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.