Multi-omics reveals aging-related pathway in natural aging mouse liver

Cong-Min Tang; Zhen Zhang; Yan Sun; Wen-Jing Ding; Xue-Chun Yang; Yi-Ping Song; Ming-Ying Ling; Xue-Hui Li; Rong Yan; Yu-Jing Zheng; Na Yu; Wen-Hua Zhang; Yong Wang; Shao-Peng Wang; Hai-Qing Gao; Chuan-Li Zhao; Yan-Qiu Xing

doi:10.1016/j.heliyon.2023.e21011

Multi-omics reveals aging-related pathway in natural aging mouse liver

Heliyon. 2023 Oct 19;9(11):e21011. doi: 10.1016/j.heliyon.2023.e21011. eCollection 2023 Nov.

Authors

Cong-Min Tang^{1

2

3}, Zhen Zhang^{1

4}, Yan Sun¹, Wen-Jing Ding^{1

2}, Xue-Chun Yang^{1

2}, Yi-Ping Song^{1

4}, Ming-Ying Ling^{1

4

2}, Xue-Hui Li^{1

4}, Rong Yan¹, Yu-Jing Zheng⁵, Na Yu⁵, Wen-Hua Zhang⁵, Yong Wang⁵, Shao-Peng Wang⁵, Hai-Qing Gao^{1

4}, Chuan-Li Zhao⁶, Yan-Qiu Xing^{1

4}

Affiliations

¹ Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China.
² Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China.
³ Department of Ultrasound, Shandong Provincial Third Hospital, Jinan 250031, Shandong Province, China.
⁴ Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China.
⁵ Shandong Precision Medicine Engineering Laboratory of Bacterial Anti-tumor Drugs, Jinan 250101, Shandong Province, China.
⁶ Dept of Hematology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China.

Abstract

Aging is associated with gradual changes in liver structure, altered metabolites and other physiological/pathological functions in hepatic cells. However, its characterized phenotypes based on altered metabolites and the underlying biological mechanism are unclear. Advancements in high-throughput omics technology provide new opportunities to understand the pathological process of aging. Here, in our present study, both metabolomics and phosphoproteomics were applied to identify the altered metabolites and phosphorylated proteins in liver of young (the WTY group) and naturally aged (the WTA group) mice, to find novel biomarkers and pathways, and uncover the biological mechanism. Analysis showed that the body weights, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased in the WTA group. The grips decreased with age, while the triglyceride (TG) and cholesterol (TC) did not change significantly. The increase of fibrosis, accumulation of inflammatory cells, hepatocytes degeneration, the deposition of lipid droplets and glycogen, the damaged mitochondria, and deduction of endoplasmic reticulum were observed in the aging liver under optical and electron microscopes. In addition, a network of metabolites and phosphorylated proteomes of the aging liver was established. Metabolomics detected 970 metabolites in the positive ion mode and 778 metabolites in the negative ion mode. A total of 150 pathways were pooled. Phosphoproteomics identified 2618 proteins which contained 16621 phosphosites. A total of 164 pathways were detected. 65 common pathways were detected in two omics. Phosphorylated protein heat shock protein HSP 90-alpha (HSP90A) and v-raf murine viral oncogene homolog B1(BRAF), related to cancer pathway, were significantly upregulated in aged mice liver. Western blot verified that protein expression of MEK and ERK, downstream of BRAF pathway were elevated in the liver of aging mice. However, the protein expression of BRAF was not a significant difference. Overall, these findings revealed a close link between aging and cancer and contributed to our understanding of the multi-omics changes in natural aging.

Keywords: Mouse; Phosphoproteomics; aging; liver; metabolomics.