To study telomere length dynamics in hematopoietic cells with age, we analyzed the average length of telomere repeat sequences in diverse populations of nucleated blood cells. More than 500 individuals ranging in age from 0 to 90 yr, including 36 pairs of monozygous and dizygotic twins, were analyzed using quantitative fluorescence in situ hybridization and flow cytometry. Granulocytes and naive T cells showed a parallel biphasic decline in telomere length with age that most likely reflected accumulated cell divisions in the common precursors of both cell types: hematopoietic stem cells. Telomere loss was very rapid in the first year, and continued for more than eight decades at a 30-fold lower rate. Memory T cells also showed an initial rapid decline in telomere length with age. However, in contrast to naive T cells, this decline continued for several years, and in older individuals lymphocytes typically had shorter telomeres than did granulocytes. Our findings point to a dramatic decline in stem cell turnover in early childhood and support the notion that cell divisions in hematopoietic stem cells and T cells result in loss of telomeric DNA.

Background It is widely believed that females have longer telomeres than males, although results from studies have been contradictory. Methods We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression. Results Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p = 1.00) or cell type (p = 0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error. Conclusions Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required.

This longitudinal study of the elderly and oldest old does not support the hypothesis that telomere length is a predictor for remaining lifespan once age is controlled for.

The repair pathways involved in the removal of 8-oxo-7,8-dihydroguanine (8-oxoguanine) in DNA by mammalian cell extracts have been examined. Closed circular DNA constructs containing a single 8-oxoguanine at a defined site were used as substrates to determine the patch size generated after in vitro repair by mammalian cell extracts. Restriction analysis of the repair incorporation in the vicinity of the lesion indicated that up to 75% of the 8-oxoguanine was repaired via the single nucleotide replacement mechanism in both human and mouse cell extracts. Approximately 25% of the 8-oxoguanine lesions were repaired by the long patch repair pathway. Repair incorporation 5 to the lesion, characteristic for nucleotide excision repair, was not significant. Elimination of the DNA polymerase ␤ (pol␤)-dependent single nucleotide base excision repair pathway in extracts prepared from pol␤-deficient mouse cells resulted in extension of the repair gap to 4 -5 nucleotides 3 to the lesion in 50% of the repair events, suggesting the increased involvement of the long patch repair pathway. However, about one-half of the 8-oxoguanine repair was still accomplished through replacement of only one nucleotide in the pol␤-deficient cell extracts. These data indicate the existence of an alternative pol␤-independent single nucleotide repair patch pathway for processing of 8-oxoguanine in DNA.In living cells reactive oxygen species are formed continuously as a consequence of normal cellular metabolism and are also generated by a number of external factors. The reaction of active oxygen species with DNA results in numerous forms of base damage, and 8-oxoguanine 1 is one of the most abundant lesions generated. An increased level of 8-oxoguanine has been observed after treatment of cells with UV, ionizing irradiation or chemical mutagens that generate oxygen radicals (for review, see Ref. 1). Although many different lesions are formed in DNA after oxidative stress, 8-oxoguanine is one of the most significant and the most studied lesions. 8-Oxoguanine in a syn conformation can base pair with adenine and induce transversion mutations (2, 3). This demonstrated mutagenic potential is thought to be involved in cancer and aging (4 -8). To avoid deleterious consequences, 8-oxoguanine must be efficiently removed from DNA. Based on previous studies in bacterial cells it has been established that base excision repair (BER) is the major pathway for the removal of this lesion (8). Recently human 8-oxoguanine-DNA glycosylase (hOGG1) has been cloned and purified by several groups (9 -11), thus providing an enzymatic basis for the involvement of BER in removal of this lesion in mammalian cells.There are two pathways for base excision repair involving different subsets of proteins and operating independently (12-14). Both pathways are initiated by DNA glycosylases that recognize and remove the damaged base leaving an abasic site (AP site). The AP site is recognized by AP endonuclease, which introduces a DNA strand break 5Ј to the baseless sugar, and then DNA...

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