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Pioglitazone (Piog) activates peroxisome proliferator activated receptor-γ (PPARγ) and is widely used in clinic for the treatment of diabetes mellitus. PPARγ in various tissues has the essential regulatory role of multiple metabolic function, suggest that PPARγ signaling may contribute to aging processes. However, little is known about the consequences of Piog on aging in aged animal models. We used apolipoprotein E deficient (apoE−/−) mice model to evaluate the effects of Piog on aging-related disorders. Our results showed that long-term and low-dose Piog treatment significantly reduced aortic atherosclerosis, aging-related renal glomerulosclerosis and interstitial fibrosis, and hepatic steatosis, while improved the dermis in skin atrophy, compared to the control group. These morphological alterations were linked to the role of Piog, including regulation of plasma cholesterol and triglycerides (TG) levels, increased antioxidant superoxide dismutase (SOD) activity and decreased myeloperoxidase (MPO) activity. Moreover, accompanied with up-regulation of PPARγ expression, Piog had obviously increased the mRNA levels of anti-aging genes Sirtuin1 and Klotho, decreased the p53 protein level, and altered the expression of several genes involving cholesterol excretion, TG biosynthesis and inflammation in the liver. In conclusion, Piog treatment is effective to modulate the oxidative and inflammatory status, cell senescence, and lipid metabolism, contributing to attenuate several aging-related disorders in the aged apoE−/− mice, thereby maybe a promising protective therapy of aging and age-related diseases.The effects of pioglitazone on aging-related disorders were observed in the aged apoE−/− mice.Pioglitazone reduced atherosclerosis, hepatic steatosis, renal aging and skin atrophy.Pioglitazone regulated hepatic lipid-metabolism-related genes expression.Pioglitazone reduced oxidative and inflammatory status and alters cellular aging-related marker levels.Pioglitazone has a systematic protective effect against aging-related diseases.