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Profiling Epigenetic Aging at Cell-Type Resolution Through Long-Read Sequencing.

Alec Eames1, Mahdi Moqri1, Jesse R Poganik1

  • 1Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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|July 2, 2025
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Summary
This summary is machine-generated.

This study introduces LongReadAge, a new method using long-read sequencing to measure cell type-specific DNA methylation aging. It reveals distinct aging patterns in different cell types from blood and cell-free DNA.

Keywords:
agingepigeneticslong‐read sequencing

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Area of Science:

  • Epigenetics and Genomics
  • Computational Biology
  • Aging Research

Background:

  • DNA methylation is a key biomarker for aging, but bulk tissue analysis obscures cell-specific aging differences.
  • Existing methods lack the resolution to track aging trajectories within individual cell types.
  • Long-read sequencing offers potential for cell type deconvolution of methylation profiles.

Purpose of the Study:

  • To develop a framework for cell type-specific epigenetic age prediction using long-read sequencing.
  • To introduce a probabilistic model, LongReadAge, for analyzing cell type-level methylation data.
  • To investigate aging dynamics in myeloid cells and lymphocytes without cell sorting.

Main Methods:

  • Utilized long-read sequencing for DNA methylation profiling of extended fragments.
  • Developed a computational framework to map fragments to cell types based on methylation patterns.
  • Applied the LongReadAge model to cell type-specific methylation profiles from bulk leukocytes and cell-free DNA.

Main Results:

  • Successfully generated cell type-specific methylation profiles from bulk and cell-free DNA.
  • LongReadAge accurately predicted epigenetic age at the cell type level.
  • Demonstrated robust age prediction for myeloid cells and lymphocytes, even with limited shared features.

Conclusions:

  • The developed framework enables cell type-specific epigenetic age profiling without cell sorting.
  • LongReadAge provides a novel computational approach to study aging dynamics at cellular resolution.
  • This method opens new avenues for understanding heterogeneity in biological aging processes.