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The telomere theory of reproductive senescence in women
David L. Keefea, Kerri Marquardb and Lin Liua

Purpose of review A unifying theory of reproductive aging, based on telomere shortening, is proposed. Recent findings Telomere shortening may mediate both ‘hits’ involved in reproductive aging, that is late exit from the fetal production line and long interval to ovulation in the adult.Summary As women age egg dysfunction increases, with meiotic nondisjunction, embryonic arrest, apoptosis, and miscarriage. Egg dysfunction results from two ‘hits’ – reduced formation of chiasmata during fetal oogenesis, and accumulation of reactive oxygen damage during the prolonged interval until ovulation. Late exit from a production line during oogenesis presumably contributes to the first hit. Thelater insult also involves meiotic spindle abnormalities. Telomeres, repetitive sequences of DNA, cap chromosome ends and dissipate during divisions. Oocytes do not divide, but oogonia do, and telomerase, the enzyme responsible for maintaining telomere length, is inefficient, and remains inactive in oocytes and embryos until blastocyst stage. Reactive oxygen also shortens telomeres, so theprolonged interval between birth and ovulation would further shorten telomeres from chronic exposure to reactive oxygen. In support of this theory, experimental shortening of telomeres in mice produced a phenotype similar to reproductive aging in women, with abnormal chiasmata, spindles, cell cycles, apoptosis, and genomic instability, and telomere length in human eggs correlated with in-vitrofertilization outcome. Keywords aneuploidy, meiosis, reproductive aging, telomeres
Curr Opin Obstet Gynecol 18:280–285. # 2006 Lippincott Williams & Wilkins.
a University of South Florida, Department of Obstetrics and Gynecology, Tampa, Florida, USA and bTufts-New England Medical Center, Department of Obstetrics and Gynecology, Boston, Massachusetts, USA

Introduction
Women experience a marked increasein meiotic dysfunction as they age, resulting in increased rates of infertility, miscarriage, and chromosomal nondisjunction, as well as associated miscarriages and birth defects. As women increasingly delay childbearing until their late 30s, when the effects of age on fertility become significant, reproductive senescence is a growing clinical problem. Meiotic nondisjunction is the cause of atleast 35% of first trimester miscarriages, 4% of stillbirths, and 0.3% of live borns [1,2]. Preimplantation embryos from women at the ends of their reproductive lives exhibit even higher rates (up to 80%) of aneuploidy [3,4]. Older women have depleted oocyte reserves [5,6] and their embryos exhibit high degrees of fragmentation, apoptosis and cell cycle arrest, and aneuploidy [7,8]. Sandalinas andcolleagues [8] used spectral karyotyping to identify all chromosomes and to provide an accurate estimate of the true rate of nondisjunction in human oocytes. The egg must be the major locus of reproductive senescence, because donation of eggs from young to older women completely abrogates the effects of age on fertility [9, 10]. As reproductive aging affects primarily the oocyte, great attentionhas focused on the biology of this single cell.

Biological basis of reproductive aging in women
A number of theories have been proposed to explain how aging affects oocyte function in women, including reduced formation of chiasmata during prenatal oogenesis, abnormalities in spindle structure and function during the resumption of meiosis in the adult [11], increased mitochondrial DNA (mtDNA)mutations from chronic exposure to reactive oxygen during the prolonged interval between birth of oocytes and their ovulation [12–14], and late exit from a production line during oogenesis [15,16]. A production line in oocyte formation during fetal life was thought to exist, because oocytes do not exit the mitotic phase of oogenesis all at once during fetal oogenesis, but rather enter meiosis in...
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