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

Eileen Y Xu; Claire Green; Daniel L McCartney; Laura K M Han; Kathryn L Evans; Rosie M Walker; Danni A Gadd; Douglas Steele; Gordon Waiter; Archie Campbell; Stephen M Lawrie; James H Cole; Andrew M McIntosh; Xueyi Shen; Heather C Whalley

doi:10.1016/j.bpsgos.2025.100577

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

Biol Psychiatry Glob Open Sci. 2025 Aug 5;5(6):100577. doi: 10.1016/j.bpsgos.2025.100577. eCollection 2025 Nov.

Authors

Eileen Y Xu¹, Claire Green¹, Daniel L McCartney², Laura K M Han^{3

4

5}, Kathryn L Evans², Rosie M Walker^{2

6}, Danni A Gadd², Douglas Steele⁷, Gordon Waiter⁸, Archie Campbell², Stephen M Lawrie¹, James H Cole^{9

10}, Andrew M McIntosh^{1

2}, Xueyi Shen¹, Heather C Whalley^{1

2}

Affiliations

¹ Division of Psychiatry, Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, United Kingdom.
² Center for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom.
³ Department of Psychiatry, Amsterdam University Medical Center location Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁴ Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam Neuroscience, Amsterdam, the Netherlands.
⁵ Amsterdam Public Health, Mental Health program, Amsterdam, the Netherlands.
⁶ School of Psychology, University of Exeter, Exeter, United Kingdom.
⁷ School of Medicine, University of Dundee, Dundee, United Kingdom.
⁸ Aberdeen Biomedical Imaging Centre, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, United Kingdom.
⁹ Dementia Research Center, Queen Square Institute of Neurology, University College London, London, United Kingdom.
¹⁰ UCL Hawkes Institute, Department of Computer Science, University College London, London, United Kingdom.

Abstract

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, R ² = 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.

Keywords: Biological age; Brain age; Depression; Epigenetic age; Major depressive disorder; Methylation.

Plain language summary

Depression has been linked to faster biological aging, where people with depression look biologically older than their actual age. Biological aging can be measured in different ways, e.g., chemical changes in DNA across the body or specific changes in the brain seen on brain scans. These have not often been studied together in the same people. We looked at both measures of biological age in the same groups of people with and without depression. Wefound differences in biological aging between people with and without depression, and also found that these body- and brain-based measurements did not fully overlap. This suggests that bodily and brain aging in depression may happen, at least partially, through different biological processes.