Epigenetic clock: how biological age is read from DNA methylation

What it means

DNA methylation is a chemical mark on cytosine bases that switches genes on or off. Thousands of these marks change predictably with age. An epigenetic clock is a statistical model trained to predict age — or mortality, or the pace of ageing — from a few hundred of them, read from a blood or saliva sample.

The first-generation clocks (Horvath 2013, Hannum 2013) were trained to predict chronological age. The second generation (PhenoAge 2018, GrimAge 2019) were trained to predict mortality and disease. The third (DunedinPACE, 2022) was trained on longitudinal decline and reports a rate — years of biological ageing per calendar year.

Why it matters for longevity

A clock that reads mortality risk from a tube of blood would let a person test an intervention in a year instead of a lifetime. The second- and third-generation clocks are the closest science has come to that, which is why they are used as endpoints in trials of caloric-restriction, metformin and lifestyle programmes. They are a research tool first and a consumer product second.

What the evidence says

GrimAge acceleration predicts all-cause mortality, cancer and cardiovascular disease across cohorts, with hazard ratios around 1.1 per year of acceleration. DunedinPACE tracks with physical and cognitive decline in the Dunedin cohort and slowed in the CALERIE calorie-restriction trial. Exercise, weight loss and smoking cessation all shift clock readings in the expected direction.

The caveats are real: test-retest variation on commercial clocks is often three to five years; different clocks disagree; and a 2023 TRIIM-X follow-up and other small trials reporting "age reversal" used no control groups. No trial has yet shown that lowering a clock reading lowers disease incidence.

How to measure or use it

• If you test, choose DunedinPACE or GrimAge, use the same lab, and repeat no more often than yearly; read the trend, not the reading.
• Do not change a protocol on one result. A three-year swing is within noise.
• A blood-chemistry clock from a routine panel gives most of the signal at a fraction of the cost.

Related

• Biomarkers of ageing — where clocks sit next to the routine panel
• Fasting and time-restricted eating — the CALERIE result in context
• Epithalon — a research peptide studied for telomerase — and what that does not mean