SENS: where are we now?

Preface by Steve Hill

At LEAF, we talk a lot about rejuvenation technology. Recently, Elena Milova took part in the first International Summit on Longevity and Cryopreservation in Madrid , where she talked about how best to engage in attracting the general public to support research in the field of aging and rejuvenation.



In the near future we will have a number of interesting articles on the conference, including exclusive interviews and much more, but while we are preparing them, we decided to tell you about this exciting news.



Elena had the opportunity to speak with Dr. Aubrey de Gray from the SENS Research Foundation and ask him one of the most important questions about SENS: where are we now? That's what Aubrey told us.





SENS has broken damage into seven large categories, each of which can be resolved. We summarized all these damages below, and also talked about the progress in each of them.



It is important to note that the SENS categories differ slightly from ours in the LEAF, although they are similar, with similar methods of repairing damage. We consider our approaches compatible and support both.

RepleniSENS: cell loss and tissue atrophy

Our cells are damaged from various sources, including injuries, exposure to environmental toxins, oxidative stress, and so on. Sometimes the damaged cells are repaired, sometimes they are destroyed, become non-functional and stop dividing (aging), sometimes they are so damaged that they destroy themselves (apoptosis) to protect the body.



They should be replaced by new ones from the pool of specialized stem cells specific for the tissue, but over time these reserves decrease, and their reduction leads to less and less efficient repair.



During life, long-lived tissues such as the brain, heart, and skeletal muscle gradually lose their cells and work worse. This leads to loss of muscle strength, poor recovery from injuries and muscle atrophy - sarcopenia is one of the reasons why older people are sick and frail.



The brain also loses neurons, which leads to cognitive dysfunction and dementia, as well as to a decrease in controlled muscle movements and, ultimately, Parkinson's disease. The immune system also suffers, for the thymus gradually diminishes and loses its ability to produce immune cells, leaving you vulnerable to disease.

Where are we now?

Fortunately, this is a well-developed area. SENS does not need to participate in it, because it is well funded and moving very quickly. It was only this month that we first discovered hematopoietic stem cells, and research in this area is advancing at a phenomenal rate.



It is likely that in the near future we will be able to produce every type of cell inside our body to replace age loss. This will allow us to improve the immune system, repair damage caused by neurodegenerative diseases such as Alzheimer's and Parkinson's, and regenerate organs.

OncoSENS: cancer cells

Two types of damage accumulate in our genes as they age: mutations and epimutations. Mutations are the result of direct damage to the DNA itself, and epimutations are damage to the mechanisms that control gene expression. Both forms of damage lead to abnormal gene expression, and provoke a malfunction of the cell. The most common form of cell impairment is uncontrolled growth, better known as cancer.



Cancer can use two different paths: telomerase expression and the mechanism of alternative telomere elongation (ALT). Both allow the cancer to maintain its telomeres, while remaining immortal. Therapies that may impede these pathways can be combined and could defeat all types of cancer.

Where are we now?

ALT therapies have evolved after successfully collecting funds for Lifespan.io last year, raising as much as $ 72,000. SENS develops high-throughput screening for ALT, allowing for an effective evaluation of drug candidates who can inhibit or destroy cancer cells that use ALT. Over the next year, a company should be created using ALT therapy.



And telomerase inhibiting therapies are being developed by a number of organizations and companies, so the SENS research fund does not need to participate in them. They are already undergoing clinical trials and are well funded.

MitoSENS: mitochondrial mutations

Mitochondria are the power stations of the cell; they convert the energy of a substance from food into the chemical energy of an ATP molecule that provides cellular function. Unlike other organelles, mitochondria have their own DNA, known as mtDNA, which is located outside the cell nucleus.



The problem is that, since mitochondria produce ATP, they also generate various wastes, for example, highly active molecules, called free radicals. Free radicals can damage and damage parts of the cell, including mtDNA, which is very vulnerable to them due to its close proximity to the source of free radicals.



They can cause deletions in mtDNA, leaving mitochondria unable to produce ATP. Worse, these damaged mutant mitochondria enter an abnormal state in order to stay alive. They produce little energy and generate a lot of waste that the cell cannot recycle.



Ironically, the cell even saves these damaged mitochondria instead of getting rid of them and sends healthy ones for processing. Alas, mutant mitochondria and their offspring can quickly capture a whole cell. More and more cells with damaged mitochondria that pollute the body, causing an increase in oxidative stress and triggering the aging process.



The solution to this problem is to move the mtDNA into the cell nucleus, where it will be much better protected from free radicals. Indeed, evolution has already begun to do this in our cells and transferred about 1000 mitochondrial genes into the nucleus. SENS Research Foundation offers to speed up the process.

Where are we now?

SENS Research Foundation successfully financed the MitoSENS project on Lifespan.io back in 2015. They presented the results in September 2016 in the prestigious journal Nucleic Acids Research.



Thanks to the support of the community, MitoSENS succeeded for the first time in the world to transfer not one but two mitochondrial genes into the cell nucleus. Since then, progress has gone faster, and now they have almost transferred 4 of 13 mitochondrial genes. They are currently developing standardized therapy based on it.

ApoptoSENS: old cells

Our cells have a built-in security mechanism, known as apoptosis, allowing them to collapse when they are damaged or non-functional, and are marked for removal by the immune system. However, as we age, the cells get rid of themselves worse and worse and enter a state known as aging.



Aging cells do not replicate and do not help with the tissue in which they enter. Instead, they send pro-inflammatory signals that poison their healthy neighbors, causing them to age.



The same pro-inflammatory signals block the activity of stem cells and do not allow them to restore tissue. As we age, more of these cells accumulate and lead to increasingly poor tissue repair and regeneration. The solution to this problem is to periodically remove aging cells to help repair and maintain tissue. Substances that remove senescent cells are known as senolithics ; they have received much attention in the past year.

Where are we now?

In the past year or two, there has been tremendous interest in aging cells, and a number of companies are currently developing senolithics. Unity Biotechnology has scheduled clinical trials of the first generation of senolithic in humans this year. After successfully financing Jeff Bezos from Amazon and several other major investors.



However, the race continues, as other companies have come close to removing aging cells using more sophisticated approaches, such as plasmid solutions from Oisin Biotechnologies and synthetic biological solution from CellAge , which was successfully funded on Lifespan.io last year.



The SENS Research Foundation is also working on a joint project with the Buck Institute for the Study of Aging Cells, focusing on the immune system.

GlycoSENS: protein stitches

Most of our body is made up of proteins that are created at an early age. Many of our parts are either not replaced at all, or regenerate very slowly. Their health depends on the proteins that cause them to maintain their proper structure.



These proteins are responsible for the elasticity of the tissue, for example, in the skin and blood vessels, as well as for the transparency of the lens of the eye. Unfortunately, blood glucose and other molecules react with these structural proteins and, by binding to them, create cross-links.



The stitches link adjacent proteins together, disrupting their movement and function. In the artery wall, cross-linked collagen prevents the artery from flexing during a pulse, which leads to hypertension and high blood pressure.



The loss of flexibility increases over time, and the energy of the blood goes directly to the organs, damaging them, rather than being absorbed into the wall of the blood vessels. Over time, this leads to organ damage and an increased risk of stroke.



The SENS Research Foundation proposes to find ways to destroy these crosslinks in order to restore structural proteins and, thus, reverse the consequences of their formation. There are several types of cross-links that accumulate in the body, but the focus is on glucosepan, which is the main type of cross-linking and is very slowly destroyed in the body.

Where are we now?

For years, the problem has been to obtain a large amount of glucoseepan to test therapy. Thanks to funding from the SENS Foundation, Yale University found a way to get a lot of glucoseepane, and now researchers can study it and look for antibodies and enzymes to dissolve accumulated crosslinks.



Some antibodies to glucose have already been found in Yale. It is expected that by the end of the year monoclonal antibodies will be available, and scientists have discovered bacteria with enzymes that destroy glucosepan.

AmyloSENS: extracellular aggregation

Incorrectly folded proteins formed in the cell are usually destroyed and processed in it. However, with aging, more and more accumulated proteins accumulate, forming sticky aggregations. These deformed proteins disrupt the functioning of cells and tissues.



Extracellular debris is known as amyloid and comes in various forms. Amyloids contribute to the development of Alzheimer's disease, Parkinson's disease, ALS and other similar diseases in the brain. Islet amyloids have been found in type 2 diabetes and senile cardiac amyloidosis.



The solution is to remove these aggregations from the brain and other areas of the body, using specialized antibodies that target them and remove them from the tissue. It can help prevent or reverse the various diseases mentioned above.

Where are we now?

SENS's work, begun at UT Houston in the Sudhir Paul laboratory, is now continued at his company Covalent Biosciences . We hope in the near future we will hear good news from them.



Fortunately, a number of alternatives are under development, such as the GAIM system, which was funded by the Michael J. Fock Foundation, and it is capable of cleaving several types of amyloid, including those associated with Alzheimer's, Parkinson's and amyloidosis. The protein targeting system AdPROM is used in the selective degradation of amyloids and other proteins for the treatment of age-related diseases.

LysoSENS: intracellular aggregation

Over time, the proteins and other components of our cells are damaged due to wear. Cells have a number of systems for the destruction of such proteins. Lysosome is one of them. Lysosome can be considered as a kind of incinerator, which contains powerful enzymes to destroy harmful substances.



However, sometimes the garbage is very durable, and even the lysosome can not destroy it. The garbage remains in the cage, and over time, more and more of it accumulates until it begins to disrupt the function of the lysosome. A big problem for cells that live long, such as heart cells and nerve cells, and as more and more of them become non-functional due to problems in the lysosome, age-related diseases appear.



For example, in heart diseases, macrophages are responsible for cleaning the toxic by-products of cholesterol metabolism in order to protect our arteries. Macrophages ingest these toxic materials and send them to the lysosome for recycling and processing.



However, over time, their lysosomes are overflowing with toxic materials that they cannot destroy, which ultimately kills them, and they are stuck to the artery wall. Over time, the number of these non-functional macrophages increases and forms plaques that cause atherosclerosis. Ultimately, plaque builds up, damage swells and causes heart attacks and strokes.



The solution to this problem, proposed by SENS, is to identify new enzymes that can cleave these insoluble wastes and supply them with macrophages.

Where are we now?

Ichor therapeutics uses SENS technology in the treatment of macular degeneration using therapy that removes the vitamin A derivative that accumulates in the eye and causes blindness. Ichor successfully passed the initial stage and received $ 15 million. In less than a year we are waiting for human clinical trials.

findings

We are full of optimism. The ideas proposed by SENS more than a decade ago and widely criticized in the past are now being used by scientists with might and main, as it is becoming increasingly obvious that aging is treatable. What they scoffed at a little more than ten years ago has now become a generally accepted approach to the treatment of age-related diseases, as well as the repair-based approach to aging is more popular.



However, we still lack knowledge of several age-related changes. That is why supporting fundamental research on the underlying mechanisms of aging should remain the number one priority for our society.

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