DNMT inhibitors/activators [do they increase/decrease epigenetic aging *and* rate of aging?]

We illustrated the utility of ClockBase by discovering zebularine, a potent DNMT inhibitor, which affects the methylation status of the samples by directly targeting the DNA methylation machinery 44. Our data suggest that zebularine is a candidate longevity intervention, as it significantly reduced the epigenetic age of cultured cells based on almost all clock models. However, as zebularine affects the DNA methylation machinery, DNA methylation clocks should be used with caution. Further investigation and in vivo studies are required to understand the role of zebularine in the aging process.

But so many ppl advocate “pro-methylation agents” like Kara Fitzgerald (eg advocating diets full of methyl donors). I know MANY scientists have issues with Kara’s research however.

I know aging is ON AVERAGE associated with global hypomethylation of CpGs [directionality might be wrong, need to look up] and global hypermethylation of CpG promoters but the directionalities are everywhere

Epigenetic cues upregulate DNMT1, DNMT3a, and
DNMT3b, resulting in the promoter hypermethylation and expression
suppressions of KLOTHO and NRF2, which accelerate D-gal-induced renal
aging. DNA hypomethylations by DNA-demethylating agents correct the
epigenetic alterations, recover the of KLOTHO and NRF2 losses, and
reduce the renal aging alterations.

The genomic hypomethylation hypothesis of aging proposes that an overall decrease in global DNA methylation occurs with age, and it has been argued that the decrease in global DNA methylation could be an important factor in aging, resulting in the relaxation of gene expression regulation and abnormal gene expression.Jan 24, 2018


Revisiting the genomic hypomethylation hypothesis of aging

National Institutes of Health (.gov)
https://www.ncbi.nlm.nih.gov › articles › PMC5934293
](Revisiting the genomic hypomethylation hypothesis of aging - PMC)

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