Today's open access paper focuses on albumin and is a great example of the role played by oxidation of proteins in aging, the way in which it can act as a link between fundamental damage and secondary damage, and between damage in one location in the body and consequences in another. Oxidation of many common proteins increases with advancing age, firstly because more oxidation is taking place due to damaged or overactive cellular processes, and secondly because the systems intended to clear out oxidized proteins become damaged and less efficient themselves. All proteins are in effect small machines, or interchangeable parts of larger assemblies of machinery, and when altered by oxidative reactions they tend not to work properly, causing a chain of localized malfunctions. Cells react to the presence of this type of damage with increased housekeeping or calls for help to the immune system, but higher levels of such damage can tip matters over into serious dysfunction, chronic inflammation, and the creation of senescent cells, among other consequences, contributing to the progression of aging and age-related diseases.
Oxidation of proteins that are carried far and wide in the blood stream, like albumin, is one of the ways in which localized age-related cellular damage can produce global consequences throughout the body. Take damage to mitochondrial DNA, for example. As we age, a small but significant fraction of our cells become taken over by dysfunctional mitochondria as a result of rare mutational damage to their DNA. Most such damage is repaired very rapidly, but large deletions can cause a form of malfunction that makes mitochondria more resistant to removal by quality control mechanisms. Cells packed full of these broken mitochondria become dysfunctional themselves, exporting reactive oxidizing molecules in large volumes into the surrounding tissues. Some will react with proteins in the bloodstream, and those oxidized proteins will most likely end up stuck in a blood vessel wall somewhere, irritating the local environment. This is how atherosclerosis starts and is reinforced: damaged proteins to start with, followed by an overreaction on the part of local cells, then immune cells pile in, and a growing local disaster zone of inflammation, dying cells, and continued signals for help is created. Ultimately this creates fatty plaques that remodel and narrow blood vessel walls, causing cardiovascular disease at best, and which at worst can fragment to block vital blood vessels, causing death or serious injury.
This unfortunate set of circumstances is one of the reasons why repairing broken mitochondria is an important component of any comprehensive future toolkit of rejuvenation therapies. There are numerous possible approaches to that goal, most of which are either nearly or actually possible today, at least in cell cultures. For a decade or so the SENS Research Foundation has championed allotopic expression, creating copies of mitochondrial genes in the cell nucleus as backups, so that the necessary protein machinery will be created and delivered to mitochondria regardless of damage to the mitochondrial genome. Today Gensight is developing this technology for a single mitochondrial gene, while the SENS Research Foundation is moving more slowly, and with much less funding, towards completing the necessary groundwork for all thirteen genes of interest.
Aging is associated with well-known changes in protein conformation that are involved in aging-related disease. Among this modification, probably the protein oxidation is the most relevant mechanism of pathogenesis in the elderly subjects. Oxidative modifications generally cause loss of catalytic or structural function in the affected proteins; it is likely that the level of oxidatively modified proteins observed during aging will have serious deleterious effects on cellular and organ function. Proteins are major targets for reactive oxygen species (ROS) because of their abundance in biological systems. In addition, proteins are primarily responsible for most functional processes within the cells. The major protein present in the plasma is albumin, which constitutes ~55% of the plasma proteins. As a result, it is most susceptible to suffer an oxidative process. In this manner, the oxidation of albumin may cause endothelial damage. Nevertheless, there are no studies analyzing the effects of oxidized albumin in aging, and as a consequence endothelial damage.
It is now recognized that the oxidative modification of proteins by reactive species, especially ROS, is implicated in the progression of an important number of diseases. Compared to control samples, proteins are more oxidized in tissues of animals and patients suffering from many of the age-related diseases. Cardiovascular diseases show a significantly elevated mortality in elderly patients and have been associated with endothelial cell injury. Furthermore, cardiovascular diseases have been proven to cause a decline in endothelial function. In addition, oxidized proteins have been demonstrated to be a critical contributor to the development of atherosclerosis, contributing to the formation, progression, and complications of atherosclerotic plaques. Noteworthy, in another study, oxidized proteins lead to endothelial dysfunction. As a result, there is great interest in studying new target therapies to prevent or reverse the aging-induced oxidative stress in endothelial cells.
The mechanism by which endothelial cells undergo senescence is still largely unclear and yet to be discovered. Although this mechanism probably involves a multifactorial response, oxidative stress has been proposed as a mediator to explain the process of cellular senescence. Oxidative stress is characterized by excess free radical activity and plays an important role in the oxidation of proteins. Several studies have implicated the oxidation of low-density lipoprotein (LDL) in atherosclerosis. However, there is no evidence that relates the oxidized albumin, which is the most abundant protein in serum, with endothelial injury. Therefore, in this study, we investigated whether aging induced an increase in oxidized protein and whether oxidized albumin may be involved in aging-related endothelial damage.
Endothelial microparticles (EMPs) have been used as biomarkers of cell damage and activation. These are a heterogeneous population of small membrane fragments shed from various cell types. The endothelium is one of the primary targets of circulating microparticles, and microparticles isolated from blood have been considered biomarkers of vascular injury and inflammation. In this study, oxidized albumin-treated human umbilical vein endothelial cells (HUVECs) cause the release of EMPs and an increment of apoptosis levels. These findings support the idea that the endothelial cells are suffering from an endothelial activation, which is an apoptosis phenomenon not observed with native albumin treatment. Recent evidence also suggests that the endothelial cell is damaged as a consequence of cardiovascular disease. Furthermore, released EMPs are considered a marker of endothelial damage in patients. Several studies have demonstrated that adhesion molecules are secreted by activated endothelial cells and contributed to endothelial cell injury. Supporting this, our results demonstrate an increase of VCAM-1 and ICAM-1.
In addition, other studies have indicated the increase of modification proteins may be associated with oxidative stress development in aging. In this regard, there is a wealth of data evidencing the fact that protein modifications cause ROS production. As the results showed, oxidized albumin results in ROS production increment in endothelial cells as well as in the amount of ROS per cell. The enhancement of oxidative stress is considered a key mechanism in cellular senescence development. In this study, the upregulation of ROS induced by oxidized albumin is correlated with an increase in the number of senescent cells. These data support the idea that the oxidized albumin may be considered a cardiovascular risk factor to induce oxidative stress. As a consequence, the cell may suffer senescence processes to prevent a possible damage due to oxidative stress. Research is needed to explore the possibility of utilizing oxidized albumin as a potential therapeutic target.