A clear association between depression, especially the major depressive disorder, oxidative stress, and accelerated aging is supported by research.

Depression, major depressive disorder more specifically, is one of the most striking problems of modern society. Millions of people worldwide suffer from depression, with many patients not experiencing relief from symptoms. Depression is associated with increased mortality from age-related conditions, such as cardiovascular disease and cancer. Researchers have suggested that depression is associated with increased oxidative stress and a disturbed immune response, which may accelerate aging and increase susceptibility to age-related disorders.

One of the proven indicators of cellular aging is the length of telomeres. Telomeres are nucleoprotein complexes that cap the end of chromosomal DNA and serve to protect chromosomal integrity. They become shorter with each round of replication and cell division, meaning that normally they become shorter with age. When telomeres reach a critically short length, the cells undergo apoptosis, i.e., programmed death. Leukocyte telomere length has been typically used in clinical studies as a marker of cellular aging. They shortening accelerates in the cells subjected to oxidative stress.

Multiple studies, including some meta-analysis, have questioned the association between leukocyte telomere length and major depressive disorder. For instance, one meta-analysis compared the length of telomeres between depressed and healthy individuals and found significantly shorter telomeres in groups with depression. A very recent prospective study including over 100 participants aged from 18 to 70 with or without major depressive disorder assessed telomere length at baseline and at two years follow-up. The authors concluded that individuals with major depressive disorder at baseline had significantly larger shortening of telomeres over the period of 2 years, supporting the association between depression and accelerated aging.

Major depressive disorder is typically classified as a mental illness, but its pathology is evident in cells throughout the body. According to some researchers, several biological mediators are deregulated in this disorder that contribute to accelerated aging. These changes affect levels of genetic and epigenetic mediators (i.e., the variants of genes), and biochemical mediators such as glucocorticoids and neurosteroids. This can alter immune functions, oxidative processes, and levels of factors regulating the metabolism of glucose and production of insulin.

It is evident that deregulation of some of these biological mediators leads to oxidative stress, which seems to be highly correlated with the aging process. Oxidative damage occurs when the body can’t cope with psychological and physical stressors. In other words, oxidative stress refers to the excessive production of free radicals that cannot be completely neutralized by the body’s antioxidative mechanisms. Elevated markers of oxidative stress, along with decreased antioxidant capacity, have been reported in subjects with depression.

Oxidative damage is associated with the aging process, while markers of oxidative stress correlate with the decreased activity of an enzyme called telomerase. This enzyme is responsible for extending the length of telomeres. When telomerase is absent, the telomeres shorten faster. Thus, the link between the depression and accelerated aging can partly be explained by an increased cellular oxidative stress.

Animal studies have also been conducted in order to elucidate the mechanisms underlying major depressive disorder-mediated accelerated aging. For instance, in one study, the researchers exposed rats to mild chronic stress in order to induce the symptoms of major depressive disorder. The animals that developed these symptoms were found to have shorter telomeres and decreased telomerase activity, along with an increase in oxidative damage and decreased antioxidant enzyme activity. In addition, damaged mitochondria and reduced mitochondrial DNA content were also reported in rats with depressive symptoms. This research provided clear cellular evidence of accelerated aging associated with major depressive disorder.

A group of researchers proposed that early treatment (i.e., in the first half of life) of psychiatric disorders, including depression, could extend life expectancy and significantly reduce the burden of age-related disorders (such as cardiovascular disease, cerebrovascular disease, and cancer). They demonstrated that the persistence of some psychiatric disorder from the ages of 11 to 38 years led to the dose-dependent shortening of telomere length by the age of 38. Analyses of blood samples collected at the age of 26 and 38 revealed an accelerated erosion of telomeric ends in males diagnosed with the psychiatric disorder such as depression. Interestingly, there was no such association in females with a psychiatric disorder in the interim assessment at the age of 26. This research points to the link between psychiatric disorders and accelerated biological aging, which may be particularly emphasized in men.

Recently, one study investigated the association between major depressive disorder and age-related changes of the basal ganglia. The basal ganglia are a set of subcortical structures involved in reward processing, which is often dysfunctional in subjects with major depressive disorder. Based on images from the brains of patients with depression and healthy controls, the authors assessed the grey matter volume of basal ganglia in their different parts. They found a negative correlation between the size of the putamen (a region of the basal ganglia located in the base of the forebrain) and age. Importantly, this association was twice as big in patients with major depressive disorder in comparison with healthy subjects. The finding of a greater age-related volume decrease in the depressed subjects, suggests that major depressive syndrome is clearly associated with accelerated aging.

It seems that although various biochemical mediators are responsible for the clear association between depression and accelerated aging, oxidative stress is the largest contributor to this phenomenon. Thus, it is most likely that cellular oxidative damage caused by different psychological and physical stressors represents the underlying mechanism of depression-related accelerated aging.

References

Lin, P.Y., Huang, Y.C., Hung, C.F. (2016) Shortened telomere length in patients with depression: A meta-analytic study. Journal of Psychiatric Research. 76: 84-93. doi: 10.1016/j.jpsychires.2016.01.015

Vance, M.C., Bui, E., Hoeppner, S.S., et al. (2018) Prospective association between major depressive disorder and leukocyte telomere length over two years. Psychoneuroendocrinology. 90: 157-164. doi: 10.1016/j.psyneuen.2018.02.015

Wolkowitz, O.M., Reus, V.I., Mellon, S.H. (2011) Of sound mind and body: depression, disease, and accelerated aging. Dialogues in Clinical Neuroscience. 13(1): 25-39. PMID: 21485744

Xie, X., Chen, Y., Ma, L., Shen, Q., Huang, L., Zhao, B., Wu, T., Fu, Z. (2017) Major depressive disorder mediates accelerated aging in rats subjected to chronic mild stress. Behavioural Brain Research. 329: 96-103. doi: 10.1016/j.bbr.2017.04.022

Shalev, I., Moffitt, T.E., Braithwaite, A.W., et al. (2014) Internalizing disorders and leukocyte telomere erosion: a prospective study of depression, generalized anxiety disorder, and post-traumatic stress disorder. Molecular Psychiatry. 19(11): 1163-1170. doi: 10.1038/mp.2013.183

Sacchet, M.D., Camacho, M.C., Livermore, E.E., Thomas, E.A.C, Gotlib, I.H. (2017) Accelerated aging of the putamen in patients with major depressive disorder. Journal of Psychiatry and Neuroscience. 42(3): 164-171. PMID: 27749245

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