All for the fight against the aging molecule!
Progress towards the elimination of protein crosslinking is one of the causes of aging of the body
The Present State of Progress Towards Clearing Glucosepane Cross-Links, a Contributing Cause of Degenerative Aging
Fight Aging!, 26 Jan 2016
Translated by Al Mehdiyev, SENS Volunteers group
Cross-linking is damage that occurs during metabolism, and therefore is a common effect of the normal operation of cellular biochemistry.
Various types of glycated molecules, known as advanced glycation end products (AGE), accumulate between cells and interact with the extracellular matrix, linking its various structures. The organization and composition of these structures endow tissues with their characteristic properties, such as elasticity (skin and blood vessels), strength (cartilage and bone tissue), etc.
Cross-links accumulating in large numbers violate these properties. The mechanisms of violation are different. For example, cross-links interfere with the free passage of long parallel molecular structures over each other. There is also evidence that glycation products lead to an increase in the level of chronic inflammation, altering cellular function through the corresponding receptor (RAGE). Inflammatory processes contribute to the pathology of all the most common age-related diseases.
Most of the cross-links formed are rapidly destroyed, and their role is probably noticeable only in metabolic disorders, for example, in obesity or type 2 diabetes mellitus. At the moment, it is believed that the main problem leading to age–related deterioration of skin elasticity and vascular stiffness is associated with one specific type of cross-linking formed by one type of AGE - the molecule glucosepane (glucosepane).
Studies show that glucosepan forms the vast majority of cross–links in the body of an elderly person - so strong that the body simply does not have natural mechanisms for their destruction.
Since we are talking about only one compound, all that is needed to significantly reduce its contribution to aging is one sufficiently effective means that can destroy this compound. The target market of the drug is more than half of the human population (almost all over 30 years old).
However, the broad community of researchers does not show interest in this task, which is due to the lack of tools for working with glucosepane. Any research group taking on this problem will have to start from scratch, which means that almost everyone who took the time to think about it eventually chose others that are more accessible to solve the problem. Such a situation requires philanthropy to get things moving.
The only significant source of funding for glucosepan research over the past few years has been the SENS Research Foundation, thanks to philanthropists such as Jason Hope, as well as the support of our community.
Nevertheless, since the problem described above is quite narrow – the search for one candidate for one molecule, in my opinion, it is the next SENS technology in the queue for financial support, after the purification of aging cells (senescent cell clearance). This method is currently being developed at Oisin Biotechnology, and after it, competition for funding from SENS is planned between the project for the destruction of glucosepane and therapy for the removal of transtiretin amyloid with the project for the restoration of mitochondrial DNA, which started a couple of years ago. However, my understanding of the latest trends is a little behind the times, so I recently talked to several people involved in this field. My interlocutors were Aubrey de Grey (SENS), David Spiegel (Yale) and William Baines, who collaborates with a huge number of researchers in various fields, including the one under discussion. The result of these conversations is outlined schematically below.
Obtaining glucosepan is a big step forward
In 2015, David Spiegel's laboratory developed a reliable method for producing glucosepane. This is an important event, because now people who previously had no opportunity to participate in this field of research can now start their own research projects. This also guarantees, at least in the near future, uniformity in what is meant by glucosepane and its molecular structure.
A full consensus on glucosepan has not yet been reached
The fact that glucosepan is responsible for most of the dangerous crosslinking is increasingly being questioned. However, according to current data, the fight against glucosepan as the main goal is justified.
David Spiegel is optimistic about this and believes that a suitable remedy will inevitably be found. Aubrey de Grey, however, is more cautious in his assessments, whereas William Baines is completely disappointed with the poor quality of past research. Of course, after the victory over glucosepan, doubts will be resolved in one direction or another, but for now it is a question of the future.
The SENS Foundation is currently sponsoring Jonathan Clark's joint research at the Babraham Institute aimed at more precisely clarifying the role of glucosepane, confirming modern ideas about its structure (it is essential to know not only the composition, but also the spatial organization of the molecule that determines its properties) and searching for other possible molecules responsible for the formation of stable cross-links leading to pathologies.
A candidate for the drugs has not yet been found
At the moment, there is not even an approximate idea of how to find the necessary drug among the huge catalog of existing and developing drugs. The lack of an idea stems from the lack of research on the organization of similar molecules in pharmacology. The selection of a suitable drug is the main obstacle that lies in the way of creating a company that will draw a line in the fight against glucosepan.
The work of testing the drug is much easier than finding a suitable candidate. To analyze its effectiveness, it is enough to organize testing of glucosepan levels before and after treatment. One of the standard approaches here is to use antibodies introduced into the immune system that interact with glucosepan as markers.
Most likely, a suitable candidate will appear in the process of studying bacteria
The Spiegel Laboratory uses the same approach as used in the LysoSENS research program. Its essence lies in the fact that enzymes are being sought among bacteria that can effectively destroy glucosepan. These enzymes definitely exist, if only because our cemeteries can hardly be called a warehouse of digested sugar. The fact that LysoSENS' research in this direction was conducted for ten years before they found the first applicants for the desired enzyme and received financial support from Human Rejuvenation Technologies may seem discouraging. However, only in the last few years has significant progress been made in the cultivation of bacteria, and thus researchers now have an advantage that was not available to the earlier LysoSENS project.
One of the open problems so far has been the fact that 99% of all bacterial species could not be grown in the laboratory. However, after a relatively simple technological breakthrough, things have changed. Everything that has been achieved by scientists so far has been obtained as a result of studying only 1% of bacterial species, now all of them can be subjected to regular research. As a result, the space for work has increased a hundred times.
Employees of the Spiegel laboratory have already isolated and learned how to grow certain types of bacteria that can probably absorb glucosepan. David Spiegel believes that at the current level of funding, it will take about two years to figure out the mechanism of the takeover. Perhaps the presence of a simple enzyme is sufficient for absorption; perhaps the process is more complex.
If it's a matter of one enzyme, then it can quickly become the desired drug, if not, then you will have to investigate a larger number of bacteria, among which there will be a more suitable candidate. This work can progress faster if funding is increased, since research on different bacteria can be conducted in parallel by a large number of researchers. However, finding financing in this area is a problem in itself.
I will note that I omit the difficulties that will arise when extracting the necessary enzymes from bacteria and producing medicines based on them. Undesirable effects, such as a negative reaction of the immune system, are quite likely to occur. This problem cannot be solved by simply placing the necessary drugs in a protective capsule, since its contents are supposed to enter the intercellular space. The list goes on. But all these obstacles look surmountable, additional work will require the use of new technologies and approaches that may come from other fields of science.
Two models of future commercialization
Starting from this point, two ways of commercial development are possible. The first is to find a risk-willing investor who will invest $2 million and wait patiently for two years until David Spiegel, William Baines and Jonathan Clark finish their work. This scenario is implemented in many areas of research, but it requires good connections and a thick wallet. That is why contracts of this kind are usually concluded with pharmaceutical companies, as, for example, happened with the development of therapy based on transthyretin amyloid clearance therapy based on CPHPC.
The second way is to encourage the researchers and support them as much as we can with our donations, perhaps for several years until a suitable enzyme is found. When it comes close to testing the drug on rats and mice, you can organize a startup based on seed funding. Such a scenario is much easier in our community – if Oisin Biotechnology managed to get funding from the SENS foundation, a company developing a therapy against glucosepan can do the same in a couple of years.
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