Major Depressive Disorder and Measures of Cellular Aging: An Integrative Review

Major depressive disorder (MDD) affects millions of individuals and causes significant suffering worldwide. It has been speculated that MDD is associated with accelerated aging-related biological and functional decline. To examine the accelerated aging hypothesis, one of the biomarkers under study is leukocyte telomeres, and specifically the measure of telomere length and telomerase activity. This review integrates findings from eleven human studies which evaluated telomere length and telomerase activity, in order to synthesize the state of the current science and to inform the development of new knowledge and enhance nursing research of depression using appropriate biobehavioral measures. Although preliminary, the findings from this integrated review suggest that there is evidence to support a conceptualization of depression as a stress-related condition in which telomeres shorten over time in relation to cumulative exposure to the chronic stress of depression. For the purposes of testing in future nursing research, visual representations of the theoretical connection between stress vulnerabilities, depression, and health outcomes and key moderators and mediators involved in this conceptualization are provided. The findings from this review and the conceptual framework provided may be a useful step towards advancing therapeutic nursing interventions for this debilitating chronic condition.

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Variable telomere length across post-mortem human brain regions and specific reduction in the hippocampus of major depressive disorder

Translational Psychiatry ◽

10.1038/tp.2015.134 ◽

2015 ◽

Vol 5 (9) ◽

pp. e636-e636 ◽

Cited By ~ 51

Author(s):

F Mamdani ◽

B Rollins ◽

L Morgan ◽

R M Myers ◽

J D Barchas ◽

...

Keyword(s):

Major Depressive Disorder ◽

Prefrontal Cortex ◽

Depressive Disorder ◽

Telomere Length ◽

Dorsolateral Prefrontal Cortex ◽

Brain Regions ◽

Cellular Aging ◽

Post Mortem ◽

Major Depressive ◽

Dorsolateral Prefrontal

Abstract Stress can be a predisposing factor to psychiatric disorders and has been associated with decreased neurogenesis and reduced hippocampal volume especially in depression. Similarly, in white blood cells chronic psychological stress has been associated with telomere shortening and with mood disorders and schizophrenia (SZ). However, in previous post-mortem brain studies from occipital cortex and cerebellum, no difference in telomere length was observed in depression. We hypothesized that in psychiatric disorders, stress-driven accelerated cellular aging can be observed in brain regions particularly sensitive to stress. Telomere length was measured by quantitative-PCR in five brain regions (dorsolateral prefrontal cortex, hippocampus (HIPP), amygdala, nucleus accumbens and substantia nigra (SN)) in major depressive disorder (MDD), bipolar disorder, SZ and normal control subjects (N=40, 10 subjects per group). We observed significant differences in telomere length across brain regions suggesting variable levels of cell aging, with SN and HIPP having the longest telomeres and the dorsolateral prefrontal cortex the shortest. A significant decrease (P<0.02) in telomere length was observed specifically in the HIPP of MDD subjects even after controlling for age. In the HIPP of MDD subjects, several genes involved in neuroprotection and in stress response (FKBP5, CRH) showed altered levels of mRNA. Our results suggest the presence of hippocampal stress-mediated accelerated cellular aging in depression. Further studies are needed to investigate the cellular specificity of these findings.

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“GrimAge,” an epigenetic predictor of mortality, is accelerated in major depressive disorder

Translational Psychiatry ◽

10.1038/s41398-021-01302-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ekaterina Protsenko ◽

Ruoting Yang ◽

Brent Nier ◽

Victor Reus ◽

Rasha Hammamieh ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Smoking Status ◽

Accelerated Aging ◽

Premature Mortality ◽

Cellular Aging ◽

Psychiatric Disease ◽

Healthy Controls ◽

Major Depressive ◽

Age Related

AbstractMajor depressive disorder (MDD) is associated with premature mortality and is an independent risk factor for a broad range of diseases, especially those associated with aging, such as cardiovascular disease, diabetes, and Alzheimer’s disease. However, the pathophysiology underlying increased rates of somatic disease in MDD remains unknown. It has been proposed that MDD represents a state of accelerated cellular aging, and several measures of cellular aging have been developed in recent years. Among such metrics, estimators of biological age based on predictable age-related patterns of DNA methylation (DNAm), so-called ‘epigenetic clocks’, have shown particular promise for their ability to capture accelerated aging in psychiatric disease. The recently developed DNAm metric known as ‘GrimAge’ is unique in that it was trained on time-to-death data and has outperformed its predecessors in predicting both morbidity and mortality. Yet, GrimAge has not been investigated in MDD. Here we measured GrimAge in 49 somatically healthy unmedicated individuals with MDD and 60 age-matched healthy controls. We found that individuals with MDD exhibited significantly greater GrimAge relative to their chronological age (‘AgeAccelGrim’) compared to healthy controls (p = 0.001), with a median of 2 years of excess cellular aging. This difference remained significant after controlling for sex, current smoking status, and body-mass index (p = 0.015). These findings are consistent with prior suggestions of accelerated cellular aging in MDD, but are the first to demonstrate this with an epigenetic metric predictive of premature mortality.

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Telomere length and telomerase activity of leukocytes as biomarkers of selective serotonin reuptake inhibitor responses in patients with major depressive disorder

Psychiatric Genetics ◽

10.1097/ypg.0000000000000305 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Raiany S. da Silva ◽

Leopoldo S. de Moraes ◽

Carlos A. M. da Rocha ◽

Hygor Ferreira-Fernandes ◽

France K. N. Yoshioka ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Telomere Length ◽

Selective Serotonin Reuptake Inhibitor ◽

Reuptake Inhibitor ◽

Serotonin Reuptake ◽

Telomerase Activity ◽

Selective Serotonin ◽

Serotonin Reuptake Inhibitor ◽

Major Depressive

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“GrimAge,” an epigenetic predictor of mortality, is accelerated in Major Depressive Disorder

10.1101/2020.12.25.20248290 ◽

2020 ◽

Author(s):

Ekaterina Protsenko ◽

Ruoting Yang ◽

Brent Nier ◽

Victor Reus ◽

Rasha Hammamieh ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Smoking Status ◽

Accelerated Aging ◽

Premature Mortality ◽

Cellular Aging ◽

Psychiatric Disease ◽

Healthy Controls ◽

Major Depressive ◽

Age Related

AbstractMajor Depressive Disorder (MDD) is associated with premature mortality and is an independent risk factor for a broad range of diseases, especially those associated with aging, such as cardiovascular disease, diabetes, and Alzheimer’s Disease. However, the pathophysiology underlying increased rates of somatic disease in MDD remains unknown. It has been proposed that MDD represents a state of accelerated cellular aging, and several measures of cellular aging have been developed in recent years. Among such metrics, estimators of biological age based on predictable age-related patterns of DNA methylation (DNAm), so called ‘epigenetic clocks’, have shown particular promise for their ability to capture accelerated aging in psychiatric disease. The recently developed DNAm metric known as ‘GrimAge’ is unique in that it was trained on time-to-death data and has outperformed its predecessors in predicting both morbidity and mortality. Yet, GrimAge has not been investigated in MDD. Here we measured GrimAge in 49 somatically healthy unmedicated individuals with MDD and 60 age-matched healthy controls. We found that individuals with MDD exhibited significantly greater GrimAge relative to their chronological age (‘AgeAccelGrim’) compared to healthy controls (p=0.001), with a median of two years of excess cellular aging. This difference remained significant after controlling for sex, current smoking status and body-mass index (p=0.015). These findings are consistent with prior suggestions of accelerated cellular aging in MDD, but are the first to demonstrate this with an epigenetic metric predictive of premature mortality.

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