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-
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
2Departmentof OB-GYN and
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,
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 (
) 3 1 (
) 21 (
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.
and earlylife adver-
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
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
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.
329 Review: 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
330 Wolkowitz 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-
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-
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
assessing an individual’s
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
332 Wolkowitz 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
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