What is an epigenetic clock, and what does it really measure?

An epigenetic clock is a method that uses age-related modifications of DNA, which regulate how genes are expressed, as a biomarker to estimate biological age. Most are based on DNA methylation: the accumulation of methyl groups at particular sites, called CpG sites, along DNA. Because these chemical tags change with age in a predictable way, a computer can read thousands of them and output an estimated age.

In 2011 a UCLA team including Steve Horvath showed that methylation in saliva could predict age with an average accuracy of 5.2 years. Horvath's 2013 clock, the first multi-tissue clock, went further: the same 353 sites and the same algorithm work for any DNA source in the body. Its median error is 3.6 years across many tissues, though the error increases for older individuals.

The interesting part is when the clock disagrees with the calendar. Centenarians were found to be 8.6 years younger than expected on the clock, and the offspring of semi-supercentenarians 5.1 years younger than age-matched controls. A blood stem cell transplant from a young donor to an older recipient rejuvenates the epigenetic age of the blood to that of the donor.

What the clock actually measures is still unknown. Blood DNA methylation age predicts all-cause mortality in later life, which has been used to argue that it relates to a process that causes ageing. But a causal site would be removed by the mortality it caused, so the 353 clock sites likely have no causal effect. Treat the clock as a readout of ageing, not as proof of its cause.