibodies were above the upper normal limit of their normal reference range.…”

Section: Methodsmentioning

confidence: 99%

“…Several mechanisms have been postulated (3,4) including neuroendocrine changes (5). Of particular interest is the role of the stress and hypothalamuspituitary-adrenal (HPA) axis activity in this process (6).…”

Section: Introductionmentioning

confidence: 99%

Lower early morning plasma cortisol levels are associated with thyroid autoimmunity in the elderly

Terzidis

Panoutsopoulos²,

Mantzou³

et al. 2010

European Journal of Endocrinology

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Objectives: Thyroid autoimmunity decreases in the very old. We investigated whether glucocorticoid (GC) activity, which increases in old age, is involved in this process. Subjects and methods: A total of 321 ambulatory subjects (age 51-95 years, median 71, 207 female) were studied. Thyroid function tests, cortisol, glucose, insulin and biochemical parameters were measured. A modified overnight dexamethasone suppression test (0.25 mg) was performed as an index of GC sensitivity. Results: Forty subjects had positive anti-thyroid peroxidase antibodies and 36 had positive antithyroglobulin antibodies, while 57 had either one or the other or both thyroid autoantibodies (ThAbs) positive. Mean basal cortisol levels were significantly lower in the ThAbs (C) groups (320G125 vs 378G128 nmol/l, PZ0.002). Triiodothyronine, free thyroxine, post-dexamethasone cortisol levels, C-reactive protein, homeostasis model assessment-insulin-resistance-index and body mass index did not differ between these two groups. Mean age of ThAbs (C) subjects was lower compared to the ThAbs (K) group (67.38G7.38 vs 71.64G8.57 years, PZ0.001). Conclusions: Reduced GC activity is associated with an increased prevalence of ThAbs positivity in older ambulatory subjects. Subjects without ThAbs in this population sample are relatively older. It is not known whether this is related to increasing GC activity with age.

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Age related microsatellite instability in T cells from healthy individuals

Cited by 51 publications

References 12 publications

DNA mismatch repair: Molecular mechanism, cancer, and ageing

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Telomerase inhibition by an siRNA directed against hTERT leads to telomere attrition in HT29 cells

Lower early morning plasma cortisol levels are associated with thyroid autoimmunity in the elderly

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