From Steatosis to Immunosenescence: The Impact of Metabolic Dysfunction on Immune Aging in HIV and Non-HIV Populations

Immunosenescence, defined as the progressive decline of immune function with age, is increasingly recognized as a determinant of morbidity in people living with HIV (PLWH) and in individuals with metabolic dysfunction. The coexistence of chronic viral infection and systemic metabolic alterations—including metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus—creates a pro-inflammatory state (“metaflammation”) that accelerates immune aging. This narrative review synthesizes current clinical, translational, and experimental evidence on the cellular, molecular, and metabolic mechanisms underlying immunosenescence in HIV-positive and HIV-negative populations with metabolic dysfunction. Key converging pathways include chronic inflammation, mitochondrial dysfunction, microbial translocation, and altered immunometabolic signaling, leading to features such as CD8+CD28− T-cell expansion, reduced CD4/CD8 ratios, and impaired vaccine responses. Biomarkers such as iAge, IMM-AGE, and the triglyceride–glucose (TyG) index have emerged as promising tools to quantify immune aging beyond chronological measures. Understanding these interconnected mechanisms offers opportunities for targeted interventions—such as metabolic reprogramming, microbiota modulation, and geroscience-based strategies—aimed at preserving immune resilience and promoting healthy aging in high-risk populations.