Telomere associated gene expression as well as TERT protein level and telomerase activity are altered in the ovarian follicles of aged mice

Abstract

Telomeres cap the ends of eukaryotic chromosomes to maintain genomic stability and integrity during an organism’s lifespan. The length of telomeres inevitably shortens due to DNA replication, genotoxic agents, and biological aging. A limited number of cell types, e.g., stem cells, germline cells, and early embryos can elongate shortened telomeres via the enzymatic action of telomerase, which is composed of telomerase reverse transcriptase (TERT) and telomerase RNA component (Terc). Additionally, telomere-associated proteins including telomeric repeat binding factor 1 (TRF1) and 2 (TRF2), as well as protection of telomeres 1a (POT1a), bind to telomeres to maintain their structural integrity and length. During ovarian aging in mammals, telomeres progressively shorten, accompanied by fertility loss; however, the molecular mechanism underlying this attrition during follicle development remains unclear. In this study, the primary, secondary, preantral, and antral follicles were obtained either from 6-week-old adult (n = 19) or 52-week-old aged (n = 12) mice. We revealed that the Tert, Terc, Trf1, Trf2, and Pot1a gene expression (P < 0.001) and TERT protein (P < 0.01) levels significantly decreased in certain ovarian follicles of the aged group when compared to those of the adult group. Also, telomerase activity exhibited remarkable changes in the follicles of both groups. Consequently, altered telomere-associated gene expression and reduced TERT protein levels in the follicles of aged mice may be a determinant of telomere shortening during ovarian aging, and infertility appearing in the later decades of reproductive lifespan. Further investigations are required to determine the molecular mechanisms underlying these alterations in the follicles during ovarian aging.

The role of oxidative stress in ovarian aging: a review

“…Clinical studies have also found that the length of telomeres in the granulosa cells of POI patients is significantly shorter, and that telomerase activity is significantly reduced [ 64 ]. Telomere damage was also observed in naturally aged ovarian cells, along with reduced expression levels of telomerase (TERC), telomeric reverse transcriptase (TERT) and telomere-related proteins (TRF1, TRF2, POT1) [ 65 , 66 ]. The relative length of telomeres in cumulus cells is closely related to oocyte and embryo quality and can be used as a potential marker for screening high-quality oocytes in the field of assisted reproductive technology (ART) [ 67 ].…”

Alteration of relative telomere length and telomerase reverse transcriptase expression in the granulosa cells of women during aging and assessment of in vitro fertilization outcomes

“…The data in the present study also indicate that TERT expression alters in GCs with aging, but RNA-sequencing data (data not shown) did not detect any significant changes in TERT expression between old and young human oocytes. Kosebent and Ozturk ( 38 ) suggested that TERT expression was differentially expressed at different developmental follicular stages in both young and old mice. These seemingly discordant results indicate that the regulation of TERT expression is tissue- and stage-dependent.…”

“…Specifically, telomerase activity in GCs is controlled by growth factors and female steroid hormones ( 29 ). The TERT gene promoter contains an estrogen response element ( 38 ). The microenvironment of GCs contains estrogens that are reported to influence telomerase activity and length ( 41 ).…”

Telomeres, aging and reproduction

“…Previously, a lack of TA and shorter telomeres have been found in granulosa cells of women with occult ovarian insufficiency [27] and in women with primary ovarian insufficiency [28]. Recent evidence shows a decrease in telomere length, shelterin genes and TERT expression, from fetal to postmenopausal life in ovaries and follicles of both murine models [29 ▪ ,30] and humans [31]. In contrast, higher TA has been found in cumulus cells of women with polycystic ovary syndrome as they have a high number of small antral follicles [32].…”