Revealing age-related changes in the intraocular microenvironment and senescence modulators based on aqueous humor proteomics via machine learning

Sheng Xiao Huang¹Tiansheng Chou^2,3Xinhua Liu¹Kun Zeng¹Liangnan Sun¹Zonghui Yan¹Shaoyi Mei¹Wenqun Xi¹Zongyi Zhan¹Yi Liu¹Songguo Dong¹Siqi Liu^2*Jun Zhao^4*

• ¹Shenzhen Eye Hospital, Shenzhen, China
• ²Beijing Genomics Institute (BGI), Shenzhen, China
• ³Xiangya Hospital, Central South University, Changsha, Hunan Province, China
• ⁴Shenzhen People's Hospital, Shenzhen, China

Background: In conjunction with age, aqueous humor (AH) proteomics can affect the occurrence and development of age-related eye diseases, which are short in understanding.We characterized the proteomic changes in AH throughout the aging process to gain a better understand the aging mechanisms of the intraocular environment, as the majority of available studies did not include young individuals as healthy controls.We analyzed the AH proteomes of 33 older and 19 younger individuals using LC-MS/MS, from which we clustered similar expression trajectories of AH proteomics using local regression analysis. Aging proteins (APs) and their functional enrichment were evaluated using various statistical and bioinformatics methods, while aging modulators were predicted using multiple machine-learning models.Results: AH proteomic expression patterns exhibited various types of linear and nonlinear changes across the age groups. A set of 179 proteins identified as significant APs were enriched in various eye processes, such as detoxification, eye development, negative regulation of hydrolase activity, and humoral immune response. According to AH proteomics, hallmarks of aging include oxidative damage, defective extracellular matrices, and loss of proteostasis. A total of 11 APs were considered as senescence signatures for predicting AH age with strong predictive ability. Furthermore, 22 APs were classified as modulators or decelerators that may affect the aging process in the eye.Conclusions: These findings establish a framework for age-related changes in the AH proteome and provide potential senescence biomarkers and therapeutic targets for age-related eye diseases.