Epigenetic Clocks Identify Harmful Epigenetic Aging Linked to Depression Severity and Cognitive Deficits in Major Depressive Disorder.

Major depressive disorder (MDD) is a prevalent mental illness characterized by significant morbidity and mortality. Cognitive impairment is a common feature of MDD, closely related to the aging process. Epigenetic aging calculated using DNA methylation is an important marker of biological aging. This study aims to investigate the relationships among MDD, epigenetic aging, and cognitive function. We assessed age acceleration using epigenetic clocks based on DNA methylation data in discovery dataset with 39 MDD patients and 40 healthy controls, and then validated the results in one independent MDD cohort with 359 cases and 68 controls. The results revealed that patients with MDD exhibited significantly greater age acceleration as measured by the DamAge clock and elevated mortality risk as indicated by the Zhang clock. Notably, the age acceleration of DamAge was positively correlated with depressive symptom severity. Epigenome-wide association study of the age acceleration of DamAge identified 1,472 significant CpG sites. Enrichment analyses further revealed that these CpG sites are potentially involved in cytoskeletal mechanisms, signaling pathways, and inflammatory response. Cognitive assessments showed significant correlations between emotion recognition task performance and age acceleration from multiple epigenetic clocks, suggesting a link between accelerated epigenetic aging and cognitive impairment in MDD. Our results underscore the potential role of epigenetic aging in understanding the biological underpinnings of MDD and its associated cognitive dysfunctions.