Evolutionary and Functional Roles of DNA Methylation in Human Senescence Regulation

The regulation of human senescent protein expression is crucial for understanding the aging process. However, their evolutionarily acquired biological functions and relevance in diseases are poorly understood. Therefore, in this study, we performed an in silico analysis of 305 human senescent proteins, which were then categorized into five classes based on their evolutionary origins: chordates (Class 1: 104 proteins), metazoans (Class 2: 117 proteins), metazoans and plants (Class 3: 16 proteins), eukaryotes (Class 4: 58 proteins), and metazoans and fungi (Class 5: 10 proteins). Our findings suggest that senescence‐associated pathways were formed and became complexduring the evolution of chordates. During evolution, human senescent proteins played roles in nucleotide excision repair pathways, chemical carcinogenesis, and immune and cancer pathways. Differences in the average DNA methylation levels in the regulatory regions of genes that encode human senescent proteins were observed in proteins conserved in chordates, metazoans, and eukaryotes. In contrast, differences between the testes and ovaries were specifically observed for chordate-conserved proteins. We speculate that the precise modification of DNA methylation in the genes encoding key senescence‐associated pathways regulators, such as ERCC5/XPG, ACP1/PTP, CDKN1A/p21, and IFNB1, plays an important role in the development of the senescence‐associated pathway during evolution.