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.