Jiahao Wang, Kameyama Jun, Udono Miyako, Katakura Yoshinori
Graduate School of Bioresources and Bioenvironmental Sciences, Kyushu University, Fukuoka, 819-0395 Japan.
Faculty of Agriculture, Kyushu University, Fukuoka, 819-0395 Japan.
Cytotechnology. 2025 Aug;77(4):131. doi: 10.1007/s10616-025-00803-w. Epub 2025 Jun 30.
A large-scale longitudinal epidemiological study by the Hisayama study revealed that the concentration of one-carbon metabolism-related amino acids in the serum changes with age and that there is a link between these fluctuations and the risk of developing dementia (Hata et al. in Am J Epidemiol 188:1637-1645, 2019; Mihara et al. in Sci Rep 12:12427, 2022). Therefore, the aim of this study was to focus on age-related changes in one-carbon metabolism-related amino acids and elucidate the regulatory basis of these changes. Treatment with etoposide, an anti-cancer drug, induced cellular senescence in SH-SY5Y cells, as indicated by increased senescence-associated β galactosidase activity and upregulated expression of senescence markers and . Liquid chromatography-mass spectrometry analysis revealed that the intracellular amino acid concentrations, particularly those involved in the one-carbon metabolism, were elevated in senescent cells, including those of methionine, S-adenosylmethionine, S-adenosylhomocysteine (SAH), homocysteine (Hcys), and related metabolites. The results of the expression analysis focused on the enzyme genes involved in Hcys metabolism and revealed that the induction of cellular senescence upregulated (), which convert SAH to Hcys. Additionally, the genes involved in Hcys metabolism via the sulphuration pathway ( and ) were significantly upregulated. Because Hcys has been implicated in aging, further investigations focused on . Gene knockdown of in etoposide-treated cells reduced and expression, indicating that is essential for cellular senescence induction. These findings suggest that Hcys accumulation and its metabolic enzymes play a crucial role in cellular senescence.
The online version contains supplementary material available at 10.1007/s10616-025-00803-w.
久山研究开展的一项大规模纵向流行病学研究表明，血清中与一碳代谢相关氨基酸的浓度会随年龄变化，且这些波动与患痴呆症的风险之间存在关联（羽田等人，《美国流行病学杂志》，第188卷，第1637 - 1645页，2019年；三原等人，《科学报告》，第12卷，第12427页，2022年）。因此，本研究的目的是关注与一碳代谢相关氨基酸的年龄相关变化，并阐明这些变化的调控基础。抗癌药物依托泊苷处理可诱导SH - SY5Y细胞发生细胞衰老，衰老相关β半乳糖苷酶活性增加以及衰老标志物 和 的表达上调表明了这一点。液相色谱 - 质谱分析显示，衰老细胞内的氨基酸浓度升高，尤其是参与一碳代谢的氨基酸，包括蛋氨酸、S - 腺苷甲硫氨酸、S - 腺苷同型半胱氨酸（SAH）、同型半胱氨酸（Hcys）及相关代谢产物。针对参与Hcys代谢的酶基因的表达分析结果表明，细胞衰老的诱导会上调将SAH转化为Hcys的 （ ）。此外，通过硫化途径参与Hcys代谢的基因（ 和 ）显著上调。由于Hcys与衰老有关，进一步的研究聚焦于 。在依托泊苷处理的细胞中敲低 的基因可降低 和 的表达，表明 对于诱导细胞衰老至关重要。这些发现表明，Hcys的积累及其代谢酶在细胞衰老中起关键作用。
在线版本包含可在10.1007/s10616 - 025 - 00803 - w获取的补充材料。
