Potential health promoting properties of the triterpenoid ursolic acid as a putative mimetic of caloric reduction - studies in cultured cells and in mice

• Applicant: Professor Dr. Gerald Rimbach
• Subject Area: Nutritional Sciences
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455444862

Ursolic acid (UA) is a phytogenic pentacyclic triterpenoid. Our own previous work shows that UA improves health and life span in the fruit fly Drosophila melanogaster and ameliorates the age-related decline in locomotor activity. This finding is referred to an increase in Spargel (srl) expression. Spargel represents the orthologue of mammalian peroxisome proliferator-activated receptor gamma coactivator (PGC1). However, it is unclear whether our data in flies can be translated into mammalian species. Thus, we will address the question whether the potential life-prolonging properties of UA also exists in mammals and whether they are mediated through a change in PGC1 activity. To this end, we will follow three (I-III) experimental approaches. As Pgc1 is considered as the potential key factor for UA-mediated action, we will examine the expression of Pgc1α target genes after UA incubation in murine muscle and liver cells with siRNA and CRISPR-Cas9 silenced expression of Pgc1α. Hence, we will demonstrate a potential involvement of Pgc1α in UA mediated bioactivity in vitro (I). Secondly, we will investigate the expression of Pgc1α target genes in selected tissues (muscle, liver) and primary myocytes and hepatocytes in a Pgc1α-knock-out mouse model in response to dietary UA. UA will be complexed with γ-cyclodextrin (γCD) to increase its bioavailability. Consequently, we will verify a potential involvement of Pgc1α in UA mediated effects in vivo (II). Pgc1α expression is induced under CR and declines with age. Therefore, we will thirdly study the role of UA on Pgc1α expression and on health and life span in old mice providing a UA-γCD-supplemented diet ad libitum or restricted. We will oppose the UA-derived results to CR and illustrate any potential synergistic or additive bioactivity. Thus, we intent to clarify whether UA could be considered as a potential CR mimetic (III). Extensively, in all three experimental approaches, we will determine the activities of Pgc1α target genes, of genes encoding proteins important in mitochondrial function (via Oroboros-respirometry) and metabolism, of key factors and of selected effector molecules as well as miRNA. We will validate and characterize the UA mediated outcome in more detail via ChIP assay, in silico docking analysis and reporter gene assays. These parameters will be complemented by a comprehensive phenotyping of mice including body composition, indirect calorimetry, oral glucose tolerance, muscle strength and locomotor activity.

• DFG Programme: Research Grants