ETERNAL LIFE

Some questions are so substantial that they have been a mystery to scientists for centuries. No matter if they ever find the answers, the search for an explanation makes us wiser.

Immortality might not be impossible. And it might not even be unnatural. We meet the scientists trying to “cure” ageing.

The idea of the source of youth and eternal life has existed for as long as there have been humans on Earth. Still, it is not until the past 50 years that scientists have begun to discover why we grow old and what can be done about it. In the future, ageing will not be a fact of life, rather it will be considered a disease that can be treated. A miracle cure has not yet been developed, but scientists know where to search.

Have the first humans to live to be 150 years old already been born? Scientists who are working on solving the mystery of ageing disagree. Two American professors, Steven Austad and Jay Olshansky, took a bet in 2000. Austad claimed that the first person to celebrate his 150th birthday had already been born. Olshansky disagreed. The two scientists each placed $150 in a fund, which goes to the heirs of the one who is right. In 2016, none of them had changed their minds, and they decided to place another $300 in the fund. With a good rate of return, there might be a fortune waiting for the winner’s heirs.

So far, we have no concrete evidence of a human older than 122 years. The record holder is Jeanne Calment of France, who died in 1997. The record has remained for more than 20 years, which might seem strange, as the world population is growing ever older, so there are lots of candidates to challenge it. Right now, the number of people of 65+ is growing larger than the number of kids below the age of 5 for the very first time in world history, and according to analyses, the trend will continue, i.e. the share of elderly people will keep on rising.

According to the WHO’s most recent calculations, kids who are born now in the Western World can expect to be 79-83 years old. A decade ago, the numbers were 77-81, meaning that in just ten years, life expectancy has increased by a couple of years.

That is primarily due to the fact that we are becoming ever better at preventing, diagnosing, and treating diseases such as cancer, dementia, and arteriosclerosis. It is still those age-related diseases that most people in our part of the world die of. They just die later than they did a few decades ago.

As treatments are gradually improved, we will add more years to the average life expectancy, but according to some scientists, we are about to reach the upper limit of the life span of the human body. If we would like to live longer than that, we will have to find the fundamental causes of us becoming vulnerable to age-related diseases – i.e. the causes of ageing itself.

Ageing can be explained in many ways

Today, ageing researchers are beginning to consider ageing a disease in itself, against which they aim to find treatments and finally cure it. If they are successful, we will not only get rid of age-related diseases, we will also be able to avoid all the drawbacks of age: loose skin, weak muscles, brittle bones, poorly functioning organs, and failing vision and hearing.

The way to a cure against ageing begins with answering the question of why we get older. This can be addressed in several ways. Generally, some scientists will say that it is a natural and predetermined fact of life. Others will resort to more thorough biological explanations such as that as soon as we have had children and hence passed on our genetic material, there is no reason why we should go on living. Seen from the genetic point of view, it is much more important to be passed on to the next generation than to keep individuals alive, and so, evolution has not given “priority” to developing genes that make us live longer.

And yet others will have a more detailed approach, trying to find explanations in chemical processes in our bodies and cells. This approach is the one that could lead to longer lives for all of us. If the ageing processes can be mapped out down to the biochemical level in our cells, we might also find methods for interfering with the processes.

Mammals die after 1 billion heartbeats

Over the past century, ageing researchers have supported two different theories. According to the first one, our cells were designed for – and perhaps even programmed to – live for a specific period of time, after which they will shut down. According to the other, the unfortunate fact is that life wears down cells, so they will finally stop functioning. They sound like opposites, but both could be correct.

In 1908, German physiologist Max Rubner developed the idea that the life spans of mammals were not to be measured in days, months, and years, but rather in energy conversion. Rubner had discovered that the higher an animal’s metabolism is, the more the organism is worn down, and the shorter its life span is. The recognition made him think of using the pulse rate as a measure of metabolism and so as the factor that determines life spans. He calculated that life ends after about one billion heartbeats, no matter if you are a hamster, a horse, or an elephant. Small mammals typically have higher pulse rates at rest than large animals, and so, hamsters have shorter lives – only three years as compared to elephants, who can grow up to 70 years old.

Rubner might have been inspired by what was happening around him. The industrialization swept across Europe, and it was obvious to compare the body to a machine. When a machine works fast, converting a lot of energy as compared to its size, it will wear down quicly and break down. Perhaps the exact same thing was the case for a biological system such as an animal body.

A human life typically lasts for more heartbeats than the lives of other mammals. On his/her 75th birthday, a human being has reached about 2.5 billion heartbeats, so the body or “machine” apparently tolerates more wear than that of animals. Still, Rubner’s general idea that ageing is basically wear, that depends on the body’s energy conversion, comes quite close to several modern interpretations of ageing. That is not least so for the theory that says that ageing is due to the accumulation of waste products in the cells. This theory was introduced 50 years after Rubner’s ideas about heartbeats determining life spans. Its "father" was American chemist and physician Denham Harman, who later became a major

This theory suggests that we could use chemical methods to prolong life. DENHAM HARMAN Ageing researcher and chemist, who in 1956 developed the theory about free radicals causing the ageing process.

player in ageing research. He began to research the ageing processes of the body by coincidence. In his early career, he carried out studies supported by the American armed forces. World War II had ended with the terrifying nuclear bombs dropped on Hiroshima and Nagasaki, and the nulear arms race of the Cold War had begun. The US authorities would like to learn more about how radioactive radiation could harm the cells of the body, and whether there was any way to prevent it. Harman worked as a chemist for the Shell oil company, researching how special oxygen compounds known as free radicals behave in oil products. Other scientists had discovered that free radicals also emerged in cells that were subjected to radiation, and that aroused Harman’s interest. He realized that if he were to understand the biological processes in detpth, he needed more education, and in 1954, he had also become a doctor.

Harman was now ready to look into the idea that was to lead to a new theory about ageing. He followed a logical line of thought, by which he combined three observations. First of all, he knew that radiation seemed to boost the body’s visible signs of ageing. Secondly, he knew that radiation produces large quantities of free radicals in cells. And thirdly, he knew that a cell also produces free radicals under normal circumstances, as the free radicals are a residual product of cell energy production.

Aggressive substances attack DNA

Free radicals are vere chemically active and easily combine with other molecules, and so, Harman imagined that they could harm important structures in cells, including the cells’ DNA. He introduced his theory in a scientific article in 1956 – only three years after Nobel Prize laureates James Watson and Francis Crick solved the mystery of the structure of the DNA molecule. Harman fully realized the consequences. In the article, he writes:

“This theory suggests that we could use chemical methods to prolong life.” Harman’s theory was received with a mixture of scepticism and indifference in spite of the fact that already the next year, he published the results of experiments, which supported it. Harman had carried out experiments with mice, which he fed antioxidants, that prevent the damage of free radicals. The result was that the mice lived 20 % longer and so, Harman proved a clear relationship between free radicals and ageing.

Nevertheless, his research was overshadowed by another theory, which was introduced in 1959 by American biologist Howard J. Curtis. According to the theory, ageing is very much due to the accumulation of mutations in cells. Every time a cell divides, errors could result concerning the copying of its DNA, and such errors might finally produce cells which function poorly or not at all. The consequence of this theory is that the limit to our life spans is somehow genetic. The theory was very popular in the years after Curtis introduced it, but

since then, it has lost ground, as scientists

The world population is getting ever older. Right now, the number of people of 65+ years is exceeding the number of children under 5. According to WHO projections, the trend will continue.

have discovered a series of mechanisms in our cells that allow them to repair DNA strands. When an error develops in the DNA of a cell, it is not necessarily passed on, when the cell divides.

Cell power stations are under fire

In 1972, Harman refined his theory about free radicals, focusing on cell mitochondria, i.e. cells' integrated power stations that generate energy for all cell functions. Harman knew that free radicals would primarily hurt a cell close to the place where it is formed, so it was logical to look at the mitochondria, which are responsible for the energy conversion in cells and so for the production of the harmful free radicals.

This turned out to be a good idea. Over the decades, numerous studies have confirmed that ageing is linked with the function of the mitochondria. In 2014, scientists from the SDU university in Denmark introduced a study, in which they had scrutinized the mitochondria of the blood cells of about 1,000 test subjects. Mitochondria contain their own DNA in the shape of tiny, ring-shaped structures, and the scientists simply counted how many DNA rings the test subjects had in the mitochondria of their blood cells. The first counts were carried out in 1997 and 1998, and the scientists could see that in people of 50+, the number determined the results of different physical and mental tests.

The test subjects with the poorest grip strength and ditto working memories were also the ones with the fewest DNA rings in the mitochondria. And when the scientists followed up on the study in 2012, they could see that the test subjects with the fewest DNA rings generally died earlier than the ones who had more copies.

Studies such as this one indicate that the function of the mitochondria is important for ageing, and it is reasonable to imagine that the DNA of the mitochondria is particularly subjected to being harmed by free radicals, as Harman predicted. Moreover, it opens wide perspectives that apparently, individuals do not lose DNA in their mitochondria at the same speed. If scientists find out why this is so, they might also be able to find a way to prevent or postpone the loss.

Consequently, Harman was one of the pioneers of the line of thought that ageing is not necessarily an inevitable process. Ageing is a disease that can be combated, if we find the right means to do it. Still, Harman believed that people can only live for a limited number of years. He doubted that life expectancy would ever come to exceed 85 years. He himself died in 2014 at the age of 98. Both physically and mentally, he remained active very late in life. He went for a run every day until he was 82, and he continued even longer as an unpaid scientist of the University of Nebraska.

At the same time as Harman got onto the theory of the free radicals, another American scientist made a discovery that led to another major breakthrough. At the Wistar Institute in Philadelphia, USA, a young anatomist by the name of Leonard Hayflick in 1961 carried out studies of human cells. His cultivated his cell cultures in culture dishes, which he observed over long periods of time. That should not have been a problem, as at the time, it was commonly accepted that in principle, cells were immortal, if they were cultivated in culture dishes under optimum conditions. So, Hayflick was surprised that some of his cell cultures seemed to lose breath. The cells simply stopped dividing. Hayflick was sure that he took well care of his cultures, but nevertheless studied his notes to see if there was something that the poorly-functioning cell cultures might have in common. There was. They were all about the same age. Hayflick immediately thought that there might still be a limit to how many times a cell can divide. Together with a colleage, he made follow-up experiments, in which he found out that ordinary body cells only divide 50-70 times. Subsequently, they “retire”.

The retirement age of cells is now known as the Hayflick limit, but another 10 years were to pass from his discovery, until scientists came closer to an explanation. It happened, when Russian biologist Alexey Olovnikov discovered that when a cell divides, it does not copy the full length of its DNA strands. The hereditary material of the cell nucleus is united in the chromosomes in the shape of rolled-up DNA strands. At the end of the chromosomes, you will find a number of DNA sequences known as telomeres, which become slightly shorter for every cell division. Finally, when the Hayflick limit of 50-70 divisions has been reached, the most recent generation will no longer divide. The reason why the cell does not copy all of its DNA strand is that its integral DNA copier, also known as polymerase, moves slightly into the strand, before it starts copying, and so, everything is not included. That might seem inconvenient, but like so many other things in nature, it still makes sense.

Cell expiry date protects against cancer

The task of the telomeres is to protect the genetic contents of a chromosome’s DNA strand. They can be compared to the small "cuffs" of plastic by the ends of shoelaces, which make sure that the laces do not become frayed. Without the telomeres, the ends of the chromosomes become sticky, meaning that there is a risk that they will connect with the ends of other chromosomes, causing chaos in the genetic information that could result in the cell ceasing to function and dying. Or an even worse scenario: it develops into a cancer cell. The telomeres play a dual role in cells. They protect the cell DNA, and they make sure that the cell cannot keep on dividing indefinitely. In a cell, minor damage and DNA errors occur all the time, and although the cell includes mechanisms that can repair the errors,

We control how we age – all the way down to the interior of our cells. ELIZABETH BLACKBURN Professor Emeritus. She was awarded the Nobel Prize for the discovery of the telomerase immortality enzyme.

some of them will be passed on to the next generation. We all know what happens, when we use a photocopier to copy a page of text. If we continue to take copies of copies of copies, we end up with a result that is full of "scratches" and impurities and is impossible to read, or the text might even be misinterpreted.

All our cells have telomeres at the ends of their chromosomes, and in the vast majority of cases, they have limited lives.

Only three types of cells are different: reproductive cells, stem cells, and cancer cells. Those cells have the ability to maintain the telomeres, so they will not become shorter for every cell division. In 1984, two scientists came on the track of how they do it. It happened, when a 23-year-old, newlyeducated molecular biologist, Carol W. Greider, chose to continue her PhD studies under the guidance of biologist Elizabeth Blackburn of the University of California, Berkeley. The two scientists were both very interested in a monocellular organism by the name of Tetrahymena thermophile. The interesting thing about it was that it was apparently able to divide without any consequences. The scientists observed that its telomeres did not become shorter over time, indeed they sometimes grew longer. The secret turned out to be a completely unknown enzyme, which can reconstruct the telomeres. The scientists named the enzyme telemorase, and subsequent research has demonstrated that it is the same enzyme that allows reproductive cells, stem cells, and cancer cells to prolong their telomeres. In 2009, Greider and Blackburn were awarded the Nobel Prize for their discovery, and since then, many studies have confirmed that telomeres and telomerase play a central role in the ageing process.

Stress wears cells down

Studies have also shown that genetically speaking, we do not have the same starting points, when we are born. Different viariants of special genes mean that some of us have longer telomeres than others, but it is unclear how much it means. Studies including research animals point in different directions. Some show that individuals who are born with longer telomeres also live longer, whereas other studies fail to prove this. Finally, some studies demonstrate that people with shorter telomeres are better equipped to avoid cancer. The explanation might be that the risk of cells developing into cancer cells increases with the number of copies made. Moreover, it is not only inerited factors that determine the length of the telomeres throughout life. The environment also plays a role. In 2000-2004, Elizabeth Blackburn carried out a study of mothers who had been subjected to stress for long periods of time. It turned out that the longer the mothers had been in a stressful life situation, the shorter their telomeres were. Long-term stress exposure apparently wears down the telomeres. The study also showed that a special group of mothers had the ability to regard their situation as a challenge rather than a crisis, and this ability also influenced the telomeres. In

Ever more people live to be 100 years old. 25 years ago, about 95,000 people in the world were 100+, but now is is half a million. According to UN statisticians, 3.5 million people will be more than 100 years old 25 years from now.

these women, they had not been worn as much. The result has made Blackburn conclude that by changing our conditions of life and our perspective on life, we could also change our ageing process:

"We control how we age – all the way down to the interior of our cells," she put in in a lecture in 2017.

Diabetes drug works against ageing

Blackburn’s and other scientists’ results show that the telomeres’ influence on our life spans depends on both nurture and nature. But what about the medical possibilities? One obvious idea is that we could prolong our lives, if we were able to step up the production of telomerase or perhaps simply add the enzyme to our cells from the outside. Experiments with the C. elegans worm demonstrate that the creature lives longer, when scientists improve the effect of the enzyme, making its telomeres become longer. But at the same time, other experiments show that the length of the telomeres is not crucial. Strangely enough, mouse cells live for a very much shorter period of time in the lab than human cells do, though the mouse cells have much longer telomeres.

Most scientists recognize that we need much more research to get the full impression of both telomerase and the function of telomeres, so even though telomerase has been named the “immortality enzyme”, a miracle cure against ageing is not imminent. Moreover, it seems that there is a very delicate balance between the body’s need for our cells to divide and the body’s precautions against the fact that too many copies lead to cancer cells. Consequently, it is probably too risky to feed our ordinary cells telomerase. Instead, some scientists are developing the idea of improving the telomerase in stem cells. Studies have demonstrated that the enzyme’s function in stem cells is reduced with age, and recently, scientists found out why. Researchers from the Arizona State University in the US discovered that telomerase includes a pause function that limits the speed at which the enzyme is working, as it is adding new DNA sequences to the telomeres. If the scientists manage to counter this pause function, they can improve stem cells’ ability to restore body bones and organs.

The telomere theory and the theory of the free radicals are now very central to ageing research. One explains why we get worse at producing new cells, as we grow older. The other provides the answer as to why our old cells function more poorly over time. Those are the two areas that we need to focus on, if we would like to find a cure against ageing. There is every indication that the key to the cure is to be found in cell mitochondria. In 2014, a study showed that over the past 60 years, diabetics have consumed a drug that prolongs life. The drug, which is known as metformin, helps regulate the blood sugar level of diabetics, but over the past decades, scientists have become aware that it also has other beneficial effects on age-related diseases. Hence, a team of scientists from the Cardiff University in England decided to study the life spans of a group of diabetics who took metformin. Amazingly, it turned out that on average, they lived 18 % longer than a control group made up of healthy people. Several scientists now plan experiments, in which they intend to give the drug to healthy people. Steven Austad from the American Federation for Aging Research is trying to raise USD 65 million for what he has named “the first test of an antiageing drug on humans.” According to Austad, the major effect of the drug is due to the fact that in some way, it makes the mitochondria’s energy production more efficient, so fewer free radicals are released to possibly harm cells.

As evidenced by Austad’s bet with his colleague, he is an optimist, when it comes to the life spans of future generations. And he is not the only one. English ageing researcher Aubrey de Grey has drawn attention to himself with even more wide-ranging predictions concerning the length of life. According to de Grey, ageing is basically to be considered the damage that is caused to our bodies and cells. He has arranged those into seven categories, and he believes that we are quite close to being able to repair all of them. The consequence is that according to de Grey, there is no upper limit to our life spans, and he predicts that in the very near future, we will experience medical breakthroughs that will make them accelerate. According to de Grey, the development can be compared to what we have experienced with aeroplanes. Only 115 years have passed, since the Wright brothers were the first to make an aircraft fly, but since then, the development towards the fighters and airliners that we know today has been extremely fast. Likewise, the breakthroughs within the seven damage categories will result in a number of practical treatmens, that will make our life spans increase drastically. De Grey’s only reservation is that it is impossible to predict when the vital breakthrough will be made. In 2005, he put it like this:

"The first person to live to be 1,000 years old will probably only be 10 years younger than the first one to grow 150 years old."

Consequently, we cannot know when we will be able to determine, whether de Grey will be right. But we can with other of his predictions - such as this one that he made in 2018: "It is highly likely that people who are born today could grow 1,000 years old."

A hungry stomach boosts stem cells

While we are waiting for scientists to make us immortal, there are luckily ways in which we can prolong our lives ourselves. A well-known dietary recommendation is to choose food that includes lots of antioxidants such as the beta-carotene of carrots and the vitamin C of lemons. The idea is that the antioxidants can neutralize the free radicals, before they harm the interior of the cells. In recent years, questions have been raised about whether the antioxidants

It is highly likely that people who are born today could grow 1,000 years old. AUBREY DE GREY Ageing researcher, mathematician, and the author of several books about ageing

that we consume have any effect on the free radicals in cells, but a new study from 2018 shows that they might. Scientists from the University of Colorado, USA, studied the effect of a special antioxidant by the name of MitoQ, which they had altered chemically, allowing it to stick to cell mitochondria. The scientists gave it to a group of people who suffered from arteriosclerosis, and it turned out to have a major effect. Already after two weeks on MitoQ, the patients’ blood vessels had changed so much that they seemed 15-20 years younger.

It is also a good idea to eat less. For decades, scientists have known that people who have a very low calorie intake or even fast generally live longer. There might be several explanations of this. Roundworm studies have shown that fast increases cells’ ability to read a DNA strands’ protein formulas correctly. And a brand new study involving mice indicates that fast directly influences the activity of stem cells. Scientists from the Massachusetts Institute of Technology (MIT) in the US made mice fast for 24 hours, subsequently studying the activity of the stem cells that provide the intestinal system with new cells. It turned out to be much higher than in stem cells from mice that had not fasted. The explanation is that the stem cells start to break down fatty acids instead of sugar, and that is apparently also a signal for doubling the production of new cells.

Finally, if we do not like to fast nor eat fruit and vegetables, we could choose to do what Jeanne Calment did. The old woman from France explained her longevity with the fact that throughout life, she had consumed her fair share of port, chocolate, and olive oil. Since then, research has confirmed that she was on to something. Moderate quantities of alcohol are good for the body, dark chocolate boosts the brain, and olive oil contains the healthy type of fat. On the other hand, it would be a good idea to quit smoking earlier than Calment did. She gave up tobacco when she was 117.

The hydra polyp almost solely consists of stem cells that can keep on dividing infinitely. So, scientists think that the creature could in principle live forever. It does not age, meaning that it is impossible to determine the age of an individual. SHUTTERSTOCK, MARTIN CAMM/ NATUREPL, FRANCO BANFI/GETTY IMAGES & BANGOR UNIVERSITY