A High Level View of Progress in SENS Rejuvenation Research in Recent Years

The Life Extension Advocacy Foundation folk have put together a compact summary of some of the progress towards SENS rejuvenation therapies that has taken place in recent years. These treatments, some existing in prototype forms, and some yet to be constructed, are based on repair of the forms of cell and tissue damage known to cause aging. It is a good article to show to a friend who has expressed interest in greater human longevity, or to mine for talking points to use when you next bring up the topic with those unfamiliar with the current state of the science. You might also compare it with my bullet point list of the high points in SENS advocacy, research, and fundraising over the past fifteen years.

Efforts to explain the history and progress to date of SENS rejuvenation research are useful and necessary. The SENS Research Foundation does a good job in summarizing the causes of aging and the research programs that will tackle each cause. The staff also do a good job in listing and explaining the work they carry out year by year, funded by philanthropic donations, in their annual reports. They don't however, tend to publish much that links all of the stories together, to show the scope of progress over the lifetime of the SENS programs, and the positive changes that SENS researchers and advocates have created in the culture of aging research. Fortunately, we can do that, and I think that we must do that: this is some of the most convincing evidence to show that it is all worth it, that the wheel is turning, and that we are much further ahead than we were a decade ago.

Science moves very slowly. It usually takes years for the results of fundraisers and advocacy to bear fruit, and so in this age of instant gratification, it is necessary to show those who are new to SENS that this isn't just another flash in the pan - that present efforts are part of a long upward curve towards the technologies of human longevity, and that past efforts have resulted in success. The dots have to be joined to show that the radical change in the attitudes of the research community with respect to treating aging as a medical condition didn't just happen on its own, that young companies advancing potential rejuvenation biotechnologies didn't just materialize out of nothing. A great deal of work went into these changes, both inside and outside the laboratory, and a sizable fraction of that work was carried out by the SENS Research Foundation and allies such as the Methuselah Foundation.

SENS Research: Progress in the Fight Against Age-related Diseases

Today, there are many drugs and therapies that we take for granted. However, we should not forget that what is common and easily accessible today didn't just magically appear out of thin air; rather, at some point, it used to be an unclear subject of study on which "more research was needed", and even earlier, it was just a conjecture in some researcher's head. Hopefully, one day not too far into the future, rejuvenation biotechnologies will be normal and widespread as aspirin is today, but right now, we're in the R&D phase, so we should be patient and remind ourselves that the fact we can't rejuvenate people today doesn't mean nothing is being done or that nothing has been achieved to that end. On the contrary, we are witnessing exciting progress in basic research - the fundamental building blocks without which rejuvenation, or any new technology at all, would stay a conjecture.

A mitochondrion is a component of the cell in charge of converting food nutrients into ATP, a chemical that powers cellular function. Each mitochondrion is equipped with its own DNA. Mitochondria with damaged DNA may become unable to produce ATP or even produce large amounts of waste that cells cannot get rid of. To add insult to injury, mutant mitochondria have a tendency to outlive normal ones and take over the cells they reside in, turning them into waste production facilities that increase oxidative stress - one of the driving factors of aging.

Cell nuclei are far less exposed to oxidative stress than mitochondria, which makes nuclear DNA less susceptible to mutations. For this reason, the cell nucleus would be a much better place for mitochondrial genes, and in fact, evolution has driven around 1000 of them there. Through a technique called allotopic expression, we could migrate the remaining genes to the nucleus and solve the problem of mitochondrial mutations. The SENS Research Foundation (SRF) team managed to achieve stable allotopic expression of two mitochondrial genes in cell culture. As Aubrey de Grey explains, of the 13 genes SRF is focusing on, it's now managed to migrate almost four. This had never been done before and is a huge step towards addressing this aspect of aging in humans. In the past few months, the SRF team has presented its results around the world and worked on some problems encountered in the project.

Lysosomes are digestive organelles within cells that dispose of intracellular garbage - harmful byproducts that would otherwise harm cells. Enzymes within lysosomes can dispose of most of the waste that normally accumulates within cells, but some types of waste, collectively known as lipofuscin, turn out to be impossible to break down. As a result, this waste accumulates within the lysosomes, eventually making it harder for them to degrade even other types of waste.

As normal lysosomal enzymes cannot break down lipofuscin, a possible therapy could equip lysosomes with better enzymes that can do the job. The approach suggested by SRF originates with ERT - enzyme replacement therapy - for lysosomal storage diseases. This involves identifying enzymes capable of breaking down different types of intracellular junk, identifying genes that encode for these enzymes, and finally delivering the enzyme in different ways, depending on the tissues and cell types involved.

SRF funded a preliminary research project on lipofuscin clearance therapeutics and another project relating to atherosclerosis and the clearance of 7-ketocholesterol (found in lipofuscin), which eventually spun into human.bio, an early-stage private startup. Another SRF-based approach is currently being pursued by Ichor Therapeutics, where the staff are working on an ERT treatment for age-related macular degeneration. The treatment consists of providing an enzyme capable of breaking down a type of intracellular waste known as A2E. The company earlier this year announced a series A offering to start Phase I clinical trials of its product.

As cells divide, their telomeres - the end-parts of chromosomes protecting them from damage - shorten. Once a critical length has been reached, cells stop dividing altogether and enter a state known as senescence. Senescent cells are known to secrete a cocktail of chemicals called SASP (Senescence Associated Secretory Phenotype), which promotes inflammation and is associated with several age-related conditions. Normally, senescent cells destroy themselves, but some of them manage to escape destruction. The result is that late in life, senescent cells have accumulated to unhealthy amounts and significantly contribute to the development of age-related diseases.

The proposed SENS solution is straightforward: if senescent cells become too numerous, then they need to be purged. Since they are useful in small amounts, the optimal solution would be periodically removing excess senescent cells. This could potentially be achieved by either senolytic drugs or gene therapies that selectively target senescent cells. SRF has funded a number of studies on the subject of cellular senescence, and it's recently begun working on a project in collaboration with the Buck Institute for Research on Aging, which is focusing on the immune system and its role in clearing senescent cells. Another extramural project, again with the Buck Institute, is focused on SASP inhibition. Further, in conjunction with Methuselah Foundation, SRF provided seed funding for Oisin Biotechnologies, a company working on a gene therapy approach to destroying senescent cells.

The extracellular matrix is a collection of proteins that act as scaffolding for the cells in our body. The component parts of this scaffolding eventually end up being improperly linked to each other through a process called glycation. The resulting cross-links impair the function and movement of the linked proteins, ultimately stiffening the extracellular matrix, which makes organs and blood vessels more rigid. Eventually, this leads to high blood pressure, loss of skin elasticity, and organ damage, among other problems.

In order to eliminate unwanted cross-links, the SENS approach proposes to develop molecules that sever the linkages and return tissues to their original flexibility. In order to do this, cross-link molecules need to be available to researchers attempting to combat them with drugs, and especially in the case of glucosepane, this has been a problem for years. The lack of tools to work with glucosepane has been greatly hampering the progress of cross-link breaking research, but thankfully, this problem is now solved thanks to a collaboration between the Spiegel Lab at Yale University and the SENS Research Foundation, which supported the study financially. It is now possible to fully synthesize glucosepane, allowing for researchers to create it on demand and at a cost-effective price. The Spiegel Lab's scientists are now developing anti-glucosepane monoclonal antibodies to cleave unwanted cross-links.


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