Pharma & drug development

The telomerase trick

The enzyme telomerase, which reverses chromosome deterioration in cells, is strongly implicated in the ageing process. But could stimulating its production prevent ageing, or might the risks outweigh the benefits? We find out.

Telomerase has gained a reputation as no ordinary enzyme. As the protein responsible for protecting the tips of chromosomes, it plays a regenerative role, slowing the process of cellular ageing. It wouldn’t be too much of a stretch to call it a fountain of youth.

The enzyme works by acting upon the telomeres, caps of repetitive DNA at the tips of every chromosome. These strings – which prevent the chromosome from deteriorating or fusing with other chromosomes – grow a little shorter every time the cell divides, as chromosomes cannot completely replicate their ends. Eventually, the aged cell reaches its ‘Hayflick limit’, at which point it can no longer divide.

Long-telomere cells therefore have a natural advantage: they can keep dividing and restoring the tissue for longer. This forestalls cell death, organ deterioration, and many of the diseases of old age.

Reversing the inevitable

A number of prospective studies have found links between telomere length and mortality. In one 2003 study, subjects with shorter telomeres were over three times as likely to die from heart disease, and nearly nine times as likely to die from infectious diseases. Another study, published in 2010 found a correlation between short telomeres and deaths from cancer.

Luckily, the body has a built-in mechanism for reversing its cells’ inevitable decline. Telomerase (also known as terminal transferase) reverses the shortening of telomeres by replacing the lost string of DNA. Without this enzyme, human cells would reach their Hayflick limit after 50-70 divisions. In its presence, however – abundant in stem cell tissue and immune cells – cells could theoretically continue to divide forever.

Since its discovery in the 1980s, the enzyme has attracted intense scrutiny. Might it be possible to increase its activation, making sure cells continue to regenerate? And is these even a desirable outcome, given the association between unchecked cell division and tumour growth? Below, we run through some of the latest thinking in the field.

Stimulating production

In August this year, a team of Brazilian and US researchers found that sex hormones could stimulate the production of telomerase. In essence, androgens in the body (which convert to oestrogen) bind to receptors in the telomerase gene promoter region, causing an increase in enzyme activity.

This idea was nothing new – the team had demonstrated the process in the lab back in 2009. However, it was the first time it had been shown to occur in the human body, and the first time the therapeutic possibilities had been evinced.

The researchers, based at various Brazilian institutions in collaboration with the National Institutes of Health, recruited 27 patients with aplastic anaemia for a phase 1 and 2 clinical trial. These patients, some of whom also suffered from pulmonary fibrosis, had mutations in the gene that coded for telomerase and a resulting telomerase deficiency.

As researcher Rodrigo Calado, a professor at the University of São Paulo’s Ribeirão Preto Medical School, explained: “In a healthy adult, telomere length varies from 7,000 to 9,000 base pairs on average. A normal person’s telomeres lose 50 to 60 base pairs per year, but a patient with telomerase deficiency can lose between 100 and 300 base pairs per year.”

These patients were treated with danazol, a synthetic male sex hormone. The results were staggering: over the course of the two-year trial, their telomere length increased by 386 base pairs. In addition, their haemoglobin mass increased to near-normal levels, while for those suffering with pulmonary fibrosis, degeneration was paused.

Because danazol, like all anabolic steroids, comes with some undesirable side effects, the researchers are now trialling the same approach with a different synthetic male hormone. The drug in question, nandrolone, has a lower risk profile and has so far shown promising results.

Implications for ageing

This is good news for patients with telemorase deficiency. However, the obvious follow-up question is whether there might be benefits for healthy people too. Might administering sex hormones help slow down their own ageing process?

It’s certainly an interesting area of enquiry. In recent years, we have seen a growing market for testosterone supplementation, which advocates treating testosterone as something of an anti-ageing panacea. Meanwhile, studies have suggested that hormone replacement therapy for women can reduce telomere attrition.

But according to Calado, this kind of supplementation may come down to a trade-off between the benefits and the risks.

“Post-menopausal hormone replacement therapy offers a number of benefits, including maintenance of bone mass, libido and cardiovascular health,” he said. “However, it increases the risk of breast cancer, so it’s no longer recommended indiscriminately. Excessive telomere lengthening might facilitate the development of cancer by favouring cell proliferation. All this needs to be investigated further.”

Telomerase and tumour growth 

The relationship between telomerase and cancer is notoriously complex. On one hand, too little telomerase can reduce the body’s regenerative potential, therefore increasing susceptibility to cancer. On the other hand, too much telomerase can promote the replication of cancer cells – telomerase upregulation is a feature in over 90% of cancers.

As a result, telomerase inhibition is becoming an important field of research. The principle is straightforward: if cancer cells switched off their telomerase production, the fast replicating cells would eventually degenerate, reach their Hayflick limit and die.

Of course, any anti-telomerase drug would need to induce cell death in cancer cells while minimising the effects on healthy tissue – a conundrum with no straightforward solutions. Some promising candidates have emerged, such as Geron’s drug Imetelstat, which is due to undergo further clinical trials. But the field in general is still stymied by a lack of understanding about the underlying mechanisms.

As the Nobel Laureate Thomas Cech, of the University of Colorado Cancer Center, has explained: “Right now we don’t have a great telomerase inhibitor. We don’t know at which step our first generation of these drugs is interfering so we don’t know how to optimise these drug candidates for anti-cancer effect. Knowing where a drug blocks the ability of telomerase to lengthen telomeres could have broad applicability for diverse cancers.”

Coch recently led a study that used CRISPR gene editing technology and live-cell, single molecule microscopy to watch how telomerase and telomeres interact. His results, published in the journal Cell, could have profound ramifications – not just for visualising the interaction, but for aiding the development of therapies that stop it in its tracks.

Approach with caution

Evidently, telomerase is not a magic bullet for anti-ageing, but rather an instrument that should be wielded with caution. If telomerase therapy is ever used to prolong the human lifespan, scientists will need to overcome the significant safety challenges, beyond which ethical issues may also come into play.

There are plenty of clinicians who do hold out hope for telomerase. One prominent example is Michael Fosser, the founder of the biotech company, Telocyte, which hopes to develop telomerase as a l treatment. His 2015 book The Telomerase Revolution cites mindset as the obstacle to success: the revolution hasn’t happened yet, he claims, because of “our assumption that change is impossible”.

However, given the complexities of this field, it’s easy to see where that assumption comes from. Three decades after the enzyme was discovered, there is little scientific consensus about its potential: even if telomerase therapies do become safe, would they be effective or even desirable? Despite the wealth of research underway, we are still dealing with many unknowns.

This article appears in the November 2016 edition of Pharma Technology Focus

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