Mechanisms of oocyte aneuploidy associated with advanced maternal age

Mikwar, Myy; MacFarlane, Amanda J.; Marchetti, Francesco

doi:10.1016/j.mrrev.2020.108320

Cited by 181 publications

(133 citation statements)

References 216 publications

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“…On the basis of these observations, infertility patients were recruited for a proof-of-principle investigation of antioxidant supplementation prior to an IVF cycle to analyze its feasibility. In AMA patients 39 years of age or older compared to their younger counterparts, IVF and FET outcomes were similar with the exception of aneuploidy rates that were higher for the AMA patients, as extensively documented in the literature [48]. The 21 patients who did not undergo FET due to aneuploidy were significantly older than the antioxidant-supplemented patients who underwent FET (41.5 ± 1.7 vs. 37.4 ± 3.4 years old, p < 0.0001).…”

Section: Discussionsupporting

confidence: 69%

Antioxidant Intervention Attenuates Aging-Related Changes in the Murine Ovary and Oocyte

Katz‐Jaffe

Lane

Parks

et al. 2020

Life

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Advanced maternal age (AMA) is associated with reduced fertility due in part to diminished ovarian follicle quantity, inferior oocyte quality, chromosome aneuploidy, and lower implantation rates. Ovarian aging is accompanied by increased oxidative stress and blunted antioxidant signaling, such that antioxidant intervention could improve reproductive potential. The first aim of this study was to determine the molecular effects of antioxidant intervention in the ovaries and oocytes of aged mice, utilizing a supplement containing only naturally occurring açaí (Euterpe oleracea) with an oxygen radical absorbance capacity of 208,628 μmol Trolox equivalent (TE)/100 g indicating high antioxidant activity. Nine month old female CF-1 mice were administered 80 mg/day antioxidants (n = 12) or standard diet (n = 12) for 12 weeks. In the ovary, antioxidant treatment upregulated β-adrenergic signaling, downregulated apoptosis and proinflammatory signaling, and variably affected cell growth and antioxidant pathways (p < 0.05). Exogenous antioxidants also increased the oocyte expression of antioxidant genes GPX1, SOD2, and GSR (p < 0.05). A feasibility analysis was then conducted on female AMA infertility patients as a proof-of-principle investigation. Patients (n = 121; <45 years old) consented to receiving 600 mg antioxidants three times daily for ≥8 weeks preceding infertility treatment. Preliminary results indicate promising outcomes for AMA patients, warranting further investigation.

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Section: Discussionsupporting

confidence: 69%

Antioxidant Intervention Attenuates Aging-Related Changes in the Murine Ovary and Oocyte

Katz‐Jaffe

Lane

Parks

et al. 2020

Life

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“…Although ENM is a composite outcome of multiple clinical factors, we were not able to directly capture factors driving the patterns observed in this cohort as it was based on national database with limited information. However, maternal age-related factors that are known to be associated with perinatal death, such as congenital birth defect 14 , preterm birth 18 , and preeclampsia 26 , and these factors are likely to be more severe in each category for > 40 years 7 , 17 . Thus, it can be carefully speculated that the reason ENM remained still high in the mothers over 40 years of age despite the degree of social support, may be accountable to congenital anomalies, chromosomal abnormality and extremely preterm or very low birth weight complicating neonates.…”

Section: Discussionmentioning

confidence: 99%

“…Age cut-off of 35 to define AMA was based on studies on age-related adverse pregnancy outcome 10 , where outcome was a composite of maternal 11 , 12 , fetal 13 , 14 , and perinatal outcomes 15 – 18 . The proportion of AMA in these relatively older studies was small compared to the more contemporary cohort.…”

Section: Introductionmentioning

confidence: 99%

Maternal age and risk of early neonatal mortality: a national cohort study

Kim

Choi

Kim

et al. 2021

Sci Rep

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Advanced maternal age (AMA) is a growing trend world-wide and is traditionally defined as childbearing in women over 35 years of age. The purpose of our study was to determine the maternal age group within the Korean population, in which the risk of early neonatal mortality is increased. Korean birth and mortality data from 2011 to 2015 were used to estimate the influence of maternal age on the risk of early neonatal mortality. A Poisson regression was used for the analysis of multiple clinical variables such as year of delivery, maternal age, gestational age, infant gender, birth weight, multiple birth, parity, and socioeconomic variables. Furthermore, a generalized additive model was used to determine the maternal age at which the risk for neonatal mortality increases. We included 2,161,908 participants and found that 49.4% of mothers were 30–34 years of age at delivery. The proportion of mothers aged 35 and above increased over the 5-year analysis period. A maternal age lower than 29 years or higher than 40 years was associated with a relatively higher risk of early neonatal mortality. The trend and magnitude of the age-related risk on early neonatal mortality were independent of maternal socioeconomic factors such as living in an obstetrically underserved area, education level, and employment status. Furthermore, we showed that the risk for early neonatal mortality was higher until the maternal age of 28. However, there were no significant changes in the risk between the age of 35 and 40 years. According to recent national-wide data, age-related risk for early neonatal mortality is only apparent for mothers ≥ 40 years old whereas, age between 35 and 39 are not at increased risk for early neonatal mortality, despite being classified as AMA.

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“…Meiosis in human oocytes is especially error prone with aneuploidy rates ranging from 15% in younger women to a staggering 30-70% in oocytes from older women and, by comparison, spermatozoa have an average aneuploidy rate of 1-4% (Nagaoka et al, 2012;Ottolini et al, 2015;Greaney et al, 2018;Gruhn et al, 2019). While elegant studies of DNA damage, spindle abnormalities and meiotic errors have provided unique insight into oocyte aging and meiotic failure (Mihajlović and FitzHarris, 2018;Gruhn et al, 2019;Zielinska et al, 2019;Hassold et al, 2020;Mikwar et al, 2020), advances in the application of proteomic and RNA-sequencing technology to oocytes are beginning to reveal an additional layer of complexity to this process whereby declining proteostasis contributes widely to maternal aging processes (Duncan et al, 2017). Our improved understanding of reproductive failure has been marked by the discovery that proteins critical for meiosis, such as those comprising the cohesion complex, are in fact extremely long-lived with no capacity for renewal during oocyte development (Revenkova et al, 2010;Tachibana-Konwalski et al, 2010;Burkhardt et al, 2016;Lee, 2020).…”

Section: Protein Health During Reproductive Aging In Womenmentioning

confidence: 99%

Proteostasis in the Male and Female Germline: A New Outlook on the Maintenance of Reproductive Health

Cafe

Nixon

Ecroyd

et al. 2021

Front. Cell Dev. Biol.

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For fully differentiated, long lived cells the maintenance of protein homeostasis (proteostasis) becomes a crucial determinant of cellular function and viability. Neurons are the most well-known example of this phenomenon where the majority of these cells must survive the entire course of life. However, male and female germ cells are also uniquely dependent on the maintenance of proteostasis to achieve successful fertilization. Oocytes, also long-lived cells, are subjected to prolonged periods of arrest and are largely reliant on the translation of stored mRNAs, accumulated during the growth period, to support meiotic maturation and subsequent embryogenesis. Conversely, sperm cells, while relatively ephemeral, are completely reliant on proteostasis due to the absence of both transcription and translation. Despite these remarkable, cell-specific features there has been little focus on understanding protein homeostasis in reproductive cells and how/whether proteostasis is “reset” during embryogenesis. Here, we seek to capture the momentum of this growing field by highlighting novel findings regarding germline proteostasis and how this knowledge can be used to promote reproductive health. In this review we capture proteostasis in the context of both somatic cell and germline aging and discuss the influence of oxidative stress on protein function. In particular, we highlight the contributions of proteostasis changes to oocyte aging and encourage a focus in this area that may complement the extensive analyses of DNA damage and aneuploidy that have long occupied the oocyte aging field. Moreover, we discuss the influence of common non-enzymatic protein modifications on the stability of proteins in the male germline, how these changes affect sperm function, and how they may be prevented to preserve fertility. Through this review we aim to bring to light a new trajectory for our field and highlight the potential to harness the germ cell’s natural proteostasis mechanisms to improve reproductive health. This manuscript will be of interest to those in the fields of proteostasis, aging, male and female gamete reproductive biology, embryogenesis, and life course health.

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Mechanisms of oocyte aneuploidy associated with advanced maternal age

Cited by 181 publications

References 216 publications

Antioxidant Intervention Attenuates Aging-Related Changes in the Murine Ovary and Oocyte

Antioxidant Intervention Attenuates Aging-Related Changes in the Murine Ovary and Oocyte

Maternal age and risk of early neonatal mortality: a national cohort study

Proteostasis in the Male and Female Germline: A New Outlook on the Maintenance of Reproductive Health

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