Evidence for 7-Ketocholesterol Accumulation to Contribute to Heart Failure

The processes of cellular maintenance decline in effectiveness and activity with age, and this leads to a form of garbage catastrophe, a feedback loop of dysfunction and failure that starts with recycling systems. Metabolic waste accumulates constantly in cells, but is also cleared out constantly. Unfortunately, some fraction of that waste is made up of compounds that our biochemistry is not well equipped to handle. The maintenance process of interest here is autophagy, in which unwanted cell structures and other molecules are tagged and delivered to one of the cell's lysosomes to be broken down and recycled. Resilient forms of unwanted compound still end up in the lysosomes, and there they accumulate because they cannot be effectively broken down. As a result, the lysosomes in old tissues become bloated and dysfunctional, and this is particularly noteworthy in tissues with comparatively little cell replication and turnover, such as the nervous system and heart muscle. In turn, this means that recycling of other garbage declines.

What I have just described is one of the root causes of aging: a process that operates in a normal, youthful metabolism and acts to gradually destroy its function. There are other root causes of aging, but in this case the best way forward to rejuvenation therapies is to identify the problem metabolic waste compounds and then develop therapies to safely break them down. Periodic application of these therapies would hold back this contribution to the aging process indefinitely. Unfortunately there are a sizable number of these compounds, and so this task will keep the research community busy for a while, assuming they ever get around to getting started in a meaningful way. For now, progress is carried forward by just a few researchers through philanthropic funding, led by the SENS Research Foundation and a couple of allied research groups. We can hope that the compounds they have identified - and found candidate drugs to clear - are among the more important.

One of these compounds is 7-ketocholesterol, a form of cholesterol damaged by being oxidized. Oxidization is a common theme among the problem compounds that show up in old lysosomes. If you look at the literature, you will find that 7-ketocholesterol is implicated in all sorts of dysfunction in aged tissues. One of the most prominent conditions in which it plays a part is atherosclerosis, the irritation of blood vessel walls that grows inexorably into inflammatory, fatty plaques, and eventually causes death due to blood vessel or plaque rupture. The SENS Research Foundation uncovered potential drug candidates for 7-ketocholesterol a few years ago, and that work is being carried forward by human.bio, though with no public indications of progress since then. In the open access paper below, the authors provide evidence linking the presence of 7-ketocholesterol and other oxidized metabolic waste compounds to heart failure. This is yet another reason, atop all of the existing data, to support greater efforts to develop a means to safely break down these unwanted, harmful compounds.

Lipidomics reveals accumulation of the oxidized cholesterol in erythrocytes of heart failure patients

Cardiovascular disease is a major health problem and the leading cause of death globally. Cardiac function deterioration hampers the ability of the heart to support blood circulation, resulting in heart failure (HF). The pathogenic mechanism leading to this end stage is complicated. Myocardial infarction, hypertension, cardiomyopathy, valvular heart disease, and inflammation-induced oxidative stress are known risk factors for disease progression.

Changes in metabolites have been identified in plasma and are associated with clinical outcomes in patients with HF. These findings suggest that metabolic remodeling in patients may occur during HF progression, and the metabolite profile can thus be used as a biomarker panel for a variety of assessment purposes. Lipid metabolism alterations have been increasingly demonstrated to underlie the pathogenesis of cardiovascular disease. Currently, research on lipids has focused on the analysis of plasma lipids such as cholesterol, triacylglyceride, and phospholipids. Reports seldom indicate specific fatty acids and total cholesterol in erythrocytes (red blood cells) as a predictor of cardiovascular events. Given the relatively long life (approximately 120 days) of erythrocytes, any change in the lipid profile of erythrocyte membrane may reflect pathophysiologic changes associated with disease progression.

Few studies have reported on the comprehensive assessment of the metabolome and lipidome of erythrocytes, especially in the scenario of HF. The aim of this study was to identify lipid profiles of HF erythrocytes using high-throughput liquid chromatography time-of-flight mass spectrometry. Our findings suggested that the erythrocyte lipid profiles of patients with HF were significantly different from those of normal subjects. The levels of phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), and sphingomyelins (SMs) decreased in HF erythrocytes. However, the levels of lysoPCs, lysoPEs, and ceramides increased in these cells. Of these lipids, 7-ketocholesterol (7KCh) accumulated in the erythrocytes of patients with HF. This accumulation may be of significance as a potential discriminator and as a player in the pathogenesis of HF. At molecular level, we demonstrated that intracellular 7KCh accumulation caused reactive oxygen species (ROS) formation and cardiomyocyte death.

Chronic inflammation is associated with HF progression. A number of proinflammatory cytokines, such as tumor necrosis factor α, interleukin (IL)-1, and IL-6, were implicated in this process. In general, chronic inflammation leads to increased oxidative stress and damage and probably accounts for some of the observed changes in HF erythrocytes. Oxidative stress induces phospholipase activity, which leads to a decline in phospholipid levels and an increase in lysophospholipids levels. Moreover, 7KCh, an oxidation product of cholesterol, accumulates as a consequence of oxidative stress. Previous studies have revealed that oxidative damage products, such as oxidized LDL and oxysterols, are found in patients with cardiovascular disease. 7KCh is considered an important metabolite for monitoring cardiovascular disease outcomes and mortality as well as for predicting the incidence of cardiovascular disease events in general population. Accumulation of 7KCh in HF erythrocytes suggests that 7KCh is a risk factor for HF, with a potential for clinical applications.

Comments

I find it a bit worrying that human.bio have been quiet for years on end now.

Posted by: Jim at November 7th, 2017 7:17 AM

@Jim: silence is very much in character for the owner, but yes, probably a sign that there wasn't a quick path forward. For the other side of the coin, it did require some effort on the part of Ichor Therapeutics to progress beyond the enzymes produced by the LysoSENS program to a viable candidate for development as LysoClear - it wasn't an immediate and obvious path ahead.

Posted by: Reason at November 7th, 2017 1:11 PM

The last paragraph in the article has to do with the problem of chronic inflammation regarding HF progression. They name some of the pro-inflammatory cytokines implicated in this process including Tumor necrosis factor alpha, and interleukin IL-1 and IL-6. It so happens that there are longevity alleles for SNP's for each of these cytokines. For TNFa rs1800629 and rs351525 you want to be homozygous for the G alleles, for IL-1a rs16944 you want to be homozygous for the A allele, for IL-1b rs1143634 you want to be homozygous for the G allele, and for Il-6 rs1800795 you want to be homozygous for the longevity allele C. I happen to have all of the above longevity alleles. Perhaps in the future, with CRISPR technology, you could have the longevity alleles transplanted to your genome if you do not have them.

Posted by: Biotechy at November 7th, 2017 5:20 PM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.