Telomere length, epigenetic age and T cells in women who give birth at an older age

This project aims to investigate female fecundity in the context of three major indices of biological age: telomere length, epigenetic age, and immune status. The hypothesis is that women with a longer telomere length, younger epigenetic age and healthier immune status than their peers have an increased ability to give birth to their first child at an older age. DNA samples of 2,000 trios (mother, father and newborn) from the Norwegian Mother and Child Cohort Study (MoBa) were selected for this project. Rutgers University (NJ, United States) will measure leukocyte telomere length in these 2,000 trios, whereas the University of California Los Angeles (CA, United States) will measure DNA methylation in 1000 of the mothers aged 32 years and above. The reason for examining DNA methylation is because it is a major index for quantifying epigenetic age and immune status. This work is important for understanding the biological basis that may help explain why women differ in their ability to conceive children at older ages.

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This project will use the mother-father-newborn (MFN) trio design to investigate the relationship between female fecundity and maternal LTL, epigenetic age, and immune status. Our central hypothesis hinges on a synthesis of three major findings. First, women with delayed menopause and those who conceive later in life show less CVD and live longer. Second, women with constitutively long LTL have delayed menopause, show less CVD, and live longer. Third, children born to older women typically have older fathers and older fathers have longer sperm TL. We propose that, because LTL is highly heritable and offspring's LTL is positively correlated with paternal age at the time of conception, LTL of offspring conceived by older women might be constitutively longer due to these joint effects. This central hypothesis and its corollary will be tested in 2,000 MFN trios from the Norwegian Mother and Child Cohort Study (MoBa), based on LTL data that will be generated through a complementary grant from the US National Institutes of Health (NIH). In the current proposal, we will extend the above LTL analyses by investigating two additional leading indices of biological age: epigenetic age and immune status. Epigenetic age will be constructed using data from DNA-methylation of CpG sites, and immune status will be assessed by the proportion of naive to memory CD8+ T cells in 1000 mothers who gave birth to their first child at the age of 35 years or above. We hypothesize that women who give birth at an older age will display not only a longer LTL, but also a younger epigenetic age and younger immune status. By using the MFN trio model, our approach to examining the link between women's reproductive ability and LTL, epigenetic age and immune status enables a more profound investigation of women's fecundity. This knowledge is critical for public health, given that LTL is associated with a host of aging-related disorders and with longevity in contemporary humans.