The impact of 3D chromatin remodeling on cellular senescence and aging

Cellular senescence is a stress-induced and stable cellular state that contributes to organismal aging and a broad spectrum of age-related diseases. Among the multifaceted senescence-associated alterations, progressive reorganization of higher-order chromatin structure has emerged as a pivotal regulatory layer. The three-dimensional (3D) architecture of chromatin, including lamin-associated domains (LADs), A/B compartments, topologically associating domains (TADs), and chromatin loops, undergoes profound and dynamic remodeling during cellular senescence and in aging contexts. Accumulating evidence suggests that such architectural changes are closely associated with key senescence-related phenotypes, including genomic instability, transcriptional dysregulation, stem cell functional decline, and chronic inflammatory signaling. Enabled by technologies such as Hi-C and Chromatin Interaction Analysis by Paired-End Tag sequencing (ChIA-PET), recent studies have begun to map tissue- and context-dependent patterns of 3D genome remodeling and connect them to age-associated pathologies, ranging from Alzheimer’s disease (AD) and hematopoietic dysfunction to cancer. This review synthesizes advances in understanding how multiscale chromatin reconfiguration influences gene regulation and cellular identity in senescence, and summarizes representative disease settings and implicated structural layers. We further discuss major technical challenges, including limited resolution of cellular heterogeneity, constraints of fixed-cell assays for capturing chromatin dynamics, and difficulties in robust multi-omics integration, and propose future directions for leveraging single-cell and spatiotemporal 3D genomics to dissect mechanisms linking senescence to organismal aging and to inform therapeutic development.