Gene therapy has increased life expectancy

By targeting specific genes, it is possible to increase the average lifespan of many animal species, including mammals, as has been proven in many studies. However, until now this meant irreversibly changing the genes of animals at the embryonic stage of development, an approach that is not feasible for the human body. Scientists from the Spanish National Cancer Research Center (Centro Nacional de Investigaciones Oncologicas, CNIO), led by its director María Blasco, have shown that the lifespan of mice can be increased by a single injection of a drug that directly targets the genes of the animal in adulthood. They did this using gene therapy, a strategy that has never been used to combat aging. The use of this method on mice has been recognized as safe and effective.

The results of the study were published in the journal EMBO Molecular Medicine. Using gene therapy, scientists from CNIO, in collaboration with Eduard Ayuso and Fátima Bosch from the Centre of Animal Biotechnology and Gene Therapy of the Autonomous University of Barcelona (Universitat Autònoma de Barcelona), achieved a “rejuvenating” effect in experiments on adult (one-year-old) and old (two-year-old) mice.

Mice treated at one year of age lived an average of 24% longer, and at two years of age, an average of 13%. The treatment also led to significant improvements in the animals’ health, delaying the development of age-related diseases such as osteoporosis and insulin resistance and improving markers of aging such as neuromuscular coordination.

The gene therapy used involved injecting animals with a virus containing modified DNA, in which the viral genes were replaced with genes for the enzyme telomerase, which plays a key role in aging. Telomerase repairs the end sections of chromosomes, known as telomeres, and thus slows down the biological clock of the cell and, therefore, the entire organism. The virus acts as a vehicle, delivering the telomerase gene to the cells.

The study “shows that it is possible to develop telomerase-based anti-aging gene therapy without increasing cancer incidence,” the authors say. “As organisms age, they accumulate DNA damage due to shortening of telomeres, and [this study] shows that telomerase-based gene therapy can repair or delay the onset of such damage.”

Telomeres protect the ends of chromosomes, but they can't do this indefinitely: with each cell division, telomeres become shorter until they become so short that they lose their functionality entirely. As a result, the cell stops dividing and ages or dies. Telomerase prevents this by preventing telomere shortening or even restoring their length. Essentially, what it does is stop or reset the cell's biological clock.

But in most cells, the telomerase gene is active only before birth; in adult cells, with a few exceptions, telomerase is not expressed. These exceptions are adult stem cells and unlimitedly dividing cancer cells, which are therefore immortal: a number of studies have shown that the key to the immortality of tumor cells is precisely the expression of telomerase.

It is this risk – an increased likelihood of developing cancerous tumors – that is holding up research into the development of telomerase-based anti-aging drugs.

In 2007, Blasco's group demonstrated that it was possible to extend the lifespan of transgenic mice whose genomes had been irreversibly altered at the embryonic stage: the scientists forced their cells to express telomerase and, in addition, inserted into them extra copies of cancer-resistant genes. Such animals live 40% longer than usual, without getting cancer.

The mice that received gene therapy in the current experiments are also cancer-free. The Spanish scientists believe this is because the treatment begins when the animals are adults and therefore do not have time to accumulate enough aberrant divisions to cause tumors.

In addition, the type of virus used to deliver the telomerase gene to cells is of great importance. The authors chose apparently safe viruses that have been successfully used in gene therapy for hemophilia and eye diseases. In particular, these are non-replicating viruses obtained from others that are not pathogenic for humans.

This study is seen primarily as a proof of concept that telomerase gene-based therapy is a feasible and generally safe approach to extending disease-free lifespan and treating diseases associated with short telomeres.

While this method may not have any application as an anti-aging treatment for humans, at least in the short term, it could open up new possibilities for treating diseases associated with abnormally short telomeres in tissues, such as some cases of human pulmonary fibrosis.

According to Blasco, "Aging is not currently considered a disease, but scientists are increasingly considering it as a common cause of conditions such as insulin resistance or cardiovascular disease, which increase in incidence with age. By treating cellular aging, we could prevent these diseases."

“Because the vector we used expresses the target gene (telomerase) over a long period, we were able to limit it to a single administration,” explains Bosch. “This may be the only practical solution for anti-aging therapy, since other strategies would require administration of the drug throughout the patient’s life, increasing the risk of side effects.”

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