Fight Aging!

Researchers have been testing telomerase gene therapies in mice for more than a decade now, demonstrating extension of life, improved stem cell and tissue function, reduced cancer incidence, and so forth. The research results here, treating neurodegeneration in mice, are a representative example of the sort of work that has emerged in recent years. Telomerase primarily acts to lengthen telomeres, the repeated DNA sequences at the ends of chromosomes. Telomeres shorten with each cell division, a part of the mechanism determining the Hayflick limit to cell replication. Thus the general upregulation of telomerase should result in greater cell activity.

Telomerase upregulation was also widely expected to raise the risk of cancer, by putting damaged cells back to work, but so far that hasn't emerged in animal studies. If anything, the risk is reduced, perhaps due to increased activity in those parts of the immune system responsible for destroying cancerous and precancerous cells. One challenge in translating this work to human medicine is that telomere and telomerase dynamics are very different in mice and humans, and thus the balance of cancer risk versus improved regeneration may be quite different - though clearly clinical development is progressing, at Libella Gene Therapeutics and elsewhere.

Preventing accumulation of short telomeres may prevent or ameliorate brain aging by allowing stem cells to proliferate and regenerate damaged tissue. We have previously demonstrated that preventing accumulation of short telomeres through telomerase gene therapy can ameliorate the symptoms of cardiovascular disease, pulmonary fibrosis, aplastic anemia, and aging in general. Thus, to demonstrate that telomere shortening may be one of the causes of brain aging, here we studied the potential therapeutic effects of a telomerase gene therapy in ameliorating molecular signs of neurodegeneration associated with physiological mouse aging as well as in the context of the telomerase-deficient mouse model.

Our findings demonstrate that AAV9-Tert treatment can ameliorate signs of neurodegeneration with aging in wild-type mice as well as in the context of the telomerase-deficient mouse model with the presence of short telomeres. Our treatment was applied through an intravenous tail injection, and therefore, many other cell types throughout the body would be infected in addition to the cells in the brain. Improvements of health in other organs may have an impact on the brain and investigating the nature of this relationship could be interesting for future studies. Note also that we did not observe any increased incidence of cancer in the mice treated with AAV9-Tert, which matched our expectations since several other articles have demonstrated that telomerase reactivation alone does not lead to tumorigenesis in vivo.

Of note, the AAV9 serotype used here to express telomerase in the brain primarily transfects neurons and astrocytes but fails to transduce microglia. In our experimental setting, we found that less than 5% of the cells in the brain received the transgene using our vector and delivery method. Interestingly, in spite of the low transduction efficiency, we observed significant effects of AAV9-Tert gene therapy in decreasing DNA damage, increasing neurogenesis as indicated by increased doublecortin expression, as well as decreasing neuroinflammation (decreased GFAP expression). These findings suggest that even a small number of neurons transduced with Tert may increase the health of the environment and benefit cells that were not infected, for instance, through changing the secretory profile of cells. Even more benefits from telomerase gene therapy may be observed if higher transduction efficiencies are obtained.

Link: https://doi.org/10.18632/aging.101982