SENS: Where are we now?

SENS: Where are we now?

Steve Hill and Elena Milova, LIFE EXTENSION Translation: Ariel VA Feinerman, Madrobots blog, Geektimes

Foreword 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 they talked about how best to engage the general public in supporting research in the field of aging and rejuvenation.

In the near future we will have a number of interesting articles about 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 talk to Dr. Aubrey de Grey 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 the damage into seven large categories, each of which can be solved. We have listed all these damages below, and also talked about the progress in each of them.

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

ReplaciSENS: cell loss and tissue atrophy

Our cells are damaged from various sources, including trauma, exposure to environmental toxins, oxidative stress, and so on. Sometimes 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 with new ones from the pool of specialized stem cells specific to the tissue, but over time these reserves decrease, and their decrease leads to less effective repair.

Over the course of life, long-lived tissues such as the brain, heart and skeletal muscles gradually lose cells and work worse. This leads to a loss of muscle strength, poor recovery after injuries and muscle atrophy – sarcopenia – one of the reasons why older people are sickly and frail.

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

Where are we now?

Fortunately, this is already a well-developed area. SENS does not need to participate in it, as it is well funded and progresses very quickly. Only this month we tested hematopoietic stem cells for the first time, and research in this area is progressing 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-related losses. 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 we 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 in the cell. The most common form of cell disruption is uncontrolled growth, more commonly known as cancer.

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

Where are we now?

ALT therapies were developed after successful fundraising on Lifespan.io last year, which raised a whole $72000. SENS is developing high-performance ALT screening to enable effective evaluation of drug candidates that can inhibit or destroy cancer cells using ALT. A company using ALT therapy should be created within the next year.

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

MitoSENS: mitochondrial mutations

Mitochondria are the power plants of the cell, they convert the energy of matter from food into the chemical energy of the ATP molecule, which 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 waste products, for example, highly active molecules called free radicals. Free radicals can infect 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 dispose of.

Ironically, the cell even preserves these damaged mitochondria instead of getting rid of them and sending healthy ones for recycling. Alas, mutant mitochondria and their offspring can quickly take over an entire cell. There are more and more cells with damaged mitochondria that pollute the body, causing an increase in the level of oxidative stress and triggering the aging process.

The solution to this problem is to move 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 has transferred about 1,000 mitochondrial genes to the nucleus. The SENS Research Foundation suggests speeding up the process.

Where are we now?

The SENS Research Foundation has successfully funded the MitoSENS project on Lifespan.io back in 2015. They presented the results in September 2016 in the prestigious journal Nuclear Acids Research.

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

ApoptoSENS: old cells

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

Aging cells do not replicate and do not help the tissue they enter in any way. 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 prevent them from restoring 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 the tissue. Substances that remove aging cells are known as senolytics, and they have attracted a lot of attention in the last year.

Where are we now?

In the last year or two, there has been a huge interest in aging cells, and currently a number of companies are developing senolytics. Unity Biotechnology has planned clinical trials of the first generation of senolytics on humans this year. After successful financing by Jeff Bezos from Amazon and a number of other major investors.

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

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

GlycoSENS: protein crosslinking

Most of our body consists of proteins that are created at an early age. Many of our parts are either not replaced at all, or regenerates very slowly. Their health depends on proteins that make them 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 eye lens. Unfortunately, glucose in the blood and other molecules react with these structural proteins and bind to them, creating crosslinking.

Crosslinking binds neighboring proteins together, disrupting their movement and function. In the artery wall, cross-linked collagen prevents the artery from bending at the pulse, which leads to hypertension and increased blood pressure.

The loss of flexibility increases over time, and the energy of the blood pulse enters directly into the organs, damaging them, and is not absorbed in the wall of blood vessels. Over time, this leads to organ damage and an increased risk of stroke.

The SENS Research Foundation suggests finding ways to destroy these cross-links in order to restore structural proteins and thus reverse the effects of their formation. There are several types of crosslinking that accumulate in the body, but the main focus is on glucosepane, which is the main type of crosslinking and is very slowly destroyed in the body.

Where are we now?

For many years, the problem has been getting large amounts of glucosepan to test therapy. Thanks to funding from the SENS Foundation, Yale University has found a way to get a lot of glucosepane, and now researchers can study it and look for antibodies and enzymes to dissolve accumulated crosslinking.

Yale has already found some antibodies to glucosepan. Monoclonal antibodies are expected to be available by the end of the year, and scientists have discovered bacteria with enzymes that destroy glucosepane.

AmyloSENS: extracellular aggregations

Improperly folded proteins formed in the cell are usually destroyed and processed in it. However, as we age, more and more accumulated proteins accumulate, forming sticky aggregations. These deformed proteins disrupt the work 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. Insular amyloids are 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 targeting them and removing them from the tissue. It can help prevent or reverse the various diseases mentioned above.

Where are we now?

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

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

LysoSENS: intracellular aggregations

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

However, sometimes the garbage turns out to be very durable, and even the lysosome cannot destroy it. Garbage remains in the cell, 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 for a long time, such as heart 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 clearing toxic byproducts of cholesterol metabolism in order to protect our arteries. Macrophages ingest these toxic materials and send them to the lysosome for disposal and recycling.

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

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

Where are we now?

Ichor therapeutics uses SENS technology in the treatment of macular degeneration with a therapy that removes a 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.

Conclusions

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 becomes increasingly obvious that aging is treatable. What was mocked a little more than a decade ago has now become a generally accepted approach to the treatment of age–related diseases, as well as a repair-based approach to aging is more popular.

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

Portal "Eternal youth" http://vechnayamolodost.ru  30.08.2017