Mechanisms through which lithocholic acid delays yeast chronological aging under caloric restriction conditions

Abstract

All presently known geroprotective chemical compounds of plant and microbial origin are caloric restriction mimetics because they can mimic the beneficial lifespan- and healthspan-extending effects of caloric restriction diets without the need to limit calorie supply. We have discovered a geroprotective chemical compound of mammalian origin, a bile acid called lithocholic acid, which can delay chronological aging of the budding yeast Saccharomyces cerevisiae under caloric restriction conditions. Here, we investigated mechanisms through which lithocholic acid can delay chronological aging of yeast limited in calorie supply. We provide evidence that lithocholic acid causes a stepwise development and maintenance of an aging-delaying cellular pattern throughout the entire chronological lifespan of yeast cultured under caloric restriction conditions. We show that lithocholic acid stimulates the aging-delaying cellular pattern and preserves such pattern because it specifically modulates the spatiotemporal dynamics of a complex cellular network. We demonstrate that this cellular network integrates certain pathways of lipid and carbohydrate metabolism, some intercompartmental communications, mitochondrial morphology and functionality, and liponecrotic and apoptotic modes of aging-associated cell death. Our findings indicate that lithocholic acid prolongs longevity of chronologically aging yeast because it decreases the risk of aging-associated cell death, thus increasing the chance of elderly cells to survive.

Lipid metabolism and lipid signals in aging and longevity

“…CA supplementation extends both lifespan and health span in progeroid mice (Ba ´rcena et al, 2018). Furthermore, LCA was identified from a chemical screen to prolong the lifespan of yeast cells (Arlia-Ciommo et al, 2018) and fruit flies (Staats et al, 2018). In C. elegans, there is another cholesterol-derived lipid messenger, called dafachronic acid (DA) that modulates lifespan through DAF-12, the FXR homolog (Gerisch et al, 2007).…”

Mechanisms by which PE21, an extract from the white willow Salix alba, delays chronological aging in budding yeast

“…Third mechanism: the present study reveals that PE21 alters the membrane lipidome of mitochondria by rising PS and PE concentrations and lowering CL concentration in these organelles (Figure 1D, 1E and 1H; Supplementary Figure 2). A body of evidence supports the notion that the composition of mitochondrial membrane lipids is an essential contributor to mitochondrial functionality and as such, the mitochondrial membrane lipidome defines longevity of yeast and multicellular eukaryotes [32, 34, 77, 87, 97, 103, 104, 108, 203–209]. Notable, PE21 not only prolongs yeast longevity but also amends the pattern of age-related changes in several key aspects of mitochondrial functionality, including mitochondrial respiration, mitochondrial membrane potential and mitochondrial ROS production [55].…”

The Effect of Lithocholic Acid on the Gut-Liver Axis

“…Contrary to the previous reports, recent studies revealed that LCA might be a protector in restraining hepatic and intestinal inflammation (Hamilton et al, 2007;Ward et al, 2017;Sinha et al, 2020). Some other studies have found that LCA also potentiates anti-aging and antitumor effects (Burstein et al, 2012;Arlia-Ciommo et al, 2014;Arlia-Ciommo et al, 2018). For example, galactosylated poly (ethyleneglycol)-LCA, a nanoparticle formulation can selectively induce apoptosis in hepatocellular carcinoma cells without adverse effects on normal liver cells (Gankhuyag et al, 2015).…”