Maternal Tauroursodeoxycholic Acid Supplementation under Isocaloric High-Fat Diet Alleviates Oxidative Stress and Extends Lifespan through a whd-Dependent Mechanism in Drosophila Offspring.

<h4>Background</h4>Maternal nutrition and metabolic signals during development can influence oxidative stress and aging. Tauroursodeoxycholic acid (TUDCA) is a bile acid derivative with antioxidant and mitochondrial protective effects, yet its molecular mechanisms in aging remain poorly defined.<h4>Objectives</h4>Because Drosophila melanogaster does not synthesize endogenous bile acids, we used it as a model to examine how maternal isocaloric high-fat diet and TUDCA supplementation influence offspring lifespan.<h4>Methods</h4>Female flies were fed a normal control diet (NC), an isocaloric high-fat diet (mIHF), or a high-fat diet, with or without TUDCA, until oviposition. All male offspring developed on the NC diet. Offspring lifespan, exercise capacity, oxidative stress, and mitochondrial function were evaluated. The tub-Gal80^ts/tub-Gal4 system was used to manipulate withered (whd) (a homolog of carnitine palmitoyltransferase 1, CPT1) at the adult stage, and transgenic flies were fed the same diets as wild-type flies.<h4>Results</h4>The mIHF+TUDCA diet significantly prolonged offspring lifespan compared with NC+TUDCA (+19.10%, P < 0.0001) and improved climbing performance at days 0 and 40 (P < 0.05). Offspring in the mIHF+TUDCA group showed improved systemic redox status across aging, with higher glutathione and lower malondialdehyde levels at days 0, 20, and 40 (P < 0.05). In the fat body, mIHF+TUDCA reduced reactive oxygen species (ROS) and increased mitochondrial membrane potential (MMP) (P < 0.05). Mechanistically, whd knockdown shortened lifespan under NC, mIHF, and mIHF+TUDCA conditions (P < 0.0001) and abolished the lifespan extension induced by mIHF+TUDCA. Moreover, whd knockdown increased ROS and reduced MMP in the fat body, and these changes were not reversed by TUDCA. In contrast, whd overexpression restored these phenotypes toward control levels without further lifespan extension.<h4>Conclusions</h4>These findings reveal a diet-dependent regulatory role of TUDCA, suggesting that the mIHF+TUDCA diet alleviates oxidative stress in offspring largely via whd activity and promotes healthy aging.