Methylation-associated Gene Expression (MaGE): a non-invasive, in vivo measure of cellular senescence.

Cellular senescence is a central hallmark of aging, but measuring it in humans has been invasive, low-throughput, and tissue-specific, which has precluded population-scale study.

The authors developed Methylation-associated Gene Expression (MaGE) predictors: whole-blood DNA methylation proxies of p14ARF, p16INK4A, and p21CIP1 expression, plus a composite score. They describe this as the first scalable measure of senescence-marker expression.

Deployed across Generation Scotland (n=18,859), MaGE yielded 45 Bonferroni-significant associations spanning 18 incident diseases and all-cause mortality. The two strongest associations recapitulated the established tissue specificity of p21CIP1 and p16INK4A activation: MaGE-p21 was associated with incident alcoholic liver disease, while MaGE-p16 was associated with pulmonary fibrosis. In a separate study, MaGE tracked disease severity and treatment response in Crohn's disease.

MaGE is positioned as a scalable, interpretable biomarker of senescence that enables senescence to be studied at population scale and offers a route to patient stratification in senolytic trials.