There are lots of exciting companies working in the aging field, and it’s a great time to tell you about three of the more interesting ones. Most of these companies are a while away from human trials yet, but their innovations could possibly be truly game changing.
Atherosclerosis is the number one killer worldwide, and it currently has no totally effective solution. There are three ways in which current medicine tries to address it: Lifestyle changes, including diet and exercise; drugs that slow down the rate of cholesterol accumulation; and interventions such as stents and bypass surgery.
None of these approaches really addresses the root problem nor cures the disease, which is why Underdog Pharmaceuticals’ proposal is so compelling.
Underdog is developing a therapeutic approach that could potentially prevent or reverse atherosclerosis by removing a harmful lipid known as 7-ketocholesterol (7KC) from the arterial walls.
What is 7-ketocholesterol?
7KC is a harmful, oxidized byproduct of cholesterol. It is highly toxic with no redeeming qualities; it serves no purpose in our bodies aside from allowing heart disease to develop. Once 7KC becomes lodged in the arterial wall and an atherosclerotic lesion begins to form, the immune system responds and sends specific immune cells, known as macrophages, as the cleanup crew to remove it.
Unfortunately, macrophages are unable to metabolize 7KC, but they keep absorbing it until they become bloated. At this point, they become “foam cells”, huge bloated cells that are unable to process waste at all and form a large part of what make up atherosclerotic plaques.
The bad news is that as these engorged foam cells become stuck in the arterial walls and slowly die, they call other macrophages to the scene; and these reinforcements become trapped as well. Ironically, in trying to fix the problem, our own cells become part of it.
Underdog is developing a therapy that could potentially remove 7KC from the bloated macrophages, allowing them to return to healthy function, by delivering them a molecule that can extract the oxidized waste.
The therapy is based on a variant of cyclodextrin, an existing drug that is already approved by the FDA and has a good safety profile. This should cut down on the time it takes to get the new therapy approved, and the company has a plan to reach human trials in the next three or four years. If successful, this would offer a way to reverse atherosclerosis and put an end to the number one global killer.
Juvena Therapeutics is a company focused on discovering and developing pluripotent stem cell-derived protein therapeutics; to put it another way, pluripotent stem cells secrete signaling proteins to other cells, causing them to regenerate and function like younger cells.
Rejuvenation using blood factors
While there are likely hundreds of signaling proteins involved in rejuvenation of tissue, the current evidence suggests that there are only a handful of primary signals that act like master regulators and orchestrate the entire process.
Juvena is working out which signaling factors are the most important to achieve this. Once the key signals that regulate rejuvenation are known, they could then be mass produced and used as a therapy in older people to spur the healthy regeneration of tissues and organs.
The company is focusing initially on sarcopenia, the age-related loss of muscle mass that leads to frailty and can result in lethal falls and serious injury in the elderly. Juvena is also looking at using these therapies for acute injury, trauma and wound healing for the elderly, who generally have poor tissue repair.
The unique drug discovery platform that the company has developed could allow it to target multiple tissues for whole body rejuvenation and to address things like neurodegeneration, cardiovascular disease, and lung fibrosis.
Revel Pharmaceuticals is another spin-off biotech company based on years of research funded by the SENS Research Foundation and conducted at the Spiegel Lab at Yale. This company is developing a therapy that can break down glucosepane cross-links in our tissues which form as we age and cause our arteries to stiffen.
What are cross-links?
A proposed reason why we age is the accumulation of sugary metabolic wastes known as advanced glycation end-products (AGEs). AGEs are harmful compounds that are created when proteins or fats combine with sugars in the bloodstream in a process known as glycation. AGEs can also be encountered in foods, particularly foods that have been exposed to high temperatures, such as in grilling or frying.
AGEs can cause random damage by altering protein structure and function, but the inflammation they cause is thought to be a primary contributor to the background of chronic, age-related inflammation typically seen in older people. AGEs contribute to a variety of microvascular and macrovascular complications via the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by interacting with the receptor for advanced glycation end products (RAGE).
This interaction with RAGE leads to oxidative stress and the activation of protein complex NF-?B, a master regulator of inflammation, DNA transcription, and cell survival. This activation leads to excessive levels of NF-?B activity and is thought to be responsible for AGE-associated inflammation and cellular damage.
High levels of AGEs are linked to a number of age-related diseases, including diabetes, heart disease, and Alzheimer’s. There is also evidence to support that people who have high blood sugar, such as people with diabetes, have a higher risk of producing more AGEs that can accumulate in the body faster than they can be cleared, thus contributing to the decline of multiple organs.
Our bodies have ways to eliminate these harmful compounds, including antioxidants and enzymes; however, these mechanisms have their limits, and if we consume too many AGEs, or too many appear through the normal operation of metabolism, they can begin to accumulate, leading to increasing numbers of cross-links, oxidative stress, and inflammation.
There are many types of AGEs, each with its own unique chemical composition. The body is able to remove some of them but lacks the biological tools needed to break down others; unfortunately, glucosepane falls into the latter category.
Glucosepane is the most abundant AGE in the body, and this particular AGE and its resulting cross-links cannot be broken down by the body at all. Instead, they continue to build up throughout our lives.
The Spiegel lab has been working on ways to break down AGEs, particularly glucosepane, for many years. This molecule has proven to be a considerable challenge, initially because it was hard to manufacture the substance outside the body in order to test interventions against it, and because doing so is simply difficult in general.
In 2015, this all changed when, thanks to funding from SENS Research Foundation, the Spiegel lab successfully developed a way to create glucosepane on demand. From there, the lab identified bacterial enzymes that could break down glucosepane cross-links, and now things have reached the point at which those enzymes are ready to be developed into a therapy.
Now that Revel Pharmaceuticals has been created, the race to develop glucosepane breakers and take them to market has finally begun. Of all the companies in this article, this one is likely to have the longest road to achieve its goal, but it is a goal that could be transformative in healthcare.
These three biotech companies are merely a fraction of the companies now working in this space, but we find them to be the most exciting because of what they are trying to achieve.