Of sound mind and body: depression, disease, and accelerated aging

Figures & data

Figure 1. Model of multiple pathways leading to psychiatric and physical llness and cell aging. In conjunction with genetic and epigenetic moderators, elevated cortisol levels, associated with downregulation of glucocorticoid receptor (GC) function (GC resistance) may result in altered immune function, leading to excessive synthesis of proinflammatory cytokines. Changes in glucocorticoidmediated activities also result in genomic changes (altered levels of certain neurotransmitters, neurotrophins, and other mediators), as well as dysregulation of the limbic-hypothalamicpituitary adrenal (LHPA) axis that might contribute to neuroendangerment or neurotoxicity, perhaps leading to depressive or cognitive symptoms. Dysregulation of the LPHA axis can also lead to intracellular glucose deficiency, glutamatergic hyperactivity, increased cellular calcium concentrations, mitochondrial damage, free radial generation, and increased oxidative stress. This cascade of events, coupled with a milieu of increased inflammatory cytokines, may lead to accelerated cellular aging via effects on the telomere/telomerase maintenance system. Dysregulation of normal compensatory mechanisms, such as increased neurosteroid or neurotrophin production, may further result in inability to reduce cellular damage, and thereby exacerbate destructive processes. This juxtaposition of enhanced destructive processes with diminished protective/restorative processes may culminate in cellular damage, apoptosis, and physical disease. Allopreg, allopregnanolone; BDNF, brain-derived neurotrophic factor; CRH, corticotropin releasing hormone; DHEA, dehydroepiandrosterone; GR, glucocorticoid receptor

Table I. Possibly damaging and protective mediators in major depression LHPA, limbic-hypothalamic-pituitary-adrenal; DHEA, dehydroepiandrosterone; BDNF, brain-derived neurotrophic factor. * Evidence is mixed as to whether DHEA concentrations are elevated or lowered in depression. ** Evidence is mixed as to whether the anti-inflammatory/immunomodulatory cytokine, IL10, is elevated or lowered in depression. *** Evidence is mixed as to whether telomerase activity is elevated or lowered in states of chronic stress and depression.

Table II. Potential mechanism-based therapeutic interventions. LHPA, limbic-hypothalamic-pituitary-adrenal; GC, glucocorticoid; GR, glucocorticoid receptor; CRH, corticotrophin-releasing hormone; DHEA, dehydroepiandrosterone; BDNF brain-derived neurotrophic factor; TNF, tumor necrosis factor; SSRI, selective serotonin reuptake inhibitor

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