《生命科学》 2026, 38(6): 1124-1134

基于代谢分子探针的细胞衰老动态检测新方法

王傲雪^1,2 , 池佼妮^1,3 , 夏亚乐¹ , 陈亚琼¹ , 张 卓^1,2,* , 赵玉政^1,2,*

¹华东理工大学药学院，生物反应器工程全国重点实验室，上海市细胞代谢光遗传学技术前沿科学研究基地，上海市新药设计重点实验室，光遗传学与合成生物学交叉研究中心，上海 200237 ²中国医学科学院 细胞代谢监测成像新技术创新单元，北京 100730 ³中国医学科学院北京协和医学院北京协和医院变态反 应科，疑难重症及罕见病全国重点实验室，北京 100730

摘　要：

细胞衰老蕴含复杂的机制，包括端粒缩短、氧化损伤、炎性因子分泌、代谢重塑等。当前的突出问题是用于鉴定细胞衰老的生物标志物，如常用的半乳糖苷酶染色、端粒长度分析、衰老相关分泌因子检测等，均难以示踪细胞衰老过程中的动态变化以及刻画细胞之间的异质性。这里我们提出采用基于代谢分子探针的细胞衰老动态检测新方法。代谢重塑不仅是细胞衰老的标志物，其在推动细胞衰老演变过程中也发挥了关键作用。采用基于遗传编码荧光探针的代谢示踪方法，除了可以在单细胞、亚细胞水平原位实时地显示代谢衰老的动态变化，还可以分析不同亚群中代谢与衰老之间的复杂联系，是研究代谢衰老的强有力工具。本文聚焦与衰老密切相关的代谢物NAD+、乳糖/半乳糖、α-酮戊二酸和多胺，总结其在机体和细胞衰老中的变化和功能，以及相关遗传编码荧光探针的发展现状，分析了针对关键衰老代谢物开发高性能探针面临的技术挑战，并讨论了这些前沿工具在衰老代谢研究中的重要机遇。

通讯作者：张 卓 , Email:zhangzhuo@ecust.edu.cn 赵玉政 , Email:yuzhengzhao@ecust.edu.cn

New methods for dynamic monitoring of cellular senescence based on metabolite biosensors

WANG Ao-Xue^1,2 , CHI Jiao-Ni^1,3 , XIA Ya-Le¹ , CHEN Ya-Qiong¹ , ZHANG Zhuo^1,2,* , ZHAO Yu-Zheng^1,2,*

¹Optogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Key Laboratory of New Drug Design, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China ²Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing 100730, China ³Department of Allergy, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China

Abstract:

Cellular senescence can be induced through multiple mechanisms, including telomere shortening, DNA damage, replicative stress via oncogene activation, oxidative stress, mitochondrial dysfunction, and metabolic remodeling. A prominent challenge in current research is that biomarkers commonly used to identify cellular senescence, such as cellular morphology remodeling, β-galactosidase activity, expression of key genes like p16, senescence-associated secretory phenotypes, and DNA damage foci, are difficult to use for tracking the dynamic changes of senescence in living cells or capturing phenotypic heterogeneity among cells. Here, we propose a novel metabolite-biosensor-based approach to dynamically detect cellular senescence. Metabolic remodeling is not only a hallmark of cellular senescence but also a crucial driver of its progression. By using genetically encoded fluorescent sensors, this method will not only enable real-time, in situ visualization of senescent cell phenotypes at the single-cell and subcellular level, but also offer new insights into the metabolic roots of cellular senescence, making it a powerful tool for studying metabolic senescence. Considering the universality and specificity of metabolites as senescence biomarkers, we highlight a few key metabolites closely associated with cellular senescence, including NAD+, lactose/galactose, α-ketoglutarate, and polyamines, and summarize their fluctuations and roles in organismal and cellular aging, as well as the current research status of fluorescent biosensors for these metabolites. We analyze the technical challenges in developing high-performance sensors for these metabolites and discuss the potential applications of these advanced tools in aging research, including in situ, dynamic monitoring of senescent cells and functional analysis of cellular subpopulations.

Communication Author：ZHANG Zhuo , Email:zhangzhuo@ecust.edu.cn ZHAO Yu-Zheng , Email:yuzhengzhao@ecust.edu.cn