Abstract

To discover novel aging-delaying and longevity-extending chemical compounds of plant origin, we conducted a screen for plant extracts that can prolong yeast chronological lifespan. Our screen revealed six plant extracts that increase yeast chronological lifespan. One of these six plant extracts is PE21, an extract from the white willow Salix alba. We found that PE21 extends the longevity of chronologically aging yeast to a significantly greater extent than any of the presently known longevity-extending chemical compounds. We demonstrated that PE21 is a geroprotector which delays the onset and slows the progression of yeast chronological aging by eliciting a hormetic stress response. We showed that PE21 has the following effects on cellular processes known to define longevity in organisms across phyla: 1) PE21 amplifies mitochondrial respiration and membrane potential; 2) PE21 alters the pattern of age-related changes in the intracellular concentration of reactive oxygen species; 3) PE21 reduces oxidative damage to cellular proteins, membrane lipids, and mitochondrial and nuclear genomes; 4) PE21 enhances cell resistance to oxidative and thermal stresses; and 5) PE21 accelerates degradation of neutral lipids deposited in lipid droplets. We found that PE21 causes a remodeling of lipid metabolism in chronologically aging yeast, thereby instigating changes in the concentrations of several lipid classes. We demonstrated 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 mechanism underlying aging delay and longevity extension by PE21 consists in its ability to change concentrations of some lipids 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.