Early-Life Obesity Leaves a Metabolic Memory That Accelerates Aging-Related Decline Through the Gut Microbiota-GABA...

Childhood obesity is a critical public health concern. Whether diet-induced transient obesity during development negatively impacts later-life health remains unclear, and mechanisms are poorly understood. This study investigates whether these effects persist into aging and employs integrated omics to explore underlying mechanisms. Using a high-fat diet (HFD) to induce transient developmental obesity in post-weaning rats and larval Drosophila, we examined the long-term effects on aging metabolic health in both species. Transient developmental obesity in rats was linked to accelerated aging, weight loss, worsened metabolism, colonic inflammation, and oxidative stress. Metabolomics revealed persistent gamma aminobutyric acid (GABA) dysregulation associated with intestinal ammonia levels, and gut metagenomics showed a reduction in Lactobacillales, correlating with adverse health outcomes. In Drosophila, exogenous GABA extended HF-diet lifespan. It reduced trehalose, triglycerides (TG), and oxidative stress; concurrently, it restored intestinal Lactobacillus and activated the phosphotransferase system (PTS), thereby improving metabolic homeostasis and redox status. Transient developmental obesity is associated with reduced gut Lactobacillus abundance, which may contribute to decreased GABA levels and subsequent disruption of glucose (GLU) metabolism, potentially involving the PTS pathway. These interconnected alterations may ultimately lead to systemic dysregulation of GLU and lipid metabolism and redox homeostasis in later life, compromising overall health and longevity.