Beyond 5mC: 5hmC in the aging epigenome.

Anna Reale, Dario Di Bari, Katsiaryna Karpach, Giuseppe Zardo, Angiolina Catizone, Michele Zampieri

Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy. Electronic address: [email protected] of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy. Electronic address: [email protected]. · pubmed

Paper

Abstract

Quantifying biological aging and predicting age-related functional decline are increasingly important for reducing the health and socioeconomic burden of population aging. DNA methylation is one of the most extensively studied epigenetic features of aging and underlies epigenetic clocks, promising quantitative biomarkers of biological age. However, the molecular processes driving age-associated DNA methylation changes and the biological signals captured by these clocks remain unclear. A major unresolved issue is the contribution of oxidized 5-methylcytosine (5mC) derivatives to epigenetic remodeling during aging. These derivatives, including 5-hydroxymethylcytosine (5hmC), 5-formylcytosine and 5-carboxylcytosine, are generated through TET-mediated oxidation of 5mC. Although they can act as intermediates of DNA demethylation, they may also represent epigenetic signals with regulatory functions distinct from 5mC. This review summarizes current evidence on oxidized 5mC derivatives in mammalian aging, focusing on 5hmC. Aging is associated with context-dependent changes in global 5hmC levels and genome-wide distribution. Age-associated differentially hydroxymethylated regions occur in genes, regulatory elements, repetitive sequences and transposable elements. 5hmC and 5mC changes often show distinct genomic distributions, suggesting partially independent epigenetic processes. 5hmC may regulate transcriptional stability, cellular identity, inflammation and tissue vulnerability. Understanding the TET/5hmC pathway may improve interpretation of epigenetic aging and support 5hmC-based clocks and healthy-aging strategies.

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Research summary

The paper reviews evidence that 5-hydroxymethylcytosine (5hmC) undergoes distinct, context-dependent changes during aging that are partially independent of 5mC, suggesting it captures unique biological signals for epigenetic clocks. This is relevant because it addresses the fundamental molecular mechanisms of epigenetic aging and proposes 5hmC as a potential biomarker for biological age, which is central to understanding and potentially intervening in the aging process, though as a review it offers no new experimental data or direct interventions.

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