OPINION | GENE THERAPY | protecting the telomeres has prompted
a great deal of research into the relationship between telomerase and ageing. Four years ago, the same Spanish team that has just published the gene therapy data, reported that telomerase expression in mice engineered to be highly cancer resistant was linked not only to a much greater median lifespan, but also to a reduction in the incidence of disorders associated with ageing. This was the first time that telomerase
had been shown to have anti-ageing and rejuvenating properties. However, because the researchers avoided the risk of promoting cancer by using cancer-resistant animals, the findings cannot be translated directly into the human situation because humans are not cancer-resistant.
The challenge ahead The challenge, therefore, has been to find a way in which to activate telomerase expression temporarily, so that the shortened telomeres in ÔoldÕ cells are repaired, but potentially cancerous cells do not become immortalised. This approach might allow normal cells to maintain their function for a few more years, while helping to ward off age-related disorders such as diabetes, cardiovascular disease, and cognitive impairment. The latest Spanish research brings this
objective a step closer. Other studies have investigated the feasibility of repairing damaged telomeres using a telomerase activator, but because the mechanism of action of such agents is poorly understood, they are difficult to control. Rather, the team, based at the Spanish National Cancer Centre in Madrid, used an adeno-associated virus (AAV) vector expressing mouse TERT (mTERT), the first time that TERT-based gene therapy has been studied in this way. More specifically, they used the AAV9 serotype virus because it has shown efficient transduction in a number of tissues, it has high tropism for liver, heart and skeletal muscle, and it is able to cross the bloodÐb rain barrier. The mice used in this experiment
normally live for approximately 3 years. Consequently, the researchers tested the effects of gene therapy in ÔadultÕ (aged 420 days) and ÔoldÕ (720 days) mice. Expression of the virus could be detected for at least 8 months post-injection.
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A number of aspects of ageing were
studied, all of which pointed to a beneficial effect of AAV9Ð mTERT: ■ As bone loss is a sign of ageing, the researchers measured bone mineral density in the experimental mice. Not unexpectedly, there was a significantly lower bone mineral density in the 720-day-old mice compared with the 420-day-old mice. However, boneÐ mineral density was significantly higher 3Ð 6 months after treatment with AAV9Ð mTERT, and this increase correlated with an increase in mTERT RNA levels in the treated mice
■ Another biomarker of ageing is loss of subcutaneous adipose tissue, a phenomenon associated with a range of skin pathologies. In the experimental mice, skin thickness was lower in the 720-day-old mice compared with the 420-day-old mice, but not in mice treated with AAV9Ð mTERT
■ Glucose intolerance and insulin resistance are both signs of ageing. In the Spanish study, AAV9Ð mTERT- treated mice had significantly lower fasting insulin levels. This suggests improved insulin sensitivity in the treated mice
■ Another aspect of ageing is loss of neuromuscular coordination. Using techniques such as the rotarod test (the ability of the mouse to stay on a rotating rod) and the tightrope test (the ability of the mouse to negotiate a tightrope), AAV9Ð mTERT-treated mice in both age groups were found to have improved neuromuscular coordination.
Possibly most significantly, median
lifespan was significantly increased in both age groups following AAV9Ð mTERT treatment: by 24% in the 420-day-old mice and by 13% in the 720-day-old mice. Furthermore, all mice underwent pathological examination at the time of their death, and AAV9Ð mTERT-treated mice of either age group showed no increase in the incidence of cancer. Lastly, most tissues from AAV9Ð mTERT treated mice of both age groups had longer telomeres than the controls. The researchers comment that their
results constitute a proof of the role of mTERT in delaying physiological ageing, improving health span, and extending longevity in normal mice, and that the gene therapy they report represents a novel type of therapeutic intervention against a variety of age-related diseases.
Conclusions So where do we go from here? Clearly, the clinical application of this research is still some way off, and a number of questions remain unanswered. For example, does the gene therapy approach increase the risk of cancer in humans, and if so, is that risk acceptable? Until now, gene therapy has been viewed as a means of delivering genes to adult tissues in order to correct a genetic defect or other disease, and this is the first time that such an approach has been considered with regard to ageing. Perhaps some studies in species with a longer lifespan than mice might throw some light on the subject. Another issue is the fact that, at
present, it is not possible to direct the AAV vector to any particular group of cells in the body, which would be highly desirable. For that matter, it is not even clear which cells should be targeted in the context of ageing. Even so, the Spanish study gives cause for cautious optimism, and the next few years could bring us closer to the alchemistsÕ goal of, if not immortality, then at least longer and healthier lives.
The mice used in this experiment
normally live for approximately 3 years.
July/August 2012 |
prime-journal.com
Reference
de Jesus BB, Vera E, Schneeberger K et al. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med 2012; 4: 1–14
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