<p>Aging is the progressive decline in function at the cellular, tissue, and organismal levels that ultimately leads to mortality. The longevity of an organism is influenced by various internal and external factors, including nutrition, exercise, metabolic dysfunction, genomic instability, and epigenetic imbalance. Histone modifications, such as acetylation, methylation, phosphorylation, and ubiquitination, play a critical role in aging. These modifications illustrate histone changes crucial for regulating chromatin architecture and gene expression. The epigenetic clock signifies the impact of aging on our cells and is essential for accurately determining biological age. It demonstrates significant associations with histone modifications, underscoring their mechanistic importance in age-related changes. Histone alterations are closely associated with age-related diseases such as cancer, neurological disorders, and cardiovascular conditions. While the mechanistic function of histone modifications in biological aging is well-established, clinical application remains constrained. Emerging clinical studies targeting histone-modifying enzymes are beginning to investigate their potential as therapeutic options for age-related disorders. This review seeks to provide a comprehensive examination of histone modifications, including acetylation, methylation, and phosphorylation, as well as the impact of histone alterations on biological age, age-related diseases, and the importance of the epigenetic clock, with the aim of enhancing understanding of the epigenetic mechanisms associated with aging and facilitating the development of therapies to promote healthy aging. In this review, we also focus on the current status of such clinical trials and discuss future directions for translating these epigenetic insights into clinical applications.</p>