Gene therapy of aging

Mice had their lives extended with nasal gene therapy

Polina Loseva, N+1

The life of a mouse can be increased by a third or even more if a viral vector with an additional gene is injected into its body once a month. This was demonstrated by a group of researchers associated with the company BioViva — its founder Elizabeth Parrish once claimed to have tested a similar technique on herself. In a new experiment, it turned out that telomerase or follistatin is suitable for gene therapy, and the drug itself works even if it is sprayed in the nose. The article was published in the journal Proceedings of the National Academy of Sciences (Jaijyan et al., New intranasal and injectable gene therapy for healthy life extension).

In 2015, Elizabeth Parrish She stated that she received an injection of an adenovirus vector with the telomerase gene, an enzyme that elongates DNA. It is believed that the shortening of telomeres (the end sections of chromosomes) may be one of the causes of aging, and Parrish thus assumed, if not to prolong her life, then at least to reduce her biological age.

Whether Parrish has actually become healthier is unknown. Later, she claimed that her telomeres had indeed lengthened — however, there is no other information about her health, and this one was obtained outside the framework of a scientific experiment. At first, Parrish was going to sell such gene therapy for aging with the help of her company BioViva, whose scientific consultant was, among others, the famous geneticist George Church. However, so far the company has not had major experimental publications on this topic, and the site offers to buy only tests to determine biological age.

Now BioViva has released a large study, the leaders of which are Parrish herself, as well as her scientific consultants: George Church and Hua Zhu (Hua Zhu). In this work, scientists tested two types of gene therapy on mice. In the first case, the telomerase gene was added to the mice — according to previous studies, it is already known that such therapy can make their lives longer. In the second case , the follistatin gene: it is an inhibitor molecule of many signaling substances, including myostatin, which inhibits muscle growth. In early studies, follistatin helped mice gain muscle mass, but the effect on life expectancy was not calculated in them.

As a means of delivery, the authors of the work used viral vectors based on cytomegalovirus — since they are quite large (which means they can accommodate large genes), they are not embedded in the human genome and, as is known from clinical trials of other drugs, do not cause side effects. At the same time, they tried to inject viral vectors in two ways: classical, intraperitoneally (injection into the peritoneum), and intranasally (spraying in the form of a spray in the nose). In total, seven groups of animals were thus obtained: the control group received an injection without a vaccine, two more received an injection or spray of an "empty" vector, two received an injection or spray with the telomerase gene and two received an injection or spray with the follistatin gene.

All mice were "treated" when they were 18 months old — according to the authors of the article, this corresponds to 56 years in humans. They received one dose per month for up to 29 months (about 80 "human" years) — by this time, all the animals in the control groups had died. But at 32 months, the scientists decided to continue therapy to find out how it affects the maximum life expectancy.

It turned out that both genes in the viral vectors allow mice to live significantly longer than in the control: follistatin — by 32.5 percent on average, telomerase — by 41.4 percent. And the maximum life expectancy was about 37 months for follistatin and 40 months for telomerase. At the same time, the method of administration practically did not affect the length of life.

Comparison of the age of mice in the experiment and humans. From left to right: an "empty" viral vector, a vector with follistatin and a vector with telomerase. Drawings from the article by Jaijyan et al.

Scientists have checked whether the concentrations of the corresponding proteins really change at the same time. And they noticed that they grow both in blood and in tissues — but in different tissues in different ways. Perhaps this is due to the fact that the viral vector is unevenly distributed throughout the body or can not penetrate everywhere. At the same time, the telomere length increased in all the tissues studied and almost reached the level characteristic of a young 8-month-old mouse.

Relative increase (compared to the total level of RNA in the cell) of the work of the follistatin (blue) and telomerase (green) genes in different tissues.

In addition, the researchers found that after gene therapy, mice retain weight better and go bald less than ordinary elderly animals. And they have lower blood glucose levels — that is, less predisposition to diabetes, which often develops with age. And in all these cases, the method of administration again did not play a role.

Not all of these results were unexpected for the authors of the work. For example, they already knew that mouse cytomegalovirus colonizes the body well when administered through the nose — therefore, it is not difficult to explain that both methods of vector administration worked the same way. But they did not expect that both follistatin and telomerase would have a similar effect on blood glucose levels — because here the mechanisms of their action do not coincide at all.

Researchers believe that such gene therapy can be tested as a remedy for various age-related diseases. But before moving from mice to humans, it will be necessary to check whether this method will not lose its effectiveness. It is unknown whether the human cytomegalovirus will penetrate well through the nasal mucosa, and whether the vector will be able to reach different tissues. In addition, human telomeres are much shorter than those of a mouse, and the expression level of its own telomerase is much lower, so the effect may be different here.

The authors of the article also expect that in the future, using the cytomegalovirus vector, it will be possible to deliver several genes at once, for example, telomerase and follistatin simultaneously. This approach has already been used by their colleagues: we used to talk about how gerontologists cured mice of age—related diseases with the help of two genes and extended the life of flies with a cocktail of three.

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