A Gut‐Centric View of Ageing: A Pilot Analysis Mapping Age‐Associated Immune and Molecular Alterations in Colonic Mucosa Using Spatial Proteomics

Investigating age‐associated changes in intestine and understanding immune‐related intestinal dysfunctions is essential for promoting healthy ageing. Mucosal surfaces represent a distinct immune compartment enriched with specialised lymphocytes that interact dynamically with the epithelial layer. In this study, we present novel spatially resolved insights into the cellular and molecular alterations in the ageing murine gut mucosa. Our findings reveal a complex network of interdependent age‐related changes, including accumulation of senescent T cells near the epithelial layer, increased expression of ribosomal protein S6 kinase (mTOR target), upregulation of glycolytic enzyme (GAPDH) linked with metabolic reprogramming and elevated apoptosis activity (caspase 3). Together, these molecular signatures point to a progressive dysregulation of mucosal immune homeostasis highlighting reduced tissue resilience as we age. Furthermore, our assessment revealing increased gut‐homing of aged naïve human T cells towards the mucosa suggests that exposure to antigenic stimulation at the mucosa is driving this senescence state. Although further investigations are needed to elucidate the causal mechanisms. Our findings highlight the therapeutic potential of pharmacological drugs (e.g., metformin, senolytics) and lifestyle‐based approaches (such as caloric restriction) targeting key pathways reported to modulate the immune‐epithelial interactions and support intestinal homeostasis during ageing.