Low-grade chronic adipose tissue inflammation contributes to the onset and development of aging-related insulin resistance and type 2 diabetes. In the current study, α-mangostin, a xanthone isolated from mangosteen (Garcinia mangostana), was identified to ameliorate lipopolysaccharides-induced acute adipose tissue inflammation in mice, by reducing the expression of pro-inflammatory cytokines and chemokines. In a cohort of young (3 months) and old (18-20 months) mice, α-mangostin mitigated aging-associated adiposity, hyperlipidemia, and insulin resistance. Further study showed that α-mangostin alleviated aging-related adipose tissue inflammation by reducing macrophage content and shifting pro-inflammatory macrophage polarization. Moreover, α-mangostin protected the old mice against liver injury through suppressing the secretion of microRNA-155-5p from macrophages. The above results demonstrated that α-mangostin represents a new scaffold to alleviate adipose tissue inflammation, which might be a novel candidate to treat aging-related metabolic disorders.