Biomedicina

Telomeres and human reproduction
Keri Horan Kalmbach, M.S.,a Danielle Mota Fontes Antunes, M.S.,a,b Roberta Caetano Dracxler, M.D.,a,c
Taylor Warner Knier, B.A.,a Michelle Louise Seth-Smith, B.S.,a Fang Wang, Ph.D.,a Lin Liu, Ph.D.,d
and David Lawrence Keefe, M.D.a
a

Department of Obstetrics and Gynecology, New York University, Langone Medical Center, New York City, New York;
GraduateProgram in Pathology, Fluminense Federal University, Rio de Janeiro, and CAPES Foundation, Ministry of
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Education of Brazil, Brasilia, Brazil; c Sao Paulo University, Sao Paulo, Brazil; and d College of Life Sciences, Nankai
University, Tianjin, People’s Republic of China
b

Telomeres mediate biologic aging in organisms as diverse as plants, yeast, and mammals. We propose a telomere theoryof 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 byexpressing 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
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Key Words: Reproductive aging, telomeres
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T

elomeres are short, tandem
repeats of DNAthat cap linear
chromosome ends by binding
members of the shelterin protein
complex to form protective telomere
loops (Fig. 1). An insufficient number
of telomere repeats leads to chromosome uncapping, cell senescence, and
death. Telomere length decreases with
age, provides a surrogate marker for
biological age, and predicts a number
of age-related conditions, including
diabetes mellitus(1), cardiovascular
disease (2), liver disorders (3, 4),
cancer (5), and death from all causes
(6). Conservation of telomere length

predicts exceptional longevity and
health in old age (7). Generalized
longevity is correlated with reproductive longevity in women (8–11), so
common mechanisms may underlie
both.
Aging of the reproductive system
in women poses a paradox: the somatictissues of the uterus remain receptive
throughout a woman’s life, but the
germ line in women, unlike in men, exhibits precocious and profound aging.
As women increasingly delay attempts
at childbearing, oocyte aging poses
the major challenge to reproductive
medicine. By their late 30s, while the

Received October 15, 2012; revised and accepted November 20, 2012.
K.H.K. has nothing to disclose.D.M.F.A. received a grant from the CAPES Foundation, the Ministry of
Education of Brazil, and travel support from the New York University Department of Obstetrics
and Gynecology. R.C.D. received a grant from Sao Paolo University. T.W.K. has nothing to disclose. M.L.S.-S. has nothing to disclose. F.W. has nothing to disclose. L.L. has nothing to disclose.
D.L.K. has received honoraria and...