Aging: Google search

Biotechnologies of the future

Alexander Mikhaylov, vc.ru

Have you ever wondered why we get older with age? Why do we look different at 30 than at 20? It is so natural for us that we cannot imagine how it could be otherwise. However, sooner or later everyone thinks about it. Today, the aging process is poorly understood. However, every year in the field of biotechnology there are more and more studies that shed light on the internal mechanisms of our body.

Before the release of the article, I had doubts whether it was worth publishing it. No matter how much I tried to simplify the information, the article still turned out to be technical. However, I see a growing interest in this topic among my friends, so I decided that the information I have systematized for myself will be useful to others.

I have systematized everything into a short list of Google queries for which you can get basic knowledge on the topic of aging in a couple of days. Therefore, if you decide to study this area, then you need to consistently type search queries from the article, which are highlighted in bold, and read the material offered in the search. It is not necessary to try to do this in one day, it is quite normal if it takes a couple of months to study the material. But again, this is just basic knowledge. But if you study everything carefully and realize it, it will turn your worldview picture around.

General questions, looking for:

Gerontology is a science that studies aspects of aging. Just general information.
Negligible aging – the complete solution to the problem of age-related aging is to achieve a state of negligible aging.
The structure of the cell – you will have to refresh your school knowledge of biology. You will need to remember that the body consists of cells, that they have DNA, RNA, mitochondria, etc.

External aging, looking for:

Wrinkles, pigmentation – you need to understand what are the external signs of aging.
Extracellular matrix – the structure of the skin is similar to a layer cake. On top is the outer layer, which is held by an inner layer of elastin and collagen.
Elastin is a protein that has the property of stretching well.
Collagen is a protein that has the property of strength and elasticity. The structure is similar to a spiral.
Skin turgor is the elasticity of the skin, its ability to take its former shape after stretching. The elasticity of the skin is provided by collagen and elastin, which eventually lose their function. With age, the elasticity of the skin decreases, which is the cause of wrinkles and lowering the lines of the face down.
Collagen in the skin (look at Google Image) – you can find cool pictures that will show how these two proteins do not allow the skin to stretch under the influence of gravity. Figuratively speaking, it looks like a mattress with springs. You can press on the edge of the mattress or stretch it, it will instantly return to its original state. This is how the skin condition normally looks up to 25-30 years old.

Mechanisms of cell renewal, looking for:

The lifetime of cells – you need to understand that the body constantly needs to update its cells. The lifetime of liver cells is from 150 to 500 days, skin 2-4 weeks. Renewal occurs by division and periodic death of old cells.
Apoptosis is a natural process of self–destruction of cells. The term appeared in 1971.
Collagen catabolism – collagen and elastin proteins, which are responsible for the elasticity of the skin, need constant renewal. The half-life of collagen is about a month. Therefore, the body provides mechanisms for the permanent destruction and synthesis of collagen and other proteins that provide skin functions. Violation of the process of destruction and synthesis of collagen, leads to a decrease in skin elasticity.
Fibroblasts are skin cells that produce the synthesis of collagen and elastin proteins. Fibroblasts, like other cells of the body, have the ability to renew.

Mechanisms of restriction of cell division, we are looking for:

The Hayflick limit is that any cell of the body from the moment of birth can share no more than 50 times on average. Discovered experimentally in 1961 by Leonard Hayflick. For a long time, the effect had no scientific explanation.
Telomeres are the end sections of DNA. They do not carry information, they can be figuratively represented as protective caps at the ends of DNA chains. In 1971, scientist Alexey Olovnikov put forward an explanation of the Hayflick limit. He suggested that in the process of cell division, information is lost at the ends of DNA every time. In turn, the new cell generates a daughter cell with even shorter DNA. This process is repeated until, as a result of division, the cell fails and malfunctions.
Telomerase is an enzyme that allows you to build up the end sections of DNA and overcome the Hayflick limit. Normally present only in germ and stem cells, absent in other cells. The mechanism of enzyme synthesis is activated during the appearance of cancer cells, which allows such cells to divide forever. The presence of telomerase in cells can be one of the ways to detect cancer cells and destroy them (Google: nucleotide 5-FdUTP).

Mechanisms of natural aging of cells, we are looking for:

DNA methylation is a mechanism that allows you to turn off certain parts of DNA. In humans, about 1% of DNA is methylated (disabled).
Epigenetic drift is a change in the DNA methylation profile during the life of an organism. It is present in every person. As a result, some of the genes that were previously disabled are turned on, and the other part is turned off.
Horvath's watch is a mathematical model that allows you to determine the age of an organism with an accuracy of 3 years based on the methylation profile of your DNA. It was opened in 2013.
Transposons are sections of DNA that are able to move and copy within the genome (a collection of DNA).
Retrotransposons are sections of DNA that are a subclass of transposons. They can reproduce themselves. Of these, 42% consists of the human genome. Up to 90% of the methylated human genome is accounted for by retrotransposons.
Alu-repeat – retrotransposon, makes up 11% of our DNA. It can lead to mutations and interchromosomal rearrangements. Alu repeats in cells are methylated. During the evolution, the activity of Alu decreased. Now a new element insertion is carried out approximately once every 20 generations.
DNA methyltransferases are enzymes that are responsible for the process of DNA methylation. DNMT-3 attaches methyl groups to DNA.
Methylation is a protective mechanism – elevated levels of DNA methylation are more inherent in non-coding DNA sites. Some viruses can be blocked by methylation.
Folate methylation cycle – in this cycle, the transfer of methyl groups occurs. The folate cycle may fail due to a deficiency of methionine, folic acid and other vitamins of group B. There is a deficiency of the main donor of methyl groups. The cycle requires vitamins B9 (folic acid), B6 and B12.
Calorie reduction DNA methylation – we read about the relationship between the calorie content of food and disorders in DNA methylation.

Mechanisms of work of antioxidants, we are looking for:

Reactive oxygen species are formed in cells by mitochondria during the digestion of oxygen by the cell. About 98% of oxygen is reduced to water by mitochondria, the remaining 2% is converted into dangerous forms of oxygen. Due to the presence of an unpaired electron, such a molecule is ready to react instantly with any compound.
SkQ is a class of antioxidants that work at the mitochondrial level.
ROS viruses – we find out that in addition to the harm of ROS, they also benefit. They participate in the antiviral protection of the body.

Other information on the topic, we are looking for:

p66Shc is a rare aging gene. Its protein product influences the level of intracellular ROS (active oxygen form) and the regulation of apoptosis (cell self-destruction).
p66Shc knockout – shutdown (repression) of the p66Shc gene increases the body's resistance to oxidative processes, but increases the risk of tumors.
hTERT expression – leads to an increase in telomerase activity and telomere length. hTERT RNA therapy extended the lifespan of fibroblasts and was accompanied by signs of fibroblast rejuvenation (2017 study).
CRISPR/cas9 is a genome editing technology.

On the topic of stem cells, we are looking for:

Pluripotent stem cells are cells (embryonic or induced) that have not yet decided who they will be in the body. They are the ancestors of all the cells of the body.
Stem cell bank is a technology that allows you to preserve stem cells.
Induced pluripotent stem cells are a technology that allows ordinary cells (for example, skin cells) to be converted back into stem cells. When ordinary cells are converted back into stem cells, their methylation profile is restored to its original state, and the telomere length is restored. In the future, they can be converted back into cells of any tissue. In its pure form, iPSCs are not used, since it is unknown into which cells they are converted in the body.
Yamanaki cocktail is a cocktail of signaling proteins that allows the transformation of an ordinary cell into an induced stem cell (2006 work). It was discovered by Japanese scientist Shinya Yamanaka, for which he won the Nobel Prize in 2012.
Yamanaki cocktail binary is a gradual process of converting an ordinary cell into a stem cell, it is possible to roll back epigenetic markers (for example, DNA methylation profile) of a cell without changing its type. The research started in 2017.

Let's try to systematize everything

In the first part, you can find the main factors that influence the determination of a person's external age. The elasticity of the skin is the main factor, the violation of which leads to the appearance of wrinkles and a decrease in facial lines. We also determine a person's age by skin pigmentation. It can be noticed that the color of our skin becomes less uniform with age. If the process of pigmentation is not fully understood, then the appearance of wrinkles is associated with a violation of the regeneration of elastin and collagen proteins. Violation of the process of collagen and elastin renewal is associated with a decrease in the activity of fibroblast cells. A decrease in the activity of fibroblasts is associated with the achievement of the Hayflick limit, which is due to a reduction in the length of telomeres during cell division.

The next part describes the second factor of age–related aging - the change in the methylation profile with age, which is probably one of the main mechanisms that causes age-related changes after 45 years and has a significant impact on the human body. The displacement of the methylation profile is dangerous because the chains of Alu repeats, which are mostly disabled, can be activated, which in turn can lead to mutations in DNA and self-destruction of cells.

What's next?

The first technology to hide age-related changes was to tighten the contours of the face with threads, but the technology hides only the cause. Later, the technology of injections of collagen and hyaluronic acid appeared. Collagen performs the function of elasticity, hyaluronic acid binds water. Recently, the technology of injection of fibroblast cells has appeared. However, this technology has a big disadvantage: the cost of the course can reach 500,000 rubles and the result disappears within a year (see the average lifetime of fibroblasts).

So far, technologies that allow overcoming the Hayflick limit are slowly beginning to appear. This would probably extend the lifetime of fibroblasts and delay age-related changes by 15-20 years. In 2015, Elizabeth Parrish, director of a pharmaceutical company, became the first person in the world who decided to modify their genes using the AAV virus. According to Elizabeth Parrish herself, she began to feel younger and better. From 2016 to 2018, her telomeres increased from 7.33 thousand to 8.12 thousand base pairs, which is equivalent to rejuvenation for 20 years.

However, one of the possibly key mechanisms of aging remains unresolved – the shift in the DNA methylation profile. There are studies according to which a decrease in the caloric content of food leads to a decrease in the rate of displacement of the methylation profile. It is also important to have a balanced diet to prevent a deficiency of methionine (found in milk and cheeses), folic acid and B vitamins. It is also possible that taking antioxidants can reduce the rate of profile displacement. In this regard, an interesting project is the development of the antioxidant SkQ, which penetrates into the mitochondria of cells and extinguishes the activity of ROS.

Technologies to combat age–related changes will never make a person's life eternal - this is utopia. In the future, this will raise the limit of the average age of life, but it will always be finite. It's just that people of the future will live, perhaps, a little longer, but without age changes, life.

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