International Journal of Molecular Sciences · Nov 3, 2026
Metabolic Rewiring by Pomegranate Juice and Punicalagin Is Associated with NHR-49/MDT-15-Related Responses and Enhanced Stress Resilience
By Todorova MN, Binev BK, Ploumi C et al.
Metabolic homeostasis is a key determinant of stress resilience and healthy ageing. Pomegranate juice (PGJ) and its characteristic ellagitannin punicalagin (PUN) have been associated with beneficial metabolic effects, but the mechanisms through which they influence metabolic adaptation and healthspan, and whether they act through shared or distinct pathways, remain poorly defined. We investigated the effects of lyophilized PGJ (50, 100, and 200 μg/mL) and PUN (25, 50, and 100 μM) on metabolic regulation and stress resilience in Caenorhabditis elegans. Nuclear magnetic resonance spectroscopy was employed for metabolic profiling of PGJ, whereas ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry enabled the quantification of PUN at 2.4 ± 0.127 µg/mg lyophilized juice. Under glucose-enriched conditions, PGJ (200 μg/mL) and PUN (100 μM) reduced normalised Nile Red fluorescence to 0.53 and 0.59 of vehicle levels. On day 10 of adulthood, both treatments increased mean survival under oxidative stress by 1.73- and 1.50-fold, respectively. Both treatments increased MDT-15 reporter response (1.13- and 1.44-fold, respectively), whereas PGJ preferentially increased AAK-2- and FAT-6-associated responses and PUN elevated NHR-49- and FAT-7 expression. PUN also improved locomotor performance under amyloid-β-induced proteotoxic stress. Overall, PGJ and PUN elicited partially overlapping metabolic responses in C. elegans, with NHR-49 and MDT-15 emerging as treatment-responsive regulators associated with lipid homeostasis.