Telomeres: The tiny keys to immortalitySave
By Tom Chivers
Why do we get old? It is, on the face of it, a puzzle. Cells can effect repairs, and divide to make new copies of themselves - they've been doing it for four billion years, give or take. So why do the cells in our bodies wear out? Why, after a few short decades, do they stop working?
The search for the key to ageing - and a means of slowing or reversing it - is far older than anything we'd call science. In ancient China around 200 bc, a Qin emperor sent an alchemist Xu Fu to the eastern seas to find the elixir of life; medieval alchemists sought the "philosopher's stone" which, as well as transmuting base metals into gold, was said to prolong the life of anyone who ate a piece of it. (They didn't find it, and many of them are believed to have suffered from mercury poisoning as a result of their investigations.)
A more scientific version of this quest is still going on. Scientists at the University of California have found that mature mice can be rejuvenated with transfusions of blood from younger ones. For the past few decades, however, the main focus of attention has been on little stretches of DNA on the end of our chromosomes, called telomeres.
'They're like the little tabs on the end of shoelaces'
"The best analogy that we have for telomeres is that they're like the little tabs on the end of shoelaces," says Dr Adam Rutherford, a geneticist and author of Creation: The Origin of Life. Just as the tabs, or "aglets'', hold the strands of the laces together, he says, telomeres - repetitive stretches of DNA on the end of each chromosome - perform the same function.
"Chromosomes are made up of a double helix, two strands of DNA, and they need an endpoint," says Rutherford. "Without telomeres they'd unravel, like two bits of string that have been tied together."
Telomeres are simple in structural terms, but play a crucial role: they're not genes, they don't code for anything, but cells cannot reproduce without them. They are also key to ageing.
"Every time the cells go through a division and the chromosome is reproduced, it loses telomeres," Rutherford explains. Our cells find it hard to copy the very tips of chromosomes and, slowly, the aglet is worn away from the end of the lace; the telomeres are depleted through repeated division.
"This seems to be a key part of why cells die during the ageing process," Rutherford says. This eventual death of cells is called senescence, from the Latin senex, meaning old man. "When a cell gets to the point that it has no telomeres left, it won't be able to divide again. Or if it does, it'll be messed up."
Restoring telomeres in elderly cells
So the next question is, if we can restore the telomeres in elderly cells, might that stop them - and us - getting old?
That's been the goal of researchers for a while. In the Nineties, Dr Elizabeth Blackburn and colleagues at the University of California won the Nobel prize for the discovery of telomerase, an enzyme that replenishes the telomeres in cells. The enzyme is usually "switched off", but there is one kind of cell in which it demonstrates its potential in an often lethal way. "In cancer cells," says Dr Kat Arney, a scientist at Cancer Research UK, "telomerase is switched on. And they become immortal." Cancer cells can divide repeatedly without ever growing old, but this sort of uncontrolled growth has the unfortunate side-effect of killing the organism it's growing in.
Telomerase may have a role to play in future treatments, according to Rutherford. "Telomeres are undoubtedly a key part of ageing, and the discovery of telomerase was a significant moment in understanding why cells don't continue to reproduce forever, why they're not immortal. If we could target that process of losing telomeres, with drugs or whatever, you could possibly maintain a longer shelf-life for a cell, it could continue reproducing far longer than its natural life. I don't think it's just science fiction; I think it's genuinely a worthy topic of research with therapeutics in mind."
A part in the fight against cancer
In the shorter term, says Arney, telomere research may play a part in the fight against cancer. Since telomerase is found in cancer cells, some scientists thought they could target cancer cells in this way. "There was a massive trial into a vaccine against telomerase, called TeloVac, training the immune system to recognise it so that it would detect it in cancer cells," says Arney. The trial showed no improvement over the standard chemotherapy treatment for the pancreatic cancer it targeted, but there is hope for other treatments in future.
Second, telomere loss is itself associated with cancers. When a cell's telomeres are depleted, the chromosomes' ends flap loose. "Cells hate loose ends of DNA," says Arney. "If they come across some, they try to stitch them together, because they assume something's gone wrong." And if they stitch two flapping chromosomes together, "you get all sorts of mutations", often causing cancer. Understanding telomerase could help prevent this.
As the function of telomeres becomes better understood, some private companies including Telomere Health and Life Length have begun offering to measure an individual's chromosomal length, and so determine their "biological age", as opposed to the chronological age. It is known that people with shorter telomeres are more likely to suffer various diseases, including diabetes, Parkinson's and Alzheimer's, and tend to die younger. One study found that people with shorter telomeres were eight times more likely to die from an infection and three times more likely to die from a heart attack.
The trouble is, says Rutherford, that the history of biology warns us that things are always complicated. "In biology, there is never one thing. For every rule that we have, we find a bunch of exceptions to it. And with genetics in particular, we've revealed a picture of complexity, rather than simplicity. In physics, things tend to get simpler the more we understand them. In biology, they tend to get more complex. Biology is messy."
Telomeres 'aren't the only show in town'
Telomeres "aren't the only show in town", says Rutherford, and there are many other research projects under way, from the serious to the seriously wacky. Research, again at the University of California, found that the lifespan of the roundworm C. elegans could be doubled by modifying two genes involved in cell repair, while this year the maverick scientist Craig Venter began a huge project sequencing human genes to find the ones that control longevity. And restricting the calorific intake of mice has been shown to extend their lives, sometimes dramatically. "Humans are trying that - there's a weird cult in California of calorific restriction people, who eat some desperately low number of calories a day," says Rutherford. There are two problems with this: one, individuals tend to be severely immune-compromised because of poor nutrition and get ill very easily, and two - "they all look absolutely miserable," he says. "They eat about four pieces of lettuce a day. They might live forever, but they're going to have an awful quality of life."
There is a question, of course, over how far we would want to extend life. As Rutherford points out, merely extending old age would not be much of an achievement - the goal must be to extend the healthy years of life. And even if we can manage that, there would be ethical questions; life expectancy is already linked to class and wealth, but this would make that link direct and explicit. Of course, the world is already struggling with overpopulation and ageing societies.
That won't stop scientists, though, and to date they agree that telomere research is the most promising avenue for extending life. "If we can slow the process of telomere loss, the fundamental cap on how often your cells can reproduce might be removed, or at least reduced," Rutherford says.
It's not an elixir of life; there will be no elixir of life. But this is the best science can do at providing one.
Photos / Thinkstock