Telomeres are "caps" of non-coding DNA sequences present at both tips of our chromosomes, which are extremely important in the aging process. These caps protect our DNA as cells go through various life cycles of replication, however, each time a cell divides these telomeres are shortened and eventually contribute to disease and cellular aging.
Now, exciting new research published in the Journal PNAS has shown that an experimental gene therapy could be used to halt the shortening of these telomere caps in mice and by doing so increase the life span of these animals by up to 41 percent compared to controls.
Telomere length can be considered a marker of biological age and its shortening is a hallmark of a process called cellular senescence, which limits the replication of DNA in old damaged cells. As we age, telomere caps become shorter and shorter until the cell's DNA becomes vulnerable to damage by cellular stresses that could lead to diseases such as cancer. Or the cell could ultimately reach senescence where it will no longer be able to replicate and so contribute to the aging process. For scientists looking at how to slow or even reverse aging, telomeres are of great interest.
One of the reasons telomeres shorten over time is due to the reduced activity of an enzyme called telomerase which is responsible for maintaining the length of the telomere caps on chromosomes. The function of telomerase relies on a complex called telomerase reverse transcriptase (TERT). This complex activates telomerase, allowing the enzyme to be biologically active in cells, which in turn lengthens the telomeres on the tips of chromosomes.
The authors of the new study developed a gene therapy protocol using cytomegaloviruses (CMV) to deliver TERT to cells in different organs of mice. They wanted to see if it could increase telomerase activity responsible for lengthening telomere tips in biologically older animals versus those given a mock delivery as a control group. They then compare the results to normal wild-type animals of a similar biological age.
The scientists were able to successfully deliver the gene to the animals using their protocol. They found the telomeres of chromosomes in some organs, such as the kidney, increased in length in TERT treated mice vs controls and that it had an overall positive effect on glucose metabolism which is known to decline during aging.
The results also showed evidence that the treatment helped to prevent hair loss and improved the animal's motor activity and coordination. Moreover, the scientists say that the treatment with TERT did not increase the cancer risk of these animals, which is normally a concern in telomere research. Overall, TERT-treated animals had an extended lifespan of 41 percent compared to mock and wild-type control animals, which is a promising result.
Alongside TERT delivery, the authors used the same protocol with a gene for follistatin in a different cohort of mice. Follistatin is involved in maintaining skeletal muscle development, which is also known to decline as we age. The animals that received follistatin also had an increased lifespan of 32 percent, with similar benefits to those seen in the TERT-treated mice, illustrating both TERT and Follissatin may be able to offset biological aging in mouse models.
"We report CMV being used successfully as both an intranasal and injectable gene therapy system to extend longevity," the authors write. "Specifically, this treatment significantly improved glucose tolerance, physical performance, as well as preventing body mass loss and alopecia.
Further, telomere shortening associated with aging was ameliorated by TERT and mitochondrial structure deterioration was halted in both treatments. Intranasal and injectable preparations performed equally well in safely and efficiently delivering gene therapy to multiple organs, with long-lasting benefits and without carcinogenicity or unwanted side effects."
Going forward the scientists say that translational studies will be required to determine whether these results could be replicated in human subjects.