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      Leukocyte Telomere Length in Major Depression: Correlations with Chronicity, Inflammation and Oxidative Stress - Preliminary Findings

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          Abstract

          Background

          Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of “accelerated aging” in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation.

          Methodology

          Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex.

          Principal Findings

          The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (≥9.2 years' cumulative duration) was 281 base pairs shorter than that in controls (p<0.05), corresponding to approximately seven years of “accelerated cell aging.” Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01) and in the controls (p<0.05) and with inflammation in the depressed subjects (p<0.05).

          Conclusions

          These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure.

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          Most cited references 126

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          Oxidative stress shortens telomeres.

          Telomeres in most human cells shorten with each round of DNA replication, because they lack the enzyme telomerase. This is not, however, the only determinant of the rate of loss of telomeric DNA. Oxidative damage is repaired less well in telomeric DNA than elsewhere in the chromosome, and oxidative stress accelerates telomere loss, whereas antioxidants decelerate it. I suggest here that oxidative stress is an important modulator of telomere loss and that telomere-driven replicative senescence is primarily a stress response. This might have evolved to block the growth of cells that have been exposed to a high risk of mutation.
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            Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion

            Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells1. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments2. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signaling, usually associated with senescence, not after transient DNA damage responses (DDR). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Further, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell cycle checkpoints and DNA repair, a novel and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.
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              Obesity, cigarette smoking, and telomere length in women.

              Obesity and smoking are important risk factors for many age-related diseases. Both are states of heightened oxidative stress, which increases the rate of telomere erosion per replication, and inflammation, which enhances white blood cell turnover. Together, these processes might accelerate telomere erosion with age. We therefore tested the hypothesis that increased body mass and smoking are associated with shortened telomere length in white blood cells. We investigated 1122 white women aged 18-76 years and found that telomere length decreased steadily with age at a mean rate of 27 bp per year. Telomeres of obese women were 240 bp shorter than those of lean women (p=0.026). A dose-dependent relation with smoking was recorded (p=0.017), and each pack-year smoked was equivalent to an additional 5 bp of telomere length lost (18%) compared with the rate in the overall cohort. Our results emphasise the pro-ageing effects of obesity and cigarette smoking.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                23 March 2011
                : 6
                : 3
                Affiliations
                [1 ]Department of Psychiatry, University of California San Francisco (UCSF) School of Medicine, San Francisco, California, United States of America
                [2 ]Department of OB-GYN and Reproductive Sciences, University of California San Francisco (UCSF) School of Medicine, San Francisco, California, United States of America
                [3 ]Department of Psychiatry and Health Psychology Program, University of California San Francisco (UCSF) School of Medicine, San Francisco, California, United States of America
                [4 ]Department of Biochemistry and Biophysics, University of California San Francisco (UCSF) School of Medicine, San Francisco, California, United States of America
                [5 ]Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, United States of America
                [6 ]Kronos Science Laboratory, Phoenix, Arizona, United States of America
                Innsbruck Medical University, Austria
                Author notes

                Conceived and designed the experiments: OMW SHM ESE FSD VIR HMB EHB. Performed the experiments: OMW SHM JL FSD YS VIR RR HMB EK JCN. Analyzed the data: OMW SHM ESE JL FSD RR HMB MC EHB. Contributed reagents/materials/analysis tools: SHM JL FSD YS EHB. Wrote the paper: OMW SHM ESE JL FSD YS VIR RR JCN EHB.

                Article
                PONE-D-10-03797
                10.1371/journal.pone.0017837
                3063175
                21448457
                Wolkowitz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 10
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Physiological Processes
                Aging
                Biochemistry
                Metabolism
                Lipid Metabolism
                Oxygen Metabolism
                Nucleic Acids
                DNA
                DNA repair
                Genomics
                Chromosome Biology
                Telomeres
                Immunology
                Immune Cells
                T Cells
                Immune System
                Cytokines
                Molecular Cell Biology
                Chromosome Biology
                Telomeres
                Nucleic Acids
                DNA
                Cell Death
                Cellular Stress Responses
                Neuroscience
                Neurobiology of Disease and Regeneration
                Medicine
                Anatomy and Physiology
                Physiological Processes
                Aging
                Clinical Immunology
                Immunity
                Inflammation
                Mental Health
                Psychiatry
                Mood Disorders
                Psychology
                Psychological Stress
                Social and Behavioral Sciences
                Psychology
                Psychological Stress

                Uncategorized

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