IMAGE: Pictured are Maria A.
Blasco and Bruno M. Bernardes de
Jesús (co-author) in the CNIO
building in Madrid.
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Public release date: 14-May-2012
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Contact: Juan J. Gomez
juanj.gomez@cnio.es
34-917-328-000-4060
Centro Nacional de Investigaciones Oncologicas (CNIO)
CNIO scientists successfully test the first gene therapy against
aging-associated decline
Mouse lifespan extended up to 24 percent with a single treatment
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 – an approach impracticable in
humans. Researchers at the Spanish National Cancer Research Centre
(CNIO), led by its director María Blasco, have proved that mouse lifespan
can be extended by the application in adult life of a single treatment acting
directly on the animal's genes. And they have done so using gene therapy,
a strategy never before employed to combat ageing. The therapy has been
found to be safe and effective in mice.
The results are published today in the journal EMBO Molecular Medicine.
The CNIO team, in collaboration with Eduard Ayuso and Fátima Bosch of
the Centre of Animal Biotechnology and Gene Therapy at the Universitat
Autònoma de Barcelona (UAB), 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, produced an
appreciable improvement in the animals' health, delaying the onset of age-
related diseases – like osteoporosis and insulin resistance – and achieving
improved readings on ageing indicators like neuromuscular coordination.
The gene therapy utilised consisted of treating the animals with a DNA-
modified virus, the viral genes having been replaced by those of the
telomerase enzyme, with a key role in ageing. Telomerase repairs the
extremes of chromosomes, known as telomeres, and in doing so slows the
cell's and therefore the body's biological 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 anti-
ageing gene therapy without increasing the incidence of cancer", the authors affirm. "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 add.
'Resetting' the biological clock
Telomeres are the caps that protect the end of chromosomes, but they cannot do so indefinitely: each time the
cell divides the telomeres get shorter, until they are so short that they lose all functionality. The cell, as a result,
stops dividing and ages or dies. Telomerase gets round this by preventing telomeres from shortening or even
rebuilding them. What it does, in essence, is stop or reset the cell's biological clock.
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 tumour cells.
It is precisely this risk of promoting tumour development that has set back the investigation of telomerase-
based anti-ageing therapies.
In 2007, Blasco's group proved 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, also, 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 test are likewise 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 tumours 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 successfully used in gene therapy treatment of haemophilia and eye
disease. Specifically, they are non-replicating viruses derived from others that are non-pathogenic 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 healthspan and treat disorders associated with short telomeres", state Virginia
Boccardi (Second University of Naples) and Utz Herbig (New Jersey Medical School-University Hospital Cancer
Centre) in a commentary published in the same journal.
Although this therapy may not find application as an anti-ageing treatment in humans, in the short term at
least, it 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.
More healthy years
As Blasco says, "ageing 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 ageing, we could prevent these diseases".
With regard to the therapy under testing, Bosch explains: "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 anti-ageing therapy, since other strategies would require the drug to be administered over the
patient's lifetime, multiplying the risk of adverse effects".
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CNIO scientists successfully test the first gene therapy against aging-associated decline