Major depressive disorder (MDD), a disease affecting up to 16% of the U.S. population at some point in their lives, has been likened to a state of accelerated aging, with an increased risk of acquiring certain diseases of aging and of premature mortality. Evidence consistent with accelerated aging is reported in the brain as well as in the periphery in MDD. The biological mechanisms underlying this process are beginning to be understood, largely by studying immune cells with shortened telomeres, which is now reported in several studies of MDD. Telomeres cap and protect the cell's DNA, and when telomeres become critically short, cells may undergo apoptosis and die. The body protects telomeres by activating a cellular enzyme, telomerase. Telomerase also has important roles in cell survival, neurogenesis and, in animal models, intrinsic antidepressant effects. These latter effects may be mediated via actions in the hippocampus and other brain regions important in MDD. Our preliminary data suggest that telomerase activity (TA) is important in achieving antidepressant response, and that TA is correlated with volume of the hippocampus and anterior cingulate gyrus, both of which are implicated in MDD. A major Aim is to determine whether cell aging in peripheral cells bespeaks a more generalized process of accelerated cell aging in unmedicated individuals with MDD, focusing on the brain. In particular, we will determine whether peripheral aging markers (leukocyte telomere length [LTL] and TA) are significantly correlated with brain structural and biochemical abnormalities in MDD, as detected by neuroimaging (magnetic resonance imaging [MRI] and magnetic spectroscopic imaging [MRS]); the existence of such relationships would tie peripheral cell aging to neural abnormalities in MDD. Our neuroimaging focuses on the corticolimbic network, which is critical in MDD and which showed strong relationships with cell aging markers in our preliminary data. Our other major Aim is to determine whether the relationship between changes in depression ratings and in cell aging markers during antidepressant treatment is mediated by changes in MRS indices (N-acetyl aspartate, a marker of neuronal integrity, and choline-containing metabolites related to glial metabolism and membrane breakdown). To accomplish this, we will recruit 48 un- medicated individuals with MDD and assess LTL and TA, along with depression ratings and MRI and MRS. Depressed individuals will then be treated with an antidepressant for 8 weeks and baseline procedures will be repeated. We will determine the relationship between cell aging markers, MDD symptoms and corticolimbic network disturbances as well as between their changes with treatment. Controls will be assessed at baseline and 8 weeks to assess natural changes in measures over time. Accomplishing these Aims will aid in developing a new mechanistic understanding of the MDD pathophysiology, which would link neural pathology with the increased somatic illness incidence in MDD. It will also point to novel mechanism-based targets for treatment development, and will foster the development of blood-based biomarkers of MDD neural pathology.

Public Health Relevance

Major depressive disorder (MDD) is a highly prevalent and costly illness; in addition to its psychiatric disability, it is associated with a high rate of serous medical illnesses and premature mortality, which may be due to accelerated aging in immune and other cells. We will test whether accelerated peripheral cell aging in MDD is also associated with changes in the brain's corticolimbic network, which is strongly implicated in MDD. This study promises to reveal innovative and previously unknown mechanisms of MDD pathophysiology, which will point to new treatment targets and will identify a readily obtainable biomarker related to peripheral as well as central pathology in MDD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-A (03)M)
Program Officer
Evans, Jovier D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Wolkowitz, Owen M (2018) Accelerated biological aging in serious mental disorders. World Psychiatry 17:144-145
Lindqvist, Daniel; Wolkowitz, Owen M; Picard, Martin et al. (2018) Circulating cell-free mitochondrial DNA, but not leukocyte mitochondrial DNA copy number, is elevated in major depressive disorder. Neuropsychopharmacology 43:1557-1564
Fair, Brittany; Mellon, Synthia H; Epel, Elissa S et al. (2017) Telomere length is inversely correlated with urinary stress hormone levels in healthy controls but not in un-medicated depressed individuals-preliminary findings. J Psychosom Res 99:177-180
Hough, Christina M; Lindqvist, Daniel; Epel, Elissa S et al. (2017) Higher serum DHEA concentrations before and after SSRI treatment are associated with remission of major depression. Psychoneuroendocrinology 77:122-130
Steenkamp, Lisa R; Hough, Christina M; Reus, Victor I et al. (2017) Severity of anxiety- but not depression- is associated with oxidative stress in Major Depressive Disorder. J Affect Disord 219:193-200
Lindqvist, Daniel; Dhabhar, Firdaus S; James, S Jill et al. (2017) Oxidative stress, inflammation and treatment response in major depression. Psychoneuroendocrinology 76:197-205
Darrow, Sabrina M; Verhoeven, Josine E; Révész, Dóra et al. (2016) The Association Between Psychiatric Disorders and Telomere Length: A Meta-Analysis Involving 14,827 Persons. Psychosom Med 78:776-87
Mellon, S H; Wolkowitz, O M; Schonemann, M D et al. (2016) Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment. Transl Psychiatry 6:e821
Hough, Christina M; Bersani, F Saverio; Mellon, Synthia H et al. (2016) Leukocyte telomere length predicts SSRI response in major depressive disorder: A preliminary report. Mol Neuropsychiatry 2:88-96
Jin, Rowen O; Mason, Sara; Mellon, Synthia H et al. (2016) Cortisol/DHEA ratio and hippocampal volume: A pilot study in major depression and healthy controls. Psychoneuroendocrinology 72:139-46

Showing the most recent 10 out of 25 publications