A Single‐Cell Metabolic Profiling Characterizes Human Aging via SlipChip‐SERS

Abstract Metabolic dysregulation is a key driver of cellular senescence, contributing to the progression of systemic aging. The heterogeneity of senescent cells and their metabolic shifts are complex and unexplored. A microfluidic SlipChip integrated with surface‐enhanced Raman spectroscopy (SERS), termed SlipChip‐SERS, is developed for single‐cell metabolism analysis. This SlipChip‐SERS enables compartmentalization of single cells, parallel delivery of saponin and nanoparticles to release intracellular metabolites and to realize SERS detection with simple slipping operations. Analysis of different cancer cell lines using SlipChip‐SERS demonstrated its capability for sensitive and multiplexed metabolic profiling of individual cells. When applied to human primary fibroblasts of different ages, it identified 12 differential metabolites, with spermine validated as a potent inducer of cellular senescence. Prolonged exposure to spermine can induce a classic senescence phenotype, such as increased senescence‐associated β‐glactosidase activity, elevated expression of senescence‐related genes and reduced LMNB1 levels. Additionally, the senescence‐inducing capacity of spermine in HUVECs and WRL‐68 cells is confirmed, and exogenous spermine treatment increased the accumulation and release of H 2 O 2 . Overall, a novel SlipChip‐SERS system is developed for single‐cell metabolic analysis, revealing spermine as a potential inducer of senescence across multiple cell types, which may offer new strategies for addressing ageing and ageing‐related diseases.