Researchers at the School of Molecular Sciences at Arizona State University have discovered a potential way to supercharge our stem cells and reverse some aspects of cellular aging.
The Hayflick limit
Normal cells cannot divide indefinitely; they have a built-in replicative limit, which is often called the Hayflick limit after its discoverer, Leonard Hayflick. This Hayflick limit means that regular human cells are unable to replicate forever; once they reach their replicative limit, they cease to divide and enter senescence, a nondividing state in which the cell destroys itself.
The Hayflick limit is directly related to the length of DNA repeats found on the ends of the chromosomes. These repeats form protective cap-like structures called telomeres, which protect the chromosomes from DNA mutations that can cause the genome to become unstable.
Every time a cell divides and makes a copy of itself, the telomeres shrink in size until they become so short that they cannot protect the chromosome ends. This continual telomere attrition is thought to be one of the reasons we age and acts like a “molecular clock” that counts down the replicative limit of cells. The loss of replicative potential in our cells is linked to the aging process, with reduced cell populations directly leading to the loss of tissue and organ function observed during aging.
A molecular fountain of youth
The enzyme telomerase helps to counteract telomere attrition by adding more DNA repeats to the caps, effectively rewinding the molecular clock to increase the lifespan of a cell and its potential to replicate. Some cells do produce telomerase, but most of our cells do not.
Our regular somatic cells do not produce telomerase, but this is not a problem because we want them to reach their replicative limit and destroy themselves via apoptosis, a programmed cell death process, once they reach their Hayflick limit. This is because aged cells may have picked up mutations during their lives, so keeping aged and potentially damaged cells alive and replicating is an invitation for cancer to develop.
The problem is that this steady loss of telomeres also affects our stem cells; these master cells can become various other types of cells, and they supply tissues with the cells they need to remain healthy. Stem cells combat telomere loss by producing telomerase, but this only serves to slow down the molecular clock and does not immortalize these cells. Stem cells are also better at repairing themselves than somatic cells.
Once stem cells start getting critically short telomeres, they also stop dividing and cannot replenish our organs and tissues. This causes another aging process, stem cell depletion, and leads to organ failure, poor tissue healing, and loss of tissue function.
Supercharging our stem cells
Understanding the underlying mechanisms of telomerase and replicative limits holds the potential to reverse telomere attrition and thus an important part of cellular aging. This has implications for preventing or reversing age-related diseases and potentially allowing us to live longer in good health.
The new study has discovered a critical step in the telomerase enzyme catalytic cycle; this cycle determines the ability of the telomerase enzyme to create extra DNA repeats on chromosome ends and thus maintain the telomeres.
The researchers show that telomerase has a kind of “braking system” that ensures the proper synthesis of DNA repeats. However, this brake also limits the overall activity of the telomerase enzyme, and finding a way to release this brake safely holds the potential to effectively restore lost telomere length in stem cells, partially reversing cellular aging and allowing tissue regeneration and the supply of fresh cells to continue.
The researchers demonstrate that this braking system relates to a pause signal that is encoded in the RNA template of telomerase. This means that once it has created a ‘GGTTAG’ repeat sequence, it pauses; when the next sequence is started and DNA synthesis begins again, this pause signal remains active and limits DNA synthesis.
This discovery also explains why a single specific nucleotide stimulates telomerase activity, solving a mystery that has eluded scientists for decades. In effect, this means that by specifically targeting the pause signal and turning it off, we remove its ability to interfere with repeat DNA synthesis. In effect, we could use this discovery to effectively supercharge telomerase, making it more efficient at replacing lost DNA repeats at a faster rate and thus keep pace with loss to a higher degree. This has the potential to rejuvenate our aging stem cells and keep our organs and tissues supplied with vital replacement cells.
It also has implications for treating various diseases that are linked to impaired telomerase activity, such as dyskeratosis congenita, aplastic anemia, and idiopathic pulmonary fibrosis.
Walk the line
While a therapy that targets this pause mechanism could partially reverse cellular aging and thereby prevent some age-related diseases, it would need to be carefully balanced. Too much of a good thing can be harmful, so a therapy would need to be carefully calibrated to maintain efficient cell regeneration without allowing unchecked cell proliferation. Essentially, we would be walking the line between highly efficient cell rejuvenation and tissue regeneration, and increased cancer risk.
The key is targeting the right cells. Somatic cells make up the majority of the cells in our bodies, and as mentioned previously, they do not produce telomerase, meaning that as they divide, they reach their Hayflick limit far sooner. This lack of telomerase activity in somatic cells is a mechanism that reduces the risk of cancer. Telomerase production is what most cancers use to fuel their rampant, uncontrolled growth, so it is a good thing that the ability to produce telomerase is turned off in our somatic cells.
The risk is that drugs that non-selectively increase telomerase activity in both stem cells and somatic cells are potentially dangerous. The researchers’ goal is to enhance telomerase activity and the production of DNA repeats selectively in stem cells while avoiding doing so in somatic cells.
The next step is to screen or design small-molecule drugs that can specifically target stem cells, turning off this pause mechanic as a path to therapies that address age-related diseases and help to restore youthful tissue and organ function to aged people.
Hopefully, we can find a way to walk the line between cancer and enhanced tissue regeneration; after all, a number of species already do, as do we during early development. The usual caveats apply here, this is only initial in vitro data and an in vivo study will need to follow to see if it is effective. Should this pan out then it has the potential to treat various age-related diseases, and that will be very welcome news indeed!
 Chen, Y., J.D. Podlevsky, D. Logeswaran and J.J.-L. Chen (2018). A single nucleotide incorporation step limits human telomerase repeat addition activity. EMBO. J. 37: e97953, DOI 10.15252/emboj.201797953.
February 27, 2018
Are there any specific surface markers on stem cells that could be used to target them?
February 28, 2018
This leaves the question as to whether the sweet spot for increased tissue regeneration without significantly increased cancer risk is higher than it’s natural position due to evolution. If so, telomere focused therapies may hold promise in themselves. If not, they will need to be combined and balanced with better immunotherapies in oncology. Stacking therapies is tricky in that the side effects multiply, calling for more therapies and so on (but that is no worse than how we treat our aging population today). A parallel study of model organisms like the naked mole rat and lobster that looks at these findings specifically may also lend additional insights.
February 28, 2018
The other place to look is at the reproductive process. The body has a natural process of generating youthful stem cells that are (usually) free of cancer as part of the reproductive process.
I am not an expert in biology but am curious whether receiving DNA from two parents is the key to facilitating error checking in the genome. The statistical understanding of gene dominance is already well understood, but within those statistics, one might question whether the healthier of two parental genes has an advantage of being passed down.
In other words, in youth, our genes are young and healthy. By the time reproduction is to occur a small amount of aging and mutation may occur, but the collective genomes of two parents generally has no problem yielding a healthy genome in which the clock towards the Hayflick limit can be safely reset.
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