Analyzing cell-free (cf)DNA methylation from liquid biopsies represents a non-invasive approach to profile various diseases, but what if it could help us understand the devious duo of inflammaging – aging and inflammation? A talented team has dealt with this “double trouble” by applying enzymatic methyl-seq (EM-seq) to evaluate cfDNA methylation patterns.
Researchers headed by Jian-Ping Cai (Chinese Academy of Medical Sciences and Peking Union Medical College) knew that cfDNA parameters change with age and thus sought to characterize alterations to methylation during inflammaging, a process characterized by age-related chronic inflammation. The team assessed methylation patterns by applying EM-seq to liquid biopsies from healthy individuals and created the first-ever cfDNA epigenetic clock!
Let’s hear from Li and colleagues on how EM-seq analysis of cfDNA resolved the double trouble of aging and inflammaging:
- Increased cfDNA concentrations in older individuals suggest higher cell turnover or cell death rates with age
- Fewer long fragments appear when analyzing younger individuals
- Higher concentrations from neutrophils and colon cells appear in old individuals
- Comparisons across ages identify approximately 2000 differentially methylated CpG sites
- Subsequent functional epigenetic module analysis identifies genes essential to nucleosomal structure
- A 48-CpG site-based cfDNA methylation biological age predictive model reveals a strong correlation between chronological and predicted biological age
- This represents the first instance of a cfDNA methylation clock and a significant advancement in the field
- Significant methylation changes (both hypermethylation and hypomethylation) at differentially methylated regions occur in older individuals
- Gene promoter analysis revealed a marked increase in inflammation-related pathways (consistent with the results from Olink proteomic analysis) that indicates a substantial link between cfDNA methylation and inflammation
These liquid biopsy-based results provide more information regarding the double trouble of aging and inflammation; specifically that cfDNA methylation could be developed as an aging biomarker to examine exacerbated inflammaging in older populations. Furthermore, the first description of a cfDNA epigenetic clock will help us understand the aging process; to this end, the lab’s research now aims to expand sample sizes and the range of age groups to enhance study robustness.
For more on how liquid biopsies linked cfDNA methylation patterns to the double trouble of aging and inflammation, see Epigenomics, May 2024.