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Hedi Raizer

Journal 6 min read

How DNA methylation changes with age

DNA methylation is an epigenetic mark that shifts with age. This page summarises research on age-related methylation changes, including partial reprogramming, disease models, and environmental influences.

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How DNA methylation changes with age

DNA methylation is the covalent addition of a methyl group to the 5′ carbon of cytosine, predominantly in the context of CpG dinucleotides. It is a primary epigenetic mechanism regulating gene expression, and its patterns are known to change with age. The formal term for this phenomenon is 'epigenetic drift' or 'DNA methylation age'. No single sequence, formula, or molecular weight defines the methylome; it is a genome-wide feature. The work described here centres on the enzymes that write, erase, and read this mark—DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) proteins—and on the signalling pathways that influence them.

Age-related methylation changes are not uniform: some CpG sites gain methylation, others lose it, and the net effect varies by tissue and cell type. This page summarises research studies that have examined these changes in various models.

Research Studies

Partial reprogramming and the methylome

Partial reprogramming, induced by combinations of Yamanaka factors, is an emerging approach to modulate DNA methylation. A secondary analysis of five publicly available DNA methylation datasets from partial reprogramming experiments across multiple mammalian species, tissues, and cell types found conserved effects on the methylome [2]. The study reported that partial reprogramming can reverse some age-related methylation changes, though the extent and durability varied by context [2].

DNA methylation and HIV viral load

In people with HIV (PWH), DNA methylation at the IFNG promoter was quantified by bisulfite sequencing in peripheral blood mononuclear cells (PBMCs). The study included groups with high (n=16; >5000 copies/µL), medium (n=18; 500–4999 copies/µL), or undetectable (n=18; ≤50 copies/µL) plasma HIV RNA. Differential CpG methylation correlated with viral load and transcriptional control of IFNG [5]. This work illustrates how methylation can track with disease state, though it does not directly address aging.

Vipr2 methylation in a rat ADHD model

In spontaneous hypertensive rats (SHRs), an animal model of ADHD, researchers examined mRNA expression and DNA methylation of the Vipr2 gene in the prefrontal cortex, nucleus accumbens, and other brain regions during early life. Vipr2 expression was upregulated in the nucleus accumbens, and methylation levels were analysed in relation to gene expression [6]. This is an animal-only study; findings may not translate to humans.

Natural compounds as epigenetic modulators in gynaecological cancers

A review synthesised evidence on epigenetic alterations in gynaecological cancers, including aberrant DNA methylation, histone modifications, and m6A RNA remodelling. It critically evaluated dietary natural compounds as potential epigenetic modulators. The authors noted that direct evidence that natural compounds modulate m6A machinery in these cancers remains absent and is considered a knowledge gap [3]. This review does not focus on aging but provides context for how methylation changes contribute to disease.

Polyphenols and epigenetic regulation in neurodegenerative diseases

Another review discussed the role of epigenetic regulation, including DNA methylation, in neurodegenerative diseases and evaluated natural polyphenolic compounds as promising candidates for neuroprotection. The review covered mechanisms such as oxidative stress, chronic inflammation, and protein misfolding, and how polyphenols might modulate these processes via epigenetic pathways [8]. This is a review of preclinical and clinical evidence; it does not establish causality.

DNA methylation and glucose metabolism in chronic low back pain

A clinical study (NCT07734714) is examining whether DNA methylation and functional protein levels predict postprandial glycemic responses to standardized drinks, meals, and real-life meals in patients with chronic low back pain (CLBP). The study builds on findings that impaired glucose metabolism is a comorbidity of CLBP and that the IGF1/GH axis plays a role in pain modulation [4]. This is an ongoing study; results are not yet available.

Hederagenin and renal senescence in diabetic kidney disease

Hederagenin, a pentacyclic triterpenoid, was studied for its ability to attenuate renal senescence in diabetic kidney disease (DKD). The research reported that hederagenin inhibits DNMT1-mediated Klotho DNA methylation, suggesting a mechanism by which it may mitigate senescence [9]. This is a preclinical study; it does not provide human dosing or efficacy data.

Piperlongumine derivatives and DNMT3A in prostate cancer

Novel piperlongumine derivatives were synthesised and tested in prostate cancer models. The study reported that these compounds exert antitumor effects via MAPK pathway activation, apoptosis induction, and DNMT3A-mediated DNA methylation reduction [11]. This is an in vitro and preclinical study; clinical relevance is not established.

sORF-encoded microproteins as emerging regulators

A review highlighted that the human genome contains hundreds of thousands of short open reading frames (sORFs) whose translational products, sORF-encoded microproteins, have been overlooked. Increasing evidence demonstrates their roles in physiology and disease, and some may influence epigenetic processes [12]. This is a review; it does not focus on aging specifically.

Mare placenta and extracellular matrix genes

In the mare placenta, a study evaluated gene transcription and expression of enzymes regulating collagen deposition (MMP2, MMP9) and their inhibitors (TIMP1, etc.) in relation to extracellular matrix and microvascularization [10]. While not directly about aging, it provides comparative data on gene regulation in a reproductive tissue.

Prader-Willi syndrome and diabetes

A case report described an adult female with Prader-Willi syndrome (PWS) and refractory diabetes mellitus that responded to tirzepatide. PWS is a genetic disorder resulting from loss of expression of paternally inherited genes in the 15q11.2-q13 region, characterised by hypotonia in infancy, hyperphagia in childhood, and severe obesity with type 2 diabetes [1]. This case does not directly address DNA methylation but illustrates the complexity of metabolic disorders that may involve epigenetic components.

Polycystic ovary syndrome in type 1 diabetes

A clinical study (NCT07490964) is investigating the pathogenic mechanisms behind functional hyperandrogenism in women with type 1 diabetes, including polycystic ovary syndrome (PCOS). The study hypothesises that individual factors expose or protect women with T1D to androgen excess, which may increase cardiometabolic risk [7]. This study does not focus on DNA methylation but is relevant to understanding sex-specific factors in metabolic disease.

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