Premature immunosenescence in AYA gastrointestinal cancer: The metabolic-inflammatory-hormonal axis as an integrative framework: A systematic review
Abstract
The global rise in gastrointestinal (GI) cancer among adolescents and young adults (AYAs; aged 15-39) represents a striking departure from traditional age-dependent epidemiology. In the present systematic review, it is proposed that premature immunosenescence may be a contributing driver of this trend and introduces the metabolic-inflammatory-hormonal axis as a working framework to explore these observations. Findings from PubMed/MEDLINE (1990-2024) were synthesized, focusing on high-impact studies and systematic reviews from the last 5 years, using keywords related to young-onset GI cancer, immunosenescence and metabolic inflammation. A PRISMA screening process was employed, with defined inclusion/exclusion criteria. The present systematic review identified several interconnected mechanisms that may drive premature immune aging in AYAs: i) T-cell exhaustion and thymic involution; ii) chronic inflammation fueled by the senescence-associated secretory phenotype and tumor-derived vesicles; and iii) metabolic perturbations, such as cholesterol buildup and lactate-mediated immunosuppression. Collectively, these changes may create an immunosuppressive microenvironment enriched with regulatory T cells, myeloid-derived suppressor cells and M2 macrophages. The metabolic-inflammatory-hormonal (M-I-H) axis integrates these pathways, potentially driving immune dysfunction independent of chronological age. The present systematic review emphasizes that this framework remains largely…
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