Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses.
Abstract
The ovary is the first organ to age in the human body, affecting both fertility and overall health. However, the biological mechanisms underlying human ovarian aging remain poorly understood. Here we present a comprehensive single-nuclei multi-omics atlas of four young (ages 23-29 years) and four reproductively aged (ages 49-54 years) human ovaries. Our analyses reveal coordinated changes in transcriptomes and chromatin accessibilities across cell types in the ovary during aging, notably mTOR signaling being a prominent ovary-specific aging pathway. Cell-type-specific regulatory networks reveal enhanced activity of the transcription factor CEBPD across cell types in the aged ovary. Integration of our multi-omics data with genetic variants associated with age at natural menopause demonstrates a global impact of functional variants on gene regulatory networks across ovarian cell types. We nominate functional non-coding regulatory variants, their target genes and ovarian cell types and regulatory mechanisms. This atlas provides a valuable resource for understanding the cellular, molecular and genetic basis of human ovarian aging.
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Research summary
The paper provides insights into the biological mechanisms of ovarian aging, which is a fundamental aspect of human aging and has implications for fertility and overall health. By utilizing single-nuclei multi-omics analyses, it identifies specific pathways and regulatory networks involved in ovarian aging, contributing to the understanding of aging at a cellular and molecular level. However, while the findings are solid and add to the existing knowledge, they do not represent a major breakthrough or transformative advancement in the field of longevity research.
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