Telomerase gene therapy as a treatment for aging is a popular topic these days, given the results in mice from past years, though I still think that more work needs to be done in mammals other than mice to address concerns related to cancer risk and effectiveness. Mice have telomere and telomerase dynamics that are quite different from those in humans, and the details of those differences might turn out to be important in the balance between greater stem cell activity and greater risk of cancer resulting from the activity of age-damaged cells. It is not unreasonable to think that adding a given amount of telomerase to cells might be good, bad, or neutral to varying degrees on a species by species basis.
Telomerase therapies are thought to work because telomerase lengthens telomeres, among other possible activities, and thus causes cells to undertake more replication and other activity than they would otherwise have done. This is particularly the case for the stem cell populations responsible for tissue maintenance. That tissue maintenance normally declines with age, an evolved reaction to rising levels of molecular damage that serves to reduce cancer risk at the cost of a slow failure of tissue function. The research here is early stage, but it suggests there might be ways to produce a telomerase therapy that works by making existing telomerase more efficient at lengthening telomeres, rather than by adding more telomerase. That means it might also be a way to find out whether the other, less well studied activities of telomerase are at all important in the observed results in animal studies of telomerase gene therapy.
Typical human cells are mortal and cannot forever renew themselves. As demonstrated a half-century ago, human cells have a limited replicative lifespan, with older cells reaching this limit sooner than younger cells. This "Hayflick limit" of cellular lifespan is directly related to the number of unique DNA repeats found at the ends of the genetic material-bearing chromosomes. These DNA repeats are part of the protective capping structures, termed "telomeres," which safeguard the ends of chromosomes from unwanted and unwarranted DNA rearrangements that destabilize the genome. Each time the cell divides, the telomeric DNA shrinks and will eventually fail to secure the chromosome ends. This continuous reduction of telomere length functions as a "molecular clock" that counts down to the end of cell growth. The diminished ability for cells to grow is strongly associated with the aging process, with the reduced cell population directly contributing to weakness, illness, and organ failure.
Telomerase lengthens telomeres by repeatedly synthesizing very short DNA repeats of six nucleotides - the building blocks of DNA - with the sequence "GGTTAG" onto the chromosome ends from an RNA template located within the enzyme itself. However, the activity of the telomerase enzyme is insufficient to completely restore the lost telomeric DNA repeats. Understanding the regulation and limitation of the telomerase enzyme holds the promise of reversing telomere shortening and cellular aging with the potential to extend human lifespan and improve the health and wellness of elderly individuals. Researchers recently uncovered a crucial step in the telomerase catalytic cycle that limits the ability of telomerase to synthesize telomeric DNA repeats onto chromosome ends. "Telomerase has a built-in braking system to ensure precise synthesis of correct telomeric DNA repeats. This safe-guarding brake, however, also limits the overall activity of the telomerase enzyme. Finding a way to properly release the brakes on the telomerase enzyme has the potential to restore the lost telomere length of adult stem cells."
This intrinsic brake of telomerase refers to a pause signal, encoded within the RNA template of telomerase itself, for the enzyme to stop DNA synthesis at the end of the sequence 'GGTTAG'. When telomerase restarts DNA synthesis for the next DNA repeat, this pause signal is still active and limits DNA synthesis. Moreover, the revelation of the braking system finally solves the decades-old mystery of why a single, specific nucleotide stimulates telomerase activity. By specifically targeting the pause signal that prevents restarting DNA repeat synthesis, telomerase enzymatic function can be supercharged to better stave off telomere length reduction, with the potential to restore the activity of aging human adult stem cells.