DNA Demethylase Activation via Klotho Reduces Arterial Stiffening in Mice
Age-related hypertension is largely a consequence of arterial stiffening, as the loss of elasticity causes the evolved feedback mechanisms that control blood pressure to run awry. For the causes of blood vessel stiffening, we can look at, for example, cross-linking in the extracellular matrix, and senescent cells and other sources of inflammation producing calcification in blood vessel walls. Other sources of dysfunction appear to involve more complex and poorly understood changes in cell behavior, however. This includes the failure of vascular smooth muscle tissue to contract and dilate appropriately, and alterations in the activities of cells responsible for maintaining the structure of the extracellular matrix that determines the physical properties of blood vessel walls.
Changes in cell behavior are more complicated than purely chemical processes such as cross-linking, but also more comfortable for researchers used to the present dominant approach in medical research, which is to deliver new instructions to cells, in an effort to partially override their reaction to damage and the aged environment. The open access paper here is an example of the type. Benefits can be achieved in this way, as the stem cell research community has demonstrated over the past few decades, even though it is not the most optimal path forward for the treatment of aging. Override one narrow reaction to underlying damage, and the damage is still there, still causing all of its other secondary and later problems.
DNA demethylation is an important process that maintains transcriptional activity of genes. An increase in methylation in the promoter region of a gene diminishes the promoter activity and gene transcription. Numerous studies showed that DNA methylation is increased with age. Coincidently, the prevalence of arterial stiffness and hypertension also increases with age. Arterial stiffening is an independent predictor of cardiovascular outcomes, such as hypertension, myocardial infarction, cognitive decline in aging, stroke, and kidney diseases. However, the relationship of DNA methylation and aging-related arterial stiffening is unclear. Whether increased methylation led to arterial stiffening has never been determined. Physiologically, an appropriate methylation level is maintained by the balanced methyltransferase and demethylase activity. In this study, we assessed if activation of the demethylase affects arterial stiffening and hypertension in aged mice.
The Klotho gene was originally identified as a putative aging-suppressor gene in mice that extended lifespan when overexpressed and caused multiple premature aging phenotypes when disrupted. The Klotho level decreases with age, while the prevalence of arterial stiffness and hypertension increases with age. At age 70 years, the serum level of Klotho is only about one half of what it was at age 40 years. Moreover, the serum Klotho level is significantly decreased in patients with arterial stiffness in chronic kidney diseases. Our recent study showed that haplodeficiency of Klotho gene caused arterial stiffness. We found, in cultured renal tubule cells, that a small compound (compound H) may be a potential inducer of Klotho gene expression. Whether compound H promotes Klotho expression and release in vivo has never been determined. In this study, we investigated whether compound H increases Klotho levels and attenuates aging-associated arterial stiffening and hypertension.
Our results demonstrated that aging-related arterial stiffening and hypertension are attributed, at least in part, to the increased DNA methylation. Compound H activates demethylases and attenuates arterial stiffening and hypertension in aged mice likely via increasing the Klotho levels. Aging-related arterial stiffness was associated with accumulation of stiffer collagen and degradation of elastin. These changes were effectively attenuated by compound H, suggesting rejuvenation of aged arteries.