The study introduces the PRC2-AgeIndex as a universal biomarker of aging and rejuvenation, based on DNA methylation (DNAm) changes in low-methylated regions (LMRs) that are highly bound by the Polycomb Repressive Complex 2 (PRC2) in human embryonic stem cells (hESCs). The PRC2-AgeIndex is defined as the average DNAm in PRC2 LMRs and reflects the age-dependent gain of DNAm, which accounts for approximately 90% of the global age-dependent DNAm gain. This index is assay-agnostic, applicable across tissues, and robust to site-specific variability and noise. It can distinguish the effects of different anti-aging interventions. The research shows that LMRs, which are enriched in regulatory regions and associated with gene promoters, gain methylation with age in various somatic cells. This methylation gain is consistent across different tissues and species, including human and mouse tissues. The PRC2-AgeIndex was validated using multiple datasets, including whole-genome bisulfite sequencing (WGBS), reduced representation bisulfite sequencing (RRBS), and microarray data. It demonstrated strong correlations with age and showed comparable performance to other established age predictors. The study also found that PRC2-bound LMRs gain methylation with age, and this process is reversible, as evidenced by the effects of rejuvenation treatments such as caloric restriction and epigenetic reprogramming. The PRC2-AgeIndex was shown to be a reliable biomarker for both aging and rejuvenation, with the ability to detect changes in methylation at the genomic level. The findings suggest that the PRC2-AgeIndex is a robust, versatile, and unbiased biomarker of epigenetic aging, applicable across different tissues and species. It provides a comprehensive and biologically interpretable measure of aging, which can be used to assess the effects of anti-aging interventions. The study highlights the importance of understanding the epigenetic mechanisms underlying aging and rejuvenation, and the potential of the PRC2-AgeIndex as a tool for future research in this area.The study introduces the PRC2-AgeIndex as a universal biomarker of aging and rejuvenation, based on DNA methylation (DNAm) changes in low-methylated regions (LMRs) that are highly bound by the Polycomb Repressive Complex 2 (PRC2) in human embryonic stem cells (hESCs). The PRC2-AgeIndex is defined as the average DNAm in PRC2 LMRs and reflects the age-dependent gain of DNAm, which accounts for approximately 90% of the global age-dependent DNAm gain. This index is assay-agnostic, applicable across tissues, and robust to site-specific variability and noise. It can distinguish the effects of different anti-aging interventions. The research shows that LMRs, which are enriched in regulatory regions and associated with gene promoters, gain methylation with age in various somatic cells. This methylation gain is consistent across different tissues and species, including human and mouse tissues. The PRC2-AgeIndex was validated using multiple datasets, including whole-genome bisulfite sequencing (WGBS), reduced representation bisulfite sequencing (RRBS), and microarray data. It demonstrated strong correlations with age and showed comparable performance to other established age predictors. The study also found that PRC2-bound LMRs gain methylation with age, and this process is reversible, as evidenced by the effects of rejuvenation treatments such as caloric restriction and epigenetic reprogramming. The PRC2-AgeIndex was shown to be a reliable biomarker for both aging and rejuvenation, with the ability to detect changes in methylation at the genomic level. The findings suggest that the PRC2-AgeIndex is a robust, versatile, and unbiased biomarker of epigenetic aging, applicable across different tissues and species. It provides a comprehensive and biologically interpretable measure of aging, which can be used to assess the effects of anti-aging interventions. The study highlights the importance of understanding the epigenetic mechanisms underlying aging and rejuvenation, and the potential of the PRC2-AgeIndex as a tool for future research in this area.