In a study printed in PNAS, researchers have shown that telomerase reverse transcriptase (TERT) can be given to cells in living mice through a viral vector, taking the idea of life-extending gene therapies from science fiction to reality.
Why a cytomegalovirus?
The human cytomegalovirus (CMV) is widely known as an endemic virus that, while usually asymptomatic, is known to cause with harmful effects in babies and older adults. However, some of its properties make this virus suitable for delivering gene therapies. As cytomegaloviruses can carry large genetic payloads and don’t overwrite the DNA of their host cells , replacing the genes of these viruses with beneficial DNA may be safer than approaches with more potential off-target effects; development in this area is ongoing, and a phase 1 human clinical trial has already been conducted .
The role of TERT
Gradually shrinking telomeres lead cells to lose their ability to divide. In ordinary cells, this is known as the Hayflick limit. Stem cells, whose purpose is to grow organisms and replace lost bodily cells, naturally produce TERT in order to restore these telomeres. Aging organisms gradually lose this ability, and previous research has shown that gene therapies that restore TERT can extend lifespan in mice .
Combining CMV gene therapies with TERT expression, the researchers hypothesized, might be a way to safely conduct such a gene therapy in human beings. The researchers also chose to try this approach with follistatin (FST), a compound that promotes muscle growth.
An easy-to-administer therapy with substantial effects
The researchers developed two forms of administration of their mouse cytomegalovirus (MCMV): through an injection and through the nose. Both of these forms were almost exactly identical in effectiveness throughout this study.
The TERT-receiving groups had their TERT production doubled by the end of the first week after injection, after which it tapered back to baseline by day 25. This shows that, while effective, CMV gene therapy does not have a permanent effect.
The lifespan portion of this experiment was conducted on standard female Black 6 mice beginning at 18 months of age, which is approximately equivalent to 56 years old for a human. Each group contained nine mice, one of which was sacrificed early for tissue analysis, and the mice were given the treatment steadily except for an interval between 29 and 32 months of age.
The lifespan effects were clear: mice given FST through MCMV lived for nearly three years, nine months longer than the control groups, while mice that received TERT lived for about two months longer than the FST group. One mouse lived for a full 41.2 months, which is approximately equivalent to a human supercentenarian. All of the control groups’ mice had died of age-related causes before a single FST or TERT mouse did.
Telomeres are effectively extended
While not all tissues were affected equally, owing to the differences in the genes and the peculiarities with the CMV vector, both FST and TERT effectively promoted their respective genes within tissue according to an mRNA analysis. Staining and then examining telomeres directly showed that the average telomere length in the TERT group was tripled from baseline, reaching nearly to the level of younger animals in all of the organs studied, including the brain, heart, muscle, kidney, lung, and liver.
The researchers also examined the mice physically, seeing what the biochemical changes did to their morphology. The FST and TERT groups were better able to handle glucose than the control groups. Body weights were fairly similar at 18 months, but the FST groups grew much larger than the others. The control groups’ body weights decreased as they died of age-related diseases, which occurred more slowly in the FST and TERT groups.
At 24 months of age, the FST and TERT mice were many times more efficient in crossing a beam than the control groups. Interestingly, their muscle mitochondria were also much better preserved, suggesting a relationship between telomere attrition and another hallmark of aging, mitochondrial dysfunction.
The researchers did not combine FST and TERT into a single gene therapy, leaving it an open question as to whether such a combination would be more effective in lifespan extension than either one individually.
While this is not a human trial, the stark results shown in this lifespan trial seem to make it a prime candidate. However, aging is not a measurable endpoint in human trials; rather, there must be some measurable physical effect that can be monitored and judged, to a level of statistical significance, over the length of the trial. Biomarkers, such as for frailty and mitochondrial function, may be of help in this respect. If the results in mice can be recapitulated in people, this approach may, in fact, be a safe and effective gene therapy for life extension.
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