The telomere theory of reproductive senescence in women

Abstract

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. The later 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 the prolonged 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-vitro fertilization outcome.

Analysis of telomere length in couples experiencing idiopathic recurrent pregnancy loss

“…It is well known that telomere is a marker for cellular aging because their length declines with each cell division, though it exhibits inter-individual variation [31]. It is possible that telomere shortening may limit the mitotic capacity of primordial germ cells during fetal growth and therefore restrict the size of the follicular pool [32]. There is high probability that shortened telomere in both sperm and ova may have additive effect in limiting the replicative potential growth of embryo, and their mechanisms need detailed investigations.…”

Reproductive ageing in women

“…The most recent theory proposed to explain the observed decline in fertility in women with increasing age is telomere shortening [151]. Telomeres are the repetitive DNA sequences at chromosomal ends, capping the chromosomes and therefore preventing end-to-end fusion of chromosomes [152,153].…”

Leukocyte telomere length and age at menopause

“…The biological plausibility of the "telomere theory of reproductive senescence" 15,17,19 further argues for studies designed to validate the current results. Even in the absence of a known biological mechanism whereby telomere length directly influences age at menopause, due to synchrony leukocyte telomere length may still predict age at menopause or, more specifically, the probability of success of assisted reproductive technologies in specific patients.…”

“…Some studies have demonstrated an association between shorter leukocyte telomere length and earlier reproductive aging, including shorter reproductive lifespan and occult ovarian insufficiency [15][16][17] or poorer IVF outcomes, 18,19 while other studies have yielded negative or conflicting results. [20][21][22] We therefore sought to investigate the relationship between leukocyte telomere length and reproductive aging, as expressed by age at menopause in a cohort of women age 65 years and older.…”