Food Bioscience · Jun 4, 2026
Ursolic acid partially mimics low-glucose effects in a senescence-like alpha mouse liver 12 (AML12) hepatocyte model
By Schwarz U, Fischer A, Rimbach GH
Aging is linked to progressive declines in cellular and mitochondrial function, partly due to impaired nutrient-sensing pathways. Caloric restriction (CR) mitigates these effects by enhancing mitochondrial efficiency and metabolic flexibility. Ursolic acid (UA), a dietary pentacyclic triterpenoid found in fruits and herbs, has been proposed as a CR mimetic. This study investigated whether UA reproduces CR benefits in a senescent-like hepatocyte model. Senescence-like (SEN) features were induced in AML12 hepatocytes using intermittent low-dose H 2 O 2 (750–1000 μmol/L) over 6 days. SEN cells were treated with 5 μmol/L UA (5UA), and low-glucose conditions (LG) served as a CR-like reference. Non-stressed cells (CON) were included for baseline comparison. Nutrient-sensing signalling, mitochondrial biogenesis, lipid accumulation, and energy metabolism were assessed. SEN cells displayed increased β-galactosidase activity, upregulation of genes encoding p16 Ink4a and p21 Cip1 , and ∼50% lower cell numbers after 48 h versus CON. Intracellular triglycerides were twofold higher in SEN, reduced by 25% with 5UA and 45% under LG. SEN induction did not markedly impair CR-related signalling except for reduced sirtuin 1 (SIRT1) activity. LG restored SIRT1 activity and doubled AMP-activated protein kinase (AMPK) phosphorylation relative to SEN, whereas UA did not exert comparable effects. Neither UA nor LG altered mitochondrial biogenesis markers. Functionally, only LG increased ATP production (+48% vs. SEN). LG conditions improved mitochondrial energy production in a senescence-like hepatocyte model, whereas UA produced only partial metabolic benefits. These data indicate that UA does not fully mimic CR-mediated nutrient-sensing activation, suggesting that sustained nutrient reduction is required to overcome stress-induced metabolic rigidity.