Once again about rejuvenation

Cold water, boiled and boiling milk

Olga Posukh, "Biomolecule"
For references, including explanatory special terms, see the original article.

Perhaps everyone who found the first wrinkle or the first gray hair, no, no, and thought about how great it would be if scientists came up with a cure for old age. The fight against aging is not an easy task, so any success in this area achieved on "our smaller brothers" is already a reason for great joy. Recently, biologists have found a way to rejuvenate the muscles of fruit flies by ridding them of mitochondria carrying harmful deletions in their DNA molecules. Another group of scientists extended the life of mice by partially reprogramming their epigenome. And there it's not far to the "rejuvenating apples" for us, Homo sapiens.

Modern ideas of scientists about aging suggest that this is not just a mechanical wear of all systems, but a process controlled by some "genetic clock" that tells our body and mind to inexorably fade away.

It is infinitely early to talk about immortality, but if you dig into the mechanism of these "genetic clocks" properly, it turns out that the aging process can still be reversed. Biomolecule paid close enough attention to this topic in a special project on aging and longevity (you can start getting acquainted with it with an introductory article [1]).

Aging, in addition to the approach of the inevitable finale, is accompanied by a mass of concomitant diseases and conditions. In particular, many of the senile diseases can be caused by the accumulation in cells, along with normal mitochondria, of mitochondria with various DNA breakdowns - mutations. The phenomenon when mitochondria with "good" and "evil" genotypes are located in the same cells is called heteroplasmia. Heteroplasmia can make its insidious contribution to the development of metabolic disorders, neurodegenerative diseases, cancer, heart disease and sarcopenia (age-related skeletal muscle atrophy), which are somehow associated with aging of the body.

Many important biological mechanisms are first discovered and studied in practically ready-made fruit flies. Normally, heteroplasmia in fruit flies, of course, occurs here and there, but to turn this phenomenon into a model for study, genetic engineering tools were needed.

A group of scientists from California created a system [2] in which the genes of enzymes specially trained for mitochondria – AflIII restrictase (mitoAflIII) and T4 DNA ligase (mitoT4lig) - were expressed under the control of a promoter working only in one of the muscles – the one that provides wing movement and flight of drosophila. This non-vital, energy-intensive tissue, characteristic only for adults, consisting of postmitotic (non-dividing) cells and containing a huge number of mitochondria, is ideal for monitoring and evaluating the effects of increased levels of heteroplasmy in an adult organism. In young flies in the mitochondria of this muscle, mitoAflIII restrictase cut mitochondrial DNA in two places. At the same time, the excised fragment with several important genes was lost, and the mitoT4lig ligase stitched the remaining ends of the DNA. So the deletion was formed. Mitochondria with such deletions accumulated in large quantities in the muscle (~76%), but this did not prevent the muscle from functioning.

Normally, mitochondria with breakdowns are destroyed by the cell using a mechanism called mitophagy (a special case of autophagy). This mechanism is controlled by PINK1 (PTEN-induced putative kinase 1) and Parkin proteins (disruption of this protein in humans leads to the development of Parkinson's disease) and functions as follows: the membrane of the broken mitochondria is depolarized, mitofusin membrane proteins are destroyed, and the mitochondria loses the ability to join the universal mitochondrial network. In the end, this lonely mitochondria is destroyed by lysosomes.

The meaning and examples of "self-eating" at different levels of the organization of living matter and in different domains of wildlife are discussed in the article "Autophagy, protophagy and the rest" [3]. Autophagy in all its manifestations turned out to be such an important and exciting process that last year it won the special favor of the Nobel Committee: "Nobel Prize in Medicine and Physiology 2016: for self-eating" [4]. – Ed.

The process of mitophagy in the muscles is not going too briskly, therefore, over time, the level of heteroplasmy still grows, and the muscle ages. But, as California scientists have found out, rejuvenation of such a muscle can be stimulated in several ways:

1. to deprive the broken mitochondria of the opportunity to join the common network, reducing the level of mitofuzins;

2. prevent repolarization of the mitochondrial membrane by producing the protein ATPIF1, which inhibits the activity of ATPase, but not ATP synthase;

3. increase the efficiency of recognition of broken mitochondria by increasing the number of PINK1 and Parkin proteins;

4. activate the mitophagy process.

These discoveries on drosophila will serve as a starting point for genetic and chemical screenings. These screenings will help to identify molecules that can cleanse tissues of broken mitochondria and therefore become a long-awaited cure for old age for us.

Just a month after the publication of the article about flies with rejuvenated muscles, other California biologists pleased the world with the news about the rejuvenation of mice [5], which, compared to flies, are almost human.

Mice with a mutation leading to progeria – premature aging - were chosen as a model for this experiment. The treatment of such elderly mice was based on the already well-known and studied technology for producing induced pluripotent stem cells (iPSCs). Its essence is that stem cells capable of becoming any other type of cell are obtained from differentiated cells by genetic reprogramming. Such reprogramming is achieved when the expression of only four genes is induced in cells with a predetermined fate within a few weeks: Oct4, Sox2, Klf4 and c-Myc – the so-called Yamanaka factors [6-8]. As a result, the epigenome of these cells changes – the "staffing" of the work of all genes [9]. The "genetic clock" of such a cell seems to return at 00:00.

But in the case of the fight against aging, such zeroing at the level of the whole organism would be fatal: skin cells, for example, would "forget" who they are. Therefore, scientists induced the expression of Yamanaki factors in mice with progeria for only a few days. As a result, many organs have significantly rejuvenated. Under the microscope, the tissues of the skin, spleen, kidneys and stomach simply radiated youth and health. In addition, the work of the cardiovascular system has improved in rodents, which usually wears out first with age. The process of accumulation of DNA damage accompanying progeria slowed down, and the old mice began to live for as long as 24 weeks instead of the 18 prescribed by fate.

This work proved that by fighting age-related changes in epigenetic information, it is possible not only to increase life expectancy, but also to systematically improve many organs.

Unfortunately, the technologies used in this study cannot be immediately applied to people, and according to scientists, at least 10 years should pass before clinical trials of potential drugs for old age. Nevertheless, the idea that we will be able to taste the first harvest of "rejuvenating apples" in our lifetime is infinitely pleasing.

Literature

1. Biomolecule: Senile vagaries of nature: why people stop aging, and mice do not have time to live;

2. Nikolay P. Kandul, Ting Zhang, Bruce A. Hay, Ming Guo. (2016). Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila. Nat Comms. 7, 13100;

3. Biomolecule: Autophagy, protophagy and others;

4. Biomolecule: Nobel Prize in Medicine and Physiology 2016: for self-eating;

5. Alejandro Ocampo, Pradeep Reddy, Paloma Martinez-Redondo, Aida Platero-Luengo, Fumiyuki Hatanaka, Tomoaki Hishida, et al.. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell. 167, 1719-1733.e12;

6. Biomolecule: There was a simple cell, it became a stem cell;

7. Biomolecule: Stem and branches: stem cells;

8. Biomolecule: Nobel Prize in Physiology or Medicine (2012): induced stem cells;

9. Biomolecule: Epigenetics: the invisible commander of the genome.

Portal "Eternal youth" http://vechnayamolodost.ru  14.04.2017