Current social trends of delayed reproduction to the fourth and fifth decade of life call for a better understanding of reproductive aging. Demographic studies correlated late reproduction with general health and longevity. Telomeres, the protective ends of eukaryotic chromosomes, were implicated in various aging-associated pathologies and longevity. To examine whether telomeres are also associated with reproductive aging, we measured by Southern analysis the terminal restriction fragments (TRF) in leukocytes of women delivering a healthy infant following a spontaneous pregnancy at 43–48 years of age. We compared them to age-matched previously fertile women who failed to conceive above age 41. The average TRF length in the extended fertility group (9350 bp) was significantly longer than in the normal fertility group (8850 bp; p-value = 0.03). Strikingly, excluding women with nine or more children increased the difference between the groups to over 1000 bp (9920 and 8880 bp; p-value = 0.0009). Nevertheless, we observed no apparent effects of pregnancy, delivery, or parity on telomere length. We propose that longer leukocyte telomere length reflects higher oocyte quality, which can compensate for other limiting physiological and behavioral factors and enable successful reproduction. Leukocyte telomere length should be further explored as a novel biomarker of oocyte quality for assessing reproductive potential and integrating family planning with demanding women’s careers.

Telomeres protect the chromosome ends from deleterious DNA damage response and repair activities. In humans, telomerase maintains telomere length in germ and stem cells, but not in most somatic cells. Consequently, telomeres shorten with cell division and age, limiting cell proliferation and protecting against cancer. When telomeres become critically short, they may also cause senescence, inflammation, and organ failure, which are major drivers of aging. Therefore, maintaining an optimal, age-appropriate telomere length is crucial for healthy aging. In the house mouse, Mus musculus, telomerase is active in most somatic tissues, yet its long telomeres were thought to shorten rapidly with age. We have followed telomere length over age in blood and tail of wild-type M. musculus and in two engineered mouse strains with shorter telomeres (Telomouse and HHS mouse). We also measured the precise length of single telomeres in blood leukocytes of these mouse strains by a long-read nanopore sequencing method, NanoTelSeq. We show that telomeres in blood and tail of these three mouse strains do not shorten with age. We conclude that M. musculus maintains long telomeres in blood and tail throughout life, excluding the possibility that global telomere shortening in these tissues contribute to aging-associated phenotypes.

RTEL1 is an essential DNA helicase that plays multiple roles in genome stability and telomere length regulation. The ultra-long telomeres of the house mouse hinder its utility as a model for telomere-related diseases. We have previously generated a mouse model with human-length telomeres, termed “Telomouse,” by substituting methionine 492 of mouse Rtel1 to a lysine (Rtel1M492K). In humans, a methionine to isoleucine mutation at this position causes the fatal telomere biology disorder Hoyeraal-Hreidarsson syndrome (HHS). Here, we introduced the Rtel1M492I point mutation into the mouse genome, generating another mouse model, which we termed “HHS mouse.” The HHS mouse telomeres are not as short as those of the Telomouse but nevertheless display higher levels of telomeric DNA damage, fragility, and recombination, associated with anaphase bridges and micronuclei. The HHS mouse also exhibits aberrant hematopoiesis and pre-fibrotic alterations in the lung. These observations indicate that the two mutations at the same codon separate critical functions of RTEL1: Rtel1M492K mainly reduces the telomere length setpoint, while Rtel1M492I predominantly disrupts telomere protection. The two mouse models enable dissecting the mechanistic roles of RTEL1 and the different contributions of short telomeres and DNA damage to telomere biology disorders and genomic instability.

RTEL1 is an essential DNA helicase that plays multiple roles in genome stability and telomere length regulation. A variant of RTEL1 with a lysine at position 492 is associated with short telomeres in Mus spretus , while a conserved methionine at this position is found in M. musculus , which has ultra-long telomeres. In humans, a missense mutation at this position ( Rtel1 ^M492I ) causes a fatal telomere biology disease termed Hoyeraal-Hreidarsson syndrome (HHS). Introducing the Rtel1 ^M492K mutation into M. musculus shortened the telomeres of the resulting strain, termed ‘Telomouse’, to the length of human telomeres. Here, we report on a mouse strain carrying the Rtel1 ^M492I mutation, termed ‘HHS mouse’. The HHS mouse telomeres are not as short as those of Telomice but nevertheless they display higher levels of telomeric DNA damage, fragility and recombination, associated with anaphase bridges and micronuclei. These observations indicate that the two mutations separate critical functions of RTEL1: M492K mainly reduces the telomere length setpoint, while M492I predominantly disrupts telomere protection. The two mouse models enable dissecting the mechanistic roles of RTEL1 and the different contributions of short telomeres and DNA damage to telomere biology diseases, genomic instability, cancer, and aging.

Telomeres, the ends of eukaryotic chromosomes, protect genome integrity and enable cell proliferation. Maintaining optimal telomere length in the germline and throughout life limits the risk of cancer and enables healthy aging. Telomeres in the house mouse, Mus musculus , are about five times longer than human telomeres, limiting the use of this common laboratory animal for studying the contribution of telomere biology to aging and cancer. We identified a key amino acid variation in the helicase RTEL1, naturally occurring in the short-telomere mouse species M. spretus. Introducing this variation into M. musculus is sufficient to reduce the telomere length set point in the germline and generate mice with human-length telomeres. While these mice are fertile and appear healthy, the regenerative capacity of their colonic epithelium is compromised. The engineered Telomouse reported here demonstrates a dominant role of RTEL1 in telomere length regulation and provides a unique model for aging and cancer.