Polynomial

Just the other day I was speaking to a friend about who we really were i.e. what defines ‘us’, what is real about ‘us’, what makes ‘us’ us… And after we’d finished discussing The Grand Delusion Of Self, he decided that it was our body that defined us.

Perhaps this is something we should all bear in mind… That, while we might feel solid and certain at many points in our lives, ‘WE’ really are as fickle as the dunes of the Sahara. As Nisargadatta Maharaj once said, “When you have seen the dream as a dream, you have done all that needs to be done.”

Here’s a question: how old are you? Think carefully before you reply. It’s a lot trickier than you might imagine. The correct answer, it turns out, is about 15 and a half. According to recent research, that’s the average age of your body – your muscles and guts, anyway. You might think that you have been around since the day you were born, but most of your body is a lot younger.

That may come as no surprise. It’s a common belief that the human body completely renews itself every seven years, and though biologists would hesitate to put a firm figure on it most are happy to accept that cells eventually wear out and are replaced. In some tissues – skin and blood – we know how long it takes, for example from seeing how long transfused blood cells last. Surprisingly, however, we have no idea how often most cell types are replaced, if indeed they are replaced at all. Until a few months ago it was impossible to tell. Experiments on mice had hinted that some cells are replaced more often than others, but no one was sure how relevant the findings were to humans.

Now neurologist Jonas Frisén of the Karolinska Institute in Stockholm, Sweden, has invented an ingenious technique for determining the age of adult cells. He and others are using the technique to answer questions that have intrigued scientists and laypeople for decades: does cell turnover mean that you eventually renew your entire body? If so, how many bodies do you go through in a lifetime? If you live to a ripe old age, is there anything left of the original “you”? There’s more to it than curiosity value, though. The rate of cell turnover is a hot question in neuroscience and regenerative medicine, and may provide the key to treating numerous diseases and managing the effects of ageing.

Questions about the rates of cell renewal first arose about 100 years ago, when scientists discovered that most of our neurons are formed during fetal development and persist for life. Ever since, people have been wondering if the brain’s cerebral cortex – the seat of executive functions such as attention and decision-making – ever makes new cells. In the 1960s neurologists discovered that rodents and cats may make new neurons. Then in 1999 a study in Science caused great excitement with the claim that new growth had been found in the cerebral cortex of monkeys. Despite numerous attempts, however, the results have never been repeated.

Information about the lifespan of cells has historically come from experiments on rats and mice. The method involves giving the animals radioactive nucleotides, the building blocks of DNA, either in their food or by injection. The assumption is that if cell turnover is going on, new cells will incorporate labelled nucleotides into their DNA. Post-mortem tests can later reveal how much tagged DNA there is in various tissues and hence what proportion of cells were born during the animal’s exposure to the nucleotides. These experiments undoubtedly tell us about cell turnover rates in rodents but it is unclear whether the results can be extrapolated to humans. Because humans live for decades rather than months, we might have a greater need to replace our cells.

Feeding radioactive genetic material to humans, however, is clearly not on. Some researchers have attempted to date cells by other means such as measuring the lengths of telomeres, the DNA stubs on the end of chromosomes that shorten each time a cell divides. But no one has ever been able to develop a reliable method for reading age from telomere length. What’s worse, says Frisén, “some cells, such as stem cells, appear to be able to lengthen their telomeres, which would be a problem when trying to assess the cell’s age, especially in the brain”.

Frustrated with the lack of progress, Frisén decided there had to be another way. “My train of thought ran to the ancient Egyptian papyrus scrolls, which were carbon-dated, and I wondered if there was a way we could use that,” he says.

Carbon dating relies on measuring the amount of carbon-14 in a sample of organic matter. Carbon-14, a rare and weakly radioactive isotope of carbon, is continually produced in the atmosphere when neutrons generated by cosmic rays smash into nitrogen nuclei, stripping out a proton. Carbon-14 eventually decays back to nitrogen, with a half-life of 5730 years. But before it decays, carbon-14 can be taken up by plants during photosynthesis and converted into sugars. Animals eat the plants, and in this way all living things contain small amounts of carbon-14 – about 1 in a trillion carbon atoms in your body are carbon-14 rather than carbon-12. At death, however, the organism stops taking in carbon-14, and what it already contains eventually decays away.

That slow decay is what makes carbon dating of archaeological samples possible. By measuring the ratio of carbon-14 to carbon-12 in something that was once alive you can estimate when it died – up to 60,000 years ago, after which carbon-14 levels have fallen too much to be useful.

Slow decay, however, also makes the method fairly imprecise. An archaeological radiocarbon date is accurate only to between 30 and 100 years, depending on the age of the sample – fine for ancient Egyptian artefacts but useless for dating cells in a human body.

Frisén’s eureka moment arrived when he realised he could use carbon-14 in a different way thanks to a unique episode in recent history – the cold war arms race. Between 1955 and 1963, above-ground nuclear weapons tests loaded masses of carbon-14 into the atmosphere. At the peak of such tests in 1963, atmospheric levels of carbon-14 reached twice the normal background level (see Diagram below). This “bomb spike” was accurately recorded at locations all over the world, creating a unique window of opportunity that Frisén is now exploiting.

He reasoned that while most molecules in a cell are in a constant state of flux, DNA is very stable: when a cell is born it gets a set of chromosomes that stay with it throughout its life. Therefore the level of carbon-14 in a living cell’s DNA is directly proportional to the level in the atmosphere at the time it was born, minus a tiny amount lost to radioactive decay. Before 1955 that level was always roughly the same. But during the bomb spike, atmospheric levels rose and then fell again – and so did carbon-14 levels in cells’ DNA. What that meant, Frisén realised, is that he could take cells born after 1955, measure the proportion of carbon-14 in their DNA and then consult the bomb spike curve to obtain an estimate of their date of birth.

If Frisén was right, for the first time scientists would be able to work out the average age of cells in different parts of the body and, he hoped, finally settle the question of whether the brain makes new nerve cells.

Before he could start, Frisén needed to know how long the window of opportunity was open for. Ever since the 1963 partial test ban treaty, carbon-14 in the atmosphere has been declining steadily, halving every 11 years as it is absorbed by the oceans and biosphere. Even so, Frisén found that any cell born between 1955 and 1990 would contain enough extra carbon-14 in its DNA to give a reliable date, give or take a year or so.

Last year Frisén and his team reported preliminary tests on a few body tissues taken from cadavers of people who had been alive during the bomb spike (Cell, vol 122, p 133). They revealed for the first time how many different ages one human body can be.

The body’s front-line cells endure the roughest life, last the briefest time and are constantly replaced – these include the epithelial cells lining the gut (five days), the epidermal cells covering the skin’s surface (two weeks) and red blood cells (120 days).

Cells Frisén analysed from the rib muscles of people in their late 30s had an average age of 15.1 years, a similar lifespan to cells making up the body of the gut, which he found were around 15.9 years old on average. It seems our bodies are indeed in a constant state of breakdown and renewal – even the entire skeleton is replaced every few years, he says.

Exciting though these forays into uncharted territory were, Frisén was eager to get on with his original quest, working out the age of the cells in the brain. “I am a neurologist and that is where my love lies,” he explains.

“Of course I want to know how often our body cells are replaced – we will do it little by little, and I hope that experts in all those areas take on the research and help us. But I want to explore the areas of the brain and discover whether we generate new brain cells throughout our adult lives.”

The standard view from animal studies – and one man who agreed to have labelled nucleotides injected into his brain as he was dying from cancer – is that once the brain is formed, no new neurons are generated except in two areas: the hippocampus and a region around the ventricles.

Frisén first applied his new method to cells taken from the visual cortex. Here, as expected, the neurons turned out to be the same age as the person they came from – perhaps because they need to be wired up in a very stable way so that each time an object or colour is viewed it is perceived in the same way as before, he speculates. Cells in the cerebellum, which is involved in coordinating movement, turned out to be about 2.9 years younger on average than the person, which is consistent with the idea that this region continues to develop during infancy.

“We’ve now mapped the rest of the cortex and are well on our way with the hippocampus,” says Frisén. “So far, it doesn’t look like there are any new cells being formed in the cortex – they’re as old as you are. But some regions of the hippocampus are exciting – absolutely there’s neurogenesis.”

Medical Breakthoughs

Frisén isn’t just motivated by curiosity. He hopes that by uncovering the secrets of cell turnover in the brain, he can help shed light on diseases including depression and Alzheimer’s. In 2004, a team led by Rene Hen at Columbia University in New York demonstrated that mice appeared to become depressed if hippocampal stem cells were not making enough new neurons, and that drugs such as Prozac work by stimulating neurogenesis: when the team inhibited neurogenesis, the antidepressants stopped working (Science, vol 301, p 805).

Alzheimer’s, too, has been associated with a lack of neurogenesis in the hippocampus, and other brain disorders, including Parkinson’s, are linked to cell death not being balanced by adequate cell creation. Frisén’s group is now studying cell turnover in people with neurodegenerative diseases.

The brain is not the only organ where information on cell turnover may provide clues to treating disease. Knowing how frequently healthy people produce new fat cells, for example, could help treat obesity: at the moment nobody knows whether obesity is the result of having enlarged fat cells or a greater number of them. Similarly, understanding the normal turnover of liver cells – which animal studies suggest have a lifespan of 300 to 500 days – could help physicians spot abnormalities such as cancer. And understanding the cell turnover rates in the pancreas could eventually help us to manipulate the organ’s lifespan with a view to treating diabetes.

There are other possibilities too. Experts believe heart muscle cells are not renewed when they die, leaving gaps that are filled with fibrotic material, resulting in a gradual loss of cardiac function as we get older. But no one knows for sure. Frisén’s group has just started preparing some heart tissue for analysis to see whether heart muscle cells are ever renewed.

Meanwhile, a group at the University of California, Davis, led by Krishnan Nambiar, is using Frisén’s method to investigate the lens of the eye. Cells in the transparent inner part of the lens form five weeks into embryonic life and stay with you for life. New cells are generated from the periphery, where they build up and make the lens thicker and less flexible with age, sometimes leading to cataracts. “If we could learn more about the turnover of cells in the lens, we could perhaps learn how to delay the onset of cataracts for five years and make tremendous savings in the health budget,” explains Bruce Buchholz at the Lawrence Livermore National Laboratory, who uses atomic mass spectrometry to carry out the carbon-14 analysis of Nambiar and Frisén’s samples.

It is clear, then, that a large proportion of your body is significantly younger than you are, and that raises a paradox. If your skin, for example, is so young, why don’t you retain a smooth complexion even into old age? Why can’t a 60-year-old woman, with her youthful muscle cells, flick-flack across the floor with the acrobatic agility of a 10-year-old girl?

The answer lies with mitochondrial DNA. This accumulates mutations at a faster rate than DNA in the nucleus. As soon as you are born, your mitochondria start taking hits – and there is nothing much you can do about it. So while your cells may be only a third as old as you are, the snag is that your mitochondria are the same age. In skin, for instance, mitochondrial mutations are thought to be responsible for the gradual loss in the quality of collagen, the skin’s scaffolding, which is why skin loses its shape and forms wrinkles.

There is good news, however. If we ever find ways to protect or repair mitochondrial DNA – and there are many ideas for how to do so – the discovery that most of our cells are younger than we are means that we could significantly delay ageing. Perhaps in the future people really will struggle to answer the question “How old are you?”

written by Gaia Vince

To find out more about Gaia Vince, please click here.

OR to follow her on Twitter, please click here.

And to find out where I sourced this article from, please click here.