Inhibition of DNA methyltransferase aberrations reinstates antioxidant aging suppressors and ameliorates renal aging

DNA methylation alterations play mechanistic roles in aging; however, the epigenetic regulators/mediators causally involved in renal aging remain elusive. Here, we report that natural and D‐galactose (D‐gal)‐induced aging kidneys display marked suppression of antiaging factor NRF2 (nuclear factor erythroid‐derived 2‐like 2) and KLOTHO, accompanied by upregulations of DNA methyltransferase (DNMT) 1/3a/3b and NRF2/KLOTHO gene promoter hypermethylations. Administration of a DNMT inhibitor SGI‐1072 effectively hypomethylated the promoters, derepressed NRF2/KLOTHO, and mitigated the structural and functional alterations of renal aging in D‐gal mice. Moreover, oleuropein (OLP), an olive‐derived polyphenol, also displayed similar epigenetic modulation and antiaging effects. OLP inhibited the epigenetic NRF2/KLOTHO suppressions in a gain of DNMT‐sensitive manner in cultured renal cells, demonstrating a strong DNA‐demethylating capacity. In NRF2 knockout and KLOTHO knockdown D‐gal mice, OLP exhibited reduced antiaging effects with KLOTHO displaying a prominent gene effect and effect size; consistently in KLOTHO knockdown mice, the antiaging effects of SGI‐1027 were largely abrogated. Therefore, the KLOTHO recovery is critical for the antiaging effects of DNA demethylation. Collectively, our data indicate that aberrant DNMT1/3a/3b elevations and the resultant suppression of antiaging factors contribute significantly to epigenetic renal aging, which might be targeted for epigenetic intervention by synthetic or natural DNA‐demethylating agents.