Do the Hallmarks of Aging Make SENS? – SENS Research Foundation

Cyclarity’s approach is radically different from EDTA. Based on the toxic metal hypothesis, removing lead and cadmium from atherosclerotic lesions would be expected to slow the spread and exacerbation of atherosclerotic plaques and cool the fires of inflammation and oxidative stress in and around them. The results of TACT appear to tell us that EDTA therapy can do just that in diabetics after a heart attack; TACT2 will either confirm that idea or leave us with more questions.

By contrast, Cyclarity’s UDP-003 is designed to be nothing less than a small molecule LysoSENS therapy that directly removes some of the damaged cholesterol products that turn macrophages into foam cells and thus drive the core of ASCVD. If it works as expected based on studies to date, Cyclarity’s novel cyclodextrin will not just turn off the fan driving the flames of ASCVD, but will actually prevent and reverse atherosclerosis itself.

UDP-003 is a custom-built form of cyclodextrin — a complex barrel-shaped carbohydrate that can capture and securely lock away other molecules. The path to UPD-003 began with hydroxypropyl-beta-cyclodextrin (HBCD), a common cyclodextrin used in the food, cosmetics, and drug industries. In the 1990s, scientists showed that HBCD could capture not only cholesterol itself, but an especially toxic damaged form of cholesterol known as 7-ketocholesterol (7KC). And having captured it, HBCD could by its own action draw 7KC it out of foam cells in a dish.

7-ketocholesterol is a bad actor in aging: it appears to be a major villain in the dysfunction and death of the related cells in the eye whose downfall drives age-related macular degeneration (ARMD — the leading cause of blindness in people over the age of 65). More to our immediate point, 7KC is also poisonous to macrophages, and thought to be a key culprit in turning them into foam cells. In addition to 7KC being generated when the cholesterol carried by LDL particles is oxidized while mired in the complex structures of the inner artery wall, the macrophages themselves may unintentionally generate some 7KC  during the processing of cholesterol from engulfed LDL particles, possibly because their lysosomes contain reactive iron left over from degrading iron-containing proteins and organelles.

The major takeaway from all this is that removing 7KC from macrophages and other vulnerable cells offers a potential rejuvenation biotechnology to prevent and reverse ASCVD at its root, by maintaining and restoring the ability of arterial macrophages to process the cholesterol in LDL particles. Instead of seizing up under the burden of too much total and oxidized cholesterol and degenerating into foam cells bogged down in the very tissue they went in to rescue, arterial macrophages would continue protecting the arteries from LDL particles enmeshed in their inner walls, and then leave harmlessly when their job was done. Keeping macrophages clear of 7KC would also allow the secondary macrophages that enter the lesion to clear out dying foam cells to complete their work, speeding the regression of even established plaques.

Years after the first observation that HBCD could remove cholesterol and 7KC from foam cells, scientists showed that this same common cyclodextrin could potentially treat children with Niemann-Pick C1 disease (NPC), a terrible congenital disorder that prevents them from moving cholesterol out of their cells. And in mice, treatment with this cyclodextrin was able to reverse atherosclerosis in a mouse model of the disease.

So why aren’t we all mainlining HBCD? The main problem is that HBCD is a fairly sloppy molecule: it’s too prone to draw normal cholesterol out of the cell along with 7KC. That might seem fine: we’re used to thinking of cholesterol as a villain. But the fact is that cholesterol is an absolutely necessary molecule in our bodies: it’s essential for the normal structure and functioning of cell membranes, and it’s also the raw material from which our bodies synthesize a wide range of essential biomolecules, including vitamin D, sex hormones, and the stress-adaptation hormone cortisol.

The fact that HBCD will suck unmodified cholesterol out of any structure of the body results in some critical side effects that limit its use even in children whose NPC leads to severe neurological disease. Even at the doses currently used, most children treated for neurological complications of NPC with HBCD will develop some amount of hearing loss due to damage to the nerve cells in the inner ear.