DNA Methylation is Altered with Advancing Age
The addition and removal of methyl groups from specific locations on the genome is one of the epigenetic mechanisms used to control the structure of DNA in the cell nucleus, such as which sequences are hidden via compaction into heterochromatin and which remain accessible to allow the expression of genes. That the pattern of DNA methylation changes with age in characteristic ways is what allows the existence of epigenetic clocks, the use of DNA methylation status to assess biological age. That epigenetic control over gene expression changes with age also makes it a potential target for the development of therapies to treat aging, particularly now that partial reprogramming studies have amply demonstrated that reversing age-related epigenetic changes is possible in principle.
As individuals age, the precise regulation of DNA methylation gradually deteriorates, leading to widespread epigenetic drift. This loss of control results in both global hypomethylation and site-specific hypermethylation, disrupting normal gene expression patterns. Global hypomethylation can lead to genomic instability, activation of transposable elements, and oncogene expression, while localized hypermethylation may silence tumor suppressor genes or genes critical for immune regulation and metabolic function. These changes are increasingly recognized as contributors to the development of chronic diseases. For example, aberrant DNA methylation patterns have been implicated in cancer, cardiovascular disease, type 2 diabetes, and neurodegenerative disorders such as Alzheimer's disease.
One of the most promising trends is the integration of DNA methylation data with other layers of biological information, such as transcriptomics, proteomics, metabolomics, and microbiomics. This multi-omics approach offers a holistic view of aging by capturing complex molecular interactions/network that DNA methylation alone cannot fully explain. Combining these datasets can refine biological age estimates, identify novel aging biomarkers, and uncover mechanisms driving age-related functional decline.
Parallel to these analytical advances, there is growing interest in interventions targeting epigenetic aging. Lifestyle modifications, including diet, exercise, and stress management, have demonstrated potential to modulate DNA methylation patterns and slow epigenetic age acceleration. Pharmacological approaches, such as senolytics, epigenetic modulators, and novel small molecules, are under investigation for their ability to reverse or delay methylation-based biological aging. Clinical trials integrating methylation clocks as endpoints are beginning to evaluate the efficacy of these interventions, potentially enabling real-time monitoring of biological age and intervention impact.