Mechanisms by which plant extracts delay aging in yeast by targeting certain signaling pathways and modulating lipid metabolism

The yeast Saccharomyces cerevisiae is a unicellular eukaryote that has been successfully used as a model organism for discovering signaling pathways and chemical compounds that modulate cellular aging, define organismal lifespan, and influence organismal fitness not only in yeast but also in various multicellular eukaryotes. Using a robust quantitative assay for measuring yeast chronological lifespan, we discovered six plant extracts (PE; i.e. PE4, PE5, PE6, PE8, PE12 and PE21) whose longevity‐extending efficiencies greatly exceed those of currently known natural anti‐aging compounds, such as resveratrol, rapamycin, spermidine, caffeine, and lithocholic acid. Our genetic, biochemical, and mass spectrometry‐based lipidomic analyses uncovered the following mechanisms by which these PE delay yeast chronological aging by targeting certain signaling pathways and modulating lipid metabolism: (1) PE4 attenuates the inhibiting effect of the pro‐aging TOR (target of rapamycin) signaling pathway on the anti‐aging AMP‐activated protein kinase (AMPK/Snf1), increases the intracellular concentration of phosphatidic acid (PA), and decreases the concentration of triacylglycerols (TAG; the major form of energy storage in yeast and other eukaryotes); (2) PE5 mitigates the pro‐aging cAMP/PKA (cAMP/protein kinase A) signaling pathway, greatly elevates the concentration of PA, reduces the concentration of TAG, and rises the concentration of cardiolipin (CL; a phospholipid synthesized only within mitochondria in yeast and other eukaryotes); (3) PE6 targets currently unknown pro‐ and/or anti‐aging pathways of longevity regulation, increases the concentration of PA and phospholipids other than CL, and decreases the concentration of TAG; (4) PE8 weakens the inhibiting effect of the pro‐aging cAMP/PKA signaling pathway on the anti‐aging AMPK/Snf1, enlarges the concentrations of PA, CL and all other phospholipids, and lessens the concentration of TAG; (5) PE12 activates the anti‐aging protein kinase Rim15 (on which the pro‐aging TORC1 and cAMP/PKA signaling pathways converge), and decreases the concentrations of CL and TAG; and (6) PE21 attenuates the pro‐aging protein kinase Sch9 (which is activated by the pro‐aging TOR and Pkh1/2 signaling pathways), elevates the concentrations of PA and phospholipids other than CL, and reduces the concentration of TAG. Support or Funding Information Supported by NSERC of Canada.