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