First Gene Therapy Successful Against Degeneration Caused by the Aging Process

The research provides a proof-of-principle that this “feasible and safe” approach can effectively “improve [the] health span.”

A number of studies have shown that it is possible to lengthen the average life of individuals of many species, including mammals, by acting on specific genes. To date, however, this has meant altering the animals’ genes permanently from the embryonic stage--a strategy unfeasible in humans. Scientists from the Spanish National Cancer Research Center (CNIO; Madrid, Spain), led by its director Dr. María Blasco, have demonstrated that the mouse lifespan can be extended by the application in adult life of a single treatment acting directly on the animal’s genes. Moreover, they have done so using gene therapy, a strategy never before employed to combat aging. The therapy has been deemed to be safe and effective in mice.

The study’s findings were published May 15, 2012, in the journal EMBO Molecular Medicine. The CNIO team, in collaboration with Drs. Eduard Ayuso and Fátima Bosch of the Center of Animal Biotechnology and Gene Therapy at the Universitat Autònoma de Barcelona (UAB; Spain), treated adult (one-year-old) and aged (two-year-old) mice, with the gene therapy delivering a “rejuvenating” effect in both cases, according to the authors.

Mice treated at the age of one lived longer by 24% on average, and those treated at the age of two, by 13%. The therapy, furthermore, generated a substantial improvement in the mice’s health, delaying the onset of age­-related diseases--such as osteoporosis and insulin resistance--and achieving improved readings on aging indicators like neuromuscular coordination.

The gene therapy consisted of treating the animals with a DNA--modified virus, the viral genes having been replaced by those of the telomerase enzyme, with a major role in aging. Telomerase repairs the extreme ends or tips of chromosomes, known as telomeres, and in doing so slows the cells growth and therefore the body’s biologic clock. When the animal is infected, the virus acts as a vehicle depositing the telomerase gene in the cells.

This study “shows that it is possible to develop a telomerase-based antiaging gene therapy without increasing the incidence of cancer,” the authors acknowledged. “Aged organisms accumulate damage in their DNA due to telomere shortening, [this study] finds that a gene therapy based on telomerase production can repair or delay this kind of damage,” they added.

But in most cells the telomerase gene is only active before birth; the cells of an adult organism, with few exceptions, have no telomerase. The exceptions in question are adult stem cells and cancer cells, which divide limitlessly and are therefore immortal--in fact several studies have shown that telomerase expression is the key to the immortality of tumor cells. It is exactly this risk of promoting tumor development that has pushed back the research of telomerase-based antiaging therapies. In 2007, Dr. Blasco’s team demonstrated that it was feasible to prolong the lives of transgenic mice, whose genome had been permanently altered at the embryonic stage, by causing their cells to express telomerase and extra copies of cancer resistant genes. These animals live 40% longer than is normal and do not develop cancer.

The mice subjected to the gene therapy now under assessment are similarly free of cancer. Researchers believe this is because the therapy begins when the animals are adult so do not have time to accumulate sufficient number of aberrant divisions for tumors to appear.

Also important is the kind of virus employed to carry the telomerase gene to the cells. The authors selected demonstrably safe viruses that have been effectively used in gene therapy treatment of hemophilia and eye disease. Specifically, they are nonreplicating viruses derived from others that are nonpathogenic in humans.

This study is viewed primarily as “a proof-of-principle that telomerase gene therapy is a feasible and generally safe approach to improve health span and treat disorders associated with short telomeres,” stated Virginia Boccardi, from the Second University of Naples (Italy) and Utz Herbig, from New Jersey Medical School-University Hospital Cancer Center (Newark, NJ, USA) in a commentary published in the same journal.

Although this therapy may not have use as an antiaging treatment in humans, in the short term, at least, could open up a new treatment option for ailments linked with the presence in tissue of abnormally short telomeres, as in some cases of human pulmonary fibrosis. As Dr. Blasco stated, “aging is not currently regarded as a disease, but researchers tend increasingly to view it as the common origin of conditions like insulin resistance or cardiovascular disease, whose incidence rises with age. In treating cell aging, we could prevent these diseases.”

With regard to the therapy under evaluation, Dr. Bosch explained, “Because the vector we use expresses the target gene (telomerase) over a long period, we were able to apply a single treatment. This might be the only practical solution for an antiaging therapy, since other strategies would require the drug to be administered over the patient’s lifetime, multiplying the risk of adverse effects.”

Related Links:
Spanish National Cancer Research Center
Universitat Autònoma de Barcelona