Of sound mind and body: depression, disease, and accelerated aging Sanidad del cuerpo y del espíritu: depresión, enfermedad y envejecimiento acelerado Sain de corps et d'esprit: dépression, maladie et vieillissement accéléré

Psychological stress and individual differences

Psychological stress is frequently a precipitant of depressive episodes,¹⁹ and under certain circumstances it can initiate the biochemical cascade described here.^{7,8,10,13,16,20} It is apparent, though, that individuals respond very differently to stress, due, in part, to differences in coping strategies, disposition, temperament, and cognitive attributional styles.^21-23 These can moderate stress-associated biological changes such as LHPA axis arousal,²³ inflammation,^22,24 neurogenesis,²⁵ amygdala arousal,²⁶ and cell aging. In the first study examining a personality trait and telomere length, O'Donovan et al found that pessimism was related to shorter telomere length, as well as higher IL-6 concentrations.²² In a study of the effects of early-life parental loss on later-life depression, the quality of the family and home's adaptation to the loss was the single most power-ful predictor of adult psychopathology, and was more important than the loss itself.²⁷ Biochemical aspects of resilience vs stress vulnerability will not be covered here but have recently been reviewed.²⁸

Adverse childhood events

Alexander Pope noted in 1734, that “as the twig is bent, the tree is inclined.” A rapidly expanding body of evidence suggests that early-life adversity (such as parental loss, neglect, and abuse) predisposes to adult depression^27,29 as well as to LHPA axis hyper-reactivity to stress,^27,30 increased allostatic load,^13,31 diminished hippocampal volume (although this is controversial),³² lower brain serotonin transporter binding potential,³³ and a myriad of adult physical diseases.³⁴ Childhood adversity also predisposes to alterations in many of the mediators presented in our model of stress/depression/illness/cell aging, such as: inflammation,^35,36 oxidative stress,³⁷ neurotrophic factors,³⁸ neurosteroids,³⁹ glucose/insulin/ insulin-like growth factor (IGF-1) regulation,⁴⁰ telomerase activity,⁴¹ and telomere length.^36,42-44 Alterations in LHPA axis activity (increased or decreased) have been well described in victims of childhood adversity, even when the individuals are not currently depressed.^27,30 In fact, several instances of neurobiological changes reported in MDD may be more attributable to histories of early-life adversity,^30,32 which are over-represented among individuals with MDD, than to the MDD itself. Thus, early-life adversity seems capable of “reprogramming” the individual to a certain lifetime repertoire of altered physiological responses to stress and to vulnerability to psychiatric and physical illness. This reprogramming toward stress arousal and preparedness may be adaptive when the individual is likely to be confronted with a lifetime of continuous adversity, but is clearly disadvantageous otherwise. The causes of early adversity-induced behavioral and biochemical changes, and the explanation for the very long-lasting effects of such adversity, are the subject of intense investigation. One explanation that has attracted much attention is epigenetic changes,^45,46 discussed in the next section.

Genetic and epigenetic moderators

A number of variants in candidate genes have been implicated in contributing to maladaptive and resilient responses that underlie alterations in neuronal plasticity and subsequent behavioral depression.⁴⁷ Evidence is strongest for genes involved in HPA regulation and stress (corticotrophin-releasing hormone [CRH]1; glucocorticoid receptor [GR]), regulatory neurotransmitters, transporters, and receptors (serotonin (5-HT)1A, 5HT2, 5-HTTLPR, NET), neurotrophic factors, (brain-derived neurotrophic factor [BDNF], nuclear factor-kappaB, mitogen-activated protein kinase-1) and transcription factors (cAMP response element binding, Re-1 silencing transcription factor, delta FosB), but variations in other secondary modulatory factors (g-aminobutyric acid [GABA], catechol-O-methyl transferase, monoamine oxidase, dynorphin, neuropeptide-Y) have also been hypothesized to be important in determining individual differences in stress response.⁴⁸ Studies of the CRH-1 gene in humans, for example, have shown that specific variants are associated with differential hormonal responses to stress, and with differing rates of depression and suicidal behavior.⁴⁹ Increasingly, such genetic effects have themselves been found to be modulated by individual variation in environmental context and history (gene x environment, GxE).⁴⁵ Epigenetics, which focuses on nongenomic alterations of gene expression, provides a mechanism for understanding such findings, through alteration of DNA methylation and subsequent silencing of gene expression or through physical changes in DNA packaging into histones.⁵⁰ A comprehensive review of this literature is beyond the scope of this article, but the findings of selective recent studies in these areas are illustrative of the regulatory complexity that influences the possible translation of stressful experiences into depression. Long-lasting epigenetic effects of early life experience on hypothalamicpituitary-adrenal (HPA) responses have been demonstrated most clearly in animal models of differential maternal behavior and social isolation.^45,46 Augmented maternal care was associated with reduced hypothalamic response to stress in rat pups and altered expression of CRH into adulthood.⁵¹ Suggestive human data compatible with these mechanisms have been reported.^28,52 Oberlander et al,⁵³ for example, found that prenatal exposure to third trimester maternal depression was associated with increased methylation of the glucocorticoid receptor gene at 3 months of age in the newborn child, while McGowan⁴⁵ reported decreased levels of GR expression in the hippocampus of suicide victims with a history of childhood abuse, in comparison with those without such history and to controls. Tyrka and colleagues⁵⁴ have also shown that variants in the CRH1 receptor gene appear to interact with a history of childhood abuse in determining cortical response to CRH. A separate body of research has focused on genetic investigations in components of serotonergic function, most commonly on a variant in the serotonin promoter (5HTTLPR), and, to a lesser extent, on serotonin receptor genes.⁵⁵ In a small-scale study that remains controversial, Caspi et al⁵⁶ reported that the effect of a variant in 5HTTLPR on increasing risk of depression was dependent upon a history of previous life stresses; several large-scale attempts at replication failed to support these conclusions and subsequent meta-analyses have been both positive and negative.^57,58 Ressler et al⁵⁹ have suggested that gene x gene x environment interactions may be involved, and reported that 5-HTTLPR alleles interacted with CRH1 haplotypes and child abuse history in predicting depressive symptoms. Others, however, have found it hard to demonstrate such effects.⁵⁵ Yet another example of a potential GxGxE interaction was found in a study by Kauffman et al⁶⁰ of child abuse victims, in whom BDNF and 5-HTTLPR genotypes interacted with maltreatment history in predicting depression, with social support showing some moderating influence. Despite the persuasive empirical animal data, the clinical relevance of epigenetic effects of stress on human emotional behavior is yet to be convincingly established.

Glucocorticoids

Elevated circulating GC levels are often observed in depressed individuals (especially in those with severe, melancholic, psychotic, or inpatient depressions), although considerable variability exists between studies, between individuals, and even within individuals over time, and some individuals are even hypocortisolemic.^61,62 The physiological significance of increased circulating GC levels remains unknown, and it is debatable whether hypercortisolemia results in hypercortisolism at the cellular level, or, rather, in hypocortisolism, perhaps due to downregulation of the GR (often referred to as “GC resistance”).²⁰ Thus, determination of “net” GC activity in depressed individuals at the intracellular level has remained elusive.^63,64 In fact, different subclasses of depressed individuals may show opposite patterns of limbic-hypothalamic-pituitary-adrenal (LHPA) axis activity,¹⁵ and levels of LHPA activation may be more related to individual depressive symptoms than to the depressive syndrome per se.⁶⁵ Further, it is possible that both hypo- and hypercortisolism are related to depression, in an inverted-U shaped manner.⁶² Complicating our understanding of this issue, novel treatment strategies that decrease or increase GC activity may show antidepressant effects in certain patients.^66-69 The “hypocortisolism” hypothesis is supported by findings that proinflammatory cytokine levels (eg, tumor necrosis factor [TNF]-a, interleukin [IL]-1ß and IL-6) tend to be increased in the serum of depressed patients, and that proinflammatory cytokines may contribute to depressive symptomatology. Since cortisol typically has anti-inflammatory actions and suppresses proinflammatory cytokines (although there are instances to the contrary [eg, ref 70]), the coexistence of elevated cortisol and elevated proinflammatory cytokine levels suggests an insensitivity to cortisol at the level of the lymphocyte GR.²⁰ Further supporting this notion, inflammatory cytokines downregulate GRs.²⁰ Also, antidepressants typically increase GR binding activity,²⁰ although in so doing, negative feedback onto the HPA axis is increased.⁷¹ On the other hand, the “hypercortisolism” hypothesis is supported by certain phenotypic somatic features suggestive of cortisol excess and end-organ cortisol receptor overactivation in some individuals with depression, eg, osteoporosis, insulin resistance, type 2 diabetes, a relative hypokalemic alkalosis accompanied by neutrophilia and lymphocytosis, hypertension, metabolic syndrome, and visceral/intra-abdominal adiposity.^72,73 Further support of net GC overactivation is provided by evidence of altered expression of target genes such as BDNF, which are believed to be under negative regulatory control by cortisol.⁷⁴

Pathologically elevated or diminished GC activity might have adverse neurobehavioral and physical health sequellae.^72,75 Chronic hypercortisolemia, in particular, has been proposed by Sapolsky and others¹⁶ to result in a biochemical “cascade,” which can culminate in cell endangerment or cell death in certain cells, including cells in the hippocampus. In the simplest description of this model, GC excess engenders a state of intracellular glucoprivation (insufficient intracellular glucose energy stores) in certain cells, impairing the ability of glia and other cells to clear synaptic glutamate. The resulting excitotoxicity results in excessive influx and release of calcium into the cytoplasm, which contributes to oxidative damage, proteolysis, and cytoskeletal damage. Unchecked, these processes can culminate in diminished cell viability or cell death.

Neurosteroids

Although cortisol concentrations are often reported as elevated in depression, CSF concentrations of the potent GABA-A receptor agonist neurosteroid, allopregnanolone, are decreased in unmedicated depressives, and CSF levels of allopregnanolone increase with treatment in direct proportion to the antidepressant effect.⁷⁶ Selective serotonin reuptake inhibitor (SSRI) antidepressants rapidly increase allopregnanolone synthesis, and this may contribute to their anxiolytic effects.^77,78 Another neurosteroid, DHEA, which may have “anticortisol” effects, has been reported to be both high and low in depression.¹⁷ Notably, both of these neurosteroids modulate HPA axis activity^17,18 and immune system activity,^17,79 antagonize oxidative stress^17,80 and have certain neuroprotective effects.^17,81 Depressed patients entering remission show decreases in plasma cortisol concentrations along with increases in plasma allopregnanolone concentrations.⁸² Endogenous decreases in this neurosteroid concentrations or exogenously produced increases in their concentrations might be expected to have damaging or beneficial effects, respectively, in the context of depression,^17,78,83,84 and treatment trials have demonstrated significant antidepressant effects of exogenously administered DHEA.¹⁷ Animal models suggest that 3 a hydroxy-5 a reduced steroids (allopregnanolone and allotetrahydrodeoxycorticosterone) are responsive to stress⁸⁵ and may function to restore normal g-aminobutyric acid (GABA)-ergic and hypothalamicpituitary-adrenal function following stress.^18,85 In vitro, allopregnanolone suppresses release of gonadotropinreleasing hormone⁸⁶ or CRH⁸⁷ via a GABA-A mediated mechanism. Allopregnanolone or allotetrahydrodeoxycorticosterone can also attenuate stress-induced increases in plasma ACTH and corticosterone and can affect arginine vasopression transcription in the hypothalamus (paraventricular nucleus).¹⁸ Under chronic stress or in psychiatric disorders, dysregulation of the HPA axis could be exacerbated if there is insufficient activity of these “counter-regulatory” neurosteroids. In addition to protection against acute or chronic stress, neurosteroids such as allopregnanolone and allotetrahydrodeoxycorticosterone may be neuroprotective against early life stressors⁸⁸ or against deleterious effects of social isolation.⁸⁹ In this way, these neurosteroids may be neuroprotective during development and may affect future responsiveness to stress.

The detrimental effects of neurosteroid dysregulation on stress responses has been particularly documented in women with premenstrual dysphoric disorder (PMDD).^90,91 PMDD is a depressive disorder that is characterized by cyclic recurrence, during the luteal phase of the menstrual cycle, of a variety of physical and emotional symptoms that are so severe as to interfere with daily activities. In these studies in women with PMDD, both high and low concentrations of allopregnanolone during the luteal phase of the menstrual have been reported. However, women with PMDD have reduced responsiveness to neurosteroids (on GABA-A receptors)⁹² as well as a blunted stress response (failing to demonstrate an increase in allopregnanolone concentrations after acute stress) in women with PMDD and a prior history of depression.⁹⁰ Furthermore, women with PMDD who also had prior histories of depression showed significant decreases in allopregnanolone after acute stress.⁹⁰ These data highlight that long-term histories of depression may be associated with persistent, long-term effects on the responsivity of the neurosteroid system, as well as long-term effects on modulation of the HPA axis following stress.

Glucose and insulin regulation

Abnormalities of glucose homeostasis (eg, insulin resistance and impaired glucose tolerance) are seen in MDD, even in individuals who are nonobese and not diabetic.⁹³ These glucose and insulin abnormalities are most pronounced in hypercortisolemic depressed individuals,⁹⁴ as would be predicted based on cortisol's well-known antiinsulin effects. Hypercortisolemic depressives, compared with normocortisolemic ones, are also at increased risk of having increased abdominal (visceral) fat deposition⁹⁵ and the metabolic syndrome,⁹⁶ which are also risk factors for cardiovascular disease. Insulin resistance and diminished cellular glucose uptake can also lead to a dangerous “energetic crisis.”^7,16 When this occurs in the hippocampus,¹⁶ for example, hippocampal excitotoxicity may develop, since there is insufficient energy available to clear glutamate from the synapse. Thereafter, cytosolic calcium is mobilized, triggering oxygen free radical formation and cytoskeletal proteolysis. The relevance of this in humans was demonstrated in a PET scan study, in which cortisol administration to normal individuals resulted in significant reductions in hippocampal glucose utilization.⁹⁷ The importance of hippocampal insulin resistance for depression and cognitive disorders (eg, Alzheimer's disease) is the subject of active investigation.^98,99

Over and above these direct effects on energy balance, prolonged exposure to glucose intolerance and insulin resistance is associated with accelerated biological aging^7,100 including shortened telomere length,¹⁰¹ and visceral adiposity is associated with increased inflammation and oxidation,^102,103 both of which, themselves, promote accelerated biological aging.⁷ These will be further discussed below in the sections on inflammation, oxidation, and cell aging.

Immune function

Dysregulation of the LHPA axis contributes to immune dysregulation in depression, and immune dysregulation, in turn, can activate the HPA axis and precipitate depressive symptoms.²⁰ Immune dysregulation may be an important pathway by which depression heightens the risk of serious medical comorbidity.^7,104,105 Several major proinflammatory cytokines, such as IL-1ß, IL-2, IL-6 and TNF-a, are elevated in depression, either basally or in response to mitogen stimulation or acute stress.^20,106,107 Conversely, certain anti-inflammatory or immunomodulatory cytokines, such as IL-1 receptor antagonist and IL10 may be decreased or dysregulated.¹⁰⁶ Indeed, the ratio of proinflammatory to anti-inflammatory/ immunomodulatory cytokines may be disturbed in depression and could result in net increased inflammatory activity¹⁰⁶ as well as in oxidative stress.¹⁰⁸ Converging findings suggest that high peripheral levels of inflammatory cytokines, such as IL-6, are associated with the activation of central inflammatory mechanisms that can adversely affect the hippocampus, where IL-6 receptors are abundantly expressed.¹⁰⁹ High proinflammatory cytokine levels, for example, may directly contribute to depression, decreased neurotrophic support, and altered glutamate release/reuptake and hippocampal neurodegeneration,¹¹⁰ and, plasma IL-6 levels are inversely correlated with hippocampal gray matter in healthy humans.¹¹¹ Further, inappropriately and chronically elevated proinflammatory cytokines can contribute to accelerated biological aging (eg, premature shortening of immune cell telomeres¹¹²). Interestingly, the development of immunosenescence (eg, the loss of the CD28 marker from CD8⁺ T cells), can further aggravate the proinflammatory milieu, since CD8⁺CD28^- cells hypersecrete IL-6.¹¹³ It should be noted, however, that due to the complexity of cytokine actions in neurons and glia, the end effect of individual cytokines may be either detrimental or protective, depending on the circumstances.¹⁰⁶

Oxidation

Stress and increased LHPA axis activity can also increase oxidative stress and decrease antioxidant defenses.^{5 ,7,114} Oxidative stress often increases with aging and various disease states, while antioxidant and antiinflammatory activities decrease, resulting in a heightened likelihood of cellular damage and of a senescent phenotype.^7,115 The co-occurrence of oxidative stress and inflammation (the so-called “evil twins” of brain aging¹¹⁵), as may be seen in depression, post-traumatic stress disorder (PTSD), stroke, Alzheimer's disease, and others, can be especially detrimental. Oxidative stress occurs when the production of oxygen free radicals (and other oxidized molecules) exceeds the capacity of the body's antioxidants to neutralize them. Oxidative stress damages DNA, protein, lipids, and other macromolecules in many tissues, with telomeres (discussed below) and the brain being particularly sensitive. Elevated plasma and/or urine oxidative stress markers (eg, increased F2-isoprostanes and 8-hydroxydeoxyguanosine [8-OHdG], along with decreased antioxidant compounds, such as Vitamin C, Vitamin E, and Coenzyme Q) have been reported in individuals with depression and in those with chronic psychological stress, and the concentration of peripheral oxidative stress markers is positively correlated with the severity and chronicity of depression.^114,116 Further, the ratio of serum oxidized lipids (F2-isoprostanes) to antioxidants (Vitamin E) is directly related to psychological stress.⁸ Importantly, this ratio (and the ratio of F2-isoprostanes to another antioxidant, Vitamin C) is inversely related to telomere length in chronically stressed caregivers⁸ and in individuals with major depression.¹¹⁷ Oxidative stress markers are also correlated with decreased telomerase activity.¹¹⁸ Further, diminished levels of antioxidants reportedly lower BDNF activity.¹¹⁹ Interestingly, antidepressants decrease oxidative stress.¹²⁰ Since cellular oxidative damage may be an important component of the aging process, prolonged or repeated exposure to oxidative stress might accelerate aspects of biological aging and promote the development of aging-related diseases in depressed individuals.¹¹⁴ It is unknown whether antioxidant treatment would retard stress- or depressionrelated aging; this is discussed below under “novel treatment implications.”

Brain-derived neurotrophic factor

The “neurotrophic model” of depression⁷⁴ emphasizes the centrality of neurogenesis and neuronal plasticity in the pathophysiology of depression. It posits that diminished hippocampal BDNF activity, caused by stress or excessive GCs, impairs the ability of stem cells in the subgranular zone of the dentate gyrus (as well as cells in the subventricular zone, projecting to the prefrontal cortex) to remain viable and to proliferate into mature cells. It is not known whether such effects can cause depression, but they may be relevant to the mechanism of action of antidepressant treatments.¹²¹ Unmedicated patients with depression have decreased hippocampal (at autopsy) and serum concentrations of BDNF^121,122 Over 20 studies have documented decreased serum concentrations of BDNF in unmedicated depressed individuals; this is now one of the most consistently replicated biochemical findings in major depression.^121,123 Further, serum BDNF concentrations increase with antidepressant treatment.^121,123 The relationship of peripheral BDNF concentrations to central ones is not known, but even peripherally administered BDNF abrogates depressive and anxiety-like behaviors and increases hippocampal neurogenesis in mice, suggesting that serum BDNF concentrations are functionally significant for brain function and are more than merely a biomarker.¹²⁴ A role of BDNF in antidepressant mechanisms of action is supported by findings that hippocampal neurogenesis (in animals) and serum BDNF concentrations (in depressed humans) increase with antidepressant treatment,^121,123 and that hippocampal neurogenesis and intact BDNF expression are required for behavioral effects of antidepressants in animals.^125,126

Apart from its direct neurotrophic actions, BDNF also has anti-inflammatory and antioxidant effects that may contribute to its neuroprotective efficacy,¹²⁷ and BDNF, in concert with telomerase (discussed below) promotes the growth of developing neurons.¹²⁸ In addition, BDNF (despite its name) has significant peripheral actions that are important for physical health, and the low levels of BDNF seen in MDD may be involved in certain comorbid illnesses such as cardiovascular disease, diabetes, obesity, and metabolic syndrome.¹²⁹ For example, BDNF improves glucose and lipid profiles, enhances glucose utilization, suppresses food intake, has an insulinotropic effect and protects cells in the islets of Langerhans (reviewed in ref 129). Plasma levels of BDNF are low in type 2 diabetes and are inversely correlated with fasting glucose levels.¹²⁹ Indeed, BDNF is increasingly considered not only a neurotrophin but a metabotrophin,¹²⁹ and its dysregulation has been proposed as a unifying feature of several clustered conditions, such as MDD, Alzheimer's disease, and diabetes.¹³⁰