A new style, novel functionalities, and a better overall product; we always want our smartwatches to employ the latest technology, and why not?! Now, a well-timed update involving cell-free DNA (cfDNA) nucleosomics-based technology provides for a significantly upgraded epigenetic clock, which may boost aging-based research.
A punctual team led by Vladimir B. Teif (University of Essex) that sought to determine the changes occurring to genomic nucleosome positions during aging knew that cfDNA comprises nucleosome-protected genomic regions resistant to digestion by nucleases. Overall, nucleosome repeat lengths (the average distance between centers of neighboring nucleosomes) become altered in some cancers and have been employed to stratify patients. To decipher whether age-associated nucleosome rearrangement undergoes systematic trends, the team reconstructed nucleosome maps from cfDNA isolated from liquid biopsies from patient cohorts of varied ages and then applied this information to create an updated and upgraded novel, accurate, and straightforward epigenetic clock.
Let’s hear more from Shtumpf and colleagues about the novel epigenetic clock upgrade provided by cfDNA nucleosomics:
- The analysis of combined liquid biopsy data from four small-scale and large-scale studies of patients of widely varying ages reveals that nucleosomes tend to become separated by more considerable genomic distances in older patients
- An analysis of cfDNA occupancy landscapes reveals a ~1.5 bp larger nucleosome repeat length in centenarians than in young and middle-aged people
- Longer nucleosome repeat length during aging may reflect decreased gene activity with age
- Deep-sequenced cfDNA samples from one of the four cohorts and linear regression machine learning models combine to create a novel type of epigenetic clock that predicts a person’s age from DNA fragment size distribution or distances between nucleosomes
- Both predictors display a similar robust level of performance, with a median absolute error for cell-free DNA-based aging of 3.0 and 3.5 years
- These values compare well to methylation-based clocks and significantly outperform epigenetic clocks based on chromatin accessibility in blood cells
- This first epigenetic clock based on cfDNA nucleosomics enables the classification of samples based on age
- Predictors based on nucleosome–nucleosome distances and cfDNA fragment sizes robustly split ≤ 55-year-olds and > 55-year-olds into separate groups
Overall, this cfDNA nucleosomics technology update has seriously upgraded our epigenetic clocks, revealing that older patients display longer genomic distances between nucleosomes and that the number of nucleosomes protected from digestion decreases with age. These exciting data also supported the development of a novel epigenetic clock that can stratify patients by age and predict age from an easy-to-access patient liquid biopsy.
For more on how a cfDNA nucleosomics technology update seriously upgrades epigenetic clocks, see Aging Cell, February 2024.