Abstract
We have recently found that PE21, an extract from the white willow Salix alba, slows chronological aging and prolongs longevity of the yeast Saccharomyces cerevisiae more efficiently than any of the previously known pharmacological interventions. Here, we investigated mechanisms through which PE21 delays yeast chronological aging and extends yeast longevity. We show that PE21 causes a remodeling of lipid metabolism in chronologically aging yeast, thereby instigating changes in the concentrations of several lipid classes. We demonstrate that such changes in the cellular lipidome initiate three mechanisms of aging delay and longevity extension. The first mechanism through which PE21 slows aging and prolongs longevity consists in its ability to decrease the intracellular concentration of free fatty acids. This postpones an age-related onset of liponecrotic cell death promoted by excessive concentrations of free fatty acids. The second mechanism of aging delay and longevity extension by PE21 consists in its ability to decrease the concentrations of triacylglycerols and to increase the concentrations of glycerophospholipids within the endoplasmic reticulum membrane. This activates the unfolded protein response system in the endoplasmic reticulum, which then decelerates an age-related decline in protein and lipid homeostasis and slows down an aging-associated deterioration of cell resistance to stress. The third mechanisms underlying aging delay and longevity extension by PE21 consists in its ability to change lipid concentrations in the mitochondrial membranes. This alters certain catabolic and anabolic processes in mitochondria, thus amending the pattern of aging-associated changes in several key aspects of mitochondrial functionality.