Biomarkers and ageing: The clock-watcher

Brad Swonetz/Redux/Eyevine

As a teenager in Germany, Steve Horvath, his identical twin Markus and their friend Jrg Zimmermann formed 'the Gilgamesh project', which involved regular meetings where the three discussed mathematics, physics and philosophy. The inspiration for the name, Horvath says, was the ancient Sumerian epic in which a king of Uruk searches for a plant that can restore youth. Fittingly, talk at the meetings often turned to ideas for how science might extend lifespan.

At their final meeting in 1989, the trio made a solemn pact: to dedicate their careers to pursuing science that could prolong healthy human life. Jrg set his eye on computer science and artificial intelligence, Markus on biochemistry and genetics, and Steve says that he planned to use mathematical modelling and gene networks to understand how to extend life. Jrg did end up working in artificial intelligence, as a computer scientist at the University of Bonn in Germany, but Markus fell off the wagon, his brother says, and became a psychiatrist.

Steve, now a human geneticist and biostatistician at the University of California, Los Angeles (UCLA), says that he finally feels poised to make good on the promise. Through a hard-fought project that involved years of solo work, multiple rejections by editors and reviewers and battling through the loss of a child, he has gathered and analysed data on more than 13,000 human tissue samples1. The result is the a cellular biological clock that has impressed researchers with its accuracy, how easy it is to read and the fact that it ticks at the same rate in many parts of the body with some intriguing exceptions that might provide clues to the nature of ageing and its maladies.

Horvath's clock emerges from epigenetics, the study of chemical and structural modifications made to the genome that do not alter the DNA sequence but that are passed along as cells divide and can influence how genes are expressed. As cells age, the pattern of epigenetic alterations shifts, and some of the changes seem to mark time. To determine a person's age, Horvath explores data for hundreds of far-flung positions on DNA from a sample of cells and notes how often those positions are methylated that is, have a methyl group attached.

He has discovered an algorithm, based on the methylation status of a set of these genomic positions, that provides a remarkably accurate age estimate not of the cells, but of the person the cells inhabit. White blood cells, for example, which may be just a few days or weeks old, will carry the signature of the 50-year-old donor they came from, plus or minus a few years. The same is true for DNA extracted from a cheek swab, the brain, the colon and numerous other organs. This sets the method apart from tests that rely on biomarkers of age that work in only one or two tissues, including the gold-standard dating procedure, aspartic acid racemization, which analyses proteins that are locked away for a lifetime in tooth or bone.

I wanted to develop a method that would work in many or most tissues. It was a very risky project, Horvath says. But now the gamble seems to be paying off. By the time his findings were finally published last year1, the clock's median error was 3.6 years, meaning that it could guess the age of half the donors to within 43 months for a broad selection of tissues. That accuracy improves to 2.7 years for saliva alone, 1.9 years for certain types of white blood cell and 1.5 years for the brain cortex. The clock shows stem cells removed from embryos to be extremely young and the brains of centenarians to be about 100.

Such tight correlations suggest there is something seemingly immutable going on in cells, says Elizabeth Blackburn of the University of California, San Francisco, who won a Nobel prize for her research on telomeres caps on the ends of chromosomes that shorten with age. It could be a clue to undiscovered biology, she suggests. And there may be medical implications in cases in which epigenetic estimates do not match a person's birth certificate.

In the months since Horvath's paper appeared, other researchers have replicated and extended the results. The study has stirred up excitement about potential applications, but also debate about the underlying biology at work.

It's something new, says Peter Visscher, chair of quantitative genetics at the University of Queensland in Australia. If he's right that there is something like an inherently epigenetic clock at work in ageing, that is very interesting. It must be important.

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Biomarkers and ageing: The clock-watcher