DEPRESSION AND ANXIETY 27:327–338 (2010)
DEPRESSION GETS OLD FAST: DO STRESS AND
DEPRESSION ACCELERATE CELL AGING?
Owen M. Wolkowitz, M.D.,1?Elissa S. Epel, Ph.D.,1Victor I. Reus, M.D.,1and Synthia H. Mellon, Ph.D.2
Depression has been likened to a state of ‘‘accelerated aging,’’ and depressed
individuals have a higher incidence of various diseases of aging, such as
cardiovascular and cerebrovascular diseases, metabolic syndrome, and demen-
tia. Chronic exposure to certain interlinked biochemical pathways that mediate
stress-related depression may contribute to ‘‘accelerated aging,’’ cell damage,
and certain comorbid medical illnesses. Biochemical mediators explored in this
theoretical 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 the
telomere/telomerase maintenance system. A better appreciation of the role of
these mediators in depressive illness could lead to refined models of depression, to
a re-conceptualization of depression as a whole body disease rather than just a
‘‘mental illness,’’ and to the rational development of new classes of medications
to treat depression and its related medical comorbidities. Depression and
Anxiety 27:327–338, 2010.
rrrr2010 Wiley-Liss, Inc.
Key words: depression; stress; aging; cortisol; BDNF; DHEA; telomeres;
oxidation; inflammation; allopregnanolone
Depression has been likened to a state of ‘‘accelerated
aging,’’ affecting the hippocampus and the cardiovas-
cular (CV), cerebrovascular, neuroendocrine, meta-
bolic, andimmune systems,[1–3]
individuals have a higher incidence of various diseases
often associated with aging, such as Type II diabetes,
metabolic syndrome, osteoporosis, CV disease, stroke,
and pathological cognitive aging, including Alzheimer’s
disease and other dementias.[2,4–8]Depression is also
associated with significantly worse outcomes in a
number of medical conditions, and depression is an
independent risk factor for early mortality (even after
accounting for sociodemographic factors, suicide,
and biological and behavioral risk factors, such as
smoking, alcohol, and physical illness).[9–13]Various
explanations for ‘‘accelerated aging’’ in depression
have been proposed, such as the ‘‘glucocorticoid
cascade’’ hypothesis[14,15]and ‘‘allostatic load.’’In
this review, we explore the additional possibility
that ‘‘accelerated aging’’ in depression occurs at the
level of the individual cell and that it can be traced to
specific biochemical mediators that are altered in
depression. Discovering pathological processes in
depression at the cellular level could help identify
novel targets for treating depression and its comorbid
We propose a depression model that accounts for
certain linked pathogenic processes, which occur in the
brain and in the periphery, and which can culminate in
Published online in Wiley InterScience (www.interscience.wiley.com).
Received for publication 9 November 2009; Revised 12 February
2010; Accepted 13 February 2010
The authors disclose the following financial relationships within the past
3 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.
1Department of Psychiatry, University of California School of
Medicine, San Francisco, California
2Department of OB-GYNand
University of California School of Medicine, San Francisco,
rrrr 2010 Wiley-Liss, Inc.
cellular aging and damage and disease (Fig. 1). There is
widespread recognition that certain physical stressors,
such as oxidative and inflammatory stress, can accel-
erate aging in cells.[17–21]
appreciated that psychological stress can also prema-
turely age cells, possibly by invoking similar physical
It has recently been
processes.[15,20,22–32]Major depression and its asso-
ciated biological perturbations are the focus of this
review. To the extent similar processes are seen in other
conditions (e.g., chronic psychological stress, posttrau-
matic stress disorder, schizophrenia, certain neurode-
generative disorders, etc.), aspects of this model might
also be applicable. Indeed, some of the data supporting
this model were derived from chronically stressed, but
not necessarily depressed, populations; such data will
be identified in the text. In brief, stress-related
dysregulation of the hypothalamic–pituitary–adrenal
(HPA) axis, as moderated by genetic[33–36]and epige-
neticfactors and by cognitive appraisal,[38,39]social
support,[40,41]and coping styles,[42,43]leads to cortisol-
induced changes in gene expression (including genes
related to monoaminergic and peptidergic neurotrans-
mission), neuroendangering or neurotoxic effects in
certain brain areas (e.g., prefrontal cortex and hippo-
(or ‘‘neuroinflammation’’), and accelerated cell aging
(via effects on the telomere/telomerase maintenance
system), as described below. In this context, normal
compensatory or reparative processes are diminished,
e.g., decreased counterregulatory neurosteroids (e.g.,
dehydroepiandrosterone [DHEA]) and allopregnano-
lone), decreased antioxidant compounds (e.g., Vitamin
C or E), diminished anti-inflammatory/immunomodu-
latory cytokines (e.g., IL-10), decreased activity of
neurotrophic factors (e.g., brain-derived neurotrophic
factor [BDNF]) and decreased activity or effectiveness
of the telomere-lengthening enzyme, telomerase. The
juxtaposition of enhanced toxic processes with dimin-
ished protective or restorative ones can culminate in
cellular damage and physical disease(Table 1). The
presentation of this model here will be relatively
concise, but related reviews of this and similar models
are published elsewhere.[20,22,23,36,45–53]This review
represents an update and refinement of models
we have presented earlier.[45–48]This model is not
meant to be complete or all-encompassing, nor is it
meant to apply to all individuals with major depression,
because different endophenotypes
components.[45,54,55]Instead, this broadly sketched
model is meant to highlight and connect certain
interesting new findings in the study of stress
and depression, and to provide testable hypotheses
that could guide research and treatment in new
The physiological significance of increased circulat-
ing GC levels remains unknown, and it is even
debatable whether ‘‘hypercortisolemia’’ results in net
hypercortisol-ism at the cellular level, or rather in net
) 3 (
) 2 (
) 4 (
) 5 (
) 6 (
) 7 (
) 31 (
) 2 1 (
Cell Endangerment and Medical/ Psychiatric Symptoms
(1, 10, 11)•••••••••••• (1, 8, 9)•••••••
Figure 1. Theoretical model of cell ‘‘aging’’ or cell endanger-
ment in depression. This overly simplified schematic model is
explained in the text (last paragraph). The mediators presented
here are plausibly related to cell damage or dysfunction, but it
remains unknown whether such cellular effects translate into
psychiatric and medical symptoms. Bracketed numbers refer to
potential sites of therapeutic intervention, also described in the
text. Not depicted in this model are important monoaminergic
mediators, which interact with many of the mediators that are
depicted here, as well as certain mediators not discussed in this
review, e.g., neuropeptide Y[51,97]and gamma-aminobutyric
acid.[48,212]Also not depicted here are important moderators of
stress and other effects, such as genetic polymorphisms,[33–36]
sity.[52,67,213–215]To reduce the complexity of the Figure, we
also do not depict multiple linked pathways between the
individual mediators, because many of them are intertwined
and multidetermined, and we also do not indicate compensatory
pathways, which can attenuate certain of the proposed effects
(e.g.,[112,160]). Abbreviations: GR, glucocorticoid receptor; CRH,
corticotropin releasing hormone; DHEA, dehydroepiandro-
neurotrophic factor; Telom, telomere.
328Wolkowitz et al.
Depression and Anxiety
hypocortisolism, perhaps due to downregulation of the
glucocorticoid receptor (GR) (referred to as ‘‘GC
resistance’’).[45,56]It is possible but not proven that
hyper- and hypocortisolism identify different subtypes
of depression or map onto different symptom clus-
ters.[45,54,57–59]It should also be recognized that the
effects of either state are likely to differ, depending on
the target tissue involved and that ‘‘relative’’ conditions
of either hyper- or hypocortisolism may exist at the
same time within organisms, making any global
statements a simplification of the underlying endocrine
state.[60–63]For example, different GR polymorphisms
can significantly affect
GCs,[35,64]and alternative splicing of the GR mRNA
can lead to different GR isoforms with different actions
in different tissues.[65,66]Furthermore, early life events,
such as childhood abuse, can epigenetically reprogram
GR expression and splicing, leading to important inter-
individual differences in GC responsivity.The
‘‘hypocortisolism’’ hypothesis is supported by findings
that proinflammatory cytokine levels (e.g., tumor
necrosis factor [TNF]-a, IL-1b, and IL-6) tend to be
increased in the plasma of depressed patients, and that
proinflammatory cytokines can contribute to depres-
sive symptomatology. Because cortisol typically has
anti-inflammatory actions and suppresses proinflam-
matory cytokines (although there are instances to the
contrary[68–71]), the coexistence of elevated cortisol and
proinflammatory cytokine levels suggests an insensi-
tivity to cortisol at the level of the lymphocyte GR.
This possibility is supported by the finding that
peripheral GR sensitivity in depressed individuals
(assessed by cutaneous vasoconstrictive responses to
topically applied GCs) is inversely correlated with
TNF-a concentrations.The ‘‘hypocortisolism’’ hypo-
thesis is also supported by recent genome-wide
expression microarray analyses on monocytes from
stressed (but not necessarily depressed) caregivers
compared to controls.
cortisol secretory patterns, the caregivers in that
study showed diminished expression of glucocorticoid
response element transcripts and heightened expression
individuals’ responses to
Despite having similar
of transcripts with response elements for NF-kappaB, a
key proinflammatory transcription factor.
On the other hand, the ‘‘hypercortisolism’’ hypothesis
is supported by phenotypic somatic features suggestive
of cortisol excess and of increased end-organ cortisol
signaling in depression, e.g., osteoporosis, insulin
resistance, Type II diabetes, a relative hypokalemic
alkalosis accompanied by neutrophilia and lympho-
cytosis, hypertension, metabolic syndrome and visceral/
Further support of net GC over-activation is provided
by evidence of altered expression of target genes
such as BDNF, which are believed to be under
negative regulatory control by cortisol.It remains
related to hippocampal atrophy often reported in
Pathologically elevated or diminished GC activity
could, via genomic mechanisms, alter transcription of
genes involved in synthesis and degradation of mono-
amine neurotransmitters and other substances,[83–87]
and could have neurobehavioral sequellae.Chronic
hypercortisolemia, in particular, has been proposed by
Sapolsky and others,to result in a biochemical
‘‘cascade,’’ which can culminate in cell endangerment
or cell death in certain hippocampal cells. In the
simplest description of this model, GC excess engen-
ders 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 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 cell
death. For example, GCs can, via non-genomic
mechanisms, directly modulate mitochondrial calcium
and oxidation in an inverted U-shaped manner,
with chronically elevated levels leading to cellular
damage.In the present model, we expand upon
these earlier GC models by integrating effects on
neurotrophic factors, neurosteroids, inflammation, and
TABLE 1. Possible detrimental changes seen in depression and/or chronic stress
mPotentially damaging mediators
kPotentially protective or restorative mediators
Hypercortisolemia (with hyper- or hypocortisolism)
Synaptic glutamate (excitotoxicity)
Free radicals (oxidative stress)
Neurosteroids (allopregnanolone, DHEAa)
aEvidence is mixed as to whether major depression is characterized by excessive or diminished levels of DHEA, but it is often low with
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 no
published data on telomerase activity in major depression.
329Review: Do Stress and Depression Accelerate Cell Aging?
Depression and Anxiety
the telomere/telomerase maintenance system, an im-
portant aspect of cell aging.
Although circulating cortisol concentrations are
frequently elevated in depression, plasma and CSF
concentrations of the GABA-A receptor agonist
neurosteroid, allopregnanolone, are decreased in unme-
dicated depressives, plasma and CSF levels of allo-
reuptake inhibitor (SSRI) treatment in proportion to
their antidepressant effect.[92,93]SSRI antidepressants
rapidly increase allopregnanolone synthesis, and this
may contribute to their anxiolytic effects.[92,94,95]
Another neurosteroid, DHEA, which can have ‘‘anti-
cortisol’’ effects (reviewed in), and which promotes
psychological resilience,[51,97]has been reported to be
both high and low in depression,but DHEA
treatment is generally reported as having significant
neurosteroids modulate HPA,BDNF[96,98,99]and
stress[103,104]and have neuroprotective or neuroregen-
erative effects.[96,98–101]Allopregnanolone also inhbits
stress-induced corticotropin-releasing hormone re-
lease.Endogenous decreases in these neurosteroids
or exogenously produced increases in their effects
would be expected to have damaging or beneficial
effects, respectively, in the context of depression or
Stress-related dysregulation of HPA axis and of GC
activity also contributes to immune dysregulation in
depression,and proinflammatory cytokines further
alter HPA axis activity.[108,109]Immune dysregulation
may be an important pathway by which depression and
chronic stress heighten the risk of serious medical
comorbidity.[20,30,102,110,111]Several major proinflam-
matory cytokines, such as IL-1b, IL-2, IL-6, and
TNF-a, are elevated in depression, either basally or in
stress.[107,112,113]Conversely, certain anti-inflammatory
or immunomodulatory cytokines, such as IL-1 receptor
antagonist and IL-10, may be increased or decreased or
may be dysregulated relative to proinflammatory
cytokines.[112,114,115]In particular, the ratio of proin-
flammatory to anti-inflammatory/immunomodulatory
cytokines may be heightened in depression and could
result in increased inflammationand, subsequently,
in increased free radical production and oxidative
Converging findings suggest that high
peripheral levels of inflammatory cytokines, such as
IL-6, are associated with the activation of central
inflammatory mechanisms that, under some circum-
stances, adversely affect the hippocampus, where IL-6
receptors are abundantly expressed.Hippocampal
neurogenesis is also suppressed by microglial acti-
vation, which leads to brain inflammation,and
high proinflammatory cytokine concentrations can
contribute to hippocampal neurodegeneration.In
wild-type mice, stress increases hippocampal IL-6
concentrations, but IL-6 (?/?) knockout mice are
resistant to stress-induced learned helplessness, an
animal model of depression.In healthy humans,
plasma IL-6 concentrations are inversely correlated
with hippocampal gray matter,and elevated pre-
treatment inflammatory cytokine levels predict poorer
response to antidepressant medications in individuals
with major depression.
cytokine levels also directly contribute to monoamine
dysregulation, HPA axis stimulation, depression, and
cellular and organismic senescence.[119,123]It should be
noted, however, that due to the complexity of cytokine
actions in neurons and glia, the end effect of individual
cytokines can be either detrimental or protective,
depending on the circumstances.
Stress and altered HPA axis activity can also
increase oxidative damage and decrease antioxidant
defenses.[20,29,46,124]Oxidative stress, together with
inflammatory cytokines, often increase with aging and
in various disease states, whereas antioxidant and anti-
inflammatory activities paradoxically decrease, result-
ing in a heightened likelihood of cellular damage and of
a senescent phenotype.[20,125]Oxidative stress occurs
when the production of oxygen-free radicals 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 brainbeing
particularly sensitive. Elevated plasma and/or urine
oxidative stress markers (e.g., increased F2-isopros-
tanes and 8-hydroxydeoxyguanosine [8-OHdG] along
with decreased antioxidant compounds, such as Vita-
mins C and E) have been reported in individuals with
depression and in those with chronic psychological
stress,[27,29,127,128]and the concentration of peripheral
oxidative stress markers is positively correlated with the
severity and chronicity of depression,[29,129,130]as well
as with evidence of accelerated apoptosis in polymor-
phonuclear blood cells.Furthermore, the ratio of
serum oxidized lipids (F2-isoprostanes) to antioxidants
(Vitamin E) is directly related to psychological stress,
and is inversely related to telomere length and
telomerase activity (both discussed below) in chroni-
cally stressed caregivers.Conversely, antidepressants
decrease oxidative stress.Because cellular oxidative
damage is an important component of the aging process,
prolonged or repeated exposure to oxidative stress could
accelerate aspects of biological aging and promote
aging-related comorbid diseases in depression.For
example, oxidative stress potentiates TNF-a-induced
activation of the cell death cascade.Stress- or
depression-related increases in oxidative stress addition-
ally blunt certain protective or reparative processes,
because oxidative stress is inversely correlated with
330Wolkowitz et al.
Depression and Anxiety
telomerase activity as well as telomere length (discussed
below),[126,134]and because increased oxidative stress
(and lower antioxidant protection) is associated with
lower BDNF activity[135,136](discussed below).
The ‘‘neurotrophic model’’ of depressionposits 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 proliferate into mature cells that remain viable.
It is not known whether such processes can cause
depression and whether they are relevant to the mechan-
ism of action of antidepressant drugs; evidence is
somewhat stronger for BDNF involvement in antide-
pressant effects than in the etiology of depression.[137,138]
Furthermore, unmedicated patients with depression have
decreased hippocampal (at autopsy) and serum concen-
trations of BDNF.[137,139,140]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,[137,140]and that
hippocampal neurogenesis is required for behavioral
effects of antidepressants in animals.Apart from its
direct neurotrophic actions, BDNF also has anti-
inflammatory and antioxidant effects and improves the
efficiency of brain mitochondrial oxygen utilization,
which may contribute to its neuroprotective effi-
cacy,[142,143]BDNF attenuates glucocorticoid-induced
neuronal death,and BDNF activity synergizes with
telomerase activity (discussed below) in promoting the
growth of developing neurons.
CELL AGING: TELOMERES AND
Telomeres are DNA-protein complexes that cap the
ends of linear DNA strands, protecting DNA from
damage.When telomeres reach a critically short
length, as happens when cells undergo repeated mitotic
divisions without adequate telomerase activity (e.g.,
immune cells and stem cells, including neurogenic stem
cells in the hippocampus), cells become susceptible to
apoptosis and death. Even in nondividing cells, such as
mature neurons, telomeres can become shortened by
oxidative stress, which preferentially damages telo-
meres toa greater extent
DNA.[126,147]This non-mitotic type of telomere short-
ening also increases susceptibly to apoptosis and cell
death. Telomere length is a indicator of ‘‘biological
age’’ (as opposed to just chronological age) and
represents a cumulative log of the number of cell
divisions and a cumulative record of exposure to
genotoxic and cytotoxic processes, such as oxida-
tion.[20,22,23,126,146,148]Telomere length may also repre-
senta biomarker for
cumulative exposure to, or ability to cope with, stressful
conditions. For example, preliminary data point to
accelerated leukocyte telomere shortening, a sign of
cellular aging, in chronically stressed[22,23]and in
depressedindividuals. The telomere shortening
may, at least in part, be related to increases in stress-
related cortisol and catecholamine output.[23,150]The
estimated magnitude of the acceleration of biological
aging is not trivial; it was estimated as approximately
9–17 additional years of chronological aging in the
stressed caregivers and as much as 10 years in the
depressed individuals. It should be noted that the
subjects in the depression study had very chronic
courses of depression (an average of nearly 26 years of
lifetime depression).Preliminary data suggest that
telomere shortening is a function of the duration of the
lifetime exposure to depression (Wolkowitz et al.,
unpublished) and may not be present in individuals
with short lifetime exposures to depression. In non-
depressed populations, shortening of leukocyte telo-
meres is associated with atherosclerosis and CV
disease,[151–153]osteoporosisand cognitive impair-
ment,and with increased medical morbidity and
earlier mortality from a number of causes, including
CV and infectious disease, and dementia.For
example, shortened telomeres are associated with a
greater 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 infectious
disease.In a more recent study, baseline telomere
length (in women) and prospective rate of change in
telomere length over a 2.5 year period (in men)
predicted CV mortality over a 12-year period.
Thus, cell aging (manifest as shortened telomeres),
associated with any of the mediators discussed above,
provides a conceptual link between depression and its
Telomerase is a reverse transcriptase enzyme that
rebuilds telomere length, thereby delaying cell senes-
cence, apoptosis, and cell death.Telomerase also
has antiaging or cell survival-promoting effects in-
dependent of its effects on telomere length by
regulating transcription of growth factors, synergizing
with the neurotrophic effects of BDNF, having
antioxidant effects and intrinsic antiapoptotic effects,
protecting cells from necrosis, and stimulating cell
growth in adverse conditions.[145,158,159]Telomerase
activity has not yet been characterized in individuals
with major depression, but it has been reported to be
diminishedor increasedin stressed caregivers
compared to low stress controls. Several of the
mediators discussed above can contribute to dimin-
ished telomere length and/or telomerase activity
(e.g., cortisol,oxidative stress,and inflamma-
tory cytokines[160,161]), highlighting the interlinked
nature of cell-damaging and cell-protective mediators
331Review: Do Stress and Depression Accelerate Cell Aging?
Depression and Anxiety
in stress and depression. Important moderators of
telomere length are rapidly being discovered (e.g.,
childhood maltreatment,socioeconomic status,
race,[164,165]physical exercise,and dispositional
DO STRESS AND DEPRESSION
ACCELERATE CELL AGING?
We have briefly reviewed evidence of biochemical
abnormalities in depression, some of which are
consistent with an aged phenotype that could con-
tribute to certain medical comorbidities seen with
depression. They could also contribute to the depres-
sive state itself, but that has not been adequately tested.
In particular, depression (and perhaps chronic stress, as
well) may be associated with increased cell damaging
processes and decreased cell protective or restorative
ones (Table 1). We propose a model in which these
abnormalities are causally interlinked and may derive,
directly or indirectly, from altered HPA axis and GC
activity seen in depression (Fig. 1). It remains uncertain
whether the brain in depressed individuals is subject to
net hypo- or hypercortisolism, and even within the
brain, individual component tissues, such as neurons
and glia, may differ in their response to altered
circulating GC levels as a result of differing receptor
expression or metabolic enzymes.
We have couched this model in terms of ‘‘accelerated
aging’’ at the cell level, although whether cell aging is
actually accelerated in depression remains to be
determined in prospective trials. It is important to
recognize that this model is unlikely to apply to all
individuals with depression (many of whom do not
have discernible HPA axis dysregulation), and that
many of these changes are not specific to major
depression. Also, various genetic and epigenetic mod-
erators, not discussed here, are undoubtedly impor-
The major importance of this
hypothetical model is that it identifies certain non-
traditional targets for pharmacological and nonphar-
macological treatment, and thus could lead to new
theory-driven therapies. In particular, treatments di-
rected at the targets identified here have the potential
not only to treat depression but also to treat
certain medical comorbidities that occur alongside
antidepressant medications, which putatively work
via monoaminergic actions, affect many of the novel
targets described here[95,109,128,171–177](see Fig. 1), even
though they were not developed with those purposes in
mind. Last, the identification of novel biomarkers of
depression may discriminate separate endophenotypes
of depression that respond differently to different
treatments,[54,55,122,174]although some of the endocri-
nological and neurochemical differences reported may
be dependent more on the target tissue examined than
reflective of a global endophenotype. This will hope-
fully accelerate the era of personalized antidepressant
THEORETICAL MODEL AND
A schematic overview of our model is presented in
Figure 1. The condensed and simplified nature of this
schematic precludes depiction of numerous other
mediators and moderators and interactions that are
involved. Therefore, this depiction should be viewed
as a ‘‘broad brush stroke’’ theoretical model. The
bracketed numbers in Figure 1 are keyed to potential
sites of therapeutic intervention described below. In
this model, elevated cortisol levels are associated with
downregulation of GRs (‘‘GC resistance’’); the ‘‘net’’
GC activity remains uncertain and could even differ in
different tissues. A deficit in GR function can precede
or result from the hypercortisolemia. To the extent that
lymphocyte GRs become GC resistant, immune
function is altered and excessive proinflammatory
cytokine effects can occur. Changes in cortisol activity
also result in multiple genomic changes, e.g., altered
levels of certain neurotransmitters (e.g., decreased
serotonin and increased dopamine activity in certain
brain regions, which could contribute to depressive or
psychotic symptoms). To the extent GC activity is
‘‘excessive’’ in certain brain regions, a cascade of
events can follow, characterized by diminished insulin
signaling, intraneuronal glucoprivation and diminished
energy availability, defective clearance of intrasynaptic
calcium, generation of oxygen-free radicals (oxidative
stress), diminution of telomerase activity and cellular
damage or cell death. Increased oxidative stress can
damage the enzyme telomerase and shorten telomeres,
at least in certain cells in the body. In nondepressed
individuals, leukocyte telomere shortening is associated
with a host of physical illnesses and premature
mortality. If this occurs in depressed individuals as
well, it could help explain the surfeit of medical illness
and the shortened life expectancy seen with chronic
depression. Chronic stress and depression and/or
excessive cortisol exposure can also be associated with
underproduction 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/or
increased cortisol activity can downregulate BDNF
activity, which further diminishes neuroreparative
capacity and attenuates neurogenesis.
To the extent this theoretical model is accurate,
several potential treatment loci emerge, as indicated
numerically in Figure 1: (1) traditional antidepressants
have several novel functions apart from increasing intra-
synaptic monoamine concentrations: they up-regulate
332Wolkowitz et al.
Depression and Anxiety
GR function,increase allopregnanolone synthesis
(certain SSRIs),increase BDNF levels,and have
(2) CRH antagonists;(3) stress reduction, medita-
tion, and other behavioral and lifestyle interven-
energy supplementation or insulin receptor sensiti-
zers;[187–189](6) glutamate antagonists;[190–194](7) cal-
cium blockers[195,196]and antioxidants; (8) DHEA;
stimulators (including SSRIs), which increase allopreg-
nanolone synthesis[94,95]; (10) environmental enrichment,
exercise[198–201]; (11) BDNF administration via novel
routes of administration[202–204]; (12) telomerase activa-
tion,[205,206]and (13) anti-inflammatory drugs, TNF-a
antagonists, etc.[109,174,207–211]It is possible that, by
targeting such ‘‘upstream’’ mediators of the biochemical
milieu, additional therapeutic leverage might be gained.
Already, preliminary studies are testing many of these
strategies, with preliminary signs of success.
generosity of the O’Shaughnessy Foundation, which
supplied major funding. Additional funding was
supplied by the University of California, San Francisco,
Academic Senate. The authors are also grateful to
Dr. Jue Lin, who has provided expert advice and
technical aid in the field of cell aging and Dr. Elizabeth
Blackburn, a pioneer in the field of cell aging, whose
guidance has been indispensible.
Financial disclosures: Dr. Wolkowitz has received
lecture honoraria from Jazz Pharmaceuticals and
Merck Pharmaceuticals, and has served on an Advisory
Board for Pfizer Pharmaceuticals. No other authors
have financial ties to these or any other pharmaceutical
The authors acknowledge the
1. Heuser I.
premature aging? Maturitas 2002;41:S19–S23.
2. McIntyre RS, Soczynska JK, Konarski JZ et al. Should depressive
syndromes be reclassified as ‘‘metabolic syndrome type II’’? Ann
Clin Psychiatry 2007;19:257–264.
3. Bauer ME. Chronic stress and immunosenescence: a review.
4. Evans DL, Charney DS, Lewis L et al. Mood disorders in the
medically ill: scientific review and recommendations. Biol
5. McIntyre RS, Rasgon NL, Kemp DE et al. Metabolic syndrome
and major depressive disorder: co-occurrence and pathophysio-
logic overlap. Curr Diab Rep 2009;9:51–59.
6. Brown ES, Varghese FP, McEwen BS. Association of depression
with medical illness: does cortisol play a role? Biol Psychiatry
7. Vogelzangs N, Suthers K, Ferrucci L et al. Hypercortisolemic
depression is associated with the metabolic syndrome in late-life.
Depression, endocrinologically asyndrome of
8. Speck CE, Kukull WA, Brenner DE et al. History of depression
as a risk factor for Alzheimer’s disease. Epidemiology 1995;
9. Chodosh J, Kado DM, Seeman TE, Karlamangla AS. Depressive
symptoms as a predictor of cognitive decline: MacArthur studies
of successful aging. Am J Geriatr Psychiatry 2007;15:406–415.
10. Gump BB, Matthews KA, Eberly LE, Chang YF. Depressive
symptoms and mortality in men: results from the multiple risk
factor intervention trial. Stroke 2005;36:98–102.
11. McCusker J, Cole M, Ciampi A, Latimer E, Windholz S,
Belzile E. Major depression in older medical inpatients predicts
poor physical and mental health status over 12 months. Gen
Hosp Psychiatry 2007;29:340–348.
12. Musselman DL, Evans DL, Nemeroff CB. The relationship of
depression to cardiovascular disease: epidemiology, biology, and
treatment. Arch Gen Psychiatry 1998;55:580–592.
13. Schulz R, Beach SR, Ives DG, Martire LM, Ariyo AA, Kop WJ.
Association between depression and mortality in older adults: the
Cardiovascular Health Study. Arch Intern Med 2000;160:
14. Sapolsky RM, Krey LC, McEwen BS. The neuroendocrinology
of stress and aging: the glucocorticoid cascade hypothesis.
Endocr Rev 1986;7:284–301.
15. Sapolsky RM. Glucocorticoids, stress, and their adverse neuro-
logical effects: relevance to aging. Exp Gerontol 1999;34:
16. McEwen BS. Protective and damaging effects of stress mediators:
the good and bad sides of the response to stress. Metabolism
17. Mattson MP, Maudsley S, Martin B. A neural signaling
triumvirate that influences ageing and age-related disease:
insulin/IGF-1, BDNF and serotonin. Ageing Res Rev 2004;
18. McEwen JE, Zimniak P, Mehta JL, Reis RJ. Molecular pathology
of aging and its implications for senescent coronary athero-
sclerosis. Curr Opin Cardiol 2005;20:399–406.
19. Voss P, Siems W. Clinical oxidation parameters of aging. Free
Radic Res 2006;40:1339–1349.
20. Epel ES. Psychological and metabolic stress: a recipe for
accelerated cellular aging? Hormones (Athens) 2009;8:7–22.
21. Sarkar D, Fisher PB. Molecular mechanisms of aging-associated
inflammation. Cancer Lett 2006;236:13–23.
22. Epel ES, Blackburn EH, Lin J et al. Accelerated telomere
shortening in response to life stress. Proc Natl Acad Sci USA
23. Epel ES, Lin J, Wilhelm FH et al. Cell aging in relation to stress
arousal and cardiovascular disease risk factors. Psychoneuroen-
24. Epel ES, Lin J, Dhabhar FS et al. Dynamics of telomerase
activity in response to acute psychological stress. Brain Behav
Immun 2010, in press.
25. Sapolsky RM. Organismal stress and telomeric aging: an
unexpected connection. Proc Natl Acad Sci USA 2004;101:
26. Forlenza MJ, Latimer JJ, Baum A. The effects of stress on DNA
repair capacity. Psychol Health 2000;15:881–891.
27. Forlenza MJ, Miller GE. Increased serum levels of 8-hydroxy-2’-
deoxyguanosine in clinical depression. Psychosom Med 2006;68:
28. Irie M, Asami S, Nagata S, Ikeda M, Miyata M, Kasai H.
Psychosocial factors as a potential trigger of oxidative DNA
damage in human leukocytes. Jpn J Cancer Res 2001;92:367–376.
29. Irie M, Miyata M, Kasai H. Depression and possible cancer risk
due to oxidative DNA damage. J Psychiatr Res 2005;39:553–560.
333Review: Do Stress and Depression Accelerate Cell Aging?
Depression and Anxiety
30. Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C,
Malarkey WB, Glaser R. Chronic stress and age-related increases
in the proinflammatory cytokine IL-6. Proc Natl Acad Sci USA
31. Miller DB, O’Callaghan JP. Effects of aging and stress on
hippocampal structure and function. Metabolism 2003;52:17–21.
32. McEwen BS. Protective and damaging effects of stress mediators:
central role of the brain. Dialogues Clin Neurosci 2006;8:
33. Wust S, Federenko IS, van Rossum EF et al. A psychobiological
perspective on genetic determinants of hypothalamus-pituitary-
adrenal axis activity. Ann N Y Acad Sci 2004;1032:52–62.
34. Kaufman J, Yang BZ, Douglas-Palumberi H et al. Brain-derived
neurotrophic factor-5-HTTLPR gene interactions and environ-
mental modifiers of depression in children. Biol Psychiatry 2006;
35. DeRijk R, de Kloet ER. Corticosteroid receptor genetic
polymorphisms and stress responsivity. Endocrine 2005;28:
36. Charney DS, Manji HK. Life stress, genes, and depression:
multiple pathways lead to increased risk and new opportunities
for intervention. Sci STKE 2004;2004:re5.
37. Mesquita AR, Wegerich Y, Patchev AVet al. Glucocorticoids and
neuro- and behavioural development. Semin Fetal Neonatal Med
38. Folkman S, Lazarus RS. Stress-processes and depressive symp-
tomatology. J Abnorm Psychol 1986;95:107–113.
39. O’Donovan A, Lin J, Dhabhar FS et al. Pessimism correlates
with leukocyte telomere shortness and elevated interleukin-6 in
post-menopausal women. Brain Behav Immun 2009;23:446–449.
40. Ozbay F, Fitterling H, Charney D, Southwick S. Social support
and resilience to stress across the life span: a neurobiologic
framework. Curr Psychiatry Rep 2008;10:304–310.
41. DeLongis A, Folkman S, Lazarus RS. The impact of daily stress
on health and mood: psychological and social resources as
mediators. J Pers Soc Psychol 1988;54:486–495.
42. Aldwin CM, Revenson TA. Does coping help? A reexamination
of the relation between coping and mental health. J Pers Soc
43. Kemeny ME, Gruenewald TL. Psychoneuroimmunology update.
Semin Gastrointest Dis 1999;10:20–29.
44. Mattson MP, Duan W, Chan SL et al. Neuroprotective and
neurorestorative signal transduction mechanisms in brain aging:
modification by genes, diet and behavior. Neurobiol Aging
45. Wolkowitz OM, Burke H, Epel ES, Reus VI. Glucocorticoids:
mood, memory and mechanisms. Ann NY Acad Sci 2009;
46. Wolkowitz OM, Epel ES, Mellon S. When blue turns to grey: do
stress and depression accelerate cell aging? World J Biol
47. Wolkowitz OM, Epel ES, Reus VI. Stress hormone-related
psychopathology: pathophysiological and treatment implications.
World J Biol Psychiatry 2001;2:115–143.
48. Wolkowitz OM, Reus VI. Neurotransmitters, neurosteroids and
neurotrophins: new models of the pathophysiology and treat-
ment of depression. World J Biol Psychiatry 2003;4:98–102.
49. Wolkowitz OM, Epel ES, Reus VI. Antiglucocorticoid strategies
in treating major depression and improving health outcome. In:
Thakore J, ed. The Physical Consequences of Depression.
50. Epel ES, Burke H, Wolkowitz OM. The psychoneuroendocri-
nology of aging. In: Aldwin CM, Park CL, Spior III A, eds.
Handbook of Health Psychology and Aging. New York: Guilford
Publications, Inc.; 2007:119–141.
51. Charney DS. Psychobiological mechanisms of resilience and
vulnerability: implications for successful adaptation to extreme
stress. Am J Psychiatry 2004;161:195–216.
52. aan het Rot M, Mathew SJ, Charney DS. Neurobiological
mechanisms in major depressive disorder. Can Med Assoc J 2009;
53. Manji HK, Duman RS. Impairments of neuroplasticity and
cellular resilience in severe mood disorders: implications for the
development of novel therapeutics. Psychopharmacol Bull 2001;
54. Hasler G, Drevets WC, Manji HK, Charney DS. Discovering
endophenotypes for major depression. Neuropsychopharmacol-
55. Gottesman, II, Gould TD. The endophenotype concept in
psychiatry: etymology and strategic intentions. Am J Psychiatry
56. Raison CL, Miller AH. When not enough is too much: the role
of insufficient glucocorticoid signaling in the pathophysiology of
stress-related disorders. Am J Psychiatry 2003;160:1554–1565.
57. Bremmer MA, Deeg DJ, Beekman AT, Penninx BW, Lips P,
Hoogendijk WJ. Major depression in late life is associated with
both hypo- and hypercortisolemia. Biol Psychiatry 2007;62:
58. Fries E, Hesse J, Hellhammer J, Hellhammer DH. A new view on
hypocortisolism. Psychoneuroendocrinology 2005;30:1010–1016.
59. Heim C, Ehlert U, Hellhammer DH. The potential role of
hypocortisolism in the pathophysiology of stress-related bodily
disorders. Psychoneuroendocrinology 2000;25:1–35.
60. Ebrecht M, Buske-Kirschbaum A, Hellhammer DSK, Rohleder
NBW, Kirschbaum C. Tissue specificity of glucocorticoid sensiti-
vity in healthy adults. J Clin Endocrinol Metab 2000;85:3733–3739.
61. Webster MJ, Knable MB, O’Grady J, Orthmann J, Weickert CS.
Regional specificity of brain glucocorticoid receptor mRNA
alterations in subjects with schizophrenia and mood disorders.
Mol Psychiatry 2002;7:985–994.
62. Lu NZ, Cidlowski JA. Glucocorticoid receptor isoforms generate
transcription specificity. Trends Cell Biol 2006;16:301–307.
63. Yudt MR, Cidlowski JA. The glucocorticoid receptor: coding a
diversity of proteins and responses through a single gene. Mol
64. Russcher H, Smit P, van den Akker EL et al. Two polymorphisms
in the glucocorticoid receptor gene directly affect glucocorti-
coid-regulated gene expression. J Clin Endocrinol Metab 2005;
65. Zhou J, Cidlowski JA. The human glucocorticoid receptor: one
gene, multiple proteins and diverse responses. Steroids 2005;70:
66. Chrousos GP, Kino T. Glucocorticoid action networks and complex
psychiatric and/or somatic disorders. Stress 2007;10:213–219.
67. McGowan PO, Sasaki A, D’Alessio AC et al. Epigenetic regula-
tion of the glucocorticoid receptor in human brain associates
with childhood abuse. Nat Neurosci 2009;12:342–348.
68. Frank MG, Miguel ZD, Watkins LR, Maier SF. Prior exposure
to glucocorticoids sensitizes the neuroinflammatory and peri-
pheral inflammatory responses to E. coli lipopolysaccharide.
Brain Behav Immun 2010;24:19–30.
69. MacPherson A, Dinkel K, Sapolsky R. Glucocorticoids worsen
excitotoxin-induced expression of pro-inflammatory cytokines in
hippocampal cultures. Exp Neurol 2005;194:376–383.
70. Sorrells SF, Sapolsky RM. A pro-inflammatory review of
glucocorticoid actions in the CNS. Brain Behav Immun 2007;21:
334 Wolkowitz et al.
Depression and Anxiety
71. Schuld A, Schmid DA, Haack M, Holsboer F, Friess E,
patients with depressive disorders is correlated with baseline
cytokine levels, but not with cytokine responses to hydrocorti-
sone. J Psychiatr Res 2003;37:463–470.
72. Pace TW, Hu F, Miller AH. Cytokine-effects on glucocorticoid
receptor function: relevance to glucocorticoid resistance and the
pathophysiology and treatment of major depression. Brain Behav
73. Fitzgerald P, O’Brien SM, Scully P, Rijkers K, Scott LV,
Dinan TG. Cutaneous glucocorticoid receptor sensitivity and
pro-inflammatory cytokine levels in antidepressant-resistant
depression. Psychol Med 2006;36:37–43.
74. Miller GE, Chen E, Sze J et al. A functional genomic fingerprint
of chronic stress in humans: blunted glucocorticoid and increased
NF-kappaB signaling. Biol Psychiatry 2008;64:266–272.
75. Duman RS, Monteggia LM. A neurotrophic model for stress-
related mood disorders. Biol Psychiatry 2006;59:1116–1127.
76. Mu ¨ller MB, Lucassen PJ, Yassouridis A, Hoogendijk WJ,
Holsboer F, Swaab DF. Neither major depression nor gluco-
corticoid treatment affects the cellular integrity of the human
hippocampus. Eur J Neurosci 2001;14:1603–1612.
77. Lucassen PJ, Heine VM, Muller MB et al Stress, depression and
hippocampal apoptosis. CNS Neurol Disord Drug Targets
78. Campbell S, Marriott M, Nahmias C, MacQueen GM. Lower
hippocampal volume in patients suffering from depression: a
meta-analysis. Am J Psychiatry 2004;161:598–607.
79. Videbech P, Ravnkilde B. Hippocampal volume and depression: a
meta-analysis of MRI studies. Am J Psychiatry 2004;161:
80. Sheline YI. 3D MRI studies of neuroanatomic changes in
unipolar major depression: the role of stress and medical co-
morbidity. Biol Psychiatry 2000;48:791–800.
81. Bremner JD. Does stress damage the brain? Biol Psychiatry
82. Sapolsky RM. Glucocorticoids and hippocampal atrophy in
neuropsychiatric disorders. Arch Gen Psychiatry 2000;57:
83. Dinan TG. Noradrenergic and serotonergic abnormalities in
depression: stress- induced dysfunction? J Clin Psychiatry 1996;
84. McEwen BS. Glucocorticoid-biogenic amine interactions in
relation to mood and behavior. Biochem Pharmacol 1987;36:
85. Wolkowitz OM, Doran AR, Breier A et al. The effects of
dexamethasone on plasma homovanillic acid and 3-methoxy-4-
hydroxyphenylglycol. Evidence for abnormal corticosteroid-
catecholamine interactions in major depression. Arch Gen
86. Wolkowitz OM. Prospective controlled studies of the behavioral
and biological effects of exogenous corticosteroids. Psychoneuro-
87. Lesch KP, Lerer B. The 5-HT receptor—G-protein—effector
system complex in depression. I. Effect of glucocorticoids.
J Neural Transm Gen Sect 1991;84:3–18.
88. Lee AL, Ogle WO, Sapolsky RM. Stress and depression: possible
links to neuron death in the hippocampus. Bipolar Disord
89. Sapolsky RM. The possibility of neurotoxicity in the hippo-
campus in major depression: a primer on neuron death. Biol
90. Facheris M, Beretta S, Ferrarese C. Peripheral markers of
oxidative stress and excitotoxicity in neurodegenerative disorders:
tools for diagnosis and therapy? J Alzheimers Dis 2004;6:
91. Du J, McEwen B, Manji HK. Glucocorticoid receptors modulate
mitochondrial function: a novel mechanism for neuroprotection.
Commun Integr Biol 2009;2:350–352.
92. Uzunova V, Sheline Y, Davis JM et al. Increase in the
cerebrospinal fluid content of neurosteroids in patients with
unipolar major depression who are receiving fluoxetine or
fluvoxamine. Proc Natl Acad Sci U S A 1998;95:3239–3244.
93. Strohle A, Romeo E, Hermann B et al. Concentrations of
3a-reduced neuroactive steroids and their precursors in plasma of
patients with major depression and after clinical recovery. Biol
94. Griffin LD, Mellon SH. Selective serotonin reuptake inhibitors
directly alter activity of neurosteroidogenic enzymes. Proc Natl
Acad Sci 1999;96:13512–13517.
95. Guidotti A, Costa E. Can the antidysphoric and anxiolytic
profiles of selective serotonin reuptake inhibitors be related to
their ability to increase brain allopregnanolone availability? Biol
96. Maninger N, Wolkowitz OM, Reus VI, Epel ES, Mellon SH.
Neurobiological and neuropsychiatric effects of dehydroepian-
drosterone (DHEA) and DHEA sulfate (DHEAS). Front
97. Yehuda R, Flory JD, Southwick S, Charney DS. Developing an
agenda for translational studies of resilience and vulnerability
following trauma exposure. Ann N Y Acad Sci 2006;1071:
98. Naert G, Maurice T, Tapia-Arancibia L, Givalois L. Neuroactive
steroids modulate HPA axis activity and cerebral brain-derived
neurotrophic factor (BDNF) protein levels in adult male rats.
99. Patchev VK, Hassan AH, Holsboer DF, Almeida OF. The
neurosteroid tetrahydroprogesterone attenuates the endocrine
response to stress and exerts glucocorticoid-like effects on
vasopressin gene transcription in the rat hypothalamus. Neuro-
100. Wang JM, Irwin RW, Liu L, Chen S, Brinton RD. Regenera-
tion in a degenerating brain: potential of allopregnanolone
as a neuroregenerative agent. Curr Alzheimer Res 2007;4:
101. He J, Evans CO, Hoffman SW, Oyesiku NM, Stein DG.
Progesterone and allopregnanolone reduce inflammatory cyto-
kines after traumatic brain injury. Exp Neurol 2004;189:
102. Bauer ME, Jeckel CM, Luz C. The role of stress factors during
aging of the immune system. Ann N Y Acad Sci 2009;1153:
103. Zampieri S, Mellon SH, Butters TD et al. Oxidative stress in
NPC1 deficient cells: protective effect of allopregnanolone.
J Cell Mol Med 2008;13:3786–3796.
104. Hu Y, Cardounel A, Gursoy E, Anderson P, Kalimi M. Anti-
stress effects of dehydroepiandrosterone: protection of rats
against repeated immobilization stress-induced weight loss,
glucocorticoid receptor production, and lipid peroxidation.
Biochem Pharmacol 2000;59:753–762.
105. Rupprecht R. Neuroactive steroids: mechanisms of action and
neuropsychopharmacological properties. Psychoneuroendocri-
106. Wolkowitz OM, Brizendine L, Reus VI. The role of
dehydroepiandrosterone (DHEA) in psychiatry. Psychiatr Ann
107. Raison CL, Miller AH. The neuroimmunology of stress and
depression. Semin Clin Neuropsychiatry 2001;6:277–294.
335 Review: Do Stress and Depression Accelerate Cell Aging?
Depression and Anxiety
108. Schiepers OJ, Wichers MC, Maes M. Cytokines and major
109. O’Brien SM, Scott LV, Dinan TG. Cytokines: abnormalities in
major depression and implications for pharmacological treat-
ment. Hum Psychopharmacol 2004;19:397–403.
110. Mercanoglu G, Safran N, Uzun H, Eroglu L. Chronic
emotional stress exposure increases infarct size in rats: the role
of oxidative and nitrosative damage in response to sympathetic
hyperactivity. Methods Find Exp Clin Pharmacol 2008;30:
111. Kiecolt-Glaser JK, Glaser R. Depression and immune function:
central pathways to morbidity and mortality. J Psychosom Res
112. Dhabhar FS, Burke HM, Epel ES et al. Low serum IL-10
concentrations and loss of regulatory association between IL-6
and IL-10 in adults with major depression. J Psychiatr Res
113. Dowlati Y, Herrmann N, Swardfager Wet al. A meta-analysis of
cytokines in major depression. Biol Psychiatry 2010;67:446–457.
114. Simon NM, McNamara K, Chow CW et al. A detailed
examination of cytokine abnormalities in major depressive
disorder. Eur Neuropsychopharmacol 2008;18:230–233.
115. Song C, Halbreich U, Han C, Leonard BE, Luo H. Imbalance
between pro- and anti-inflammatory cytokines, and between
Th1 and Th2 cytokines in depressed patients: the effect of
electroacupuncture or fluoxetine treatment. Pharmacopsychiatry
116. Kaur K, Sharma AK, Dhingra S, Singal PK. Interplay of TNF-
alpha and IL-10 in regulating oxidative stress in isolated adult
cardiac myocytes. J Mol Cell Cardiol 2006;41:1023–1030.
117. Pickering M, O’Connor JJ. Pro-inflammatory cytokines and their
effects in the dentate gyrus. Prog Brain Res 2007;163:339–354.
118. Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O.
Inflammation is detrimental for neurogenesis in adult brain.
Proc Natl Acad Sci USA 2003;100:13632–13637.
119. Wichers M, Maes M. The psychoneuroimmuno-pathophysiol-
ogy of cytokine-induced depression in humans. Int J Neurop-
120. Chourbaji S, Urani A, Inta I et al. IL-6 knockout mice exhibit
resistance to stress-induced development of depression-like
behaviors. Neurobiol Dis 2006;23:587–594.
121. Marsland AL, Gianaros PJ, Abramowitch SM, Manuck SB,
Hariri AR. Interleukin-6 covaries inversely with hippocampal
grey matter volume in middle-aged adults. Biol Psychiatry
122. Miller AH, Maletic V, Raison CL. Inflammation and its
discontents: the role of cytokines in the pathophysiology of
major depression. Biol Psychiatry 2009;65:732–741.
123. Davis T, Kipling D. Werner syndrome as an example of
inflamm-aging: possible therapeutic opportunities for a proger-
oid syndrome? Rejuvenation Res 2006;9:402–407.
124. McIntosh LJ, Sapolsky RM. Glucocorticoids may enhance
125. Joseph JA, Shukitt-Hale B, Casadesus G, Fisher D. Oxidative
stress and inflammation in brain aging: nutritional considera-
tions. Neurochem Res 2005;30:927–935.
126. Houben JM, Moonen HJ, van Schooten FJ, Hageman GJ.
Telomere length assessment: biomarker of chronic oxidative
stress? Free Radic Biol Med 2008;44:235–246.
127. Ng F, Berk M, Dean O, Bush AI. Oxidative stress in psychiatric
disorders: evidence base and therapeutic implications. Int J
128. Cumurcu BE, Ozyurt H, Etikan I, Demir S, Karlidag R. Total
antioxidant capacity and total oxidant status in patients with
major depression: impact of antidepressant treatment. Psychia-
try Clin Neurosci 2009;63:639–645.
129. Irie M, Asami S, Nagata S, Miyata M, Kasai H. Relationships
between perceived workload, stress and oxidative DNA damage.
Int Arch Occup Environ Health 2001;74:153–157.
130. Sarandol A, Sarandol E, Eker SS, Erdinc S, Vatansever E,
Kirli S. Major depressive disorder is accompanied with oxidative
stress: short-term antidepressant treatment does not alter
oxidative-antioxidative systems. Hum Psychopharmacol 2007;
131. Szuster-Ciesielska A, Slotwinska M, Stachura A et al. Acceler-
ated apoptosis of blood leukocytes and oxidative stress in blood
of patients with major depression. Prog Neuropsychopharmacol
Biol Psychiatry 2008;32:686–694.
132. Zafir A, Ara A, Banu N. Invivo antioxidant status: a putative
target of antidepressant action. Prog Neuropsychopharmacol
Biol Psychiatry 2009;33:220–228.
133. Shen HM, Pervaiz S. TNF receptor superfamily-induced cell
134. Tsirpanlis G, Chatzipanagiotou S, Boufidou F et al. Serum
oxidized low-density lipoprotein is inversely correlated to
telomerase activity in peripheral blood mononuclear cells of
135. Kapczinski F, Frey BN, Andreazza AC, Kauer-Sant’Anna M,
Cunha AB, Post RM. Increased oxidative stress as a mechanism
for decreased BDNF levels in acute manic episodes. Rev Bras
136. Grant MM, Barber VS, Griffiths HR. The presence of
ascorbate induces expression of brain derived neurotrophic
factor in SH-SY5Y neuroblastoma cells after peroxide insult,
which is associatedwith
137. Groves JO. Is it time to reassess the BDNF hypothesis of
depression? Mol Psychiatry 2007;12:1079–1088.
138. Li Y, Luikart BW, Birnbaum S et al. TrkB regulates
hippocampal neurogenesis and governs sensitivity to antide-
pressive treatment. Neuron 2008;59:399–412.
139. Chen B, Dowlatshahi D, MacQueen GM, Wang J-F, Young LT.
Increased hippocampal BDNF immunoreactivity in subjects
140. Hashimoto K, Shimizu E, Iyo M. Critical role of brain-derived
neurotrophic factor in mood disorders. Brain Res Brain Res Rev
141. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S.
Requirement of hippocampal neurogenisis for the behavioral
effects of antidepressants. Science 2003;301:805–809.
142. Joosten EA, Houweling DA. Local acute application of BDNF
in the lesioned spinal cord anti-inflammatory and anti-oxidant
effects. Neuroreport 2004;15:1163–1166.
143. Markham A, Cameron I, Franklin P, Spedding M. BDNF
increases rat brain mitochondrial respiratory coupling at complex
I, but not complex II. Eur J Neurosci 2004;20:1189–1196.
144. Nitta A, Ohmiya M, Sometani A et al. Brain-derived
neurotrophic factor prevents neuronal cell death induced by
corticosterone. J Neurosci Res 1999;57:227–235.
145. Fu W, Lu C, Mattson MP. Telomerase mediates the cell
survival-promoting actions of brain-derived neurotrophic factor
and secreted amyloid precursor protein in developing hippo-
campal neurons. J Neurosci 2002;22:10710–10719.
increased survival. Proteomics
336 Wolkowitz et al.
Depression and Anxiety
146. Blackburn EH, Greider CW, Szostak JW. Telomeres and
telomerase: the path from maize, tetrahymena and yeast to
human cancer and aging. Nat Med 2006;12:1133–1138.
147. von Zglinicki T. Oxidative stress shortens telomeres. Trends
Biochem Sci 2002;27:339–344.
148. Aviv A. Telomeres and human aging: facts and fibs. Sci Aging
Knowledge Environ 2004;2004:pe43.
149. Simon NM, Smoller JW, McNamara KL et al. Telomere
shortening and mood disorders: preliminary support for a
chronic stress model of accelerated aging. Biol Psychiatry 2006;
150. Choi J, Fauce SR, Effros RB. Reduced telomerase activity in
human T lymphocytes exposed to cortisol. Brain Behav Immun
151. Fuster JJ, Andres V. Telomere biology and cardiovascular
disease. Circ Res 2006;99:1167–1180.
152. Samani NJ, Boultby R, Butler R, Thompson JR, Goodall AH.
Telomere shortening in atherosclerosis. Lancet 2001;358:
153. Serrano AL, Andres V. Telomeres and cardiovascular disease:
does size matter? Circ Res 2004;94:575–584.
154. Valdes AM, Richards JB, Gardner JP et al. Telomere
length in leukocytes correlates with bone mineral density
and is shorter in women with osteoporosis. Osteoporos Int
155. Valdes AM, Deary IJ, Gardner J et al. Leukocyte telomere
length is associated with cognitive performance in healthy
women. Neurobiol Aging (in press).
156. Epel ES, Merkin SS, Cawthon R et al. The rate of leukocyte
telomere shortening predicts mortality from cardiovascular
disease in elderly men. Aging 2009;1:81–88.
157. CawthonRM, SmithKR,
Kerber RA. Association between telomere length in blood and
mortality in people aged 60 years or older. Lancet 2003;361:
158. Park JI, Venteicher AS, Hong JY et al. Telomerase modulates
Wnt signalling by association with target gene chromatin.
159. Calado RT, Chen J. Telomerase: not just for the elongation of
telomeres. Bioessays 2006;28:109–112.
160. Damjanovic AK, Yang Y, Glaser R et al. Accelerated telomere
erosion is associated with a declining immune function of
caregivers of Alzheimer’s disease patients. J Immunol 2007;179:
161. Fitzpatrick AL, Kronmal RA, Gardner JP et al. Leukocyte
telomere length and cardiovascular disease in the cardiovascular
health study. Am J Epidemiol 2007;165:14–21.
162. Tyrka AR, Price LH, Kao HT, Porton B, Marsella SA,
Carpenter LL. Childhood maltreatment and telomere short-
ening: preliminary support for an effect of early stress on
cellular aging. Biol Psychiatry 2010;67:531–534.
163. Cherkas LF, Aviv A, Valdes AM et al. The effects of social status
on biological aging as measured by white-blood-cell telomere
length. Aging Cell 2006;5:361–365.
164. Roux AV, Ranjit N, Jenny NS et al. Race/ethnicity and telomere
length in the multi-ethnic study of atherosclerosis. Aging Cell
165. Hunt SC, Chen W, Gardner JP et al. Leukocyte telomeres are
longer in African Americans than in whites: the national heart,
lung, and blood institute family heart study and the Bogalusa
heart study. Aging Cell 2008;7:451–458.
166. Cherkas LF, Hunkin JL, Kato BS et al. The association between
physical activity in leisure time and leukocyte telomere length.
Arch Intern Med 2008;168:154–158.
167. Atkinson SP, Keith WN. Epigenetic control of cellular
senescence in disease: opportunities for therapeutic interven-
tion. Expert Rev Mol Med 2007;9:1–26.
168. Blasco MA. The epigenetic regulation of mammalian telomeres.
Nat Rev Genet 2007;8:299–309.
169. Szyf M, Weaver I, Meaney M. Maternal care, the epigenome
and phenotypic differences in behavior. Reprod Toxicol 2007;
170. Licinio J, Wong ML. The role of inflammatory mediators in
the biology of major depression: central nervous system
cytokines modulate the biological substrate of depressive symp-
toms, regulate stress-responsive systems, and contribute to
neurotoxicity and neuroprotection. Mol Psychiatry 1999;4:
171. Brustolim D, Ribeiro-dos-Santos R, Kast RE, Altschuler EL,
Soares MB. A new chapter opens in anti-inflammatory
treatments: the antidepressant bupropion lowers production of
tumor necrosis factor-alpha and interferon-gamma in mice. Int
172. Barden N, Reul JM, Holsboer F. Do antidepressants stabilize
adrenocortical system? Trends Neurosci 1995;18:6–11.
173. Kim YK, Na KS, Shin KH, Jung HY, Choi SH, Kim JB.
depressive disorder. Prog Neuropsychopharmacol Biol Psychia-
174. Maes M, Yirmyia R, Noraberg J et al. The inflammatory and
neurodegenerative (I&ND) hypothesis of depression: leads for
future research and new drug developments in depression.
Metab Brain Dis 2009;24:27–53.
175. Duman RS. Role of neurotrophic factors in the etiology and
treatment of mood disorders. Neuromolecular Med 2004;5:
176. Sen S, Duman R, Sanacora G. Serum brain-derived neuro-
trophic factor, depression, and antidepressant medications:
meta-analyses and implications. Biol Psychiatry 2008;64:
177. Khanzode SD, Dakhale GN, Khanzode SS, Saoji A, Palasodkar R.
Oxidative damage and major depression: the potential antiox-
idant action of selective serotonin re-uptake inhibitors. Redox
178. Hashioka S, McGeer PL, Monji A, Kanba S. Anti-inflammatory
effects of antidepressants: possibilities for preventives against
Alzheimer’s disease. Cent Nerv Syst Agents Med Chem 2009;9:
179. Eren I, Naziroglu M, Demirdas A. Protective effects of
lamotrigine, aripiprazole and escitalopram on depression-
induced oxidative stress in rat brain. Neurochem Res 2007;32:
180. Eren I, Naziroglu M, Demirdas A et al. Venlafaxine modulates
depression-induced oxidative stress in brain and medulla of rat.
Neurochem Res 2007;32:497–505.
181. Holsboer F, Ising M. Central CRH system in depression and
anxiety—evidence from clinical studies with CRH1 receptor
antagonists. Eur J Pharmacol 2008;583:350–357.
182. Ornish D, Lin J, Daubenmier J et al. Increased telomerase
activity and comprehensive lifestyle changes: a pilot study.
Lancet Oncol 2008;9:1048–1057.
183. Epel E, Daubenmier J, Moskowitz JT, Folkman S, Blackburn E.
Can meditation slow rate of cellular aging? Cognitive stress,
mindfulness, and telomeres. Ann N Y Acad Sci 2009;1172:
184. Belanoff J, Schatzberg AF. Glucocorticoid antagonists. Neuro-
337 Review: Do Stress and Depression Accelerate Cell Aging?
Depression and Anxiety
185. Wolkowitz OM, Reus VI. Treatment of depression with Download full-text
antiglucocorticoid drugs. Psychosom Med 1999;61:698–711.
186. Gallagher P, Malik N, Newham J, Young AH, Ferrier IN,
Mackin P. Antiglucocorticoid treatments for mood disorders.
Cochrane Database Syst Rev 2008(1):CD005168.
187. McIntyre RS, Soczynska JK, Woldeyohannes HO et al.
Thiazolidinediones: novel treatments for cognitive deficits in
188. Rasgon N, Jarvik L. Insulin resistance, affective disorders, and
Alzheimer’s disease: review and hypothesis. J Gerontol A Biol
Sci Med Sci 2004;59:178–183. Discussion 184–192.
189. Rasgon NL, Kenna HA. Insulin resistance in depressive
disorders and Alzheimer’s disease: revisiting the missing link
hypothesis. Neurobiol Aging 2005;26:103–107.
190. Mathew SJ, Keegan K, Smith L. Glutamate modulators as novel
interventions for mood disorders. Rev Bras Psiquiatr 2005;
191. Maeng S, Zarate Jr CA. The role of glutamate in mood
disorders: results from the ketamine in major depression study
and the presumed cellular mechanism underlying its anti-
depressant effects. Curr Psychiatry Rep 2007;9:467–474.
192. Skolnick P, Popik P, Trullas R. Glutamate-based antidepres-
sants: 20 years on. Trends Pharmacol Sci 2009;30:563–569.
193. Zarate CA, Manji HK. Riluzole in psychiatry: a systematic
review of the literature. Expert Opin Drug Metab Toxicol
194. Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the
glutamatergic system to develop novel, improved therapeutics
for mood disorders. Nat Rev Drug Discov 2008;7:426–437.
195. Paul IA. Antidepressant activity and calcium signaling cascades.
Hum Psychopharmacol 2001;16:71–80.
196. Dubovsky SL, Buzan R, Thomas M, Kassner C, Cullum CM.
Nicardipine improves the antidepressant action of ECT but
does not improve cognition. J Ect 2001;17:3–10.
197. Cocchi P, Silenzi M, Calabri G, Salvi G. Antidepressant effect
of vitamin C. Pediatrics 1980;65:862–863.
198. Dunn AL, Trivedi MH, Kampert JB, Clark CG, Chambliss
HO. Exercise treatment for depression: efficacy and dose
response. Am J Prev Med 2005;28:1–8.
199. Blake H, Mo P, Malik S, Thomas S. How effective are physical
activity interventions for alleviating depressive symptoms in
older people? A systematic review. Clin Rehabil 2009;23:
200. Mead GE, Morley W, Campbell P, Greig CA, McMurdo M,
Lawlor DA. Exercise for depression. Cochrane Database Syst
201. Strohle A, Stoy M, Graetz B et al. Acute exercise ameliorates
reduced brain-derived neurotrophic factor in patients with
panic disorder. Psychoneuroendocrinology 2010;35:364–368.
202. Kishino A, Katayama N, Ishige Y et al. Analysis of effects
and pharmacokinetics of subcutaneously administered BDNF.
203. Zhang Y, Pardridge WM. Conjugation of brain-derived
neurotrophic factor to a blood-brain barrier drug targeting
system enables neuroprotection in regional brain ischemia
following intravenous injection of the neurotrophin. Brain Res
204. Egleton RD, Davis TP. Development of neuropeptide drugs
that cross the blood-brain barrier. NeuroRx 2005;2:44–53.
205. Effros RB. Telomerase induction in Tcells: a cure for aging and
disease? Exp Gerontol 2007;42:416–420.
206. Fossel M. Telomerase and the aging cell: implications for
human health. J Am Med Assoc 1998;279:1732–1735.
207. Soczynska JK, Kennedy SH, Goldstein BI, Lachowski A,
Woldeyohannes HO, McIntyre RS. The effect of tumor
necrosis factor antagonists on mood and mental health-
associated quality of life: novel hypothesis-driven treatments
for bipolar depression? Neurotoxicology 2009;30:497–521.
208. Mendlewicz J, Kriwin P, Oswald P, Souery D, Alboni S,
Brunello N. Shortened onset of action of antidepressants in
major depression using acetylsalicylic acid augmentation: a
pilot open-label study. Int Clin Psychopharmacol 2006;21:
209. Nishida A, Miyaoka T, Inagaki T, Horiguchi J. New approaches
to antidepressant drug design: cytokine-regulated pathways.
Curr Pharm Des 2009;15:1683–1687.
210. Tyring S, Gottlieb A, Papp K et al. Etanercept and clinical
outcomes, fatigue, and depression in psoriasis: double-blind
placebo-controlled randomised phase III trial. Lancet 2006;367:
211. Berthold-Losleben M, Heitmann S, Himmerich H. Anti-
inflammatory drugs in psychiatry. Inflamm Allergy Drug
212. Krystal JH, Sanacora G, Blumberg H et al. Glutamate and
GABA systems as targets for novel antidepressnat and mood-
stabilizing treatments. Mol Psychiatry 2002;7:S71–S80.
213. Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB.
The link between childhood trauma and depression: insights
from HPA axis studies in humans. Psychoneuroendocrinology
214. Tyrka AR, Price LH, Kao HT, Porton B, Marsella SA,
Carpenter LL. Telomere shortening and reports of childhood
maltreatment in healthy adults: a pilot study. The Annual
Conference of the American College of Neuropsychopharma-
cology. Boca Raton, FL; 2008.
215. Anda RF, Felitti VJ, Bremner JD et al. The enduring effects of
abuse and related adverse experiences in childhood : a conver-
gence of evidence from neurobiology and epidemiology. Eur
Arch Psychiatry Clin Neurosci 2006;256:174–186.
338 Wolkowitz et al.
Depression and Anxiety