Epigenetic and Structural Brain Aging and Their Associations With Major Depressive Disorder

TY - JOUR

T1 - Epigenetic and Structural Brain Aging and Their Associations With Major Depressive Disorder

AU - Xu, Eileen Y.

AU - Green, Claire

AU - McCartney, Daniel L.

AU - Han, Laura K.M.

AU - Evans, Kathryn L.

AU - Walker, Rosie M.

AU - Gadd, Danni A.

AU - Steele, Douglas

AU - Waiter, Gordon

AU - Campbell, Archie

AU - Lawrie, Stephen M.

AU - Cole, James H.

AU - McIntosh, Andrew M.

AU - Shen, Xueyi

AU - Whalley, Heather C.

N1 - Publisher Copyright: © 2025 The Authors

PY - 2025/11

Y1 - 2025/11

N2 - Background: A growing body of evidence suggests that major depressive disorder (MDD) may be associated with premature biological aging. However, most studies reported to date have examined brain-based (BrainAge) and DNA methylation (DNAm)–based measures (DNAmAge) of biological age (BioAge) in isolation. Methods: We investigated 2 well-studied BioAge measures in lifetime and current MDD: BrainAge and DNAmAge (4 separate DNAmAge measures based on Horvath, Hannum, GrimAge, and PhenoAge clocks). We used cross-sectional cohort data from GS:STRADL (Generation Scotland: STratifying Resilience and Depression Longitudinally) (BrainAge n = 833; DNAmAge n = 587; age range 26–76 years) and used UK Biobank (UKB) data to test for replication of BrainAge associations with MDD (BrainAge n = 12,018, age range 45–80 years). Premature brain and DNAm aging were operationalized as predicted age difference (PAD), and analyses controlled for age, sex, smoking, and alcohol intake. We also tested individual and additive associations of brain- and DNAm-based PADs to lifetime/current MDD using logistic regression. Results: Individuals with lifetime MDD showed significantly higher BrainAge and DNAmAge in GS, ranging from 1.60 to 2.45 years, than individuals without MDD for all measures except for Horvath age. No differences were found for BrainAge in the UKB. In terms of PAD, lifetime MDD was significantly associated with GrimAge-PAD, PhenoAge-PAD, and Brain-PAD, ranging from odds ratio (OR) = 1.21−1.30 (and in UKB, Brain-PAD OR = 1.05). DNAm-PAD and Brain-PAD demonstrated shared and distinctive associations with lifetime MDD, where PhenoAge-PAD plus Brain-PAD explained maximum variance (area under the curve = 0.69, R2 = 9%). No significant associations were found for current MDD. Conclusions: Our findings highlight shared and distinct associations of premature brain and DNAm aging in lifetime MDD.

AB - Background: A growing body of evidence suggests that major depressive disorder (MDD) may be associated with premature biological aging. However, most studies reported to date have examined brain-based (BrainAge) and DNA methylation (DNAm)–based measures (DNAmAge) of biological age (BioAge) in isolation. Methods: We investigated 2 well-studied BioAge measures in lifetime and current MDD: BrainAge and DNAmAge (4 separate DNAmAge measures based on Horvath, Hannum, GrimAge, and PhenoAge clocks). We used cross-sectional cohort data from GS:STRADL (Generation Scotland: STratifying Resilience and Depression Longitudinally) (BrainAge n = 833; DNAmAge n = 587; age range 26–76 years) and used UK Biobank (UKB) data to test for replication of BrainAge associations with MDD (BrainAge n = 12,018, age range 45–80 years). Premature brain and DNAm aging were operationalized as predicted age difference (PAD), and analyses controlled for age, sex, smoking, and alcohol intake. We also tested individual and additive associations of brain- and DNAm-based PADs to lifetime/current MDD using logistic regression. Results: Individuals with lifetime MDD showed significantly higher BrainAge and DNAmAge in GS, ranging from 1.60 to 2.45 years, than individuals without MDD for all measures except for Horvath age. No differences were found for BrainAge in the UKB. In terms of PAD, lifetime MDD was significantly associated with GrimAge-PAD, PhenoAge-PAD, and Brain-PAD, ranging from odds ratio (OR) = 1.21−1.30 (and in UKB, Brain-PAD OR = 1.05). DNAm-PAD and Brain-PAD demonstrated shared and distinctive associations with lifetime MDD, where PhenoAge-PAD plus Brain-PAD explained maximum variance (area under the curve = 0.69, R2 = 9%). No significant associations were found for current MDD. Conclusions: Our findings highlight shared and distinct associations of premature brain and DNAm aging in lifetime MDD.

KW - Biological age

KW - Brain age

KW - Depression

KW - Epigenetic age

KW - Major depressive disorder

KW - Methylation

UR - https://www.scopus.com/pages/publications/105015306171

U2 - 10.1016/j.bpsgos.2025.100577

DO - 10.1016/j.bpsgos.2025.100577

M3 - Article

C2 - 40994835

AN - SCOPUS:105015306171

SN - 2667-1743

VL - 5

JO - Biological Psychiatry Global Open Science

JF - Biological Psychiatry Global Open Science

IS - 6

M1 - 100577

ER -