(P23-046-23) Dietary Curcumin Downregulates the Hepatic Cellular Senescence Pathway and Alters Gut Microbiota Composition in Aged Mice

Objectives: Aging is a time-dependent functional decline that causes cellular senescence in metabolic organs and dysbiosis, an imbalance of gut microbial community, eventually inducing age-related metabolic disorders. Curcumin (CUR), the primary curcuminoid of turmeric, is well-known for its antioxidant and anti-inflammatory effects, but it is still unclear whether CUR has anti-aging properties and modulates gut microbiome. This study aimed to explore the role of CUR on hepatic cellular senescence and gut microbiota composition in a diet-induced obesity (DIO) aged mouse model.

Methods: 18 to 20-month-old male C57BL/6 mice were fed a normal chow diet (NCD), a NCD with 0.4 % (w/w) CUR (NCD+CUR), a high-fat high-sugar diet (HFHSD), or an HFHSD+CUR (n = 7–9 each) for 15 weeks. To identify the differentially expressed genes (DEGs) in the liver, we used RNA-Seq based on the Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. For validation of hepatic transcriptomic data, we conducted qPCR to analyze senescence-associated secretory phenotypes (SASPs) and immunoblotting to detect proinflammatory proteins. Fecal samples before and after CUR supplementation were collected for 16S rRNA sequencing.

Results: Of 157 combined senescence gene lists from GO term and KEGG pathway analysis, 75 genes showed significant changes in CUR-fed mice compared to the controls, and most of these genes were downregulated in the HFHSD+CUR group. Based on these findings, we validated hepatic senescence markers and found CUR suppressed the phosphorylation of nuclear factor-κB (NF-κB), a downstream transcription factor of p38-MAPK, and inhibited the mRNA expressions of SASPs (Cxcl2, Cxcl10, IL-6, FoxO3). In 16S rRNA results, the abundance of Bacteroides, known to be increased in aging, was depleted in both NCD+CUR and HFHSD+CUR mice. Also, CUR enhanced amplicon sequence variants (ASVs) belonging to Akkermansia, a commensal bacterium that improves gut inflammation.

Conclusions: This study provides a potent anti-aging mechanism of curcumin in which gene and protein expression levels related to the hepatic cellular senescence pathway are suppressed and gut microbiome homeostasis is maintained.

Funding Sources: This study was supported by the NIA Intramural Research Program (IRP) and the OTTOGI HAM TAIHO Foundation.