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Biological factors influencing depression in later life: role of

aging processes and treatment implications
1,4 ✉
Sarah M. Szymkowicz1,5, Andrew R. Gerlach2,5, Damek Homiack3 and Warren D. Taylor

This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023

Late-life depression occurring in older adults is common, recurrent, and malignant. It is characterized by affective symptoms, but
also cognitive decline, medical comorbidity, and physical disability. This behavioral and cognitive presentation results from altered
function of discrete functional brain networks and circuits. A wide range of factors across the lifespan contributes to fragility and
vulnerability of those networks to dysfunction. In many cases, these factors occur earlier in life and contribute to adolescent or
earlier adulthood depressive episodes, where the onset was related to adverse childhood events, maladaptive personality traits,
reproductive events, or other factors. Other individuals exhibit a later-life onset characterized by medical comorbidity, pro-
inflammatory processes, cerebrovascular disease, or developing neurodegenerative processes. These later-life processes may not
only lead to vulnerability to the affective symptoms, but also contribute to the comorbid cognitive and physical symptoms.
Importantly, repeated depressive episodes themselves may accelerate the aging process by shifting allostatic processes to
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dysfunctional states and increasing allostatic load through the hypothalamic–pituitary–adrenal axis and inflammatory processes.
Over time, this may accelerate the path of biological aging, leading to greater brain atrophy, cognitive decline, and the
development of physical decline and frailty. It is unclear whether successful treatment of depression and avoidance of recurrent
episodes would shift biological aging processes back towards a more normative trajectory. However, current antidepressant
treatments exhibit good efficacy for older adults, including pharmacotherapy, neuromodulation, and psychotherapy, with recent
work in these areas providing new guidance on optimal treatment approaches. Moreover, there is a host of nonpharmacological
treatment approaches being examined that take advantage of resiliency factors and decrease vulnerability to depression. Thus,
while late-life depression is a recurrent yet highly heterogeneous disorder, better phenotypic characterization provides
opportunities to better utilize a range of nonspecific and targeted interventions that can promote recovery, resilience, and
maintenance of remission.

Translational Psychiatry (2023)13:160 ; https://doi.org/10.1038/s41398-023-02464-9

INTRODUCTION typically persist, and older depressed adults have an increased risk of
Late-life depression (LLD) is major depressive disorder (MDD) dementia [14].
occurring in adults age 60 years or older [1]. It is common, with Such adverse outcomes may be related to LLD’s recurrent nature
~5% of community-dwelling elders meeting DSM5 diagnostic [15]. LLD is often a recurrent or chronic illness [16], although
criteria [2] and 10–16% of older adults exhibiting clinically significant continuing antidepressant medication during remission reduces
depressive symptoms that may not meet full criteria [2, 3]. LLD is a recurrence risk [17, 18]. However, even with maintenance treatment,
malignant illness that increases disability [4], contributes to poorer ~35–40% of depressed elders experience recurrence in 2 years, with
medical outcomes [5], and is associated with increased suicide risk over 50% experiencing recurrence over four years [16, 18, 19].
and mortality [6, 7]. Recurrence is particularly relevant for individuals with an initial
LLD is further characterized by poor or impaired cognitive onset of depression in early- or midlife. These individuals often
performance. Reduced executive functioning is common, affecting experience multiple prior depressive episodes and are now in the
verbal fluency, response inhibition, set-shifting, working memory, geriatric age range. Individuals with early-onset LLD, typically
and problem-solving [8]. Individuals with LLD also exhibit poor defined as occurring before age 50–60 years, exhibit greater
performance in other cognitive domains, including episodic residual depression severity over time, more frequent suicidal
memory, visuospatial skills, and processing speed [9–11]. Slower thoughts, and a greater risk of recurrence following remission
processing speed is particularly important, partly mediating [16, 20]. Early-onset depression is characterized by stronger familial
impaired performance in other cognitive domains [11–13]. Although history and genetic loading, greater anxiety and reactions to
cognitive performance improves with successful treatment, deficits stressful life events, maladaptive personality traits, and hormonal

1
Center for Cognitive Medicine, Department of Psychiatry and Behavioral Science, Vanderbilt University Medical Center, Nashville, TN, USA. 2Department of Psychiatry, University
of Pittsburgh, Pittsburgh, PA, USA. 3Department of Psychiatry, University of Illinois-Chicago, Chicago, IL, USA. 4Geriatric Research, Education, and Clinical Center, Veterans Affairs
Tennessee Valley Health System, Nashville, TN, USA. 5These authors contributed equally: Sarah M. Szymkowicz, Andrew R. Gerlach. ✉email: [email protected]

Received: 24 November 2022 Revised: 23 April 2023 Accepted: 27 April 2023

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Fig. 1 Lifespan model of late-life depression. Symptoms of depression are the behavioral manifestation of increasingly disrupted brain
networks. Multiple influences contribute to network fragility and dysfunction across the lifespan, with some being linked to clear
developmental periods. These may be additive and cumulative over time, although other risk and resiliency factors may be modifiable and
targeted by specific treatments. Unchecked, repeated depressive episodes and their associated physiological responses may have deleterious
effects contributing to accelerated aging.

fluctuations associated with early-life reproductive events [21–26]. additional contributors [35, 36], although this has received less
Individuals with late-onset depression are more often widowed, attention in LLD [37]. These networks likely influence depressive
present with more apathy and somatic symptoms, poorer cognitive behavior across the lifespan, although the etiological factors
performance, greater cognitive decline and medical morbidity, and contributing to network dysfunction change with aging. Although
more severe atrophic and vascular changes on neuroimaging heterogeneity in LLD prevents sweeping generalizations [38],
[26–32]. Although useful for clinical characterization, this age of there is support for this network-centric model [34, 39].
onset dichotomization obfuscates potentially important differences The DMN is implicated in self-referential processes [40]
in causal factors that influence the onset or recurrence of including rumination [41], making it a target of investigation
depression across the lifespan. Moreover, it does not address a in depression [33, 42]. However, there is little consensus on how
parallel hypothesis that depression itself is toxic, with recurrent the DMN is altered in depression [43]. Early studies reported
episodes increasing the allostatic load or “wear and tear” on the hyperconnectivity within the DMN relative to healthy controls
body, contributing to accelerated brain aging and vulnerability to [42], though recent meta-analyses reported no difference in
poor longitudinal clinical, cognitive, and medical outcomes [15]. DMN connectivity [44] or even hypoconnectivity between DMN
Based on past work [15], we present a model (Fig. 1) where regions [45]. DMN functional connectivity appears to be altered
disruption of functional brain network homeostasis contributes in LLD [46, 47] and such differences may persist into
first to subclinical depressive symptoms and decreased stress remission [46].
tolerance. If unchecked, this progresses to discrete depressive The CCN is primarily involved in top-down executive functions
episodes and reduced cognitive performance. Various biological [48]. Substantial evidence suggests CCN integrity differentiates
and environmental factors across the lifespan increase the healthy controls from depressed individuals [42] and influences
vulnerability of key networks to disequilibrium, with potentially treatment response [49]. The CCN may be especially relevant in
modifiable behavioral and social factors contributing either to LLD characterized by executive dysfunction [50, 51], where
vulnerability or resilience. In turn, depressive episodes alter aberrant functional connectivity of the CCN (particularly the
physiological systems that accelerate aging processes and dorsolateral prefrontal cortex [DLPFC] hub), is associated with
contribute to adverse longer-term outcomes. executive deficits [52].
Building on this model, we first present a network-based model The ASN is implicated in switching and control of attentional
of depression. We then focus on etiological influences across the processes [53], and ASN dysfunction in depression biases
lifespan that increase depression risk, primarily focusing on those individuals towards negative stimuli and processing [54, 55].
salient to later life. Next, we consider depression as a contributor Unlike the DMN, the ASN has proven relatively reliable in
to accelerated aging. Finally, we review treatment for LLD and distinguishing between healthy controls and depressed indivi-
how interventions may support resilience to future episodes. duals [42, 44, 56]. Both structural and functional connectivity of
the ASN are reduced in LLD [57].
Alterations in the positive valence system are additive.
NEURAL NETWORKS IMPLICATED IN DEPRESSION Conceptually, much work focuses on the dopaminergic mesolim-
Altered neural network function is thought to result in the bic pathway, projecting from the ventral tegmental area to the
behavioral manifestations of depression [33]. The triple network ventral striatum, nucleus accumbens, and medial temporal
model (Fig. 2) [33, 34] posits that depression is related to the structures [37]. Dysfunction in this system influences a range of
aberrant function of the default mode network (DMN), cognitive reward functions including valuation, decision-making, effort, and
control network (CCN), and anterior salience network (ASN). learning [37, 58]. Behaviorally, this contributes to anhedonia,
Positive valence system circuits involved in reward function are motivational disturbances, and willingness to expend effort [37].

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Fig. 2 Network model of late-life depression. The model details findings within each intrinsic functional network and between functional
networks, specifically the default mode network (DMN), the cognitive control network (CCN), and the anterior salience network (ASN).
Disruption in network connectivity influences the cognitive processes, giving risk to the behavioral manifestations of depression. Impaired
function of the positive valence system involving the mesolimbic system likely also contributes to depressive behavior [37], although how this
system interacts with interacts with intrinsic functional networks in LLD is not entirely clear. The model and figure [34] used with permission.
Reprinted from Gunning et al. [34], Copyright 2021, with permission from Elsevier.

Neural networks and aging In order to influence depression risk, such genetic factors would
The connectivity and function of these networks change with age. need to directly or indirectly alter brain network function or
Cross-sectional and longitudinal studies demonstrate that frontal stability [76]. However, concerns persist about translating these
regions comprising the associative networks described above (plus findings to the individual level, both due to the contributions of
the dorsal attention network) exhibit reduced intra-network small-effect polymorphisms that may be missed on GWAS, and
connectivity and increased inter-network connectivity with aging due to diagnostic heterogeneity within MDD [77]. What risk
[59–69]. These changes may reflect a decline in network efficiency genes contribute to depression vulnerability may change across
and/or serve as a compensatory mechanism that maintains normal the lifespan, particularly if they affect brain aging. For example,
brain function in context of gray matter loss or white matter some work supports that vascular risk genes may be germane in
degradation [70, 71]. Supporting this latter hypothesis are studies LLD [78].
showing increased activation in frontal regions in older adults Adverse childhood experiences (ACEs), such as abuse, parental
compared to younger adults that are associated with better loss, and bullying, are associated with a host of health disorders,
cognitive performance with aging [72]. Increased prefrontal including depression [79]. They are also associated with differences
activation is further associated with reduced white matter integrity, on neuroimaging and cognitive testing [80]. ACEs may contribute to
again supporting compensation [73, 74]. These age-related network depression vulnerability through hypothalamic–pituitary–adrenal
changes have been replicated using both structural and functional (HPA) axis responses leading to increased activity of corticotropic
network measures, further associating aging with lower strength releasing factor neurons [81]. ACEs can further result in epigenetic
and density of structural connections and decoupling of structural changes [24] that may increase depression vulnerability by
and functional connectivity, particularly in network hubs [63]. This influencing glucocorticoid signaling, serotonergic function, and
may represent a rerouting of information flow in the brain intended neurotrophic factors [24]. The relationship between ACEs and
to circumnavigate degraded white matter pathways or avoid depression vulnerability persists into later life [82, 83], where the
regions that have suffered neuronal loss. The ability of the brain to relationship between ACEs and depression may be mediated by
successfully “rewire” during aging may be crucial for maintaining inflammation [82]. Stressful events occurring in adulthood or later
cognitive performance and reflect cognitive reserve [70]. Moreover, life also increase the risk for new depressive episodes and
age-related changes may contribute to network fragility, increasing depression persistence [84, 85].
risk for LLD. While there is some evidence that network organization Personality traits are similarly associated with depression. Traits
properties may differ according to age of onset [57], clear that influence how individuals interact with and respond to their
differences in neural network configuration between early- and environments originate from variability in functional brain networks
late-onset LLD have not been identified. [22]. They arise from a complex interplay between brain develop-
ment, genetic predisposition, and early environmental exposures.
Neuroticism, a predisposition to experience psychological distress
FACTORS CONTRIBUTING TO DEPRESSION VULNERABILITY and negative mood states, is well-studied and shares some
Early- and midlife risk factors conceptual overlap with LLD [86]. Higher levels of neuroticism in
Older depressed adults carry the same vulnerabilities that LLD are associated with poorer antidepressant response and greater
increased risk for depression earlier in life. As the list of potential risk of cognitive decline [86–88].
contributors to MDD risk is beyond this review, we focus on Reproductive events including puberty, menstrual cycling,
mechanisms of relevance to LLD. pregnancy, and menopause are associated with both new-onset
Genetic factors that influence MDD vulnerability likely persist and recurrent depression [23]. These events contribute to a higher
with aging. Genome-wide association studies (GWAS) identified risk of depression for women than men [89], particularly during
several hundred potential genetic risk variants, including genes reproductive years [90]. These relationships are due to fluctuations
involved in synaptic structure and neurotransmission [75]. of ovarian hormones that influence neurotransmitter function,

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Table 1. Support for etiological hypotheses of late-life depression.
Inflammation Vascular Neurodegeneration
Clinical • Neurovegetative symptoms (lethargy, • Dysphoria, anhedonia, apathy, • Apathy, subjective memory loss
reduced appetite) psychomotor retardation, • AD pathology or development of
• Greater medical morbidity functional disability dementia associated with poor
• Increased levels of pro-inflammatory • Higher rates of vascular risk factors antidepressant efficacy
cytokines; Decreased levels of anti- • Increased disability and mortality
inflammatory cytokines
• Associated with treatment resistance and
poor antidepressant efficacy
Cognitive • Executive dysfunction, slowed processing • Executive dysfunction, reduced • Depression co-occurring with
and motor speed, reduced memory processing speed and visuospatial dementia worsens cognitive
skills, retrieval-based memory performance
deficits • Amnestic cognitive profile (often, but
not always)
Imaging • Peripheral inflammatory markers linked • WMH volumes increase over time • LLD with greater beta-amyloid
with: • Higher WMH volumes worsen deposition have:
• altered fronto-subcortical activation cognitive outcomes • greater temporal lobe volume loss
• gray and white matter volume loss • Persistent depressive symptoms • lower functional connectivity in
• Higher markers of central inflammation exhibit greater change in WMH fronto-subcortical regions
found in anterior cingulate and temporal volume over time • functional DMN alterations
cortices
Negative • When excluding comorbid medical • Inconsistent findings between LLD, • Some report less beta-amyloid
findings conditions, studies do not show vascular burden, and deposition in LLD compared to
relationship between depression and antidepressant response. controls
inflammatory cytokines • APOE ε4 does not clearly influence
development of LLD
AD Alzheimer’s disease, APOE apolipoprotein E, CSF cerebrospinal fluid, DMN default mode network, LLD late-life depression, WMH white matter
hyperintensities.
Table inspired by and adapted from Alexopoulos [164].

neuroendocrine processes, and inflammation [91]. Menopause is associated with depression severity, suicide risk, and poor treatment
particularly relevant to aging, with decreased estrogen production response in adult and geriatric samples [105–107]. Pro-inflammatory
potentially reducing its neuroprotective effects [92]. A longer cytokines are associated with worse function in executive processes,
exposure to endogenous estrogens, operationalized as an older memory, and processing and motor speed [108].
age at menopause, is associated with a lower risk of subsequent Aging is itself associated with chronic, low-grade inflammation,
depression [93], while earlier menopause, including surgically- dubbed “inflammaging” [109]. This process has multiple contribu-
induced menopause, is associated with cognitive decline and tors, including immune system aging, mitochondrial changes, and
dementia [94]. gut microbiota [110, 111]. These changes may be secondary to
Other exposures influence MDD, including comorbid mental common pro-inflammatory medical conditions that increase depres-
health disorders, substance misuse, and traumatic brain injury sion risk, including diabetes, cardiovascular disease, autoimmune
[95]. Medical comorbidity also contributes, including a bidirec- disorders, rheumatoid arthritis, cirrhosis, and kidney disease
tional relationship between depression and obesity [96] that [112–115]. These comorbidities may explain the observed relation-
may be mediated through immune system activation and ship between depression and inflammation, as evidenced by a study
inflammation [96]. Obesity increases the risk for other morbid- that did not associate LLD with higher levels of central or peripheral
ities associated with LLD, including pain syndromes, vascular risk inflammatory cytokines. However, this study employed rigorous
factors, and disability [97, 98]. entry criteria for medical comorbidities that excluded almost 95% of
potentially eligible participants [116]. This raises issues about its
Later-life risk factors generalizability and highlights the extent of comorbidity between
Despite LLD being associated with a range of medical comorbid- LLD and medical illnesses.
ities, few may directly contribute to depression pathogenesis. Age- Although most work examines peripheral inflammatory markers,
related morbidities that are a focus of mechanistic models include it remains relevant to brain function. The CNS was long considered
inflammation, vascular disease, and neurodegeneration (Table 1). to be immunoprotected due to the blood-brain barrier. However,
immune responses via peripheral immune cell secretion of pro-
Inflammation. The inflammation hypothesis proposes that inflammatory cytokines can convey the inflammatory response to
immune dysregulation influences vulnerability to and the develop- brain microglia via humoral and neural pathways [117, 118].
ment of LLD [99]. Neurovegetative depressive symptoms are akin to Microglia can thus become activated by peripheral cytokines
immune responses to infectious diseases including lethargy, inducing a neuroinflammatory response [119]. Both aging and
cognitive slowing, and reduced appetite [100, 101]. In younger psychological stress further prime microglia toward an activated
adults, elevated pro-inflammatory cytokines levels in response to state, tilting the CNS toward a pro-inflammatory state [120, 121]. In
psychological stress are associated with depressive symptoms [101] the aged brain, activated microglia exhibit an exaggerated response
and induction of peripheral inflammation results in fatigue and to pro-inflammatory cytokines, inducing oxidative stress and
worsening of mood [102, 103]. Depressed patients across the adult delayed clearance of neurotoxic molecules, resulting in disrupted
lifespan can exhibit elevated levels of pro-inflammatory cytokines neuronal function, impaired neurogenesis, and neural degeneration
including c-reactive protein (CRP), interleukin-6 (IL-6) and tumor [119, 120]. Central inflammation further affects multiple neurotrans-
necrosis factor (TNF) alpha and lower anti-inflammatory cytokine mitter systems, contributing to reduced serotonin synthesis via
levels [104, 105]. Higher pro-inflammatory cytokine levels are induction of indoleamine 2,3-dioxygenase [100], glutamate system

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dysregulation [122–124], and altered dopamine synthesis, binding, longitudinal decline in executive functions and increased risk for
and reuptake [37, 125–128]. dementia [162]. Individuals with persistent depressive symptoms
While less examined in LLD, chronic inflammation induces an similarly exhibit greater increases in WMH volume over time
altered cellular environment in the brain parenchyma capable of [163]. Greater vascular burden may be associated with poorer
modulating neural circuits and influencing depressive behavior response to pharmacological and nonpharmacological treat-
[15]. Pro-inflammatory cytokines including CRP and IL-6 are ments [158, 164–166], although this relationship for medication
associated with global gray matter and white matter loss [129]. A response is somewhat weak [49, 78]. The higher vascular burden
meta-analysis including participants across the lifespan asso- is further associated with greater disability [167], gait and other
ciated peripheral inflammatory markers with altered activation motor deficits [168], and frailty [169]. Depression can also
of the prefrontal cortex, insula, striatum, amygdala, hippocam- worsen cardiovascular and cerebrovascular disease outcomes
pus, and various subcortical regions [130]. These regions overlap [170, 171], suggesting a bidirectional relationship.
with the DMN, ASN, limbic, and corticostriatal networks. Studies
of individuals with depression and suicide attempts report Neurodegeneration. Aging is the strongest risk factor for demen-
increased microglial activation in the anterior cingulate cortex tia [172], a collective term for cognitive impairment negatively
(ACC), a key hub of both the ASN and CCN, in individuals with affecting independent functional activities. Alzheimer’s disease
depression and suicide attempts [131, 132]. Experimental (AD), the most common dementia, is characterized by abnormal
induction of acute inflammation similarly alters glutamate accumulation of beta-amyloid plaques and tau tangles in the
metabolism in the ACC and basal ganglia [124]. brain. Early AD typically affects memory centers, including the
Treatment implications of pro-inflammatory processes are entorhinal cortex and hippocampus. With disease progression,
unclear. Work in midlife suggests that low-grade inflammation neuropathology spreads to frontal and parietal regions and affects
may decrease antidepressant efficacy [133–136]. However, success- language, executive abilities, and social behaviors.
ful antidepressant treatment can decrease pro-inflammatory Depression and dementia exhibit a bidirectional relationship.
cytokine levels [137, 138] Conversely, antidepressant augmentation Depression in mid-to-late life increases risk for AD and all-cause
with anti-inflammatory agents may reduce depressive symptom dementia [14, 173, 174]. Depression can also be a precursor to or
severity and improve treatment outcomes [139, 140]. If existing symptom of dementia, with prevalence rates ranging from 17 to
trials are supported, such interventions may most benefit indivi- 56% across all stages of AD [175]. Depression co-occurring with
duals with higher inflammatory cytokine levels, such has been seen dementia worsens cognitive performance beyond what would be
with infliximab, a TNF-alpha antagonist [141, 142]. Inflammation expected based on neuropathology alone [176]. Dementia risk
could identify a distinct phenotype [37, 143] who would benefit may be highest in individuals exhibiting persistent or worsening
from anti-inflammatory treatments. depressive symptoms over time [177].
Such observations led to work searching for common genetic
Vascular disease. Cerebrovascular system changes are common factors. While the apolipoprotein E (APOE) ε4 allele significantly
with normal aging [144]. Cerebral small vessel disease (CSVD) increases risk for AD, it does not clearly influence the development
describes leakage of the blood-brain barrier and dysfunction of of LLD [178, 179]. A genome-wide association study found that
cerebral autoregulation, neurovascular coupling, and capillary depression had a causal role in AD through Mendelian randomiza-
blood flow [145]. This causes cerebral perfusion deficits and tion, but there was no evidence for a causal role of AD on
hypoxia, triggering inflammation and neuronal death. Vascular risk depression [180]. That study identified 53 brain transcripts and
factors including hypertension, atherosclerosis, and diabetes proteins regulated by the depression GWAS signals that also were
contribute to CSVD and result in the thickening of the penetrating associated with rates of cognitive decline over time [180].
small arteries, fibrosis of the vessel wall, and depletion of vascular The “amyloid hypothesis of LLD” [181] is supported by
smooth muscle cells. observations of increased beta-amyloid deposition in older adults
The “vascular depression hypothesis” [146, 147] posits that with a depression history [182] and in LLD patients exhibiting a
CSVD may predispose, precipitate, or perpetuate LLD. This cognitive profile suggestive of amnestic Mild Cognitive Impair-
process likely begins in adulthood, as midlife cerebrovascular ment [183]. Individuals with LLD exhibiting greater beta-amyloid
burden predicts increased depression severity over time [148]. deposition show greater volume loss in the temporal lobe, lower
The neuroradiological manifestation of “vascular depression” functional connectivity in fronto-subcortical regions, and greater
includes white matter hyperintensities (WMHs) on T2-weighted functional alterations in the DMN [184, 185]. These findings are
MRI, subcortical lacunes, and microbleeds [147, 149]. Mechan- not universal, and the Alzheimer’s Disease Neuroimaging Initiative
istically, WMHs may contribute to a disconnection syndrome depression group reported less beta-amyloid deposition in LLD
where damage to communicating cortical-subcortical pathways compared to a control group [186]. While beta-amyloid deposition
involved in mood regulation and cognitive processes increases was associated with worse memory performance in that study, the
LLD vulnerability [78, 150, 151]. Further supporting a mechan- association between amyloid and cognitive performance did not
istic role, meta-analyses have shown that late-onset depression differ between diagnostic groups. More recent work has focused
show significantly greater WMH burden in late-onset LLD than in on tau pathology as others report that individuals with elevated
early-onset LLD [152, 153]. The extent of ischemic injury extends tau, but not amyloid, are twice as likely to be depressed [187].
beyond visible WMHs, as vascular risk factors compromise Poorer cognitive performance, comorbid dementia, and AD
microstructural integrity in normal-appearing white matter pathology are associated with poorer prognosis for response to
[154, 155]. Location of WMHs and microstructural changes may antidepressant medications. Both poorer cognitive performance,
be critical, as LLD is associated with damage to the cingulum particularly executive dysfunction or slowed processing speed,
bundle, uncinate fasciculus, and superior longitudinal fasciculus and dementia are associated with poorer responses to antide-
[156–159]. pressant medications [12, 165, 188, 189]. Similarly, higher levels of
These processes influence longer-term negative outcomes. beta-amyloid deposition, particularly in the temporal lobe, are
Even without depression, vascular changes are associated with associated with poor response or treatment resistance to
cognitive deficits (including executive dysfunction and retrieval- antidepressant medications, even in cognitively intact elders
based memory deficits) and altered emotion processing [160]. [190, 191]. Alternative treatment approaches are not entirely clear,
Cross-sectionally, depressive symptoms with greater WMH although some individuals with cognitive impairment may benefit
volumes worsen cognitive outcomes in the early stages of CSVD from nonpharmacological interventions such as computerized
[161]. Greater WMH volume in LLD contributes to greater cognitive training [192].

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Depression is not unique to a single neuropathological process difference between calculated brain age and chronological age was
[176]. Beyond AD, it occurs in context of alpha-synuclein, a independently replicated [205] and not associated with age of
constituent of Lewy bodies and the pathological hallmark of depression onset, recurrence, or remission [204].
synucleinopathies, including Parkinson’s disease (PD), dementia An accelerated aging hypothesis of LLD implies a bidirectional
with Lewy bodies, and multiple system atrophy. Depression is a process [206]. Depressed older adults exhibit an advanced
common non-motor symptom of PD [193] and depressed biological age on a multibiomarker index of metabolic and
individuals exhibit a 2.2-fold increase in risk of subsequent inflammatory measures [207, 208] and on structural MRI, where
parkinsonism [194]. There is a positive association between they appear approximately 4 years older than nondepressed
alpha-synuclein messenger RNA expression levels and depression individuals [198]. This accelerated brain aging is further associated
severity [195], while levels of CSF alpha-synuclein may mediate with disability and cognitive performance [198], with depression
associations between LLD, markers of synaptic dysfunction, and severity moderating the relationship between brain age and some
memory ability [196]. cognitive measures. As the difference between calculated brain age
and chronological age differs between midlife adult depressed
samples and LLD [198, 203, 204, 209], depression may be associated
DEPRESSION AND ACCELERATED AGING with an altered trajectory of biological aging [210].
Both vascular [170, 171] and neurodegenerative processes Accelerated aging also influences physical function and
[14, 173, 174] occur more frequently or more severely in LLD. contributes to physical frailty. Frailty is characterized by deficits
These may represent bidirectional relationships, where depressive in strength and mobility, decreased physical activity, and reduced
episodes may both contribute to and result from accelerated energy capacity that results from dysregulation in metabolic,
aging. Biological aging is an inevitable process at molecular, musculoskeletal, and stress-response systems [211, 212]. Frailty is
cellular, and organ levels reducing a system’s reparative or common, bidirectionally associated with LLD, and associated with
regenerative potential [197]. “Accelerated aging” is when biologi- increased mortality and poor antidepressant treatment responses
cal aging occurs more rapidly than expected, resulting in [213–215]. Frailty may be an outcome of depression, as depression
biological characteristics that are more severe than would be is associated with worsening trajectories in functional status,
expected based on chronological age [198]. In the brain, this may including reduced walking speed and hand strength [216].
include ventricular enlargement, cerebrovascular injury, or gray The model of a bidirectional relationship between depression
matter atrophy. For this review, we distinguish accelerated aging and accelerated and pathological aging (Fig. 3) may start with age-
from “pathological brain aging”, characterized by neurodegenera- related changes increasing vulnerability to depression. Individuals
tive processes involving amyloid, tau, or other abnormal protein experiencing accelerated biological aging, operationalized as
deposition. advanced medical morbidity, cerebrovascular pathology, pro-
Accelerated aging is observed in multiple neuropsychiatric inflammatory processes, or pathological aging, such as increasing
disorders and quantified using a range of markers including amyloid or tau burden, are at higher risk for LLD. Such etiological
telomere length, oxidative stress markers, epigenetic markers, factors can disrupt the structure, function, and homeostasis of key
physiological functioning, and neuroimaging [199–201]. In adult intrinsic functional networks implicated in depression [78, 164].
MDD, accelerated aging is observed on molecular and cellular These etiological factors may all occur to varying extents in the
markers, including reduced telomere length, epigenetic aging, and same individual, each challenging functional network home-
metabolomic aging [201, 202]. Accelerated aging in MDD is further ostasis. As the underlying systems become more dysregulated or
observed on both structural and functional neuroimaging, where as pathologies progress, and networks experience greater
depressed individuals appear on average 1–2 years older than homeostatic imbalance and impairment in function, the clinical
nondepressed cohorts [203, 204]. In the largest of these studies, the presentation of the depressive syndrome emerges (Fig. 1) [15]. It is

Fig. 3 Accelerated aging hypothesis of late-life depression. Aging processes such as inflammation, vascular disease, or pathological
neurodegeneration impair neurotrophic function and contribute to both gray matter atrophy and impairment of white matter microstructure.
These changes in turn alter function of key intrinsic networks, leading to the clinical manifestations of late-life depression. In turn, repeated
depressive episodes result in altered or sustained physiological responses increasing allostatic load. These effects may then further accelerate
biological aging processes, shifting an individual further away from normative aging.

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possible that the predominant underlying pathology and what resulted in a remission rate of 12.8% for older individuals, which is
brain networks are most affected influence the clinical presenta- comparable to remission rates seen in patients progressing to
tion and phenotype [37, 217]. later stages of the STAR*D study [245, 246]. A randomized trial of
Depressive episodes may also accelerate biological aging esketamine in treatment-resistant LLD resulted in a comparable
(Fig. 2). One potential mechanism involves the altered neural remission rate of 17.3%, with a NNT of 10, although that study did
and physiological responses to stress observed in depression. not detect a statistically significant difference in their primary
Such altered responses are observed across a range of systems, endpoint [247]. Secondary analyses suggested that participants
including altered function of brain regions involved in emotion with an earlier life onset of depression or who were less than 75
processing, autonomic reactivity, HPA axis function, and dysre- years of age exhibited greater improvement [247]. Both ketamine
gulation of the immune system or circadian processes [78, and esketamine were well-tolerated, with common side effects
99, 218–224]. Normally, these processes are meant to facilitate including dizziness, dissociative symptoms, fatigue, and transiently
allostasis, the body’s ability to respond to environmental elevated blood pressure [245, 247].
challenges and maintain normal functioning. However, with
repeated stressors and depressive episodes, these responses Electroconvulsive therapy (ECT)
contribute to increased allostatic load, the wear-and-tear result- ECT continues to be used for severe and treatment-resistant LLD.
ing from stress and the dysregulation of processes meant to In LLD, ECT exhibits remission rates between 70 and 90%,
maintain homeostasis [15, 225]. Such canonical stress-response although rates in community samples may be lower [248].
systems interact and over time contribute to accelerated aging, Individuals with late-onset depression tend to respond better to
leading to regional brain atrophy, development of cerebrovas- ECT than individuals with early-life depression onset [249], which
cular pathology, and reduction of neurotrophic function may be related to illness chronicity or recurrence in the early-
[226–228]. This hypothesis is supported by longitudinal studies onset group. However, strong remission rates should be balanced
associating persistent or recurrent depression with greater by high relapse rates after the initial ECT course, with 40–50% of
increases in WMH volume and greater hippocampal volume patients relapsing within 6 months [250]. Cognitive side effects in
decline [163, 229]. Other mechanisms explaining this relationship older adults tend to be limited and transient [251].
are possible, including shared genetic vulnerabilities [180]. Recent work has refined ECT to improve tolerability while
Such bidirectional relationships have long-term implications. preserving efficacy. This includes administering ECT using right
Accelerated or pathological aging also contribute to impaired unilateral electrode placement with ultrabrief pulse width stimuli,
cognitive performance [198, 230], increased risk for dementia [14], an approach with fewer cognitive side effects [252]. When
and risk of physical disability, sensory function loss, and frailty combined with venlafaxine in LLD, this results in remission rates
[230]. Accelerated brain aging may be associated with higher risk of 61% and response rates of 70% [253]. Unilateral brief pulse ECT
for depression relapse after achieving remission [15]. Even if the combined with venlafaxine only modestly affects cognitive
initial antidepressant treatment were successful, progressive aging performance, specifically letter fluency and cognitive flexibility
may further challenge functional networks and result in a return of [254]. This study also included a 24-week continuation phase,
depressive symptoms [15]. where participants were randomized to either medication only
(venlafaxine plus lithium) or venlafaxine plus continuation ECT,
administered weekly for the first month with additional sessions
UPDATES ON ESTABLISHED SOMATIC TREATMENTS as needed. Continuation ECT resulted in lower levels of depression
Currently, treatment decisions for patients with LLD are guided severity at study endpoint than medication only [255] and better
more by clinical history and patient preference than potential quality of life [256].
biological causal factors. Robust blinded clinical trials data for LLD
are scant and clinical guidelines tend to derive from expert opinion Transcranial magnetic stimulation (TMS)
or are extrapolated from data in younger populations [231]. Repetitive TMS (rTMS) uses a pulsed magnetic field to induce a
local electrical field on the brain’s surface, stimulating cortical
Antidepressant medications pathways. rTMS treatment of depression typically targets the
Antidepressants are more effective than placebo in the treatment DLPFC, with the best-studied techniques including unilateral
of LLD, although the response rate is lower for older than younger high-frequency left-sided (HFL), unilateral low-frequency right-
adults [232–234]. However, while antidepressants alter DMN and sided (LFR), or sequential bilateral treatment of LFR followed by
CCN connectivity [235], age of initial onset does not influence HFL [257]. Parallel work supports that targeting the DLPFC
antidepressant medication response rates, although early-onset modulates functional connectivity within and between the DMN
patients may respond more slowly [236, 237]. Antidepressants and CCN, with clinical benefit deriving from modulation of
remain beneficial, with a number needed to treat (NNT) for an subgenual cingulate cortex connectivity [258]. While many
antidepressant response being 6.7 (95% CI, 4.8–10) [234, 238]. As randomized trials support rTMS efficacy, few have been
in younger adults, augmentation strategies in LLD are more conducted in LLD [259, 260]. However, rTMS is well-tolerated
efficacious than strategies involving a switch to a different in older adults [261], and LLD trials generally support the efficacy
antidepressant [239]. Methylphenidate augmentation of an SSRI of HFL rTMS, with bilateral treatment being more efficacious in
is superior to monotherapy with either agent alone [240]. treatment-resistant patients [257].
Augmentation with lithium, bupropion, or aripiprazole in patients Recent work has modified rTMS to improve outcomes and
who did not respond to monotherapy can be well-tolerated and reduce burden. A sham-controlled trial in LLD that examined
improve depressive symptoms [239, 241, 242]. Despite clear bilateral deep rTMS reported efficacy and good tolerability when
benefits of augmentation, the likelihood of achieving remission administered over four weeks [262]. This deep TMS approach
decreases with increasing number of failed antidepressant trials addressed concerns that age-associated atrophy may contribute
within the current episode [243]. to poor treatment responses by increasing the distance between
Few studies examine outcomes of the N-methyl-D-aspartate the scalp and cortex [263], however it requires longer adminis-
(NMDA) receptor channel inhibitors ketamine and esketamine in tration sessions. More recent work in LLD compared rTMS to theta-
LLD. Both a small, randomized trial of subcutaneously adminis- burst stimulation (TBS), a bilateral approach that reduces session
tered ketamine and larger open-label study of intravenous administration from 47 min for rTMS to 4 min for TBS. This
ketamine improved depression severity in older adults with randomized trial established non-inferiority of TBS, with compar-
treatment-resistant depression [244, 245]. Intravenous ketamine able reductions in depression severity between groups [264].

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Table 2. Resilience factors influencing depressive episode risk in later life.
Domain Factors Resilience correlates Depression vulnerability correlates
Trait-like factors Temperament Positive emotionality Greater harm avoidance
Personality Extroversion, conscientiousness Neuroticism
Psychological factors Beliefs Self-esteem, self-efficacy, mastery, sense of Internalized self-blame or stigma
purpose
Coping Active or accommodative coping Avoidance or passive coping
Social factors Social support Social engagement Social withdrawal, loneliness
Altruism Formal volunteering Social role absences
Cognitive factors Cognitive reserve Maintained cognitive performance Poorer executive function and processing
speed
Physical factors Physical activity Exercise, regularly active Sedentary lifestyle
Sensory function Sustained or corrected vision and hearing Impaired sensory function
Healthy diet Good nutrition Poor nutrition, substance abuse
Healthy sleep Regular sleep patterns Disrupted, irregular sleep
Correlates of factors that may contribute to resilience from depression, or vulnerability to depression. Some factors are modifiable (psychological factors, social
factors, and lifestyle factors) while others are not (trait-like factors). Some depression correlates may both increase the risk of depression and also be an
outcome of depression. Table inspired by and adapted from Laird et al. [267] and Andreescu et al. [15].

RESILIENCE FACTORS: OPPORTUNITIES FOR INTERVENTION analyses in LLD support that psychotherapy is quite effective, with a
Although these treatments are effective, benefit depends on NNT of 3 [278]. More recently developed, “Engage” therapy targets
continued treatment. If pharmacotherapy or neuromodulation neurobiologically-informed processes in LLD using streamlined
stops, the risk of recurrence can be high [18, 250, 253]. This risk behavioral techniques that can be effectively applied in the
may be reduced through interventions that target vulnerability community [279, 280].
factors to depression and strengthen resiliency (Table 2).
Resilience is broadly defined as the capacity to maintain or regain Social factors: opportunities for engagement
psychological well-being despite challenges, or the adaptive Aging adults tend to maintain close social partners but have fewer
maintenance of homeostasis despite adversity [265–267]. Resilience peripheral social contacts [281]. In contrast, larger objective social
is a multidimensional, dynamic process influenced by both internal network size and greater perceived social support protects against
factors and external resources. Resilience factors may decrease the LLD and predicts a better response to depression interventions
risk of a depressive episode, reduce severity or duration of that [282–284]. Such benefits may occur through mechanisms includ-
episode, or increase likelihood of recovery [267, 268]. If depression ing emotional support, tangible assistance (instrumental support),
contributes to accelerated biological aging, then bolstering such or opportunities for pleasurable activities [285]. Recent work has
resilience factors and reducing the frequency or duration of focused on loneliness, or perceived social isolation that is distinct
depressive episodes could hypothetically shift the biological aging from having fewer objective social contacts. Loneliness is
process towards a more normal trajectory. We discuss resilience bidirectionally associated with a host of negative outcomes,
factors and their corresponding vulnerability factors (Table 2) in including depression, poor physical health, cognitive and func-
context of treatments. tional decline, and mortality [286–288]. Loneliness may be a
neuropsychiatric manifestation of preclinical AD, as it is associated
Psychological factors: role for brief psychotherapy with an elevated dementia risk and higher levels of amyloid and
While factors such as temperament and personality may be tau pathology [289–291].
challenging to target with brief therapy, progress can improve
negative beliefs and coping strategies. Individuals’ beliefs about Evidence for targeting social connectedness. Few intervention
themselves and their environment influence how they cope with studies directly target social factors in depression [292]. Group
stressors or challenges. Depression risk is associated with lower therapy benefits LLD [293] but does not typically focus on social
self-esteem, anxiety sensitivity, and an external locus of control connectedness. Recent novel work has examined remote, layperson-
(i.e., a feeling that one cannot influence outcomes in one’s life) delivered interventions intended to improve social connectedness
[269]. The converse of these beliefs contribute to resilience, as and reduce loneliness in younger and older adults. Although not
does a sense of purpose and grit, defined as perseverance in directly targeting individuals with a depression diagnosis, they
achieving goals despite setbacks [267, 270–272]. Greater self- reduced depressive and anxiety symptoms [294–297]. Modifying
efficacy enhances individuals’ ability to flexibly apply coping existing psychotherapies to target social disconnection may also
strategies, including active coping strategies that directly address reduce suicide risk [294].
the stressor, or accommodative strategies involving adaptation to
the stressor. Such a flexible approach improves mental health Cognitive factors: role for cognitive training
outcomes and reduces depression [273, 274]. As previously discussed, LLD is associated with cognitive changes in
executive functioning, processing speed, and episodic memory
Evidence for psychotherapy. Psychological factors addressing [8–11]. However, not all individuals with LLD have cognitive
vulnerability or promoting resilience may be particularly amenable difficulties. There appear to be separate cognitive phenotypes
to psychotherapy. Evidence-based treatments in LLD include within LLD: “High Normal”, “Reduced Normal” (with a relative
cognitive-behavioral, problem-solving, interpersonal, and life- weakness in episodic recall), and “Low Executive Functions” [298].
review therapies [275, 276]. Such therapies influence functional The “High Normal” phenotype maintained cognitive performance
network connectivity, such as cognitive-behavioral therapy increas- despite similar levels of depression severity as the other pheno-
ing connectivity between the amygdala and CCN [277]. Meta- types. They also had higher levels of education and less vascular risk

Translational Psychiatry (2023)13:160

 S.M. Szymkowicz et al.
9
factors, suggesting that cognitive reserve and vascular health may are associated with greater depressive symptom severity and
contribute to cognitive resilience in LLD [299]. Identifying cognitive increased risk of developing LLD [217, 330–335], particularly for
difficulties unique to the depressed individual allows for the dual sensory loss affecting both vision and hearing [336]. Several
prescription of personalized cognitive training interventions. hypotheses could explain these relationships, including how
sensory loss limits social activities, leading to isolation and
Evidence for benefits of cognitive training. For computerized worsening psychological health [332, 337]. This may not account
cognitive training to work, it must have an adequate duration and for the entire relationship, as sensory loss is further associated
be appropriately intense or difficult [300]. Evidence for the potential with physical decline [338], cognitive decline, and risk of
benefit of neurobiologically-informed computerized cognitive dementia [335, 339].
training in LLD comes from the approaches by Morimoto and
others that are optimized to treat LLD with executive dysfunction Evidence for interventions improving sensory function. Optimizing
[301]. They demonstrate that by targeting the underlying deficient sensory function benefits depressive symptoms and reduces
neural circuitry and associated cognitive deficits in LLD, cognitive depression risk. For impaired vision, improving residual vision and
functions and depressive symptoms improve, benefits transfer to self-management programs can reduce depressive symptoms
non-trained domains such as memory, and there are positive [340, 341]. Integration of psychotherapy techniques, such as
changes to underlying neural structural-functional connections behavioral activation can prevent depression in high-risk patients
[192, 300, 302]. Targeted cognitive training appears to modulate with macular degeneration [342]. A similar benefit is seen in
network functional connectivity in the DMN and CCN [303, 304]. preliminary clinical trials demonstrating that hearing aids may
Interventions targeting memory deficits (such as the Mayo Clinic’s benefit depressive symptoms, quality of life, and cognitive
Healthy Action to Benefit Independence and Thinking (HABIT) performance in older adults [343–345].
program) [305] benefit Mild Cognitive Impairment both with in-
person and virtual platforms. While this intervention has not been
conducted in LLD, the approach could translate to other popula- CONCLUSIONS
tions with primary memory issues. Similarly, processing speed We repeatedly describe bidirectional relationships between LLD
training shows benefit for up to 10-years in nondepressed older and lifespan factors such as aging, inflammation, vascular disease,
adults [306] and may be particularly favorable for LLD characterized and more. These reciprocal relationships in essence describe
by predominant cognitive and motor slowing. Augmenting positive feedback loops. In the absence of counterbalancing
cognitive training with neuromodulation approaches or other forces, such feedback loops can spiral out of control. Reframed in
nonpharmacological treatments may provide additional benefit the allostatic framework, maintaining stability requires adaptive
but need study in LLD [307]. regulation and resiliency.
This dynamic nature of allostatic processes contributes to LLD
Physical disability: need for sustainable movement-based heterogeneity. Vulnerability to developing depressive episodes
interventions results from accumulated factors, many of which have an initial
Motor deficits are common with aging, including slowing, onset earlier in life. Other vulnerability factors are unique to later life
coordination deficits, and balance difficulties [308, 309] and they and may contribute to a new diagnosis of depression or a relapse of
contribute to falls, disability, and mortality [310–314]. Depressed symptoms in previously remitted individuals. We propose that these
older adults are at increased risk for these motor problems vulnerability factors (Fig. 1) have negative effects on functional brain
[310, 314, 315]. This may be due to common contributors or networks that predispose networks towards a state of fragility and
comorbidities, such as vascular disease or other brain pathology instability.
[316, 317]. However, by increasing sedentary behavior and Etiological heterogeneity creates challenges for understanding
isolation, depression may also hasten muscle atrophy, decondi- both LLD’s neurobiology and variability in treatment responses. It
tioning, and frailty [37, 213–215]. also creates opportunities to use this heterogeneity to probe
specific mechanisms and guide focused, personalized treatment
Evidence for movement-based interventions. Structured physical approaches. Such examples include examining dopaminergic
exercise benefits depression symptoms across the adult lifespan system influences on LLD in patients with psychomotor slowing,
[318], including moderately benefitting older adults [319, 320]. It has testing anti-inflammatory medications in patients with elevated
positive benefits on hippocampal volume [321], may modulate inflammation, or using targeted cognitive training to treat patients
connectivity between key DMN and CCN regions [322, 323], and with LLD and executive dysfunction. While no single treatment
also augments the response to antidepressant medications [324]. will improve symptoms in all patients with LLD, combining
Physical activity improves global cognitive function in unimpaired established treatments such as pharmacotherapy, psychotherapy,
elders and benefits cognitive domains sensitive to aging, including and neuromodulation alongside personalized interventions that
attention, executive function, and memory [325, 326]. Similarly, bolster resilience or address comorbid disability may improve
physical exercise, particularly aerobic activity, may reduce the risk of outcomes for otherwise treatment-resistant patients.
dementia and benefit older adults with existing cognitive impair-
ment or dementia [327, 328]. Interestingly, recent work suggests
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review and meta-analysis. PLoS ONE. 2019;14:e0210036. Correspondence and requests for materials should be addressed to Warren D. Taylor.
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