ELIXIR

The Battle against Ageing

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Early-stage research shows that lifestyle changes and certain chemicals can turn back cellular ageing, but the pill of youth is still many years away

A few weeks ago, a group of researchers including maverick American physician Dean Ornish and Nobel laureate Elizabeth Blackburn published a study that caught a lot of eyeballs. In the study, which appeared in Lancet Oncology, a prestigious medical journal, Ornish’s team compared two sets of prostate cancer patients. Both had undergone dramatically different treatments for five years—one received conventional therapy while the other made drastic lifestyle changes, exercising, meditating, attending support-group sessions and eating a diet of whole foods. At the end of the study period, Ornish found that while the blood immune cells of patients in the conventional therapy group had aged as all normal human cells do, the clock had seemingly turned back in the cells of the group that had made lifestyle changes.

Normal human cells cannot pull off such a feat without external intervention; cell ageing is inexorable. Only stem cells and cancer cells are known to reverse their own ageing, rendering them potentially immortal. But now, Ornish’s study seemed to show that normal cells could turn back time too, as long as a person could surrender to the healing power of plant-based foods, exercise and social support.

The Ornish study measured ageing through telomere length—a concept that has become pivotal to anti-ageing research in the past few years. Each of our cells has a nucleus, which contains long chromosomes of genetic material. At the tips of each such chromosome are little caps that protect the genetic material inside. If one can imagine a chromosome as a shoelace, telomeres would be like the aglets at its tips that keep the lace from fraying.

These telomeres have a useful little property that makes them excellent timekeepers of cell age. Each time a cell divides, the telomeres in its daughter cells grow a little shorter. When we are born, our telomeres are at their longest. But as our body ages, telomeres keep losing genetic material like the sand in an hourglass, until they reach a critical shortness. This is a signal for our cells to call it a day and initiate programmed cell death, also known as apoptosis.

One way to disrupt this continuous whittling away of telomeres is to introduce an enzyme called telomerase in cells, which puts the telomeric caps back on our chromosomes. However, most normal cells in human beings do not make telomerase. Therefore, they are unable to put the brakes on ageing. On the other hand, stem cells, from which our body regenerates tissue, and cancer cells can synthesise their own telomerase, which renders them almost immortal.

The Ornish study found that the telomeres of cancer patients in the lifestyle-change group had grown, while the patients receiving conventional treatment had shrunken telomeres.

This study is only the latest in a long line of research trying to answer critical questions about telomeres. First, how big a role do telomeres play in ageing and disease? Second, can we do anything to lengthen them? And, third, will lengthening them really help our bodies do a Benjamin Button?

DO SHORT TELOMERES CAUSE DISEASE?

Several studies so far have shown that people with afflictions such as cancer, heart disease and Alzheimer’s disease have shorter telomeres on average. One would expect this, of course, because short telomeres seem to lead to cell death.

But this isn’t enough evidence to conclude that short telomeres cause a particular disease. There could be a number of other reasons why people with diseases tend to have short telomeres—these diseases could be causing shorter telomeres, rather than the other way round.

Or some unknown third factor could be causing both short telomeres and the diseases. For example, heavy smoking could be shortening one’s telomeres at a faster rate, while also choking up one’s arteries, leading to cardiovascular problems.

Complicating matters further, there are several other factors already known to cause ageing and disease. Oxidation, in which cell DNA is damaged by free radicals, and glycation, in which sugar binds with body cells leaving them unable to do their jobs, can both trigger disease. So how much do telomeres contribute to ill health, if at all?

In 2010, a study published in the journal Nature provided some evidence that telomeres were actually the cause of ageing-related afflictions. A group of Harvard medical researchers genetically engineered mice to stop producing telomerase, causing their telomeres to shorten faster than usual. Soon, these mice began to show various signs of ageing such as osteoporosis, poor sight, shrunken testes and brains. When the researchers then gave the mice injections to reactivate telomerase, the mice bounced dramatically back to youth—their vision improved and their testes and brains grew back to normal.

This was strong evidence of the effect short telomeres had on disease, but as David Kipling, another researcher who studies ageing at Cardiff University, told The Guardian, “Mice are not little men.” It would be wrong to assume telomerase would work exactly the same way in human beings.

In March this year, another study in Nature Genetics threw up even stronger clues suggesting causation. In this study, an international group of researchers identified seven gene variants that were together known to affect telomere length. Next, they examined whether these seven variants were also associated with diseases such as cancer, heart disease and pulmonary fibrosis, which scars the lungs. They found a high association in several cases. Since the effect of these variants on telomeres was already known, this was further proof that telomere length could indeed cause disease.

According to Richard Cawthon, a researcher who studies the genetics of human ageing at the University of Utah, low telomerase activity affects tissues that get replaced the most often, such as bone marrow, skin and intestinal tissue. People with dyskeratosis congenita, a premature ageing disorder where the skin and bone marrow are often affected, tend to have shorter telomeres, he adds.

THE PILL OF YOUTH AND ITS SIDE EFFECTS

Even as researchers look for answers to the causation question, a small cottage industry of firms is already trying to develop the pill of youth by lengthening telomeres.

In 2002, a California biotechnology company called Geron Corporation licensed the commercial rights to sell a telomere-lengthening compound to another firm called TA Sciences. This compound was branded TA-65 (TA stands for telomerase activation) and is claimed to increase telomere length by activating the enzyme telomerase. But TA-65 does not have the backing of largescale human tests required for any drug to be approved by the US Food and Drug Administration. The tests that prove its efficacy are all small in scale. And this means that TA-65 can only be sold as a nutraceutical.

There are many questions about TA-65 that need clear answers. For example, it is known that cancer cells produce telomerase, so that they can extend their lifecycles. This is one of the weapons in their arsenal that lets them divide and proliferate wildly. So, if TA-65 is kickstarting telomerase production in someone who already has a few cancerous cells in the body, could it give cancer a boost?

Of course, such a side effect of TA-65 would take years to develop. “So, one may have to test the drug for many years,” says Nilesh Samani, a professor of cardiology at University of Leicester, who was part of the Nature Genetics study on the causal role of telomeres in disease.

Cawthon further explains that when mice are engineered to overexpress telomerase throughout life, it raises cancer risk. But this does not happen when genes that suppress tumours are expressed at the same time. Therefore, the key to making a drug like TA-65 work may be to adopt a similar two-pronged approach. “For people taking TA-65, combining this with doing things that lower cancer risk, such as regular exercise and intermittent fasting would be best,” he says.

But TA Sciences CEO Noel Patton Thomas dismisses such concerns around the safety of the drug. “We have had 20,000 people taking the product for six years. It is simply not causing cancer.” And yet, this isn’t evidence enough for the nutraceutical to be approved as a drug.

Meanwhile, TA 65 has at least one satisfied customer. William H Andrews, a molecular biologist and ultra marathoner, who was a part of the team that identified telomerase at Geron, is strongly convinced that inducing telomerase activity in normal cells is a surefire way to reverse ageing. Seven years ago, he became the first paying customer for TA-65. At that time, he did not quite know what to expect, but today, he feels that both his long-distance running and vision have improved from taking the longevity supplement. Today, when he finishes an ultramarathon, he is usually at the front of the pack, rather than at the back, as he used to be before he began taking the compound. The age spots on his hands, too, have all disappeared, he says. “Were all these placebo effects?” asks Andrews, “Anything is possible, but I am very optimistic about anything that protects my telomeres or lengthens them.”

This is why Andrews set up his own firm, Sierra Sciences, 14 years ago, to develop a telomerase-inducing drug. Since then, the firm has discovered over 900 chemicals that induce telomerase expression in the lab. One of its products has been licensed to a nutraceutical firm to be marketed as supplement, while Sierra Sciences is trying to launch an anti-ageing drug for pets. “Dogs, cats, and horses have all been shown to suffer from telomere shortening. A recent study of dog breeds showed that the shorter a breed’s telomeres, shorter its average lifespan,” says Andrews.

There is another, more pragmatic reason behind Sierra’s decision to target the pet market first. This market, while more regulated than the drug-supplement segment, is less stringently monitored than the human drug market. It could be the sweet spot from which Sierra Sciences can launch itself into the anti-ageing drug market, even as data is being gathered and revenues are being generated.

Andrews is optimistic that a drug for humans will be in clinical trials soon. “We are less than three years away,” he says.

Will a telomerase-inducing drug ever become a reality? TA-65 has its critics. Carol Greider, who won the Nobel prize along with Elizabeth Blackburn for the discovery of telomerase, says the assays used by TA Sciences to measure the lengthening of telomeres are not accurate enough to say for sure if the drug really works.

But it is too early to pronounce these efforts a success or write them off.

“These companies are making early proof-of-concept drugs. There is potential that such therapies may come into the clinical arena and we can’t ignore their potential simply because there is the fear of side effects,” says Samani.

MEDITATION, LOVE AND TELOMERES

As the race to develop a telomere-based drug continues, the study by Dean Ornish suggests that the pill of youth need not be a pill, after all. Ornish is already known for his lifestyle-based interventions in cardiovascular disease.

In 1990, he published a landmark study showing that the thickening of arterial walls in heart disease could actually be reversed through a lifestyle programme devised by him.

This programme, known as the Ornish Spectrum, is not simple by any means. It is a mix of several interventions, such as switching to plant-based foods, meditation and regular exercise. The most unique feature of the programme, though, is its acknowledgement that loneliness and social isolation can cause illness and premature death more than poor diet or smoking ever can. Therefore, the Ornish Spectrum requires a person following it to seek love and intimacy. It may sound like a hopelessly vague task, but the programme recommends several ways to achieve this, such as improving communication skills, meditating, group therapy, psychotherapy and even learning how to confess and forgive.

If this holistic approach has the ring of traditional Indian medicine to it, it is because Ornish was a disciple of the Indian spiritual guru Satchidananda Saraswati for years. Ornish has said in the past that his programme borrows much from Satchidananda’s philosophy.

Ornish’s Lancet Oncology study, though, is far from conclusive. Only ten patients were tracked in the lifestyle-change group. Given that current methods of measuring telomeres are inexact, variation in telomere from one lab to another is high. This means the increase in telomere length seen by Ornish’s team could have been random variation, and unless it is repeated with larger groups of patients, it is hard to say for sure.

A DECADE OR A CENTURY?

Ornish’s study was testing if lifestyle changes could reverse cellular ageing. Within the limitations of the study, it showed that dramatic changes to lifestyle could indeed lengthen telomeres and turn back the ageing clock in cells. The question now is: how many years can such cellular changes add to a person’s life? Several scientists put this number at about 20-30 years. Beyond that, other mechanisms of ageing would kick in. Human cells can also be damaged through routes such as oxidation and glycation. Exactly how big a role our chromosomal aglets play remains a big question.

Andrews, though, is willing to place his bets on telomeres. “There are many factors that cause ageing. I like to think of each one as a stick of dynamite that is burning inside our cells. But, the most important stick of dynamite for us to be concerned about is the one with the shortest fuse. I believe that the stick with the shortest fuse in humans is telomere shortening,” he says.

As Andrews looks for ways to lengthen the fuse on the dynamite of ageing, a couple of firms have begun offering tests to measure this fuse, as it were.

In 2009, the year Elizabeth Blackburn won a Nobel for her discovery of telomerase, she started a company to measure the length of telomeres as a way to predict disease risk. While this firm, Telome Length, currently offers tests only for researchers and not individuals, another company in Spain, called Life Length, tests individuals for a cost of $500 per head. Most doctors are not yet using these tests to measure disease risk, but according to Jerry Shay, scientific advisor to Life Length, “Boutique doctor wellness groups are incorporating this with their test batteries.” Life Length has plans to open a centre in India soon, by when it hopes to bring down the cost of the test with greater automation.

Unfortunately, all the methods used to measure telomere length today are imperfect. This is a problem when researchers such as Andrews test their drugs. “[These tools] are great for large population studies where high variability can still result in trend lines. But, when looking at just one person or a few people, the variability can be too high to give meaningful data,” explains Andrews.

Before a telomere-lengthening drug becomes a reality, there are several bridges to cross—better measurement tools and more research into the cancer-causing side effects of telomerase. The final drug, according to Samani, will have to go through several experimental studies in animal models to make sure there is absolutely no risk of cancer. This could take many years. Further, it would be hard to test for such side effects in human beings. He cites the example of statins to illustrate how difficult it may be to establish a drug’s safety.

Statins, today a frontline treatment for cardiovascular disease, had to be tested for decades before their benefits could become clear. First, there was the question of whether lowering cholesterol was actually effective in fighting heart disease. Second, there was the question of side effects of statins. Merck suspended clinical trials of its Lovastatin for four years in the 1980s, when another statin was shown to trigger toxic reactions in animals. It was only in 1994 that a large Scandinavian study showed that the benefits of Simvastatin may indeed outweigh risks.

Telomere-lengthening compounds may have to take the same long and hard road. But given the miracles they promise, it may be well worth it.

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