ABSTRACT
Reproductive aging involves declines both in oocyte number and developmental capacity. Declining oocyte number alone cannot explain the manifestations of reproductive aging in women. We have proposed the Telomere Theory of Reproductive Aging to explain the complex phenotype found in oocytes from older women. Telomeres are TTAGGG repeats and associated proteins, which form loops at the ends of chromosomes to provide structural and genomic stability. Studies in mice and women show that telomere shortening in oocytes provides a parsimonious explanation for the effects of reproductive aging on oocyte quality. Measurement of polar body telomere length may predict oocyte quality in women undergoing ART.
Subject(s)
Aging/genetics , Cellular Senescence/genetics , Oocytes/metabolism , Reproduction/genetics , Telomere Shortening , Telomere/genetics , Adult , Age Factors , Aging/metabolism , Aging/pathology , Animals , Female , Fertility/genetics , Humans , Infertility, Female/genetics , Infertility, Female/metabolism , Infertility, Female/physiopathology , Infertility, Female/therapy , Middle Aged , Oocytes/pathology , Pregnancy , Reproductive Techniques, Assisted , Telomere/metabolism , Young AdultABSTRACT
Telomeres mediate biologic aging in organisms as diverse as plants, yeast, and mammals. We propose a telomere theory of reproductive aging that posits telomere shortening in the female germ line as the primary driver of reproductive aging in women. Experimental shortening of telomeres in mice, which normally do not exhibit appreciable oocyte aging, and which have exceptionally long telomeres, recapitulates the aging phenotype of human oocytes. Telomere shortening in mice reduces synapsis and chiasmata, increases embryo fragmentation, cell cycle arrest, apoptosis, spindle dysmorphologies, and chromosome abnormalities. Telomeres are shorter in the oocytes from women undergoing in vitro fertilization, who then produce fragmented, aneuploid embryos that fail to implant. In contrast, the testes are replete with spermatogonia that can rejuvenate telomere reserves throughout the life of the man by expressing telomerase. Differences in telomere dynamics across the life span of men and women may have evolved because of the difference in the inherent risks of aging on reproduction between men and women. Additionally, growing evidence links altered telomere biology to endometriosis and gynecologic cancers, thus future studies should examine the role of telomeres in pathologies of the reproductive tract.
