Identifying Aging-Related Biomarkers in Adipose Tissue Using Integrative Bioinformatics and Machine-Learning Approaches: Discovery of ELN, MXD1, and FGF21 as Key Genes

Xin Xie¹Hongyan Wang¹Fugang Xiao²Xiaoyan Jiang²Yan Chen²Chenghu Huang³Dongfeng Tang⁴Yanzhong Wang⁴Shunli Rui²Xi Cheng²Bo Deng²Gangyi Yang¹Wuquan Deng^2*

• ¹Department of Endocrinology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
• ²Department of Endocrinology and Metabolism, Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China
• ³Department of Endocrinology, Bishan Hospital of Chongqing, Bishan Hospital of Chongqing Medical University, Chongqing, China
• ⁴School of Life Course and Population Sciences, King's College London, London, United Kingdom

Background: Adipose tissue plays a critical role in aging and age-related diseases. However, the specific molecular and cellular alterations associated with aging in adipose tissue remain incompletely understood.Methods: Aging-related differentially expressed genes (DEARGs) were identified by intersecting differentially expressed genes (DEGs) in adipose tissue, age-related genes (ARGs), and human genes linked to aging. Functional enrichment analysis was conducted to explore the potential roles of these DEARGs. Protein-protein interaction (PPI) networks were analyzed using STRING, and hub DEARGs were identified via least absolute shrinkage and selection operator (LASSO) analysis. OilRed O staining was used to confirm adi-pocyte differentiation, and D-galactose treatment induced cellular senescence. Validation of hub DEARG expression was conducted in an independent dataset and confirmed using quantitative polymerase chain reaction (qPCR) both in vitro and in vivo.Results: Forty-nine DEARGs were identified, with functional enrichment analyses revealing significant roles in glucose homeostasis and key aging pathways, including the FoxO and JAK-STAT signaling pathways, Th17 cell dif-ferentiation, growth hormone signaling, the adiponectin pathway, and AMPK pathway. Five hub genes (PCK1, ELN, MXD1, STAT3, and FGF21) were selected through interaction network anal-ysis and LASSO regression. Expression levels of three DEARGs (ELN, MXD1, and FGF21) were validated by qPCR and an independent dataset. Conclusions: This study identified three DEARGs (ELN, MXD1, and FGF21) as potential biomarkers of adipose tissue aging, suggesting their role in organismal aging and age-related disease pathways.