Integrated epigenetic networks in aging: from histone to RNA modifications

Aging is a complex process characterized by the progressive decline of physiological functions. This process is accompanied by a series of genetic and epigenetic alterations. Epigenetic mechanisms, including histone modifications, chromatin remodeling, and RNA modifications, are critical due to their highly dynamic and plastic nature. These mechanisms play fundamental roles in the occurrence and progression of aging and age-related diseases. This review systematically summarizes the fundamental roles and molecular mechanisms of histone modifications (e.g., methylation and acylation such as acetylation), chromatin remodeling (encompassing heterochromatin formation, nuclear lamina association, alterations in chromatin accessibility and higher-order architecture, and TF-mediated regulation), and RNA modifications (such as m6A, m7G, and m5C) in the regulation of cellular senescence, organ functional decline, and age-related diseases, including neurodegenerative disorders, CVDs, and osteoporosis. We highlight the sophisticated interaction networks formed between these three epigenetic layers. Finally, we summarize potential anti-aging interventions targeting these mechanisms. These strategies include natural products, peptides, and specific small-molecule inhibitors or agonists. Emerging intervention methods and their potential safety considerations are also discussed. Histone modifications, chromatin remodeling, and RNA modifications constitute an interconnected and dynamically coordinated epigenetic network that synergistically regulates the aging process. A thorough elucidation of the regulatory mechanisms within this complex network will not only contribute to a fundamental understanding of the biological essence of aging, but also provide a critical theoretical foundation for the development of precise and efficient epigenetic interventions.