Dietary curcumin regulates hepatic cellular senescence in aged mice via p38‐MAPK activation pathway

Aging is a physiological decrease of several biological activities in an organ that all organisms go through. The presence of a gradual deterioration of cell functioning, due to damage accumulation in metabolic organs, accelerates biological aging. Recently, dietary interventions with food-active compounds have been linked to suppressing the accumulation of senescent cells and senescence-associated secretory phenotype (SASP). Curcumin has potent biochemical and biological activities, including antioxidant and anti-inflammatory actions. However, it largely remains unclear how curcumin has anti-aging properties such as protection of DNA damage and cell survival/cell fate decisions. The objective of this study is to examine the regulatory effect of dietary curcumin on hepatic cellular senescence in the aged mouse model. Aged (18-20 months old) male C57BL/6 mice were fed a normal chow diet (NCD) or NCD containing 0.4% (w/w) curcumin - equivalent to 2g/day for a 60 kg adult - (NCD+CUR), high fat high sugar diet (HFHSD) or a HFHSD+CUR (N=7-9 per group) for 15 weeks. Mice given an HFHSD supplemented with curcumin displayed a different metabolic phenotype compared to mice given an HFHSD alone. To examine the phenotypic plasticity led by transcriptomic alteration, we used RNA-Seq and analyzed differential gene expression in Gene Ontology (GO) terms and KEGG pathway analysis. There were 1687 and 3794 number of genes that showed a significant change with curcumin in NCD and HFHSD groups compared to their respective control groups. There were at least 8-fold higher uniquely upregulated and 6-fold uniquely downregulated genes in the HFHSD+CUR group when compared with their NCD counterparts. To this extent, curcumin supplementation altered hepatic gene expression profiling, especially in senescence pathways and their associated genes. Thus, to validate downregulation in senescence pathway involved genes from the RNA-Seq data results, we compared the distribution of hepatic senescent cells by β-gal staining in HFHSD groups. It revealed that HFHSD+CUR mice showed less density of the hepatic senescent cell (Figure A). We then mechanistically sought how curcumin regulates the hepatic senescence pathway. We found that curcumin supplementation decreased senescence effectors, specifically p38 and JNK protein expression levels in the liver (Figure B, C). Our findings suggest that the multifaceted therapeutic potential of curcumin can be used as a protective agent for age-induced metabolic diseases.