Methylation-associated Gene Expression (MaGE): a non-invasive, in vivo measure of cellular senescence.
Abstract
Cellular senescence is a central hallmark of aging, yet its measurement in humans remains invasive, low-throughput and tissue-specific, precluding population-scale study. We developed Methylation-associated Gene Expression (MaGE) predictors: whole-blood DNA methylation proxies of p14ARF, p16INK4A and p21CIP1 expression, plus a composite score, providing 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, with MaGE-p21 associating with incident alcoholic liver disease and MaGE-p16 with pulmonary fibrosis. In a separate study, MaGE tracked disease severity and treatment response in Crohn's disease. MaGE is a scalable, interpretable biomarker of senescence that enables its study at population scale and offers a route to patient stratification in senolytic trials.
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Research summary
The paper claims that whole-blood DNA methylation can serve as a scalable, non-invasive proxy for cellular senescence marker expression, enabling population-scale study of aging mechanisms. This is relevant because it addresses the critical bottleneck of measuring a core hallmark of aging (senescence) in humans without invasive biopsies, thereby facilitating the identification of senescence-associated diseases and the stratification of patients for potential senolytic interventions.
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