Assessment of Telomere Length and Mitochondrial DNA Copy Number in Granulosa Cells as Predictors of Aneuploidy Rate in Young Patients

Abstract

Background: To identify the correlation among female age, cellular aging markers, and aneuploidy rate in in vitro fertilization (IVF) and the preimplantation genetic test for aneuploidy (PGT-A) cycles. Methods: This is a prospective cohort study recruiting 110 infertile women between August 2017 and July 2018. They were divided into young-age (<38 years, n = 60) and advanced-age (≥38 years, n = 50) groups. Peripheral leukocytes were assessed, and the granulosa cells were pooled during oocyte pickup. Mitochondrial DNA (mtDNA) copy number and telomere length (TL) were measured using real-time polymerase chain reaction. PGT-A was performed on the NGS platform. Results: mtDNA copy number and TL were positively correlated in both leukocytes (rho = 0.477, p < 0.001) and granulosa cells (rho = 0.361, p < 0.001), but the two parameters in leukocytes were not correlated with those in granulosa cells. In the young-age group, TL in the granulosa cells was the only factor correlated with the aneuploidy rate (rho = −0.283, p = 0.044), whereas in the advanced-age group, age was the main factor (rho = 0.358, p = 0.018). Conclusions: TL in the granulosa cells was negatively correlated with the aneuploidy rate in the young-age group, supporting the application of PGT-A in younger women.

The Aftermath of Long-Term Cigarette Smoking on Telomere Length and Mitochondrial DNA Copy Number in Human Cumulus Cells Prior to In Vitro Fertilization—A Pilot Study

“…In the study conducted by Yu et al, a possible connection between female age, cellular aging markers, aneuploidy rates in IVF protocols, and preimplantation genetic test for aneuploidy (PGT-A) cycles was taken into account. A negative correlation was established between TL in the granulosa cells and the aneuploidy rate in the young age group, emphasizing the need for PGT-A application in younger women [ 28 ]. Keefe et al further hypothesized that ongoing shortening of telomeres, ranging from fetal oogenesis to the adult ovary, could be the cause of age-related ovarian impairment [ 29 ].…”

Ovarian aging: mechanisms and intervention strategies

“…Telomere length is pivotal for accurate chromosomal alignment as well as adequate function of the spindle assembly checkpoint during meiosis, both of which prevent aneuploidy in embryos [ 79 ]. Shorter telomere is associated with higher rates of aneuploidy among infertile women undergoing in vitro fertilization [ 58 , 85 , 86 ]. Short telomeres impede germ cell specification by upregulating mitogen-activated protein kinase (MAPK) and transforming growth factor beta (TGF-β) signaling [ 87 ].…”

“…Women carrying loss-of-function variants in CHK2 manifested ANM 3.49 years later [ 10 ]. CHK2 is a downstream effector of the ATM kinase that responds primarily to DSBs, and can also be activated by the ATR kinase that responds primarily to single stranded DNA [ 86 , 120 ]. CHK2 has important functions in checkpoint signaling during the progression of the cell cycle in mitosis and meiosis [ 10 , 104 , 105 , 119 , 121 ].…”

Potential effects of assisted reproductive technology on telomere length and telomerase activity in human oocytes and early embryos

“…For example, a recent study revealed that IVF success is not associated with telomere length in leukocytes [ 137 ]. Further, Yu et al (2022) demonstrated that telomere length in leukocytes cannot be used to predict aneuploidy rate as an alternative to preimplantation genetic test for aneuploidy (PGT-A) cycles [ 131 ]. Importantly, telomere length of lymphocytes does not correlate with those of oocytes, granulosa and cumulus cells [ 131 , 138 , 139 ], most likely because leukocytes are differently exposed to various factors, such as hormones, aging, and consecutive cell divisions [ 140 ].…”

“…Further, Yu et al (2022) demonstrated that telomere length in leukocytes cannot be used to predict aneuploidy rate as an alternative to preimplantation genetic test for aneuploidy (PGT-A) cycles [ 131 ]. Importantly, telomere length of lymphocytes does not correlate with those of oocytes, granulosa and cumulus cells [ 131 , 138 , 139 ], most likely because leukocytes are differently exposed to various factors, such as hormones, aging, and consecutive cell divisions [ 140 ]. Consequently, controversial findings consider us that telomere length results of leukocytes should be carefully evaluated to predict developmental potentiality of oocytes and embryos.…”