The proteins and other constituents of our cells are all eventually damaged as the result of biochemical accidents that occur during normal metabolism, or simply outlive their usefulness. Cells have a variety of systems for breaking down and recycling such unwanted materials, allowing them to clear garbage out of the way and reuse the raw materials. One such system is the lysosome, a kind of cellular “incinerator” that contains the most powerful enzymes in the cell for breaking mangled molecules down into manageable pieces. However, sometimes these constituents are so badly fused together that not even the lysosome is able to tear them apart. And if something can't be broken down in the lysosome, there’s nowhere else for it to go: it just stays there until either the lysosome disastrously ruptures, or the cell itself is destroyed.
Over time, the material that the lysosome has been unable to break down accumulates inside of it, and eventually the rising buildup of such material begins to interfere with the lysosome’s function. This is an especially big problem for cells that have to last for a lifetime in our bodies, such as the cells that make up the heart or the back of the eye, and nerve cells in the brain and elsewhere. And of course, when the cell’s ultimate garbage disposal system starts malfunctioning, it impairs the function of the cell as a whole. And as more and more cells become dysfunctional over time, tissue function is impaired, and age-related disease sets in.
Consider what happens to macrophages, for example – the cells from the immune system that are responsible for protecting our blood vessels from being damaged by infiltrations of toxic byproducts of cholesterol. “Macrophage” means “big eater,” and these cells protect our arteries by surrounding and swallowing these toxic materials and then sending them to the lysosome, where they are thoroughly digested and their useful raw materials are released. But as macrophages consume more and more of these toxic materials, their lysosomes become engorged with byproducts they can’t break down. Eventually, they cease functioning, and either become immobilized and dysfunctional in the artery wall or die outright. This buildup of sick and dying macrophages is the basis of atherosclerosis, the plaques in our arteries that are responsible for heart disease. As their numbers gradually increase over time, the injury swells and festers until it eventually bursts, spewing out clots and other materials that trigger heart attacks and strokes.
Similarly, the inability of particular cells to break down their specific cellular waste products is also a key factor driving several types of neurodegenerative diseases (such as Alzheimer’s and Parkinson’s), as well as macular degeneration, which is the main cause of blindness in people over the age of 65. Thus, it's very important that we find a way to clean the decades of stubborn waste buildup out of these long-lived cells.
Since the root of the problem is that the lysosome is unable to break down all of these stubborn waste products, the most direct solution is to supply them with new enzymes that can degrade those wastes. And fortunately, we know that enzymes capable of breaking down these materials exist – specifically, in the soil bacteria and fungi that help to decompose dead bodies. If such enzymes didn’t exist, then the planet would be ankle-deep in the undegraded lysosomal wastes left over from the cells of 600 million years of animal life on this planet. So the idea would be to identify the enzymes these organisms use to digest lysosomal wastes, modify them a bit to help them work in the slightly different environment of the human lysosome, and then deliver them to where they need to go in our cells.
And there’s already a good proof-of-concept for the idea of using enzymes to treat diseases caused by accumulated lysosomal wastes: the use of “enzyme replacement therapy” in lysosomal storage disorders. Lysosomal storage disorders (such as Gaucher's disease) are rare congenital disorders, in which people are born lacking the ability to deal with some of the waste products that the rest of us easily metabolize. Many of these diseases are the result of the victims either lacking the gene for an enzyme that the rest of us use to degrade particular wastes in our lysosomes, or having mutated versions of those genes, resulting in enzymes that don’t work well. Today, many of these diseases are successfully treated by injecting patients with a version of the missing or defective enzyme that has been modified to travel through the cell membrane. Further work is underway to enable the affected cells to produce the enzymes themselves, using gene therapy.
What we need is an equivalent therapy for the diseases and disabilities of aging caused by the wastes that accumulate in the lysosome over time. One such therapy would deliver enzymes capable of breaking down toxic cholesterol byproducts to the macrophages in the artery wall. This would allow still-healthy macrophages to do a better job of removing toxic materials from the artery wall, while rehabilitating diseased macrophages trapped in atherosclerotic plaques, allowing them to mobilize out of the lesions. Nascent plaques would be prevented from happening, and existing ones would regress, allowing the diseased artery to heal. The same approach would similarly arrest and reverse the loss of the key cells in the back of the eye whose death or dysfunction causes the blindness of macular degeneration, and help restore normal function in neurons in Alzheimer’s, Parkinson’s, and other neurological disorders.
Enthusiasm for this approach mounted following the National Institute on Aging's sponsorship of the fourth SENS Roundtable, a meeting focused on this intervention which took place in July 2004, attended by high-caliber scientists who contributed to the discussion and signed on to the resulting detailed proposal for the development of the therapy. In the last few years, SENS Research Foundation has been able to fund scientific research on this kind of therapy internally at the Foundation’s Research Center and at several expert universities.
Research Funded by SENS Research Foundation
Current Research at the SRF Research Center
Degradation of A2E
Age-related macular degeneration is the leading cause of blindness in people over the age of 65. It is caused or exacerbated by the accumulation of A2E (a toxic byproduct of vitamin A metabolism) in the cells in the retina of the eye. A2E is resistant to breakdown in the lysosome, and therefore accumulates in the lysosomes of retinal pigment epithelial cells throughout life, until the cells become disabled and vision begins to fade. Enzymes that could break down A2E would thus lead to a regenerative cure for age-related macular degeneration. Scientists at the SRF Research Center are testing enzymes from private libraries and common commercial collections for their ability to maintain the health of cells loaded with toxic A2E.
Degradation of 7-Ketocholesterol
Atherosclerosis – the cause of most age-related heart attacks and strokes – is thought to result from the accumulation of cholesterol (and in particular, toxic oxidized byproducts of cholesterol) in immune cells maintaining the integrity of the arteries. Likely the most important of these oxidized cholesterol products is 7-ketocholesterol (7KC). Researchers at the SRF Research Center have identified several enzymes capable of degrading 7-KC; their results are now part of the basis for extramural LysoSENS work at Rice University (see below).
Funded Research in Outside Centers
Clearing cells of age-related wastes
At Rice University, SENS Research Foundation is funding research to identify, test, and improve the function of natural enzymes in the environment capable of degrading specific wastes, with a principal focus on atherosclerosis. Most recently, the Rice University team demonstrated that an enzyme from the soil bacteria Chromobacterium sp. DS1 effectively breaks down 7-ketocholesterol and protects human cells against its toxicity.
For a more in-depth account of aggregates accumulating inside cells and how to remove them, see the chapter “Upgrading the Biological Incinerators” in Ending Aging.