SIRT1 Activation by Lignans Identified via UPLC-qTOF-MS/MS-Based Metabolomic Profiling of Piper longum L. Fruit (Long Pepper)

The fruits of <i>Piper longum</i> L. (long pepper), a spice and medicinal plant of the family <i>Piperaceae</i>, are widely used in South and Southeast Asian cuisine and traditional medicine, valued for their pungent flavor and aroma. The metabolomic profiling of <i>P. longum</i> using UPLC-qTOF-MS/MS provided a comprehensive chemical characterization of this traditional medicinal plant, revealing that lignans and amide alkaloids are the major classes of secondary metabolites. To further investigate its pharmacological potential, the bioactive ethyl acetate fraction was subjected to a SIRT1-targeted chemical investigation. This led to the isolation and structural elucidation of three previously undescribed compounds, a cadinene-type sesquiterpene (<b>1</b>) and two <i>oxo</i>-neolignan (<b>2</b> and <b>5</b>), along with four known compounds <b>3</b>, <b>4</b>, <b>6</b>, and <b>7</b>. Compounds (<b>1</b>-<b>7</b>) were evaluated for their ability to modulate p53-dependent transcriptional activity via SIRT1 activation using a luciferase reporter cell-based assay. SIRT1, a NAD⁺-dependent deacetylase, is a crucial regulator of longevity, metabolism, and cellular stress resistance, making it a key target for the treatment of age-related diseases. Compounds <b>2</b>-<b>7</b> exhibited significant SIRT1 activation, with compound <b>6</b> displaying particularly high efficacy, comparable to resveratrol, the most well-known natural SIRT1 activator. This study demonstrates that the discovery of novel chemical scaffolds through bioactivity-guided screening highlights the value of combining advanced metabolomics with pharmacological evaluation. The results support the traditional medicinal use of long pepper and its potential for development into functional foods or pharmaceuticals for healthy aging.