image: Chromatin loops, which are formed by CTCF and cohesin, mediate precise long-range gene regulation by connecting enhancers with their target promoters. During aging and cellular senescence, these loops undergo widespread collapse and reorganization, resulting in the destabilization of transcriptional programs. During cellular senescence, cohesin, a key factor mediating chromatin loop formation, undergoes redistribution, resulting in rewiring of enhancer–promoter interactions. In contrast, during cellular aging, altered activity of transcription factors such as YY1 and AP-1 contributes to progressive disruption of super-enhancer-associated chromatin loops and age-associated transcriptional reprogramming. Notably, loop dynamics are intricately linked to higher-order chromatin architecture. These structural alterations not only reflect but also actively contribute to age-related transcriptional dysregulation and the onset of aging-associated diseases. In summary, the remodeling of chromatin loops represents a central mechanism underlying 3D genomic dysfunction in aging, functionally connecting transcriptional imbalance with cellular senescence and pathology, thereby highlighting its potential as a target for therapeutic strategies. Collectively, these studies indicate that although cellular senescence and organismal aging share convergent features of 3D genome remodeling, including compartment blurring, TAD destabilization, and loop reprogramming, the underlying drivers and structural outcomes are highly context-dependent, varying across senescence modalities and aging tissues.
Credit: Aging Research, Tsinghua University Press
A research team has examined how aging and diseases are connected by exploring the aging-related remodeling of chromatin architecture. This study of chromatin architecture, the three-dimensional organization of DNA, gives scientists a better understanding of aging and its underlying mechanisms.
Their review is published in the journal Aging Research on May 8, 2026.
With senescence, or the biological process of aging, an irreversible and systemic process occurs, characterized by declining cellular functions, loss of tissue homeostasis, and deterioration of overall physiological capacity. Scientists know that aging is a primary risk factor for a variety of chronic non-communicable diseases, such as Alzheimer’s disease, Parkinson’s disease, cardiovascular disease, metabolic syndrome, and cancer.
In their review, the team synthesizes the recent studies that explore how multiscale chromatin reconfiguration influences gene regulation and cellular identity in senescence. They summarize the representative disease settings and implicated structural layers. The team further discusses the major technical challenges. These include the challenge of accurately capturing the biological and genetic differences between individual cells, the limitations of fixed-cell assays for capturing chromatin dynamics, and the difficulties in robust multi-omics integration.
The team proposes future directions for leveraging single-cell and spatiotemporal three-dimensional genomics to dissect the mechanisms linking senescence to aging and to inform the development of new therapeutic treatments.
Because the global population is rapidly aging, scientists are looking to unravel the mechanisms of aging. “Understanding the mechanisms of aging and its intrinsic connections with disease holds profound social and biomedical implications,” said Professor Zhenyu Ju from Jinan University.
The research team notes that there are two related concepts that are the driving forces behind the aging process: cellular senescence and organismal aging. Organismal aging describes the process by which multicellular organisms decline in function over time. This decline involves multiple organ systems and includes the disruption of tissue homeostasis, along with the cumulative risk of age-associated diseases.
By contrast, cellular senescence describes the stable, irreversible cellular state where damaged or old cells permanently stop dividing but do not die. This cellular state is induced by specific stresses. Current studies show that cellular senescence represents one of the key cellular foundations of organismal aging and many age-related diseases.
Cells undergo many multifaceted changes as they become senescent. Scientists have learned that progressive reorganization of higher-order chromatin structure is a pivotal regulatory layer. Chromatin is a mixture of DNA and proteins inside cells. They provide an organized storage system that folds the long strands of DNA so they fit inside the cells. This reorganization refers to the changes that occur over times as the DNA is folded into the nucleus.
The chromatin’s three-dimensional architecture goes through profound changes and dynamic remodeling as cellular senescence occurs and the cells age. Studies are showing that these architectural changes are closely related to key senescence-related changes that occur when the cells permanently stop dividing but remain active. These changes include genomic instability, transcriptional dysregulation, stem cell functional decline, and chronic inflammatory signaling.
Scientists have recently begun to map patterns of three-dimensional genome remodeling and connect them to diseases and medical conditions that occur with aging. These range from Alzheimer’s disease to blood diseases to cancer. “In recent years, advances in three-dimensional genome technologies have provided valuable tools for understanding the dynamic chromatin changes underlying aging and disease,” said Ju.
Looking ahead, the team notes that the integration of single-cell technologies with dynamic three-dimensional genome mapping may enable the construction of systematic spatiotemporal models of chromatin evolution during aging. “This approach could not only help delineate causal relationships between chromatin remodeling and aging or disease phenotypes but also advance three-dimensional genomics from theoretical studies to clinical applications, offering novel strategies for aging intervention, cancer therapy, and the prevention of complex diseases,” said Ju.
The research team includes Weicong Chen, Qiang Zhan, Feng Xiao, Zhenyu Ju, and Zhiyang Chen from the Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Department of Developmental & Regenerative Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China.
The research is funded by the National Key R&D Program of China, the National Natural Science Foundation of China, and the innovation team project of universities in Guangdong province.
DOI Link:
https://doi.org/10.26599/AGR.2025.9340072
Journal
Aging Research
Article Title
The impact of 3D chromatin remodeling on cellular senescence and aging
Article Publication Date
6-May-2026