Polyphenol-Enriched Sea Almond Extracts as Modulators of Cellular Senescence: Insights from Metabolite Profiling and in Vivo Murine Evaluation

Prolonged skin exposure to intrinsic and extrinsic factors accelerates inflammation-induced skin aging (inflammaging), resulting in structural degradation. This study highlights the effects of Terminalia catappa fruit polyphenolic-enriched extract (PEF) in counteracting D-galactose-induced skin aging. The total ethanolic extract and PEF were characterized using liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-QTOF-MS/MS) and investigated in vitro for enzymes inhibitory activities. PEF was formulated into 3% and 5% gels and applied topically in a murine mouse model of D-galactose-induced inflammaging. Oxidative stress biomarkers, pro-inflammatory cytokines, and cellular senescence markers were analyzed alongside histopathological assessment. A total of 92 metabolites were identified, with 40 reported for the first time in fruit, mainly hydrolyzable tannins and triterpenes. PEF demonstrated the highest inhibitory activity against collagenase (IC 50 = 73 ± 3 μg/mL) and elastase (IC 50 = 37 ± 2 μg/mL), outperforming the epigallocatechin gallate. The 5% PEF gel decreased oxidative stress by increasing catalase and superoxide dismutase activities alongside decreasing malondialdehyde levels. It suppressed TNF-α and IL-1β, resulting in downregulating the senescence markers (iNOS and p16, p53, and p21), correlating with improved histopathological skin integrity. These findings support the anti-inflammaging and cellular anti-senescence potential of T. catappa fruit polyphenols encouraging their inclusion in anti-aging cosmeceutical formulations. • Total methanolic extract resulted in polyphenolic-enriched and ethanolic fractions • Identified 92 metabolites, mainly hydrolyzable tannins and triterpenes • PEF exhibited potent collagenase and elastase inhibitory activities in vitro • Topical 5% PEF gel in vivo revealed a significant anti-inflammatory effect • The study evidenced by biochemical and histopathological analyses in a mouse model