Undescribed Phenylpropanoid-Substituted Ester-Type Catechins from Green Tea Exert Antiaging Effects in Caenorhabditis elegans 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 Caenorhabditis elegans (C. elegans), among which PSEC13 extended the longest lifespan by 57%, formed through the reaction between sinapic acid and EGCG with an S configuration. Moreover, PSEC13 activated the HSF-1/DAF-16 axis, upregulating heat shock proteins (HSPs). Surface plasmon resonance (SPR) analysis confirmed high-affinity binding between PSEC13 and HSP-16.2 (K_D = 0.11 μM). Molecular dynamics simulations revealed that PSEC13 forms stable hydrogen bonds with key residues (GLU³⁹, SER⁴¹, ASN⁵⁵) in the HSP-16.2 active site. This study emphasizes the potential of PSEC13 as a novel approach to enhance proteostasis and extend lifespan through the modulation of HSP-16.2.