Researchers publishing in Aging Cell have discovered how and why oleuropein (OLP), a polyphenol derived from olives, ameliorates epigenetic kidney aging.
Upregulation and downregulation
Like nearly everything in biology, this specific part of kidney aging results from a chain of events. Here, the researchers show that DNA methyltransferases (DNMTs), which methylate and thereby epigenetically suppress genes [1], are responsible for suppressing NRF2 and KLOTHO, two beneficial and antioxidant genes known to mitigate multiple aspects of aging [2,3], in the kidneys. This aspect of aging is suppressing the genes that fight other aspects of aging.
As the first step in demonstrating this, the researchers examined the kidneys of both naturally aged mice and mice that were artificially aged through the application of D-galactose (D-gal). In both sets of mice, KLOTHO and NRF2 were significantly downregulated. Fibrosis went up, macrophage infiltration went up, and the senescence marker SA-ß-gal was increased as well.
The researchers also analyzed DNMT levels in both sets of mice. Unsurprisingly, DMNTs and DNA methylation were elevated in both mouse models of aging. At 7 months in wild-type mice, DMNT1 was shown to be elevated; at 16 months, and further at 25 months, DMNT3a and DMNT3b were elevated as well. This was directly correlated with the decline in NRF2 and KLOTHO expression, whose gene sites were found to be heavily methylated.
Suppressing the suppressor
To determine a causal relationship between methylation and gene expression, and hopefully combat this aging, the researchers examined the effects of the synthetic drug SGI-1027 along with the potentially less cytotoxic OLP.
Both treatments worked as intended. Renal (kidney) DNA methylation was significantly decreased with both interventions, more so for SGI-1027 than OLP. Mice given both D-gal and OLP were shown to have only slightly higher amounts of DMNTs than control mice. The suppressor had been, itself, suppressed.
The researchers confirmed their findings by examining the downstream effects. As expected, NRF2 and KLOTHO expression were restored. The associated markers of kidney function were also restored: macrophage infiltration was largely absent; levels of blood urea nitrogen and creatinine, two markers of kidney function, became closer to those of control mice; fibrosis was significantly reduced. As a whole, the intervention was shown to be highly effective in this model.
The researchers then broke this causal chain in multiple places to prove its existence. First, they showed that using dimethyloxallyl glycine to suppress the effects of SGI-1027 and OLP on DMNT (suppressing the suppressor of the suppressor) prevented the positive changes. They also used silencing RNA to render mice deficient in KLOTHO, and these mice did not benefit from this treatment.
Conclusion
As usual, while the results were stark and highly significant, this was a mouse study. While a human study is much more expensive and involved, the significance of these results suggests that a clinical trial of OLP’s effects on kidney function might be the first step in bringing a potentially effective treatment to market, alleviating the suffering of a great many people suffering from renal disease.
Literature
[1] Maunakea, A. K., Nagarajan, R. P., Bilenky, M., Ballinger, T. J., D’Souza, C., Fouse, S. D., … & Costello, J. F. (2010). Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature, 466(7303), 253-257.
[2] Silva-Palacios, A., Ostolga-Chavarría, M., Zazueta, C., & Königsberg, M. (2018). Nrf2: Molecular and epigenetic regulation during aging. Ageing research reviews, 47, 31-40.
[3] Kim, S. J., Cheresh, P., Eren, M., Jablonski, R. P., Yeldandi, A., Ridge, K. M., … & Kamp, D. W. (2017). Klotho, an antiaging molecule, attenuates oxidant-induced alveolar epithelial cell mtDNA damage and apoptosis. American Journal of Physiology-Lung Cellular and Molecular Physiology, 313(1), L16-L26.
