DNA methylation (DNAm) is a reliable biomarker of aging across mammalian tissues. While global DNAm loss with age is well characterized, DNAm gain is less understood. Studies have shown that CpGs that gain methylation with age are enriched in Polycomb Repressive Complex 2 (PRC2) targets. However, a comprehensive examination of all PRC2 targets and their tissue-specific nature is lacking. This study demonstrates that low-methylated regions (LMRs) highly bound by PRC2 in embryonic stem cells (PRC2 LMRs) gain methylation with age in all examined somatic mitotic cells. The estimated age-dependent DNAm gain represents around 90% of the genome-wide change. Therefore, the "PRC2-AgeIndex," defined as the average DNAm in PRC2 LMRs, is proposed as a universal biomarker of cellular aging in somatic cells, capable of distinguishing the effects of different anti-aging interventions. The PRC2-AgeIndex is assay-agnostic, robust to site-specific variability and noise, and identifies age-dependent changes at the level of genomic regions, such as chromosomes. It is applicable to different tissues without prior training and exhibits a strong correlation with age, comparable to other established DNAm-based age/health predictors. The PRC2-AgeIndex also shows promise as a biomarker of rejuvenation treatments, with observed reductions in PRC2-AgeIndex in samples treated with calorie restriction and epigenetic reprogramming. The study further explores the role of cell replication in methylation gain at PRC2 targets, finding that methylation gain is cell division-dependent. The PRC2 complex is associated with high-PRC2 LMRs in fully differentiated tissues, suggesting that PRC2 binding may not be directly involved in the age-related increase of methylation at these regions. However, further mechanistic studies are needed to elucidate the biological significance of methylation gain at PRC2 targets and its impact on aging outcomes.DNA methylation (DNAm) is a reliable biomarker of aging across mammalian tissues. While global DNAm loss with age is well characterized, DNAm gain is less understood. Studies have shown that CpGs that gain methylation with age are enriched in Polycomb Repressive Complex 2 (PRC2) targets. However, a comprehensive examination of all PRC2 targets and their tissue-specific nature is lacking. This study demonstrates that low-methylated regions (LMRs) highly bound by PRC2 in embryonic stem cells (PRC2 LMRs) gain methylation with age in all examined somatic mitotic cells. The estimated age-dependent DNAm gain represents around 90% of the genome-wide change. Therefore, the "PRC2-AgeIndex," defined as the average DNAm in PRC2 LMRs, is proposed as a universal biomarker of cellular aging in somatic cells, capable of distinguishing the effects of different anti-aging interventions. The PRC2-AgeIndex is assay-agnostic, robust to site-specific variability and noise, and identifies age-dependent changes at the level of genomic regions, such as chromosomes. It is applicable to different tissues without prior training and exhibits a strong correlation with age, comparable to other established DNAm-based age/health predictors. The PRC2-AgeIndex also shows promise as a biomarker of rejuvenation treatments, with observed reductions in PRC2-AgeIndex in samples treated with calorie restriction and epigenetic reprogramming. The study further explores the role of cell replication in methylation gain at PRC2 targets, finding that methylation gain is cell division-dependent. The PRC2 complex is associated with high-PRC2 LMRs in fully differentiated tissues, suggesting that PRC2 binding may not be directly involved in the age-related increase of methylation at these regions. However, further mechanistic studies are needed to elucidate the biological significance of methylation gain at PRC2 targets and its impact on aging outcomes.