Undescribed Phenylpropanoid-Substituted Ester-Type Catechins from Green Tea Exert Antiaging Effects in <i>Caenorhabditis elegans</i> via Activating DAF-16, HSF-1, and Heat Shock Proteins

Green tea processing creates a hot acidic environment that facilitates reactions between catechins and hydroxycinnamic acids (HCAs), generating new catechins. Accordingly, we developed a one-pot method incorporating a Michael addition reaction to synthesize 13 phenylpropanoid-substituted ester-type catechins (PSECs), whose contents exhibit seasonal changes in tea leaves similar to those observed for common catechins. These PSECs showed antiaging effects in <i>Caenorhabditis elegans</i> (<i>C. elegans</i>), among which <b>PSEC13</b> extended the longest lifespan by 57%, formed through the reaction between sinapic acid and EGCG with an <i>S</i> configuration. Moreover, <b>PSEC13</b> activated the HSF-1/DAF-16 axis, upregulating heat shock proteins (HSPs). Surface plasmon resonance (SPR) analysis confirmed high-affinity binding between <b>PSEC13</b> and HSP-16.2 (<i>K</i>_D = 0.11 μM). Molecular dynamics simulations revealed that <b>PSEC13</b> forms stable hydrogen bonds with key residues (GLU³⁹, SER⁴¹, ASN⁵⁵) in the HSP-16.2 active site. This study emphasizes the potential of <b>PSEC13</b> as a novel approach to enhance proteostasis and extend lifespan through the modulation of HSP-16.2.