Ashwagandha withanolides, Withaferin-A, and Withanone for natural interventions in aging and obesity

Aging and obesity are closely connected, with obesity being a major risk factor for many age-related diseases caused by chronic inflammation and mobility problems. Lifestyle choices such as good nutrition, including medicinal herbs, and exercise are believed to influence body weight. Ashwagandha, an Ayurvedic adaptogen containing bioactive withanolides, is known to reduce stress, fight cancer, and improve energy metabolism. Its effects on lipid metabolism and obesity remain unclear. CARF (Collaborator of ARF), a protein involved in stress response and cancer regulation, was recently found to control liver lipid metabolism. We used a hepatocyte-based screening assay in which induction of fatty acid accumulation caused downregulation of CARF. On the other hand, cells treated with Ashwagandha withanolides showed CARF recovery and reduction in lipid accumulation. Molecular analyses on key regulators of stress and lipogenesis pathways supported antioxidative and antisteatotic effects of Withaferin-A (Wi-A) and Withanone (Wi-N). We discuss various antiaging activities of Ashwagandha withanolides and report computational molecular modeling-based insights into the interactions of Wi-A and Wi-N with three key targets (Fatty Acid Synthase, FASN; Sterol Regulatory Element-Binding protein-1c, SREBP-1c; and Peroxisome Proliferator-Activated Receptor, PPARγ) of the lipogenesis pathway, highlighting their potential in regulating lipid metabolism and obesity.