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Longevity Briefs: A Drug To Cleanse Arteries Of Fatty Plaques?

Posted on 22 February 2024

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Atherosclerosis is a condition in which plaque, made up of cholesterol, fat, calcium, and other substances, builds up inside the arteries, narrowing and hardening them. These plaques are time bombs within every person’s circulatory system: they tend to grow even with a healthy lifestyle and are extremely hard to shrink. Atherosclerosis is not only a major cause of death worldwide, but also a major contributor to ageing itself. Fatty plaques damage the blood vessels and the heart, and reduce blood flow to all the cells and tissues in the body. 

The root cause of atherosclerosis is the accumulation of oxidised cholesterol (a toxic form of cholesterol that cannot be degraded) within the walls of the blood vessels, combined with inflammation. Current treatments for atherosclerosis, such as statins, blood pressure drugs and surgery, only slow the progression of the disease and reduce the probability of complications. It would be far better if we could actually reverse atherosclerosis by removing existing oxidised cholesterol from the arteries. This would not only prevent complications, but would probably improve general health and delay ageing in other tissues and organs that suffer from reduced blood supply in old age, such as the brain.

The discovery:

Cyclarity Therapeutics is a biotechnology company that is developing a true disease-modifying drug for atherosclerosis (that is to say, a drug that reverses the disease itself, rather than limiting its damage). The key to this effort is a class of drug called cyclodextrins – ring-shaped molecules that can bind and transport other molecules. Cyclarity Therapeutics has designed custom-engineered cyclodextrins that can specifically target and remove oxidised cholesterol from the cells in the arterial walls, thereby restoring their function and shrinking plaque. 

With the help of machine learning, computational and synthetic chemistry tools, the company created and tested thousands of cyclodextrin candidates for effectiveness and toxicity. Their lead product, UDP-003, has shown promising results in preclinical studies and is ready to enter clinical trials relatively soon. The first trial will take place in Australia with just 12 participants, and will mainly test safety. If all goes well, another larger trial should take place in the UK.

The implications:

Dr. Matthew O’Connor, the CEO of Scientific Affairs at Cyclarity, thinks that UDP-003 might reduce the risk of strokes and heart attacks by as much as 80%. Even if effectiveness is only half that, it will be compelling evidence that targeting the root causes of ageing is a more effective approach than treating age-related diseases individually as they occur, a shift in thinking that proponents of rejuvenation research have been arguing for many years. What’s more, UDP-003 should hopefully clear oxidised cholesterol wherever it occurs throughout the body, thereby preventing other diseases such as neurodegenerative diseases, macular degeneration, lung disease and chronic kidney disease, though these won’t be looked at initially.

UDP-003 isn’t the first attempt at treating atherosclerosis by removing compounds involved in plaque formation. A controversial treatment called EDTA chelation has been under investigation for decades, and supposedly works by binding to toxic metals and to calcium in the bloodstream. The evidence in favour of EDTA is shaky, but this treatment is fundamentally different to UDP-003 for several reasons. Firstly, while the minerals and metals that EDTA binds do form part of the plaque, they are a small component in comparison to the oxidised cholesterol that UDP-003 will remove. What’s more, nobody knows if EDTA actually removes material from the plaque, which is what UDP-003 is specifically designed and proven to do in preclinical studies. 

So, there’s reason to be optimistic that UDP-003 could be a significant step forward in the treatment of not only atherosclerosis, but age-related disease in general. Though of course, even the best-designed drugs rarely survive contact with humanity…

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    Title image by DALL E 3

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