Women’s long-term health and longevity: telomere theory of aging in the management of menopause
R.K. MikheevO. R. GrigoryanE. V. SheremetyevaYu. S. AbsatarovaЖ.А. УжеговаМ. О. ЧерноваA. N. KurinovaD. V. SazonovaLarisa NikankinaЕ. Н. Андреева
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The concept of women’s long-term health and longevity implies maintaining the quality of life, including a discussion of the role of hormone replacement therapy within the ‘therapeutic window’. Aging is a complex multi-step process. It is believed that women begin to experience the effects of aging at the age of 40. The processes of age-related changes in the body are being actively studied these days and include markers, models, systems, but there is no unified concept yet. In recent decades, there has been an increase in life expectancy for women, hence there are more women in menopause, and an increase in the incidence of age-related diseases can be expected. With the onset of menopause and age-related changes, women may experience metabolic disorders, cardiovascular diseases, endothelial dysfunction, disorders of both the central and peripheral nervous systems, musculoskeletal disrders and mental health problems. Over past decades, attention has been paid to cellular markers of aging, and the telomere theory has been most developed. It is associated with shortening of telomeres – the end regions of chromosomes. Many studies in recent years have examined the mechanisms influencing the length of these regions, the activity of the telomerase enzyme, and the processes of reproductive aging associated with this theory. In the 20th and 21st centuries, the possible effect of exogenously administered estrogen on telomere length as part of hormone replacement therapy has been under active consideration. Key words: insulin resistance, menopause, telomeres, telomerase, type 2 diabetes, aging, hormone replacement therapyKeywords:
Senescence
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Abstract Background and purpose: Telomere length must be maintained throughout cancer cell progression and proliferation. In most tumours, telomerase activity maintains telomere length. Therefore, telomerase is a target for cancer treatments. However, some cancer cells maintain telomere length through an alternative mechanism termed ‘alternative lengthening of telomeres’. To determine how telomerase inhibition relates to the initiation of the alternative lengthening of telomeres pathway, we investigated telomerase activity and telomere maintenance in Hep-2 cells with and without reduced telomerase activity. Materials and methods: We investigated telomerase activity levels in a normal Hep-2 cell line and in residual cells following telomerase inhibition treatment. Additionally, we looked for expression of a marker protein for the alternative lengthening of telomeres mechanism. Results and conclusions: In the residual cells, telomerase activity was eliminated. However, these cells had higher levels of the alternative lengthening of telomeres biomarker, suggesting an alternative mechanism for telomere maintenance following telomerase inhibition. These results could have a major impact on the design of new cancer treatments.
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Activation of telomerase and stabilization of telomeres are considered to be necessary for immortalization of human tumor cells. Telomerase activity and telomere lengths were examined in adult and childhood cancer tissues. High telomerase activity was detected in over 40% samples. In these cases, the lengths of telomeres varied in wide range and the short telomere length significantly correlated with high proliferative index. The patients with short telomeres demonstrated poorer prognosis than other patients. These findings suggest that the short telomeres might be related with the malignant potential in cancers with high telomerase activity.
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Human fibroblasts expressing the catalytic component of human telomerase (hTERT) have been followed for 250–400 population doublings. As expected, telomerase activity declined in long term culture of stable transfectants. Surprisingly, however, clones with average telomere lengths several kilobases shorter than those of senescent parental cells continued to proliferate. Although the longest telomeres shortened, the size of the shortest telomeres was maintained. Cells with subsenescent telomere lengths proliferated for an additional 20 doublings after inhibiting telomerase activity with a dominant-negative hTERT mutant. These results indicate that, under conditions of limiting telomerase activity, cis-acting signals may recruit telomerase to act on the shortest telomeres, argue against the hypothesis that the mortality stage 1 mechanism of cellular senescence is regulated by telomere positional effects (in which subtelomeric loci silenced by long telomeres are expressed when telomeres become short), and suggest that catalytically active telomerase is not required to provide a protein-capping role at the end of very short telomeres.
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There is increasing evidence that telomere shortening both in vitro and in vivo is the clock that counts cell divisions and determines the onset of cellular senescence. Cells overcome the normal senescence mechanism by stabilising telomere length; probably due to the activity of telomerase activity that specifically elongates telomeres. Most human primary tumors contain telomerase, while the cells of most normal tissues lack this activity. Normal haematopoietic cells express telomerase activity. This review is a discussion of utility of telomere length and telomerase activity measurements in the diagnostics and prognosis of leukaemia as well as the potential value of antitelomerase therapy. Results of telomere lengths measurements in young recipients of allogenic transplants are also reported.
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Telomere length maintenance is essential for cellular immortalization, and thus tumorigenesis. Most human tumors and immortal cell lines maintain their telomeric DNA via the activity of a specialized reverse transcriptase, telomerase. Stabilization of telomeric repeat tracts may also be achieved through a telomerase-independent mechanism, referred to as alternative lengthening of telomeres (ALT). ALT cells are telomerase negative and are characterized by extremely long and heterogeneously sized telomeres and novel multiprotein structures called ALT-associated PML nuclear bodies which are unique to ALT cells. To determine if reconstitution of telomerase activity suppressed ALT and restored wild-type telomere lengths, we introduced the catalytic subunit of telomerase into two ALT cell lines. Initially, two clonal lines exhibited enrichment of shorter telomeres while maintaining a population of ultra-long telomeres similar to that observed in the parental line, suggesting that telomerase is stabilizing the shorter telomeres in the population. Telomere length in the third clonal line was not detectably different from that in the parental cell line. One clonal line with a phenotype of shorter telomeres maintained this pattern over time in culture while the second gradually reverted to the parental ALT telomere length pattern, concurrent with reduction of telomerase activity. All clones continued to maintain ALT-associated PML nuclear bodies regardless of whether telomerase was present. The data suggest that introduction of telomerase activity alone is not sufficient to completely repress ALT, that telomerase acts preferentially on the shortest telomeres in the culture and that the ALT and telomerase pathways may be present concurrently in mammalian cells.
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