depression gets old fast: do stress and depression accelerate cell aging?

Review

DEPRESSION AND ANXIETY 27 : 327–338 (2010)

DEPRESSION GETS OLD FAST: DO STRESS ANDDEPRESSION ACCELERATE CELL AGING?

Owen M. Wolkowitz, M.D.,1� Elissa S. Epel, Ph.D.,1 Victor I. Reus, M.D.,1 and Synthia H. Mellon, Ph.D.2

Depression has been likened to a state of ‘‘accelerated aging,’’ and depressedindividuals have a higher incidence of various diseases of aging, such ascardiovascular and cerebrovascular diseases, metabolic syndrome, and demen-tia. Chronic exposure to certain interlinked biochemical pathways that mediatestress-related depression may contribute to ‘‘accelerated aging,’’ cell damage,and certain comorbid medical illnesses. Biochemical mediators explored in thistheoretical review include the hypothalamic–pituitary–adrenal axis (e.g., hyper-or hypoactivation of glucocorticoid receptors), neurosteroids, such as dehydro-epiandrosterone and allopregnanolone, brain-derived neurotrophic factor,excitotoxicity, oxidative and inflammatory stress, and disturbances of thetelomere/telomerase maintenance system. A better appreciation of the role ofthese mediators in depressive illness could lead to refined models of depression, toa re-conceptualization of depression as a whole body disease rather than just a‘‘mental illness,’’ and to the rational development of new classes of medicationsto treat depression and its related medical comorbidities. Depression andAnxiety 27:327–338, 2010. rr 2010 Wiley-Liss, Inc.

Key words: depression; stress; aging; cortisol; BDNF; DHEA; telomeres;oxidation; inflammation; allopregnanolone

Depression has been likened to a state of ‘‘acceleratedaging,’’ affecting the hippocampus and the cardiovas-cular (CV), cerebrovascular, neuroendocrine, meta-bolic, and immune systems,[1–3] and depressedindividuals have a higher incidence of various diseasesoften associated with aging, such as Type II diabetes,metabolic syndrome, osteoporosis, CV disease, stroke,and pathological cognitive aging, including Alzheimer’sdisease and other dementias.[2,4–8] Depression is alsoassociated with significantly worse outcomes in anumber of medical conditions, and depression is anindependent risk factor for early mortality (even afteraccounting for sociodemographic factors, suicide,and biological and behavioral risk factors, such assmoking, alcohol, and physical illness).[9–13] Variousexplanations for ‘‘accelerated aging’’ in depressionhave been proposed, such as the ‘‘glucocorticoidcascade’’ hypothesis[14,15] and ‘‘allostatic load.’’[16] Inthis review, we explore the additional possibilitythat ‘‘accelerated aging’’ in depression occurs at thelevel of the individual cell and that it can be traced tospecific biochemical mediators that are altered indepression. Discovering pathological processes in

depression at the cellular level could help identifynovel targets for treating depression and its comorbidmedical conditions.

We propose a depression model that accounts forcertain linked pathogenic processes, which occur in thebrain and in the periphery, and which can culminate in

Published online in Wiley InterScience (www.interscience.wiley.com).

DOI 10.1002/da.20686

Received for publication 9 November 2009; Revised 12 February

2010; Accepted 13 February 2010

The authors disclose the following financial relationships within the past3 years: Contract grant sponsors: O’Shaughnessy Foundation;

University of California.

�Correspondence to: Owen M. Wolkowitz, 401 Parnassus Ave.,

Box F-0984, San Francisco, CA 94143-0984. E-mail: Owen.

[email protected]

1Department of Psychiatry, University of California School of

Medicine, San Francisco, California2Department of OB-GYN and Reproductive Sciences,

University of California School of Medicine, San Francisco,

California

rr 2010 Wiley-Liss, Inc.

cellular aging and damage and disease (Fig. 1). There iswidespread recognition that certain physical stressors,such as oxidative and inflammatory stress, can accel-erate aging in cells.[17–21] It has recently beenappreciated that psychological stress can also prema-turely age cells, possibly by invoking similar physical

processes.[15,20,22–32] Major depression and its asso-ciated biological perturbations are the focus of thisreview. To the extent similar processes are seen in otherconditions (e.g., chronic psychological stress, posttrau-matic stress disorder, schizophrenia, certain neurode-generative disorders, etc.), aspects of this model mightalso be applicable. Indeed, some of the data supportingthis model were derived from chronically stressed, butnot necessarily depressed, populations; such data willbe identified in the text. In brief, stress-relateddysregulation of the hypothalamic–pituitary–adrenal(HPA) axis, as moderated by genetic[33–36] and epige-netic[37] factors and by cognitive appraisal,[38,39] socialsupport,[40,41] and coping styles,[42,43] leads to cortisol-induced changes in gene expression (including genesrelated to monoaminergic and peptidergic neurotrans-mission), neuroendangering or neurotoxic effects incertain brain areas (e.g., prefrontal cortex and hippo-campus), excitotoxicity, oxidative stress, immunealterations leading to a proinflammatory milieu(or ‘‘neuroinflammation’’), and accelerated cell aging(via effects on the telomere/telomerase maintenancesystem), as described below. In this context, normalcompensatory or reparative processes are diminished,e.g., decreased counterregulatory neurosteroids (e.g.,dehydroepiandrosterone [DHEA]) and allopregnano-lone), decreased antioxidant compounds (e.g., VitaminC or E), diminished anti-inflammatory/immunomodu-latory cytokines (e.g., IL-10), decreased activity ofneurotrophic factors (e.g., brain-derived neurotrophicfactor [BDNF]) and decreased activity or effectivenessof the telomere-lengthening enzyme, telomerase. Thejuxtaposition of enhanced toxic processes with dimin-ished protective or restorative ones can culminate incellular damage and physical disease[44] (Table 1). Thepresentation of this model here will be relativelyconcise, but related reviews of this and similar modelsare published elsewhere.[20,22,23,36,45–53] This reviewrepresents an update and refinement of modelswe have presented earlier.[45–48] This model is notmeant to be complete or all-encompassing, nor is itmeant to apply to all individuals with major depression,because different endophenotypes of depressioncould well have different underlying pathologiccomponents.[45,54,55] Instead, this broadly sketchedmodel is meant to highlight and connect certaininteresting new findings in the study of stressand depression, and to provide testable hypothesesthat could guide research and treatment in newdirections.

GLUCOCORTICOIDS ANDNEUROSTEROIDS

The physiological significance of increased circulat-ing GC levels remains unknown, and it is evendebatable whether ‘‘hypercortisolemia’’ results in nethypercortisol-ism at the cellular level, or rather in net

)3(

(1)

)2(

)4(

)5(

)6(

)7(

)31(

)21(

GR

DHEA Allopreg CRH

Cortisol

GlucoseAvailability

Calcium; OxidativeStress

Telom Length; Telomerase

InflammatoryCytokines

BDNF

Cell Endangerment and Medical/ Psychiatric Symptoms

Glutamate; Excitotoxicity

(1, 10, 11)•••••••••••• (1, 8, 9)•••••••

Chronic Stress; Glucocorticoids

Figure 1. Theoretical model of cell ‘‘aging’’ or cell endanger-ment in depression. This overly simplified schematic model isexplained in the text (last paragraph). The mediators presentedhere are plausibly related to cell damage or dysfunction, but itremains unknown whether such cellular effects translate intopsychiatric and medical symptoms. Bracketed numbers refer topotential sites of therapeutic intervention, also described in thetext. Not depicted in this model are important monoaminergicmediators, which interact with many of the mediators that aredepicted here, as well as certain mediators not discussed in thisreview, e.g., neuropeptide Y[51,97] and gamma-aminobutyricacid.[48,212] Also not depicted here are important moderators ofstress and other effects, such as genetic polymorphisms,[33–36]

epigenetic changes,[37,67,167,168] and early life adver-sity.[52,67,213–215] To reduce the complexity of the Figure, wealso do not depict multiple linked pathways between theindividual mediators, because many of them are intertwinedand multidetermined, and we also do not indicate compensatorypathways, which can attenuate certain of the proposed effects(e.g.,[112,160]). Abbreviations: GR, glucocorticoid receptor; CRH,corticotropin releasing hormone; DHEA, dehydroepiandro-sterone; Allopreg, allopregnanolone; BDNF, brain-derivedneurotrophic factor; Telom, telomere.

328 Wolkowitz et al.

Depression and Anxiety

hypocortisolism, perhaps due to downregulation of theglucocorticoid receptor (GR) (referred to as ‘‘GCresistance’’).[45,56] It is possible but not proven thathyper- and hypocortisolism identify different subtypesof depression or map onto different symptom clus-ters.[45,54,57–59] It should also be recognized that theeffects of either state are likely to differ, depending onthe target tissue involved and that ‘‘relative’’ conditionsof either hyper- or hypocortisolism may exist at thesame time within organisms, making any globalstatements a simplification of the underlying endocrinestate.[60–63] For example, different GR polymorphismscan significantly affect individuals’ responses toGCs,[35,64] and alternative splicing of the GR mRNAcan lead to different GR isoforms with different actionsin different tissues.[65,66] Furthermore, early life events,such as childhood abuse, can epigenetically reprogramGR expression and splicing, leading to important inter-individual differences in GC responsivity.[67] The‘‘hypocortisolism’’ hypothesis is supported by findingsthat proinflammatory cytokine levels (e.g., tumornecrosis factor [TNF]-a, IL-1b, and IL-6) tend to beincreased in the plasma of depressed patients, and thatproinflammatory cytokines can contribute to depres-sive symptomatology. Because cortisol typically hasanti-inflammatory actions and suppresses proinflam-matory cytokines (although there are instances to thecontrary[68–71]), the coexistence of elevated cortisol andproinflammatory cytokine levels suggests an insensi-tivity to cortisol at the level of the lymphocyte GR.[72]

This possibility is supported by the finding thatperipheral GR sensitivity in depressed individuals(assessed by cutaneous vasoconstrictive responses totopically applied GCs) is inversely correlated withTNF-a concentrations.[73] The ‘‘hypocortisolism’’ hypo-thesis is also supported by recent genome-wideexpression microarray analyses on monocytes fromstressed (but not necessarily depressed) caregiverscompared to controls.[74] Despite having similarcortisol secretory patterns, the caregivers in thatstudy showed diminished expression of glucocorticoidresponse element transcripts and heightened expression

of transcripts with response elements for NF-kappaB, akey proinflammatory transcription factor.

On the other hand, the ‘‘hypercortisolism’’ hypothesisis supported by phenotypic somatic features suggestiveof cortisol excess and of increased end-organ cortisolsignaling in depression, e.g., osteoporosis, insulinresistance, Type II diabetes, a relative hypokalemicalkalosis accompanied by neutrophilia and lympho-cytosis, hypertension, metabolic syndrome and visceral/intra-abdominal adiposity (reviewed in Ref.[45]:).Further support of net GC over-activation is providedby evidence of altered expression of target genessuch as BDNF, which are believed to be undernegative regulatory control by cortisol.[75] It remainsdebatable whether hypercortisolism is causallyrelated to hippocampal atrophy often reported indepression.[32,76–82]

Pathologically elevated or diminished GC activitycould, via genomic mechanisms, alter transcription ofgenes involved in synthesis and degradation of mono-amine neurotransmitters and other substances,[83–87]

and could have neurobehavioral sequellae.[45] Chronichypercortisolemia, in particular, has been proposed bySapolsky and others,[14] to result in a biochemical‘‘cascade,’’ which can culminate in cell endangermentor cell death in certain hippocampal cells. In thesimplest description of this model, GC excess engen-ders a state of intracellular glucoprivation (insufficientintracellular glucose energy stores) in certain cells,impairing the ability of glia and other cells to clearsynaptic glutamate. The resulting excitotoxicity resultsin excessive release of calcium into the cytoplasm,which can contribute to oxidative damage, proteolysis,and cytoskeletal damage.[88–90] Unchecked, these pro-cesses can culminate in diminished cell viability or celldeath. For example, GCs can, via non-genomicmechanisms, directly modulate mitochondrial calciumand oxidation in an inverted U-shaped manner,with chronically elevated levels leading to cellulardamage.[91] In the present model, we expand uponthese earlier GC models by integrating effects onneurotrophic factors, neurosteroids, inflammation, and

TABLE 1. Possible detrimental changes seen in depression and/or chronic stress

mPotentially damaging mediators kPotentially protective or restorative mediators

INCREASED DECREASEDHypercortisolemia (with hyper- or hypocortisolism) Neurosteroids (allopregnanolone, DHEAa)Synaptic glutamate (excitotoxicity) Insulin sensitivityIntracytoplasmic calcium Intracellular glucoseFree radicals (oxidative stress) AntioxidantsInflammatory cytokines Anti-inflammatory/immunoregulatory cytokinesb

Neurotrophic factorsTelomerasec

aEvidence is mixed as to whether major depression is characterized by excessive or diminished levels of DHEA, but it is often low withpsychological stress.bEvidence is mixed as to whether the anti-inflammatory/immunoregulatory cytokine, IL-10, is elevated or diminished in major depression.cTelomerase activity has been reported as low or high (albeit less effective in preserving telomere length) in chronic stress; there are as yet nopublished data on telomerase activity in major depression.

329Review: Do Stress and Depression Accelerate Cell Aging?


the telomere/telomerase maintenance system, an im-portant aspect of cell aging.

Although circulating cortisol concentrations arefrequently elevated in depression, plasma and CSFconcentrations of the GABA-A receptor agonistneurosteroid, allopregnanolone, are decreased in unme-dicated depressives, plasma and CSF levels of allo-pregnanolone increase with selective serotoninreuptake inhibitor (SSRI) treatment in proportion totheir antidepressant effect.[92,93] SSRI antidepressantsrapidly increase allopregnanolone synthesis, and thismay contribute to their anxiolytic effects.[92,94,95]

Another neurosteroid, DHEA, which can have ‘‘anti-cortisol’’ effects (reviewed in[96]), and which promotespsychological resilience,[51,97] has been reported to beboth high and low in depression,[96] but DHEAtreatment is generally reported as having significantantidepressant effects.[96] Notably, both theseneurosteroids modulate HPA,[96] BDNF[96,98,99] andimmune[3,100–102] activity, antagonize oxidativestress[103,104] and have neuroprotective or neuroregen-erative effects.[96,98–101] Allopregnanolone also inhbitsstress-induced corticotropin-releasing hormone re-lease.[99] Endogenous decreases in these neurosteroidsor exogenously produced increases in their effectswould be expected to have damaging or beneficialeffects, respectively, in the context of depression orchronic stress.[48,92,95,96,105,106]

IMMUNE FUNCTIONStress-related dysregulation of HPA axis and of GC

activity also contributes to immune dysregulation indepression,[107] and proinflammatory cytokines furtheralter HPA axis activity.[108,109] Immune dysregulationmay be an important pathway by which depression andchronic stress heighten the risk of serious medicalcomorbidity.[20,30,102,110,111] Several major proinflam-matory cytokines, such as IL-1b, IL-2, IL-6, andTNF-a, are elevated in depression, either basally or inresponse to mitogen stimulation or acutestress.[107,112,113] Conversely, certain anti-inflammatoryor immunomodulatory cytokines, such as IL-1 receptorantagonist and IL-10, may be increased or decreased ormay be dysregulated relative to proinflammatorycytokines.[112,114,115] In particular, the ratio of proin-flammatory to anti-inflammatory/immunomodulatorycytokines may be heightened in depression and couldresult in increased inflammation[112] and, subsequently,in increased free radical production and oxidativestress.[116] Converging findings suggest that highperipheral levels of inflammatory cytokines, such asIL-6, are associated with the activation of centralinflammatory mechanisms that, under some circum-stances, adversely affect the hippocampus, where IL-6receptors are abundantly expressed.[117] Hippocampalneurogenesis is also suppressed by microglial acti-vation, which leads to brain inflammation,[118] andhigh proinflammatory cytokine concentrations can

contribute to hippocampal neurodegeneration.[119] Inwild-type mice, stress increases hippocampal IL-6concentrations, but IL-6 (�/�) knockout mice areresistant to stress-induced learned helplessness, ananimal model of depression.[120] In healthy humans,plasma IL-6 concentrations are inversely correlatedwith hippocampal gray matter,[121] and elevated pre-treatment inflammatory cytokine levels predict poorerresponse to antidepressant medications in individualswith major depression.[122] High proinflammatorycytokine levels also directly contribute to monoaminedysregulation, HPA axis stimulation, depression, andcellular and organismic senescence.[119,123] It should benoted, however, that due to the complexity of cytokineactions in neurons and glia, the end effect of individualcytokines can be either detrimental or protective,depending on the circumstances.[112]

OXIDATIONStress and altered HPA axis activity can also

increase oxidative damage and decrease antioxidantdefenses.[20,29,46,124] Oxidative stress, together withinflammatory cytokines, often increase with aging andin various disease states, whereas antioxidant and anti-inflammatory activities paradoxically decrease, result-ing in a heightened likelihood of cellular damage and ofa senescent phenotype.[20,125] Oxidative stress occurswhen the production of oxygen-free radicals exceedsthe capacity of the body’s antioxidants to neutralizethem. Oxidative stress damages DNA, protein, lipids,and other macromolecules in many tissues, withtelomeres (discussed below)[126] and the brain[90] beingparticularly sensitive. Elevated plasma and/or urineoxidative stress markers (e.g., increased F2-isopros-tanes and 8-hydroxydeoxyguanosine [8-OHdG] alongwith decreased antioxidant compounds, such as Vita-mins C and E) have been reported in individuals withdepression and in those with chronic psychologicalstress,[27,29,127,128] and the concentration of peripheraloxidative stress markers is positively correlated with theseverity and chronicity of depression,[29,129,130] as wellas with evidence of accelerated apoptosis in polymor-phonuclear blood cells.[131] Furthermore, the ratio ofserum oxidized lipids (F2-isoprostanes) to antioxidants(Vitamin E) is directly related to psychological stress,and is inversely related to telomere length andtelomerase activity (both discussed below) in chroni-cally stressed caregivers.[22] Conversely, antidepressantsdecrease oxidative stress.[132] Because cellular oxidativedamage is an important component of the aging process,prolonged or repeated exposure to oxidative stress couldaccelerate aspects of biological aging and promoteaging-related comorbid diseases in depression.[29] Forexample, oxidative stress potentiates TNF-a-inducedactivation of the cell death cascade.[133] Stress- ordepression-related increases in oxidative stress addition-ally blunt certain protective or reparative processes,because oxidative stress is inversely correlated with



telomerase activity as well as telomere length (discussedbelow),[126,134] and because increased oxidative stress(and lower antioxidant protection) is associated withlower BDNF activity[135,136] (discussed below).

BRAIN-DERIVEDNEUROTROPHIC FACTOR

The ‘‘neurotrophic model’’ of depression[75] posits thatdiminished hippocampal BDNF activity, caused by stressor excessive GCs, impairs the ability of stem cells in thesubgranular zone of the dentate gyrus (as well as cells inthe subventricular zone, projecting to the prefrontalcortex) to proliferate into mature cells that remain viable.It is not known whether such processes can causedepression and whether they are relevant to the mechan-ism of action of antidepressant drugs; evidence issomewhat stronger for BDNF involvement in antide-pressant effects than in the etiology of depression.[137,138]

Furthermore, unmedicated patients with depression havedecreased hippocampal (at autopsy) and serum concen-trations of BDNF.[137,139,140] A role of BDNF inantidepressant mechanisms of action is supported byfindings that hippocampal neurogenesis (in animals) andserum BDNF concentrations (in depressed humans)increase with antidepressant treatment,[137,140] and thathippocampal neurogenesis is required for behavioraleffects of antidepressants in animals.[141] Apart from itsdirect neurotrophic actions, BDNF also has anti-inflammatory and antioxidant effects and improves theefficiency of brain mitochondrial oxygen utilization,which may contribute to its neuroprotective effi-cacy,[142,143] BDNF attenuates glucocorticoid-inducedneuronal death,[144] and BDNF activity synergizes withtelomerase activity (discussed below) in promoting thegrowth of developing neurons.[145]

CELL AGING: TELOMERES ANDTELOMERASE

Telomeres are DNA-protein complexes that cap theends of linear DNA strands, protecting DNA fromdamage.[146] When telomeres reach a critically shortlength, as happens when cells undergo repeated mitoticdivisions without adequate telomerase activity (e.g.,immune cells and stem cells, including neurogenic stemcells in the hippocampus), cells become susceptible toapoptosis and death. Even in nondividing cells, such asmature neurons, telomeres can become shortened byoxidative stress, which preferentially damages telo-meres to a greater extent than nontelomericDNA.[126,147] This non-mitotic type of telomere short-ening also increases susceptibly to apoptosis and celldeath. Telomere length is a indicator of ‘‘biologicalage’’ (as opposed to just chronological age) andrepresents a cumulative log of the number of celldivisions and a cumulative record of exposure togenotoxic and cytotoxic processes, such as oxida-

tion.[20,22,23,126,146,148] Telomere length may also repre-sent a biomarker for assessing an individual’scumulative exposure to, or ability to cope with, stressfulconditions. For example, preliminary data point toaccelerated leukocyte telomere shortening, a sign ofcellular aging, in chronically stressed[22,23] and indepressed[149] individuals. The telomere shorteningmay, at least in part, be related to increases in stress-related cortisol and catecholamine output.[23,150] Theestimated magnitude of the acceleration of biologicalaging is not trivial; it was estimated as approximately9–17 additional years of chronological aging in thestressed caregivers and as much as 10 years in thedepressed individuals. It should be noted that thesubjects in the depression study had very chroniccourses of depression (an average of nearly 26 years oflifetime depression).[149] Preliminary data suggest thattelomere shortening is a function of the duration of thelifetime exposure to depression (Wolkowitz et al.,unpublished) and may not be present in individualswith short lifetime exposures to depression. In non-depressed populations, shortening of leukocyte telo-meres is associated with atherosclerosis and CVdisease,[151–153] osteoporosis[154] and cognitive impair-ment,[155] and with increased medical morbidity andearlier mortality from a number of causes, includingCV and infectious disease, and dementia.[156] Forexample, shortened telomeres are associated with agreater than three-fold increase in the risk of myocar-dial infarction and stroke, and with a greater than eight-fold increase in the risk of death from infectiousdisease.[157] In a more recent study, baseline telomerelength (in women) and prospective rate of change intelomere length over a 2.5 year period (in men)predicted CV mortality over a 12-year period.[156]

Thus, cell aging (manifest as shortened telomeres),associated with any of the mediators discussed above,provides a conceptual link between depression and itsassociated medical comorbidities and shortenedlife span.[20,102,148]

Telomerase is a reverse transcriptase enzyme thatrebuilds telomere length, thereby delaying cell senes-cence, apoptosis, and cell death.[146] Telomerase alsohas antiaging or cell survival-promoting effects in-dependent of its effects on telomere length byregulating transcription of growth factors, synergizingwith the neurotrophic effects of BDNF, havingantioxidant effects and intrinsic antiapoptotic effects,protecting cells from necrosis, and stimulating cellgrowth in adverse conditions.[145,158,159] Telomeraseactivity has not yet been characterized in individualswith major depression, but it has been reported to bediminished[22] or increased[160] in stressed caregiverscompared to low stress controls. Several of themediators discussed above can contribute to dimin-ished telomere length and/or telomerase activity(e.g., cortisol,[150] oxidative stress,[147] and inflamma-tory cytokines[160,161]), highlighting the interlinkednature of cell-damaging and cell-protective mediators



in stress and depression. Important moderators oftelomere length are rapidly being discovered (e.g.,childhood maltreatment,[162] socioeconomic status,[163]

race,[164,165] physical exercise,[166] and dispositionalpessimism,[39] among others).

DO STRESS AND DEPRESSIONACCELERATE CELL AGING?

We have briefly reviewed evidence of biochemicalabnormalities in depression, some of which areconsistent with an aged phenotype that could con-tribute to certain medical comorbidities seen withdepression. They could also contribute to the depres-sive state itself, but that has not been adequately tested.In particular, depression (and perhaps chronic stress, aswell) may be associated with increased cell damagingprocesses and decreased cell protective or restorativeones (Table 1). We propose a model in which theseabnormalities are causally interlinked and may derive,directly or indirectly, from altered HPA axis and GCactivity seen in depression (Fig. 1). It remains uncertainwhether the brain in depressed individuals is subject tonet hypo- or hypercortisolism, and even within thebrain, individual component tissues, such as neuronsand glia, may differ in their response to alteredcirculating GC levels as a result of differing receptorexpression or metabolic enzymes.

We have couched this model in terms of ‘‘acceleratedaging’’ at the cell level, although whether cell aging isactually accelerated in depression remains to bedetermined in prospective trials. It is important torecognize that this model is unlikely to apply to allindividuals with depression (many of whom do nothave discernible HPA axis dysregulation), and thatmany of these changes are not specific to majordepression. Also, various genetic and epigenetic mod-erators, not discussed here, are undoubtedly impor-tant.[39,52,67,167–169] The major importance of thishypothetical model is that it identifies certain non-traditional targets for pharmacological and nonphar-macological treatment, and thus could lead to newtheory-driven therapies. In particular, treatments di-rected at the targets identified here have the potentialnot only to treat depression but also to treatcertain medical comorbidities that occur alongsidedepression.[47,49,170] Interestingly, even traditionalantidepressant medications, which putatively workvia monoaminergic actions, affect many of the noveltargets described here[95,109,128,171–177] (see Fig. 1), eventhough they were not developed with those purposes inmind. Last, the identification of novel biomarkers ofdepression may discriminate separate endophenotypesof depression that respond differently to differenttreatments,[54,55,122,174] although some of the endocri-nological and neurochemical differences reported maybe dependent more on the target tissue examined thanreflective of a global endophenotype. This will hope-

fully accelerate the era of personalized antidepressanttreatment.

THEORETICAL MODEL ANDNOVEL TREATMENT

POSSIBILITIESA schematic overview of our model is presented in

Figure 1. The condensed and simplified nature of thisschematic precludes depiction of numerous othermediators and moderators and interactions that areinvolved. Therefore, this depiction should be viewedas a ‘‘broad brush stroke’’ theoretical model. Thebracketed numbers in Figure 1 are keyed to potentialsites of therapeutic intervention described below. Inthis model, elevated cortisol levels are associated withdownregulation of GRs (‘‘GC resistance’’); the ‘‘net’’GC activity remains uncertain and could even differ indifferent tissues. A deficit in GR function can precedeor result from the hypercortisolemia. To the extent thatlymphocyte GRs become GC resistant, immunefunction is altered and excessive proinflammatorycytokine effects can occur. Changes in cortisol activityalso result in multiple genomic changes, e.g., alteredlevels of certain neurotransmitters (e.g., decreasedserotonin and increased dopamine activity in certainbrain regions, which could contribute to depressive orpsychotic symptoms). To the extent GC activity is‘‘excessive’’ in certain brain regions, a cascade ofevents can follow, characterized by diminished insulinsignaling, intraneuronal glucoprivation and diminishedenergy availability, defective clearance of intrasynapticglutamate, excitotoxicity, intracellular buildup ofcalcium, generation of oxygen-free radicals (oxidativestress), diminution of telomerase activity and cellulardamage or cell death. Increased oxidative stress candamage the enzyme telomerase and shorten telomeres,at least in certain cells in the body. In nondepressedindividuals, leukocyte telomere shortening is associatedwith a host of physical illnesses and prematuremortality. If this occurs in depressed individuals aswell, it could help explain the surfeit of medical illnessand the shortened life expectancy seen with chronicdepression. Chronic stress and depression and/orexcessive cortisol exposure can also be associated withunderproduction of certain counterregulatory neuro-steroid hormones, e.g., DHEA and allopregnanolone,which could further dysregulate HPA axis activity,hamper antioxidative function, and reduce neuropro-tective capacity. Additionally, prolonged stress and/orincreased cortisol activity can downregulate BDNFactivity, which further diminishes neuroreparativecapacity and attenuates neurogenesis.

To the extent this theoretical model is accurate,several potential treatment loci emerge, as indicatednumerically in Figure 1: (1) traditional antidepressantshave several novel functions apart from increasing intra-synaptic monoamine concentrations: they up-regulate



GR function,[172] increase allopregnanolone synthesis(certain SSRIs),[95] increase BDNF levels,[75] and haveanti-inflammatory[174,178] and antioxidant[179,180] effects;(2) CRH antagonists;[181] (3) stress reduction, medita-tion, and other behavioral and lifestyle interven-tions;[20,182,183] (4) antiglucocorticoids[47,184–186]; (5)energy supplementation or insulin receptor sensiti-zers;[187–189] (6) glutamate antagonists;[190–194] (7) cal-cium blockers[195,196] and antioxidants[197]; (8) DHEA;[96]

(9) 3-a-hydroxy–steroid dehydrogenase (3-a-HSD)stimulators (including SSRIs), which increase allopreg-nanolone synthesis[94,95]; (10) environmental enrichment,exercise[198–201]; (11) BDNF administration via novelroutes of administration[202–204]; (12) telomerase activa-tion,[205,206] and (13) anti-inflammatory drugs, TNF-aantagonists, etc.[109,174,207–211] It is possible that, bytargeting such ‘‘upstream’’ mediators of the biochemicalmilieu, additional therapeutic leverage might be gained.Already, preliminary studies are testing many of thesestrategies, with preliminary signs of success.

Acknowledgments. The authors acknowledge thegenerosity of the O’Shaughnessy Foundation, whichsupplied major funding. Additional funding wassupplied by the University of California, San Francisco,Academic Senate. The authors are also grateful toDr. Jue Lin, who has provided expert advice andtechnical aid in the field of cell aging and Dr. ElizabethBlackburn, a pioneer in the field of cell aging, whoseguidance has been indispensible.

Financial disclosures: Dr. Wolkowitz has receivedlecture honoraria from Jazz Pharmaceuticals andMerck Pharmaceuticals, and has served on an AdvisoryBoard for Pfizer Pharmaceuticals. No other authorshave financial ties to these or any other pharmaceuticalcompanies.

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depression gets old fast: do stress and depression accelerate cell aging?

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