Project description:Molecular mechanisms of ovarian aging and female age-related fertility decline remain unclear. We surveyed the single-cell transcriptomic landscape of ovaries from young and aged non-human primates (NHPs) and identified seven ovarian cell types with distinct gene expression signatures, including oocyte and six types of ovarian somatic cells. In-depth dissection of gene expression dynamics of oocytes revealed four subtypes at sequential and stepwise developmental stages. Further analysis of cell type-specific aging-associated transcriptional changes uncovered the disturbance of antioxidant signaling specific to early-stage oocytes and granulosa cells, indicative of oxidative damage as a crucial factor in ovarian functional decline with age. Additionally, inactivated antioxidative pathways, increased reactive oxygen species and apoptosis were observed in granulosa cells from aged women. This study provides comprehensive understanding of the cell type-specific mechanisms underlying primate ovarian aging at single-cell resolution, revealing new diagnostic biomarkers and potential therapeutic targets for age-related human ovarian disorders.
Project description: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.
Project description:Aging is accompanied by the functional decline of all tissues, but it is still largely unknown how aging impacts different tissues in a cell type-specific manner. Here, we present the Aging Fly Cell Atlas (AFCA) that includes single-nucleus transcriptomes of the entire Drosophila head and body from both males and females at four different ages. We characterize 162 distinct cell types and present an in-depth analysis of cell type-specific aging features, including changes of cell composition, gene expression, number of expressed genes, transcriptome noise, and cell identity. By combining all aging features, including aging clock models predicting a cell’s age, we find cell-type specific aging patterns. Adipose tissues showed the highest aging score, followed by two cell types from the reproductive system. This transcriptomic atlas provides a valuable resource for the community to study fundamental principles of aging in complex organisms.
Project description:Here we describe a single-cell atlas of aging for virtually every cell type of the nematode Caenorhabditis elegans. Our findings suggest that C. elegans aging is not random in nature, but rather characterized by coordinated changes in functionally related metabolic and stress-response genes in a highly cell-type specific fashion. Aging signatures of different cell types are largely different from one another, with downregulation of energy metabolism being the only nearly universal change. Similarly, the rates at which cells aged, measured as genome-wide expression changes, differed significantly between cell types. In some, but not all, cell types, aging was characterized by an increase in cell-to-cell variance. Finally, we identified a signature for longevity transcription factors (TFs) whose activities changed coordinately across many cell types with age. We discovered new candidates, such as GEI-3, among these TFs that likely also regulate the aging rate. Our dataset can be accessed and queried at c.elegans.aging.atlas.research.calicolabs.com/.
Project description:Ovarian aging is characterized by the progressive depletion of primordial follicle reserve, leading to irregular patterns of ovulation and menopause. The basic mechanisms that underlie the ovarian aging and follicle decline is unknown. We sought to explore the role of cellular senescence and epigenomic mechanisms in ovarian aging. Here, we present the transcriptomic changes observed in the ovaries with age using the age groups 3mo, 6mo, 9mo and 12mo (n=5 per group except for 12mo which has an n=4). The age groups capture timepoints from sexual maturation to reproductive health decline.
Project description:Depletion of oocytes and follicles and reduced oocyte quality contribute to age-associated ovarian senescence and infertility. Telomere shortening and altered methylation make two major contributions to general aging. Resveratrol acts as anti-oxidant and Sirt1 activator to alleviate aging including reproductive aging. It remains elusive whether resveratrol can reprogram the aging epigenome. We sought to examine aging ovarian epigenome and the potential effects of resveratrol by combined analysis of telomere length, transcriptome and methylome mainly in oocytes and also in granulosa cells, two major cell types in the ovary.