Compensatory roles of STT3A and ALG5 in glucose metabolism of aged macaque hippocampus.

Abstract

The hippocampus (HC), a central hub for memory and cognition, exhibits unique metabolic resilience during aging despite widespread brain glucose hypometabolism. Here, we report that aged humans and macaques paradoxically display elevated HC glucose uptake (18F-FDG PET SUVR) alongside strengthened connectivity to sensory-motor and limbic networks-an adaptive rewiring revealed by graph-theoretical metabolic network analysis. Integrated multi-omics profiling identified STT3A (oligosaccharyltransferase) and ALG5 (dolichyl-phosphate β-glucosyltransferase) as key regulators of age-related HC adaptation, with their upregulation in aged macaque hippocampi driving N-glycosylation-dependent metabolic reprogramming. Mechanistically, STT3A/ALG5 silencing in aged rats reduced insulin receptor/AKT1/AS160 phosphorylation, impairing GLUT4 membrane trafficking, while enhancing GLUT3 glycosylation and neuronal glucose uptake. This dual regulation preserved synaptic integrity and spatial memory retrieval despite reduced hippocampal FDG metabolism. Behavioral assays further demonstrated STT3A knockdown-induced motor coordination improvements through GLUT3-mediated metabolic rebalancing. Our findings establish STT3A-ALG5 as a glycosylation checkpoint that sustains HC energy homeostasis via GLUT4-to-GLUT3 substrate switching, positioning 18F-FDG PET as a dynamic biomarker for monitoring HC aging and these glycosyltransferases as therapeutic targets against cognitive decline.