A group of Spanish researchers, including Dr. Maria Blasco and others at the CNIO, has published a new study that examines the consequences of short telomeres and telomerase deficiency on the brain .
This study addresses an aspect of telomere attrition, one of the primary hallmarks of aging. Telomeres are repeating sequences of DNA (TTAGGG) that can can reach a length of 15,000 base pairs and appear at the ends of chromosomes, acting as protective caps. They prevent damage, stop chromosomes from fusing with each other, and prevent chromosomes from losing base pair sequences at their end during cell replication.
Telomere length is influenced by both erosion and addition mechanisms
Telomeres control the number of times a cell can divide; with each division, roughly 25-200 base pairs are lost. When the telomere becomes critically short, the chromosome can no longer replicate, triggering a persistent DNA damage response, which initiates a self-destruct sequence in the cell known as apoptosis. This is the basis of the erosion mechanism of telomeres, which leads to cellular senescence.
Telomeres also have an addition mechanism, which is regulated by the activity of the enzyme telomerase. This enzyme is made of protein and RNA subunits that cause the chromosome to lengthen by adding more TTAGGG sequences to the end of the chromosomes, thus helping to offset the erosion mechanism. However, it is only normally found in fetal tissues, germline cells, and some stem cells; in the regular somatic cells in our body, its activity is so low as to be almost undetectable.
However, if telomerase is activated in regular cells, which can happen in cancerous tumors, the cell can continue to grow and divide indefinitely as long as telomerase is expressed. Therefore, researchers of both cancer and aging find this enzyme and its immortalization of cells interesting, as it can theoretically be used to reset part of cellular aging. This concept has encouraged multiple researchers to investigate ways in which telomerase might be used for regeneration of organs and tissues and to combat age-related diseases.
Telomerase therapy for neurodegeneration
Studies have shown that mice and humans that lack telomerase, and have short telomeres as a result, tend to experience an earlier onset of age-related diseases that are associated with the loss of tissue regenerative capacity in fast-dividing tissues, such as fibrosis. However, there have been few studies investigating the effects of short telomeres in tissues that rarely or do not divide at all, such as the brain.
The Spanish team examined a telomerase-deficient mouse model and compared these mice to ordinary aged mice. Both types of mice had similar symptoms of shortened telomeres that led to neurodegeneration.
The researchers then went on to demonstrate that the delivery of telomerase gene therapy to the brains of these mice caused the amelioration of some aspects of neurodegeneration. The researchers suggest that these findings support that short telomeres are a contributing factor in age-related neurodegenerative diseases and that telomerase gene therapy may be a potential solution to combat such conditions.
Preventing the 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 the 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 IV 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. In an analogous manner, factors found in young blood induce a younger phenotype in the recipient cells, as observed from parabiosis experiments with young blood and also treatments with specific factors in young blood such as the GDF11 protein. Nevertheless, even more benefits from telomerase gene therapy may be observed if higher transduction efficiencies are obtained.
Telomerase therapy holds a great deal of potential, especially for resetting cellular aging and some age-related epigenetic alterations. Many people predicted over a decade ago that activation of telomerase, particularly its upregulation in somatic cells, would increase cancer incidence. However, this has proven not to be the case in various animal studies; if anything, the risk of cancer appears to be reduced, as improving telomeres improves the genomic and epigenomic stability of cells, making them functionally younger in some ways.
The trick, of course, is in translating these findings from mice and taking them to clinical trials for eventual translation and human use. There is certainly plenty of enthusiasm for the approach and more than enough reason to be optimistic about it.
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 Whittemore, K., Derevyanko, A., Martinez, P., Serrano, R., Pumarola, M., Bosch, F., & Blasco, M. A. (2019). Telomerase gene therapy ameliorates the effects of neurodegeneration associated to short telomeres in mice. Aging.
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