Fight Aging!

One of the ways in which cell damage characteristic of aging can provoke inflammation is via the mislocalization of DNA. Either nuclear DNA or mitochondrial DNA can find its way to the cytosol, where it can trigger responses evolved to detect bacterial or viral infection, or severe cell damage. This creates a cascade of downstream signaling leading to an inflammatory response. In youth these events occur comparatively rarely, and in circumstances wherein immune response and potentially even cell death are beneficial. With age, however, there is a continued mild but growing level of dysfunction and consequent sustained inflammation that is never fully resolved. Such continual inflammatory signaling is disruptive to cell and tissue function, and is thought to be an important contributing factor in degenerative aging.

In today's open access paper, researchers examine the contribution of nuclear DNA mislocalization to one specific form of heart failures://en.wikipedia.org/wiki/Heart_failure">heart failure, dilated cardiomyopathy, in which the heart becomes enlarged and weakened in response to poorly understood causes. The researchers examine human tissues with an eye to validating data obtained in animal models. The overall picture is that stress on cells in the heart leads to an excessive pace of DNA double strand breaks, which in turn enables DNA fragments to escape from the nucleus into the cytosol. There, the inflammatory reaction takes over. Sustained inflammation in turns drives the dysfunctional regulation leading enlargement and weakening of heart muscle. The degree to which this mechanism is important in humans might be determined via inhibition of specific parts of the cytosolic DNA detection mechanism, a test that might be readily carried out given funding and the will to try.

Cytosolic DNA sensing protein pathway is activated in human hearts with dilated cardiomyopathy

The genome is constantly exposed to numerous stressors, which induce DNA lesions, including double-stranded DNA breaks (DSBs). DSBs are the most dangerous, as they induce genomic instability. In response to DNA damage, the cell activates nuclear DNA damage response (DDR) and the cytosolic DNA sensing protein (CDSP) pathways, the latter upon release of the DSBs to the cytosol. The CDSP pathway activates NFκB and IRF3, which induce the expression of the pro-inflammatory genes. There is scant data on the activation of the CDSP pathway in human hearts with dilated cardiomyopathy (DCM).

To our knowledge, our study results are the first documentation of increased expression levels of the protein components of the CDSP pathway, namely CGAS, TBK1, RELB, P52, and P50 in the human heart samples from patients with heart failure due to DCM. These findings by showing the upregulation of expression of the CDSPs, including the components of the NFκB pathway, complement the previous data on the activation of the nuclear DDR pathway in human heart tissues from patients with DCM. The findings in the human heart samples, being devoid of the genetic manipulations, also give credence to the findings in the model organisms.

Collectively, the data implicate increased DSBs and activation of the DDR and CDSP pathways in the pathogenesis of the DCM and set the stage for further delineation of the pathogenic role of these pathways in human primary DCM. Given the salubrious effects of targeting the CDSP pathway in mouse models of DCM, the findings raise the prospects for targeting the activated CDSP pathways for the prevention and attenuation of the phenotype in human primary DCM. Given that cell stress, including transcriptional stress, is common to various forms of cardiovascular pathology, one may speculate that increased DSBs and activation of DDR and the CDSP pathways are pervasive and ubiquitous features of cardiovascular diseases.