Aging-associated intestinal dysfunction impairs 5-heptadecylresorcinol absorption: Mechanistic insights into transporter-mediated uptake, barrier integrity and inflammatory regulation

5-heptadecylresorcinol (AR-C17), a key bioactive component of whole grain (WG) wheat and rye, has been shown to exhibit anti-aging properties. However, the intestinal absorption dynamics of AR-C17 across different intestinal segments, as well as the aging-dependent differences in absorption between young and aging mice and their underlying mechanisms, remain poorly understood. In this study, we systematically evaluated AR-C17 absorption in various intestinal regions using an Ussing chamber system and elucidated potential contributing factors. Our results revealed that the jejunum and ileum served as the principal sites for AR-C17 absorption, with total absorption rates (TAR) reaching approximately 60 % in young mice. Conversely, aging mice exhibited significantly diminished AR-C17 absorption, with TAR values reduced to 20-45 % in these segments. Aging-associated alterations in key absorption parameters-including apparent permeability coefficient, transmucosal resistance, and short-circuit current-were observed during AR-C17 absorption, ultimately leading to reduced uptake in aging mice. Histopathological analysis demonstrated aging-associated structural deterioration, characterized by villus damage with irregular crypt architecture in the jejunum and villus vacuolization in the ileum. These morphological changes were accompanied by downregulated expression of Oct1 in the jejunum and Octn2 in the ileum, which collectively contributed to impaired AR-C17 absorption in aging mice. Further mechanistic investigations indicated that the differential absorption of AR-C17 between young and aging mice was closely associated with alterations in transmembrane transporters, inflammation, and tight junction. This study provided compelling evidence that aging-associated intestinal dysfunction significantly attenuated AR-C17 absorption, providing novel insights for optimizing the bioavailability of WG-derived bioactive compounds in the elderly.