The Dietary Polyphenol Epigallocatechin Gallate Delays Biological Aging by Activating Peroxisome Biogenesis and Peroxisomal Fatty Acid β‐Oxidation

ABSTRACT

Epigallocatechin gallate (EGCG), a major tea polyphenol, has been proposed to promote healthy aging, but population‐level evidence and underlying mechanisms remain unclear. We analyzed 10,977 participants from the National Health and Nutrition Examination Survey (NHANES) and conducted mechanistic studies in Caenorhabditis elegans and AML12 hepatocytes. Compared with non‐consumers, both lower and higher EGCG intake categories were associated with lower PhenoAge acceleration, lower all‐cause mortality, and higher estimated residual life expectancy. In C. elegans , EGCG supplementation extended lifespan and health span. Transcriptomics revealed upregulation of peroxisome‐related genes. EGCG enhanced peroxisome biogenesis, as shown by increased peroxisome abundance, elevated prx‐5 and prx‐19 mRNA levels, and increases in PRX‐5 and PRX‐19 proteins. This increase in peroxisome capacity was accompanied by enhanced peroxisomal fatty acid β‐oxidation, with increased mRNA levels of acox‐1.2 , acox‐3 , and dhs‐28 , increased ACOX‐3 protein, and reduced very long‐chain fatty acids (VLCFAs). Lipidomics showed enhanced processing of VLCFAs and accumulation of shorter‐chain intermediates. Knockdown of prx‐5 , acox‐1.2 , or dhs‐28 abolished EGCG‐induced lifespan and health span benefits. In doxorubicin‐induced senescent AML12 hepatocytes, EGCG reduced the proportion of SA‐β‐gal‐positive cells and decreased p21 and p16 protein levels, while increasing peroxisome abundance and peroxisome‐related proteins, including the biogenesis factors PEX5 and PEX19, the membrane transporters ABCD1 and PMP70, and the β‐oxidation enzymes ACOX1, HSD17B4, EHHADH, and ACAA1. Conversely, the anti‐senescent effects of EGCG were attenuated by Pex5 or Acox1 knockdown. Collectively, dietary EGCG intake is associated with slower biological aging, while experimental findings support peroxisome biogenesis and peroxisomal fatty acid β‐oxidation in EGCG‐mediated anti‐aging effects.