Immunosenescence and Vaccine Efficacy in Aging: Dynamic Interplay of Gut Microbiota and mTOR Signaling Pathways

Aging significantly impairs vaccine efficacy in older adults, driven by immunosenescence, inflammaging, and disruptions in the gut microbiota-mTOR-immune axis. This review synthesizes current evidence on how aging alters vaccine-induced immune responses through the interplay of gut microbiota dysbiosis and dysregulated mTOR signaling. Age-related microbial diversity declines and reduced short-chain fatty acid (SCFA) production exacerbate inflammation, while heightened mTOR activity suppresses autophagy, promotes pro-inflammatory states, and impairs T/B cell function, collectively diminishing antibody production and immune memory formation. We highlight the bidirectional interaction between SCFAs and mTOR, where SCFAs mitigate mTOR overactivation to enhance immune regulation, and mTOR dysregulation further aggravates microbial dysbiosis, forming a vicious cycle. Critically, this review systematically stratifies the evidence, distinguishing preclinical mechanistic insights from correlative human data. Animal and human studies suggest that targeting this axis-via mTOR inhibitors, probiotics, or dietary interventions-holds promise for improving vaccine responses in the elderly. We propose future research directions, including personalized vaccine strategies leveraging microbiota profiling and mTOR modulation, to address the challenges of infection in aging populations and advance precision medicine for healthy aging.