A single-cell assay for telomere DNA content shows increasing telomere length heterogeneity, as well as increasing mean telomere length in human spermatozoa with advancing age

Antunes, Danielle Mota Fontes; Kalmbach, Keri; Wang, Fang; Dracxler, Roberta; Seth-Smith, M.L.; Kramer, Y.G.; Buldo-Licciardi, Julia; Kohlrausch, Fabiana B.; Keefe, David L.

doi:10.1007/s10815-015-0574-3

Cited by 60 publications

(39 citation statements)

References 32 publications

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“…In adult somatic cells, telomeres are composed of large noncoding sequences of approximately 1000–2000 TTAGGG tandem base pair repeats that end in a 3′ extension past the 5′ terminus [2]. In other select cells, the telomeres are maintained and can be considerably longer, such as adult human germ cells which can contain anywhere from 500–5000 repeats [3,4,5]. During each cycle of cell division telomeres are incompletely replicated, and consequently, their ends are progressively shortened [6].…”

Section: Introductionmentioning

confidence: 99%

Treating Cancer by Targeting Telomeres and Telomerase

et al. 2017

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Telomerase is expressed in more than 85% of cancer cells. Tumor cells with metastatic potential may have a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. Human telomerase primarily consists of two main components: hTERT, a catalytic subunit, and hTR, an RNA template whose sequence is complimentary to the telomeric 5′-dTTAGGG-3′ repeat. In humans, telomerase activity is typically restricted to renewing tissues, such as germ cells and stem cells, and is generally absent in normal cells. While hTR is constitutively expressed in most tissue types, hTERT expression levels are low enough that telomere length cannot be maintained, which sets a proliferative lifespan on normal cells. However, in the majority of cancers, telomerase maintains stable telomere length, thereby conferring cell immortality. Levels of hTERT mRNA are directly related to telomerase activity, thereby making it a more suitable therapeutic target than hTR. Recent data suggests that stabilization of telomeric G-quadruplexes may act to indirectly inhibit telomerase action by blocking hTR binding. Telomeric DNA has the propensity to spontaneously form intramolecular G-quadruplexes, four-stranded DNA secondary structures that are stabilized by the stacking of guanine residues in a planar arrangement. The functional roles of telomeric G-quadruplexes are not completely understood, but recent evidence suggests that they can stall the replication fork during DNA synthesis and inhibit telomere replication by preventing telomerase and related proteins from binding to the telomere. Long-term treatment with G-quadruplex stabilizers induces a gradual reduction in the length of the G-rich 3’ end of the telomere without a reduction of the total telomere length, suggesting that telomerase activity is inhibited. However, inhibition of telomerase, either directly or indirectly, has shown only moderate success in cancer patients. Another promising approach of targeting the telomere is the use of guanine-rich oligonucleotides (GROs) homologous to the 3’ telomere overhang sequence (T-oligos). T-oligos, particularly a specific 11-base oligonucleotide (5’-dGTTAGGGTTAG-3’) called T11, have been shown to induce DNA damage responses (DDRs) such as senescence, apoptosis, and cell cycle arrest in numerous cancer cell types with minimal or no cytostatic effects in normal, non-transformed cells. As a result, T-oligos and other GROs are being investigated as prospective anticancer therapeutics. Interestingly, the DDRs induced by T-oligos in cancer cells are similar to the effects seen after progressive telomere degradation in normal cells. The loss of telomeres is an important tumor suppressor mechanism that is commonly absent in transformed malignant cells, and hence, T-oligos have garnered significant interest as a novel strategy to combat cancer. However, little is known about their mechanism of action. In this review, we discuss the current understanding of how T-oligos exert their antiproliferative effe...

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Section: Introductionmentioning

confidence: 99%

Treating Cancer by Targeting Telomeres and Telomerase

et al. 2017

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“…In mice, Zscan4 expression is characteristic of two‐cell embryos and “2C‐like” embryonic stem cells, featuring rapid telomerase‐independent telomere lengthening (Zalzman et al, ). A previous study suggested that the ALT mechanism could be active during spermatogenesis in humans, based on an unexpected age‐related increase in sperm TL in the absence of telomerase (Antunes et al, ). This mechanism has been described also in the absence of telomerase activity after oocyte fertilization and activation (de Frutos et al, ; Liu et al, ).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal analysis of somatic and germ‐cell telomere dynamics in outbred mice

Ramos‐Ibeas

Pericuesta

Peral‐Sanchez

et al. 2019

Molecular Reproduction Devel

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Although telomere length (TL) shortens with age in most tissues, an age‐related increase in length has been described in sperm through a mechanism that is not yet fully understood. Changes in TL with age in the same individual have not been explored. This longitudinal study examines TL dynamics in somatic tissue and gametes during an entire lifespan in an outbred mouse population (from 8 to up to 114 weeks of age). Our findings indicate a reduced life expectancy in males compared to females (84.75 ± 9.23 vs. 113.16 ± 0.20 weeks) and significant variability in TL dynamics between individuals. While with aging, a clear reduction in TL was produced in somatic cells and oocytes, telomeres in sperm cells significantly lengthened. Finally, we found evidence indicating that telomere elongation in sperm during aging may be dependent on different mechanisms, such as the survival of spermatogonia with longer telomeres and the alternative lengthening of telomeres mechanism in meiotic and postmeiotic spermatogenic cells.

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“…Moreover, a study published in 2015 [75] reported a marked increase in sperm telomere length heterogeneity as men age and a longer length in samples with normal parameters in comparison with samples with abnormal parameters. These findings could have implications for infertile couples treated with assisted reproduction techniques due to a high probability of shorter telomere length in the offspring, taking into account the reported association between shorter telomere and depression, autism, neoplasia, and general poor health.…”

Section: Telomere Lengthmentioning

confidence: 99%

The Impact of Aging on Fertility: Similarities and Differences between Ovaries and Testes

Albu¹,

Albu²

2017

Testes and Ovaries - Functional and Clinical Differences and Similarities

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The increasing age seems to have a negative impact on reproductive functions not only in women but also in men. Therefore, our aim was to review the data available in the literature regarding the impact of advancing age on fertility and the mechanisms underlying this association in both genders. The available data suggest that the effects of age on ovarian function cause a decrease in fertility starting 13 years before menopause. Statistics show that 10% of women will have a decreased fertility starting with the age of 30. The impact of age on ovary is due to both decreased number and quality of the oocytes, resulting in a high rate of chromosomal aneuploidy in the embryo and mitochondria dysfunction. Assisted reproductive technologies aiming to identify competent embryo were created but for the moment the results are unsatisfactory. On the other hand, in men, the semen quality and testicular function were found to gradually decrease with age and most of the studies also describe a negative impact on fertility. The mechanisms underlying decreased fertility are mainly genetic and epigenetics changes. However, if the effects of age on male fertility in men can be overcome by assisted reproductive technologies is not clear yet as the results of the studies are inconsistent.

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A single-cell assay for telomere DNA content shows increasing telomere length heterogeneity, as well as increasing mean telomere length in human spermatozoa with advancing age

Cited by 60 publications

References 32 publications

Treating Cancer by Targeting Telomeres and Telomerase

Treating Cancer by Targeting Telomeres and Telomerase

Longitudinal analysis of somatic and germ‐cell telomere dynamics in outbred mice

The Impact of Aging on Fertility: Similarities and Differences between Ovaries and Testes

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