Foreword by Steve Hill
In the LEAF, we talk a lot about the technology of rejuvenation. Elena Milova recently took part in the first International Summit on Longevity and Cryopreservation in Madrid, where she 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 on 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 with Dr. Aubrey de Gray from the SENS research fund and ask him one of the most important questions about SENS: where are we now? That's what Aubrey told us.
SENS broke the damage into seven large categories, each of which can be solved. We summed up all these damage 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 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 trauma, exposure to environmental toxins, oxidative stress, and so on. Sometimes damaged cells are repaired, sometimes they break down, become nonfunctional and stop dividing (aging), sometimes they are so damaged that they destroy themselves (apoptosis) to protect the body.
They must be replaced with new ones from a pool of specialized stem cells specific for But in the course of time these reserves decrease, and their decrease leads to less and less effective repair.
Throughout life, long-lived tissues such as the brain, heart and skeletal muscles gradually lose cells and work all yu e. This leads to loss of muscle strength, poor recovery from trauma and muscle atrophy – sarcopenia – one of the reasons why the elderly are sickly and frail.
The brain also loses neurons, which leads to cognitive dysfunction and dementia, and to Reduction of controlled muscular 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 disease.
Where are we now?
Fortunately, this is already a well-developed direction. SENS does not need to participate in it, as it is well funded and is moving very fast. Only this month we first discovered hematopoietic stem cells, and research in this area is moving forward at a phenomenal rate.
It is likely that in the near future we will be able to produce each type of cells inside our body to replace age-related losses. This will allow us to improve the immune system, restore the 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 DNA itself, and epimutations are a damage to the mechanisms that control the expression of genes. Both forms of damage lead to abnormal expression of genes, and provoke a malfunction in the cell. The most common form of cell damage is uncontrolled growth, better known as cancer.
Cancer can use two different ways: telomerase expression and the alternative telomere extension (ALT) mechanism. Both allow cancer to maintain its telomeres, while remaining immortal. The therapies that can hinder these ways can be combined and could defeat all types of cancer.
Where are we now?
ALT therapies have developed following the successful fundraising at Lifespan.io last year, which collected a whopping $ 72,000. SENS develops high-performance ALT screening that allows an effective evaluation of drug candidates who can inhibit or destroy cancer cells that use ALT. A company using ALT therapy should be established within the next year.
A therapy that inhibits telomerase is 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 plants of a cell, they convert the energy of a substance from food into the chemical energy of an ATP molecule, providing a cellular function. Unlike the rest of the organelles, the mitochondria have their own DNA known as mtDNA that is outside the cell nucleus.
The problem is that because mitochondria produce ATP, they also generate different waste, 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 because of their proximity to the source of free radicals.
They can cause deletions in mtDNA, leaving the mitochondria unable to produce ATP. Worse, these damaged mutant mitochondria enter an abnormal state in order to survive. They produce little energy and generate a lot of waste that the cell can not dispose of.
Ironically, the cell even retains these damaged mitochondria instead of getting rid of them and sending the healthy to recycle. Alas, mutant mitochondria and their offspring can quickly grab a whole cage. 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 nucleus of the cell, where it will be much better protected from free radicals. Indeed, evolution has already begun to do this in our cells and transferred about 1,000 mitochondrial genes to the nucleus. The SENS Research Foundation suggests accelerating the process.
Where are we now?
The SENS Research Foundation successfully financed the MitoSENS project at Lifespan.io 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 nucleus of the cell. Since then, progress has gone faster, and now they have almost moved 4 of the 13 mitochondrial genes. Currently, they are developing on its basis standardized therapy.
ApoptoSENS: the old cells
Our cells have a built-in safety mechanism known as apoptosis, which allows them to break down when they are damaged or dysfunctional, and labeled for removal by the immune system. However, as we age, cells get rid of themselves in this way and enter a state known as aging.
Aging cells do not replicate and do not help anything the tissue into which they enter. Instead, they send pro-inflammatory signals that poison their healthy neighbors, making them grow old.
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 recovery and tissue regeneration. The solution to this problem is to periodically remove the aging cells to help repair and maintain the tissue. Substances that remove aging cells are known as senolithics, they attracted much attention in the last year.
Where are we now?
In the past year or two, there has been a huge interest in aging cells, and a number of companies are currently developing cenolithics. Unity Biotechnology has planned clinical trials of the first generation of cenolithics on humans this year. After successful financing by Jeff Bezos from Amazon and a number of other large investors.
Nevertheless, the race continues, as other companies have come close to removing aging cells using more complex approaches, for example, plasmid solutions from Oisin Biotechnologies and 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 the Research of Aging Cells, focusing on the immune system Birmingham.
GlycoSENS: protein crosslinks
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 regenerate very slowly. Their health depends on 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 eye lens. Unfortunately, glucose in the blood and other molecules react with these structural proteins and bind to them, creating cross-links.
Crosslinks link the neighboring proteins together, disrupting their movement and function. In the artery wall, cross-linked collagen prevents artery flexion at the pulse, which leads to hypertension and increased blood pressure.
The loss of flexibility increases with time, and the energy of the blood pulse goes directly to the organs, damaging them, rather than being absorbed into The wall of blood vessels. Over time, this results in damage to the organ 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 consequences of their formation. There are several types of cross-links that accumulate in the body, but the main focus is on glucose- pane, which is the main type of cross-links and very slowly degrades in the body.
Where are we now?
For many years the problem was in getting a lot of glucose azane to test the therapy. Thanks to funding from the SENS Foundation, Yale has found a way to get a lot of glucose azane, and now researchers can study it and look for antibodies and enzymes to dissolve accumulated cross-links.
Some antibodies to glucose are already 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 glucose- zane.
AmyloSENS: extracellular aggregation
Wrongly folded proteins that form in the cell are usually destroyed and processed in it. However, as you age, more accumulated proteins accumulate, forming sticky aggregations. These deformed proteins disrupt the functioning of cells and tissues.
Extracellular debris is known as amyloid and occurs in various forms. Amyloids contribute to the development of Alzheimer's, Parkinson's, ALS and other similar diseases in the brain. Islet 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 aimed at 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, begun at UT Houston in Sudhir Paul's laboratory, is now continued at his company Covalent Biosciences. We hope that in the near future we will hear good news from them.
Fortunately, a number of alternatives are being developed, such as the GAIM system, which was funded by the Michael J. Fock Foundation; it is capable of splitting several types of amyloids, including those that are 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, 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 for the destruction of harmful substances.
However, sometimes garbage is very durable, and even a lysosome can not destroy it. Garbage remains in the cage, and eventually more and more it accumulates until it begins to violate the function of the lysosome. A major problem for cells that live long, such as cardiac and nerve cells, and, as more and more of them become dysfunctional due to problems in the lysosome, age-related diseases appear.
For example, in cardiac diseases, macrophages are responsible for Purification of toxic by-products of cholesterol metabolism in order to protect our arteries. Macrophages swallow these toxic materials and send them to the lysosome for recycling and processing.
However, over time, their lysosomes are overwhelmed with toxic materials that they can not destroy, which ultimately kills them and they stick to the wall Arteries. Over time, the number of these non-functional macrophages increases and forms plaques that cause atherosclerosis. Eventually plaques build up, damage swells and causes heart attacks and strokes.
The solution to this problem proposed by SENS is to identify new enzymes that can break these insoluble waste, and supply them with macrophages.
Where we are now
Ichor therapeutics uses SENS technology to treat macular degeneration with therapy that removes the vitamin A derivative accumulating in the eye and causing blindness. Ichor successfully passed the initial stage and received $ 15 million. In less than a year, we are waiting for clinical trials on humans.
We are full of optimism. The ideas proposed by SENS more than a decade ago and widely criticized in the past are now widely used by scientists, as it becomes increasingly obvious that aging is amenable to treatment. What was laughed at just over a decade ago has now become a common approach to treating age-related diseases, as well as a repair-based approach to aging – more popular.
However, we still lack knowledge about several age-related changes . That is why supporting fundamental research on the basic mechanisms of aging should remain the number one priority for our society.