| Summary: | Obesity and aging are associated to non-alcoholic fatty liver disease (NAFLD) development. Here, we investigate whether long-term feeding with a docosahexaenoic acid (DHA)-enriched diet and aerobic exercise, alone or in combination, are effective in ameliorating NAFLD in aged obese mice. Two-month-old female C57BL/6J mice received control or high fat diet (HFD) for 4 months. Then, the diet-induced obese (DIO) mice were distributed into four groups: DIO, DIO + DHA (15% dietary lipids replaced by a DHA-rich concentrate), DIO + EX (treadmill running), and DIO + DHA + EX up to 18 months. The DHA-rich diet reduced liver steatosis in DIO mice, decreasing lipogenic genes (<i>Dgat2, Scd1, Srebp1c)</i>, and upregulated lipid catabolism genes (<i>Hsl</i>/<i>Acox</i>) expression. A similar pattern was observed in the DIO + EX group. The combination of DHA + exercise potentiated an increase in <i>Cpt1a</i> and <i>Ppara</i> genes, and AMPK activation, key regulators of fatty acid oxidation. Exercise, alone or in combination with DHA, significantly reversed the induction of proinflammatory genes (<i>Mcp1, Il6, Tnfα</i>, <i>Tlr4</i>) in DIO mice. DHA supplementation was effective in preventing the alterations induced by the HFD in endoplasmic reticulum stress-related genes (<i>Ern1/Xbp1</i>) and autophagy markers (LC3II/I ratio, p62, <i>Atg7</i>). In summary, long-term DHA supplementation and/or exercise could be helpful to delay NAFLD progression during aging in obesity.
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