Tradeoffs Between Reproduction and Aging  in the Human Epigenome

Ryan, Calen Patrick

doi:https://doi.org/10.21985/n2-0hwc-wg19

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Tradeoffs Between Reproduction and Aging in the Human Epigenome

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Evolutionary theory predicts that reproduction entails energetic costs that detract from somatic maintenance, accelerating biological aging. In women, such ‘costs of reproduction’ (CoR) are thought to arise predominantly during pregnancy and lactation, while in men the physiological effects of the steroid hormone testosterone (T) are believed to be a major driver of tradeoffs in somatic maintenance. Despite support from studies in human and non-human animals, mechanisms linking CoR to somatic maintenance and aging are poorly understood. This may be due in part to a lack of a mechanistic framework than can account for the evolved, genetic underpinnings of life history traits as well as individual plasticity in life history strategies that are believed to be central to tradeoffs between reproduction and maintenance. Epigenetic processes, such as DNA methylation (DNAm), may help fill this mechanistic gap. DNAm is a chemical modification to DNA that is associated with gene activity and cellular memory and may be particularly useful for testing hypotheses about tradeoffs between reproduction and somatic maintenance. First, genome-wide DNAm can be used to gain insights into patterns of gene regulation across the genome, which can then be used to better understand untheorized biological processes that could underlie costs of reproduction. Second, DNAm can also be used to calculate epigenetic age. Epigenetic age predicts biological age and mortality, providing a measure of cellular aging and somatic maintenance. Finally, DNAm can also be used bioinformatically-impute blood leukocyte cell proportions, a proxy for immune function. In this dissertation, I leverage the power and flexibility of genome-wide DNAm from 496 young (20-22 years old) adult participants in the Cebu Longitudinal Health and Nutrition Survey to test hypotheses about tradeoffs between reproduction and somatic maintenance. In Chapter 2, I describe epigenetic clocks in detail, including an overview of their technical application and emerging applications in human biology. I then use an epigenetic clock and telomere length – a separate measure of cellular aging – to study costs of reproduction in 394 young women in Cebu (Chapter 3). To better understand the role of the epigenome in reproduction and aging, I then examine differences in the methylome of women in differing reproductive status (Chapter 4). To aid in the interpretation of the large number of differences in DNAm between women, I then carry out a series of gene set enrichments and construct networks of biological processes. Finally, I test hypotheses about the T-associated costs of reproduction in a subset of 90 young men (Chapter 5). I examine the relationship between T and several epigenetic clocks indicative of biological aging, metabolic health, and mortality risk. To test for an immunosuppressive effect of T, I also examine bioinformatically-imputed cell type proportions, and scan the methylome for differences in T and DNAm more broadly. I show that aging based on the epigenetic clock and telomere length are both accelerated in response to gravidity, and that women appear epigenetically younger during pregnancy (Chapter 3). Differences in DNAm between nulliparous, pregnant, breastfeeding, and parous women point to changes in immune function and neurogenesis as possible biological pathways linked to aging and disease in women (Chapter 4). In men, higher T was positively related to several epigenetic clocks, although this effect was only borderline significant for two clocks, and reached statistical significance for a clock associated with metabolic health and mortality. T does not appear to exert a clear immunosuppressive effect as indexed by our methylation-based approach, and we also did not detect differential methylation with T in this relatively small sample size (Chapter 5). In Chapter 6, I conclude by discussing the ways in which epigenetic processes are providing a mechanistic framework for studying life history traits and tradeoffs between reproduction and aging, and future directions in my research on reproduction and aging in the human epigenome.

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