Telomere reprogramming during preimplantation embryo development and reproductive aging — ASN Events

Telomere reprogramming during preimplantation embryo development and reproductive aging (#175)

David Keefe 1
  1. M.D., Department of Ob/Gyn, NYU Langone Medical Center, New York, USA

The paradigm of a fixed complement of female germ cells, which decline in number and developmental competence with advancing age, continues to provide the most compelling model to explain reproductive function in mammalian females, and the experience of clinicians, who find that the woman’s age provides the most robust prognosticator of a couple’s fertility, regardless of diagnosis. To explain the seeming paradox of aging in an immortal germ line, we have proposed a Telomere Theory of Reproductive Aging- oocytes, unlike male germ cells, undergo telomere erosion with aging because of delayed exit from the production line during fetal oogenesis and from chronic effects of reactive oxygen on the telomere’s guanine rich sequence.  Experimental shortening of telomeres in mice, which normally have exceptionally long telomeres and undergo minimal age related oocyte dysfunction, produces a phenotype similar to reproductive aging in women, including reduced chiasmata, spindle abnormalities, embryonic arrest, apoptosis and genomic instability in oocytes and embryos.  Telomere length in oocytes and polar bodies also predicts embryo aneuploidy and IVF outcome in women.  If telomeres shorten in oocytes during aging, how do they reset during early development, to maintain immortality in the female germ line?  Telomerase activity is nearly absent until the blastocyst stage of development, and even then barely maintains telomere reserve, but a telomerase independent, recombination based Alternative Lengthening of Telomeres (ALT) mechanism robustly elongates telomeres during early preimplantation embryo development.  The sister chromatid exchange (SCE) underlying ALT may contribute to the extensive genomic instability so characteristic of cleavage stage embryos. 

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