Lu Ziyu, Zhang Zehao, Xu Zihan, Abdulraouf Abdulraouf, Zhou Wei, Cao Junyue
Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, USA.
The David Rockefeller Graduate Program in Bioscience, The Rockefeller University, New York, NY, USA.
bioRxiv. 2025 May 15:2025.05.12.653376. doi: 10.1101/2025.05.12.653376.
Aging leads to functional decline across tissues, often accompanied by profound changes in cellular composition and cell-intrinsic molecular states. However, a comprehensive catalog of how the population of individual cell types change with age and the associated epigenomic dynamics is lacking. Here, we constructed a single-cell chromatin accessibility atlas consisting of ~7 million cells from 21 tissue types spanning three age groups in both sexes. This dataset revealed 536 main cell types and 1,828 finer-grained subtypes, defined by unique chromatin accessibility landscapes at ~1.3 million cis-regulatory elements. We observed widespread remodeling of immune lineages, with increases in plasma cells and macrophages, and depletion of T and B cell progenitors. Additionally, non-immune cell populations, including kidney podocytes, ovary granulosa cells, muscle tenocytes and lung aerocytes, showed marked reductions with age. Meanwhile, many subtypes changed synchronously across multiple organs, underscoring the potential influence of systemic inflammatory signals or hormonal cues. At the molecular level, aging was marked by thousands of differentially accessible regions, with the most concordant changes shared across cell types linked to genes related to inflammation or development. Putative upstream factors, such as intrinsic shifts in transcription factor usages and extrinsic cytokine signatures, were identified. Notably, around 40% of aging-associated main cell types and subtypes showed sex-dependent differences, with tens of thousands of chromatin accessibility peaks altered exclusively in one sex. Together, these findings present a comprehensive framework of how aging reshapes the chromatin landscape and cellular composition across diverse tissues, offering a comprehensive resource for understanding the molecular and cellular programs underlying aging and supporting the exploration of targeted therapeutic strategies to address age-related dysfunction.
衰老会导致各组织功能衰退，常伴随着细胞组成和细胞内在分子状态的深刻变化。然而，目前缺乏关于个体细胞类型群体如何随年龄变化以及相关表观基因组动态变化的全面目录。在这里，我们构建了一个单细胞染色质可及性图谱，该图谱包含来自两性三个年龄组的21种组织类型的约700万个细胞。该数据集揭示了536种主要细胞类型和1828种更细粒度的亚型，这些细胞类型由约130万个顺式调控元件处独特的染色质可及性景观定义。我们观察到免疫谱系广泛重塑，浆细胞和巨噬细胞增加，T和B细胞祖细胞减少。此外，包括肾足细胞、卵巢颗粒细胞、肌肉腱细胞和肺气细胞在内的非免疫细胞群体随年龄增长显著减少。同时，许多亚型在多个器官中同步变化，突显了全身炎症信号或激素信号的潜在影响。在分子水平上，衰老的特征是数千个差异可及区域，细胞类型间最一致的变化与炎症或发育相关基因有关。我们还确定了推测的上游因素，如转录因子使用的内在变化和外在细胞因子特征。值得注意的是，约40%与衰老相关的主要细胞类型和亚型存在性别差异，数万染色质可及性峰仅在一种性别中发生改变。总之，这些发现呈现了衰老如何重塑不同组织中染色质景观和细胞组成的全面框架，为理解衰老背后的分子和细胞程序提供了全面资源，并支持探索针对年龄相关功能障碍的靶向治疗策略。
