Progress in LysoSENS: Bacterial Enzymes Deployed in Cell Culture to Break Down 7-Ketocholesterol
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LysoSENS is the oldest extant research program of the SENS Foundation, started back when the SENS program ran under the auspices of the Methuselah Foundation. In brief, LysoSENS is the development of a means of biomedical remediation. A whole range of harmful metabolic byproducts build up in human tissue with age, and we lack the means to break them down, or break them down fast enough. Some of these compounds simply cause harm, while others actually progressively impair the ability of cells to remove any unwanted chemicals, leading to what is known as the garbage catastrophe in aging - cells overwhelmed with broken protein machinery and waste products.

To do something about this issue we need ways to break down these waste products, such as those that make up lipofuscin, a mix of compounds that bloat and degrade the cellular recycling machinery known as lysosomes. Lipofuscin is implicated in a range of age-related diseases (as well as a class of genetic conditions known as lysosomal storage diseases). The LysoSENS project aims to discover bacterial enzymes capable of breaking down lipofuscin constituents and other important damaging compounds, and which can safely be introduced to human tissue. Researchers will then build a therapy to deliver these enzymes to where they are needed in our cells.

We have long known that such enzymes must exist, because places such as graveyards and battlefields do not exhibit a buildup of lipofuscin - something is eating it all. So the LysoSENS project started out by sifting through bacteria in soil samples, testing to see which of the bacterial species in the samples could consume harmful compounds such as 7-ketocholesterol, and then isolating the responsible enzymes.

This has been going on for a few years now, of course, and progress has been made - even at the all-too-low levels of funding available for this work. At this stage in the project a number of candidate enzymes that break down 7-ketocholesterol have been identified, and researchers are now putting them through their paces in cell cultures. One enzyme at least is worthy of a published paper.

Increased resistance to oxysterol cytotoxicity in fibroblasts transfected with a lysosomally targeted Chromobacterium oxidase

7-Ketocholesterol (7KC) is a cytotoxic oxysterol that plays a role in many age-related degenerative diseases. 7KC formation and accumulation often occurs in the lysosome, which hinders enzymatic transformations that reduce its toxicity and increase the sensitivity to lysosomal membrane permeabilization.

We assayed the potential to mitigate 7KC cytotoxicity and enhance cell viability by overexpressing 7KC-active enzymes in human fibroblasts. One of the enzymes tested, a cholesterol oxidase engineered for lysosomal targeting, significantly increased cell viability in the short term upon treatment with up to 50 µM 7KC relative to controls. These results suggest targeting the lysosome for optimal treatment of oxysterol-mediated cytotoxicity, and support the use of introducing novel catalytic function into the lysosome for therapeutic and research applications.

Some comments at the SENS Foundation:

The success of the approach employed by the team at Rice makes this enzyme, Chromobacterium sp. DS1 cholesterol oxidase, an important step toward a true rejuvenation biotechnology - a therapy that can target and repair damage that underlies the diseases and disabilities of the aging process. SENS Foundation is pleased to continue backing Dr. Mathieu's research, so that further work can move us closer to making such treatments a reality.

Given that many different harmful metabolic waste products exist, the field of biomedical remediation has enormous scope for growth - and certainly for more funding, which should hopefully start to arrive in the wake of proof of concept work like this. There is no need to slow down after finding one or more enzymes that break down 7-ketocholesterol, as firstly there could still be far better enzymes out there for this job, and secondly there remain numerous other damaging waste compounds in our cells and tissues that are worthy of biomedical remediation.

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