Steve Horvath: A Shift in an Aging Clock Does Not Prove Rejuvenation Without a Change in Function

Steve Horvath proposes comparing biological age measurements with the function of old tissue

In an interview published on 5 August, Steve Horvath, one of the developers of epigenetic clocks, which are tests that estimate biological age from chemical marks on DNA, proposed a framework for evaluating longevity claims. It distinguishes measurement reliability, the ability to predict a meaningful outcome, and an actual change in future health.

Researchers can compare blood or tissue before and after an intervention in the laboratory and observe a shift in the measurement.

“Ask whether the treated animal or person actually functions better, specifically in old but otherwise healthy tissue, and whether the biomarker reflects that improvement rather than merely accompanying it,” he says.

Horvath divides validation into three stages. First, the test must reproducibly measure what it was designed to measure. Second, the measurement must predict a meaningful outcome in a defined group of people. Third, researchers must determine whether changing the measurement changes the person’s future health. “A marker that correlates with an outcome has not yet earned the right to stand in for that outcome,” Horvath says.

Functional testing is also necessary because an intervention can change the proportions of different cell types, and a clock may interpret the new composition as rejuvenation. To distinguish sample composition from changes within cells, Horvath recommends measuring individual cells or accounting for the number of cells of each type in the sample. He also recommends comparing the analytical result with a test of how the old tissue functions.