Epigenetic controls on telomeres may play key role in aging, cancer
David Warmflash| Epigenetics Literacy Project | May 17, 2017

Do the current efforts to improve the human condition by intervening telomere length belong in the category of epigenetic biomedicine, or merely genetics?

Telomeres are  the caps at the end of each strand of DNA that protect our chromosomes. Many experts believe there is a strong connection between short telomeres and cellular aging, but the science is still out on how these telomeres may influence the aging of the entire individual.

Epigenetic changes affect phenotype by influencing the expression of genes, rather than the content of the genes themselves, and research has revealed that both epigenetic and genetic factors are protagonists in the telomere saga.  This duality dovetails with the idea that the length of telomeres can be affected both by environmental factors, such as diet, sleep, or weightlessness, and that gene therapy for the purpose of adding slack to telomeres may be a rational tactic for extending the lifespan and health span (the need for supporting clinical evidence notwithstanding).

But the same duel nature of telomere biology also suggests that the telomere story is more complex than once thought. Unlike bicycle helmets, gymnastics rest mats or the size of your parachute; it now looks as though the protection offered by telomeres to cells depends on more than just the length of each telomere strip that shields against gene loss.

Given all of this, current efforts to extend human health with gene therapies directed at lengthening telomeres universally—on all chromosomes, in all body cell types—and using one cell type, blood lymphocytes, as an indicator of one’s overall telomere status, look rather simplistic at best. At worst, they could invite danger. Either way, there’s a long road ahead before we understand enough to intervene.

Chromosome protectors and concepts for intervening with them

Telomeres are often compared with plastic ends of shoelaces. You don’t need those terms for the laces to tie and keep the shoes tight, and you can snip off part of the length of the plastic, and the lace still works just as well. But if you lose the entire plastic end, the lace is no longer protected against shriveling up. That’s a problem if some built-in process constantly chews up a little bit the plastic, but you could compensate by adding another process, one that keeps adding some plastic back.

telomere1Analogously, telomeres are DNA slack at the ends of chromosomes. The process of reproducing the genetic content within each chromosome shortens the tips in the course of each cycle of chromosomal replication. The longer the telomeres, the more cycles of cell reproduction can occur until there is gene loss. Based on this understanding, experimental therapies have been aimed at elongating telomeres using the telomerase enzyme.

In a highly publicized example, the biotech firm BioViva is running a one-subject clinical trial with its CEO, Elizabeth (Liz) Parrish as a human guinea pig. Along with the myostatin gene therapy to increase muscle mass, Parrish has received extra copies of telomerase-based on the rational that it will lengthen telomeres at the tips of her chromosomes—telomeres that, prior to initiation of treatment, were measured as being unusually short for a 40 -year-old (at least in lymphocytes from Parrish’s blood samples). For safety, Bioviva is keeping the gene therapy doses modes. But even with the attenuated doses, Parrish is taking a big risk because she isn’t accounting for the fact that telomeres are more than just DNA slack. New research published in the prestigious journal Nature Communications adds to a growing awareness that the cap itself is made of genes.

Rather than encoding protein enzymes, the genes comprising telomeric DNA code for non-coding RNA molecules. This means RNA whose genetic sequence is not translated by ribosomes into protein. Instead, the RNA itself acts as part of an enzyme system, specifically the telomerase enzyme. Similar to the enzyme that integrates human immunodeficiency virus (HIV) into the DNA of human cells, telomerase is a kind of reverse transcriptase, an enzyme that makes cellular genetics go backward. Telomerase has a protein component (made from a gene in the regular part of the genome) and an RNA component (encoded by sequences in the telomeres themselves). The protein part of telomerase is encoded by a gene called TERT and uses the RNA component as a template to create new telomeric DNA. This is how telomeres get longer, but a key finding in the Nature Communications study is that the genetic content of the RNA component—the content of the telomeres—makes a difference. You have 23 pairs of chromosomes, each with telomeres at their tips. But experimenters found that intentional deletion of telomeric genes affects different chromosomes differently. In some chromosomes, losing those sequences means losing the ability for telomerase to keep lengthening their telomeres. In other chromosomes, the change doesn’t matter.

What happens then if a person with unusually short telomeres gets TERT gene therapy to increase production of the protein component of telomerase? That’s the kind of treatment that Liz Parrish has received. The RNA component comes from the patient, because that’s in the telomeres themselves, and for all, we know this RNA may have an influence on how well the telomerase lengthens telomeres. If the impact of the RNA is significant, a possible outcome is that TERT gene therapy might lengthen telomeres of someone like Liz Parrish initially. The effects might endure with telomeres of chromosomes that do not depend on the telomeric gene content. But the content-sensitive chromosomes might lose their new telomeric slack quickly after the gene therapy ends.

Based on the growing understanding of the complexity of telomerase, gene therapy aimed at supplying people with extra copies of the TERT gene might be thwarted precisely in the very people who are thought to need the treatment, due to telomeres being unusually short, and specifically in those chromosomes that have the shortest telomeres. The reason is that of the genetic content in the telomeres that the patient seeks to lengthen –the genes that encode telomeric RNA.

Now, the gene for making the RNA component, called the TERC gene, potentially also could be a part of gene therapy, along with TERT. That might be a reasonable treatment to explore if lengthening telomeres universally through your genome is a good thing.

But this is a very big IF.

Epigenetic switch brings telomerase therapy rationale into question

The reason people have been so excited about telomeres is that they do appear to be connected with cell aging. Regarding wear and tear—to use the trite, but easy-to-understand, the comparison between one’s body and one’s car—telomeres are like tire treads or other parts of your vehicle that wear out gradually in connection with how old your vehicle gets. Build them up again and ailments connected with general wear and tear—this includes cardiovascular and cerebrovascular disease, major killers in western civilization, especially as people age—can be prevented. But there’s a flip side of the coin.

Epigenetic factors affect whether a gene is switched off or on, and to what extent it is switched on. One way to do this is by controlling how much DNA is coiled up. When twisted tightly, a gene is effectively turned off, because it’s inaccessible to the enzymes that would otherwise copy its sequence into RNA. It turns out that in many different cancers, the epigenetic control by way of coiling is set so that the telomerase gene TERT is switched to “ON,” at a high activity setting to boot. This enables the cancer cells to immortalize by keeping their chromosomes young, and by looking young, it also helps them to evade body systems that typically destroy disease cells. For this reason, several researchers have advised caution.

“We haven’t established a causal link between telomere length and health,” said Georgetown University senior investigator Dana Glei in an interview with The Scientist earlier this year. “If it’s like gray hair, dyeing your hair won’t make you live longer.”

Or, at best, if could be a risky trade-off in the form of reducing your risk for vascular disease while increasing the chances of malignancy.

“I refer to this phenomenon as the cancer cardiovascular disease compromise,” said Abraham Aviv of Rutgers University School of Medicine. “However, the idea that in the general population relatively short telomeres are bad and relatively long telomeres are good is nonsense.”

Therein lies the rub. As with many things in biomedicine, the growing capability for telomeric tampering may soon lead to a wide-scale clinical dilemma. But the growing understanding of these chromosomal protectors also highlights an ongoing theme in both genetic and epigenetic medicine: It’s complicated.

David Warmflash is an astrobiologist, physician and science writer. Follow @CosmicEvolution to read what he is saying on Twitter.

Read the research study here.