Senataxin: A New Guardian of the Female Germline Important for Delaying Ovarian Aging

Abstract

Early decline in ovarian function known as premature ovarian aging (POA) occurs in around 10% of women and is characterized by a markedly reduced ovarian reserve. Premature ovarian insufficiency (POI) affects ~1% of women and refers to the severe end of the POA spectrum in which, accelerated ovarian aging leads to menopause before 40 years of age. Ovarian reserve refers to the total number of follicle-enclosed oocytes within both ovaries. Oocyte DNA integrity is a critical determinant of ovarian reserve since damage to DNA of oocytes within primordial-stage follicles triggers follicular apoptosis leading to accelerated follicle depletion. Despite the high prevalence of POA, very little is known regarding its genetic causation. Another little-investigated aspect of oocyte DNA damage involves low-grade damage that escapes apoptosis at the primordial follicle stage and persists throughout oocyte growth and later follicle development. Senataxin (SETX) is an RNA/DNA helicase involved in repair of oxidative stress-induced DNA damage and is well-known for its roles in preventing neurodegenerative disease. Recent findings uncover an important role for SETX in protecting oocyte DNA integrity against aging-induced increases in oxidative stress. Significantly, this newly identified SETX-mediated regulation of oocyte DNA integrity is critical for preventing POA and early-onset female infertility by preventing premature depletion of the ovarian follicular pool and reducing the burden of low-grade DNA damage both in primordial and fully-grown oocytes.

Non-linear Relationship of Maternal Age With Risk of Spontaneous Abortion: A Case-Control Study in the China Birth Cohort

“…There are several reasons that help illustrate the mechanism of the association between advanced maternal age (>30 years old) and spontaneous abortion: (a) an age-related decline in reproductive capacity is due to the gradual decline in ovarian reserves and oocyte integrity ( 60 ); (b) more frequent chromosome separation errors lead to oocyte cell aneuploidy ( 47 ), which is believed to be the main cause of a mother's age-related spontaneous abortion; (c) there are multiple copies of the mitochondrial genome, but as we get older, different mtDNA copies will accumulate more and more mutations, so the risk of getting mutations is greater with age ( 61 ). In addition, mothers of advanced age are more likely to develop a medical condition during pregnancy, such as obesity, anemia, and diabetes ( 62 ).…”

Study on the clinical value of Vitamin D in recurrent spontaneous abortion

“…These results indicate that VD deficiency or insufficiency may lead to a decline in follicle quality and nondisjunction or abnormal meiosis during fertilization, which will lead to an increase in the incidence of embryo chromosome abnormalities, further resulting in spontaneous abortion. Several studies have shown that 50−70% of spontaneous abortions involve chromosomal and genetic abnormalities, 26 which may be due to the gradual decline in ovarian reserves and oocyte integrity, 27 the production of aneuploidy in abnormal chromosome meiosis during fertilization, 28 protein defects in the polymerization checkpoint of the spindle apparatus and a decrease in cohesion protein, 29 the accumulation of mtDNA copy mutations, 30 and sperm problems. Through 186 cases with ACA of medium or low titers, the study finds that there is a certain negative correlation between ACA and VD ( p < .001), which is stronger among RSA patients. Moreover, the patient's VD significantly increased, while the ACA significantly decreased after VD supplementation ( p < .001).…”

Facilitation of Ovarian Response by Mechanical Force—Latest Insight on Fertility Improvement in Women with Poor Ovarian Response or Primary Ovarian Insufficiency

“…SNPs located in genes associated with immune and mitochondrial function as well as DNA repair and maintenance processes have been linked to early age at menopause and POI [71,72]. Among them, those involved in the regulation of DNA damage/repair and cytogenetic stability are implicated in both ovarian aging and POI [73][74][75].…”