Received: 19 March 2024 | Revised: 3 June 2024 | Accepted: 3 June 2024

DOI: 10.1002/nep3.56

REVIEW

Microglial senescence in neurodegeneration: Insights,

implications, and therapeutic opportunities

Tobiloba Samuel Olajide1 | Toheeb O. Oyerinde1 | Omolabake I. Omotosho1 |

1,2 3,4 1,5
Oritoke M. Okeowo | Olayemi J. Olajide | Omamuyouwi M. Ijomone

1
Laboratory for Experimental and
Translational Neurobiology, University of Abstract
Medical Sciences, Ondo, Ondo, Nigeria The existing literature on neurodegenerative diseases (NDDs) reveals a
2
Department of Physiology, School of common pathological feature: the accumulation of misfolded proteins.
Basic Medical Science, Federal University However, the heterogeneity in disease onset mechanisms and the specific
of Technology, Akure, Ondo, Nigeria
brain regions affected complicates the understanding of the diverse clinical
3
Center for Studies in Behavioral
manifestations of individual NDDs. Dementia, a hallmark symptom across
Neurobiology, Department of Psychology,
Concordia University, Montreal, Quebec, various NDDs, serves as a multifaceted denominator, contributing to the
Canada clinical manifestations of these disorders. There is a compelling hypothesis
4
Division of Neurobiology, Department that therapeutic strategies capable of mitigating misfolded protein accu-
of Anatomy, Faculty of Basic Medical mulation and disrupting ongoing pathogenic processes may slow or even
Sciences, University of Ilorin, Ilorin, Kwara,
Nigeria
halt disease progression. Recent research has linked disease‐associated
5
microglia to their transition into a senescent state—characterized by
Department of Molecular Pharmacology,
Albert Einstein College of Medicine, Bronx, irreversible cell cycle arrest—in aging populations and NDDs. Although
New York, USA senescent microglia are consistently observed in NDDs, few studies have
utilized animal models to explore their role in disease pathology. Emerging
Correspondence evidence from experimental rat models suggests that disease‐associated
Tobiloba Samuel Olajide, Laboratory for microglia exhibit characteristics of senescence, indicating that deeper
Experimental and Translational Neurobiology,
University of Medical Sciences, Ondo, exploration of microglial senescence could enhance our understanding
Ondo 351104, Nigeria. of NDD pathogenesis and reveal novel therapeutic targets. This review
Email: [email protected] underscores the importance of investigating microglial senescence and its
Managing edior: Lili Wang/Ningning Wang potential contributions to the pathophysiology of NDDs, including Alzhei-
mer's disease, Parkinson's disease, Huntington's disease, and amyotrophic
Funding information lateral sclerosis. Additionally, it highlights the potential of targeting microglial
NIH‐FIC, Grant/Award Number:
senescence through iron chelation and senolytic therapies as innovative
K43TW011920
approaches for treating age‐related NDDs.

KEYWORDS
aging, ferritin, microglia, neurodegenerative diseases, senescence‐associated secretory
phenotype, senescent

Highlights
Significant findings of the study
• This study highlights the distinct contribution of microglial senescence
to the pathophysiology of neurodegenerative diseases.
What this study adds
• This study provides a comprehensive update on microglial senescence
in neurodegenerative diseases, current methodologies for identifying
senescent microglia, and potential therapeutic strategies, including the
use of iron chelators and senolytic agents for the treatment of age‐related
neurodegenerative diseases.

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
© 2024 The Author(s). Neuroprotection published by John Wiley & Sons Ltd on behalf of Chinese Medical Association.

Neuroprotection. 2024;1–14. wileyonlinelibrary.com/journal/nep3 | 1

2 | OLAJIDE ET AL.

1 | INTRODUCTION Neuronal viability is heavily reliant on glial support,

as neurons depend on glial cells for various essential
Aging is the most significant nonmodifiable risk factor functions.7 This has led to extensive research dedicated
for neurodegenerative diseases (NDDs). This intrinsic to understanding the role of glial cells in NDDs, with a
and irreversible biological process affects all living particular emphasis on microgliosis, astrogliosis,8 and the
organisms, leading to widespread detrimental effects senescence of these glial populations.9,10 The study of
on biological systems, particularly within the central microglial and astrocytic senescence adds complexity by
nervous system (CNS). The mechanisms underlying investigating how aging within these glial cells may influ-
aging are complex and remain poorly understood, with ence the pathophysiology of NDDs and how proteino-
systemic‐level investigations posing substantial chal- pathies might induce cellular senescence (Figure 1).
lenges. Consequently, current research has shifted Emerging evidence indicates that glial cells undergo
toward cellular senescence to elucidate fundamental senescence, potentially contributing to the pathogenesis
molecular and cellular processes that may provide in- of NDDs.11 These cells enter a state of irreversible
sights into broader systemic aging mechanisms.1 cell‐cycle arrest, characterized by the acquisition of a
Among CNS cell types, microglial cells–resident mac- senescence‐associated secretory phenotype (SASP).12
rophages of the CNS–are of particular interest due to This phenotype is defined by the secretion of pro‐
their roles in neurodevelopment, homeostasis, and inflammatory cytokines, leading to significant alterations
responses to injury, infection, and microenvironmental in the tissue microenvironment and driving progressive
changes. Unlike other CNS cells, microglia originate tissue dysfunction over time.13,14 Senescence has been
from the yolk sac rather than the neural tube.2,3 During implicated in microglia pathology, with senescent mi-
embryogenesis, microglia migrate from the yolk sac croglia, similar to disease‐associated microglia (DAM),
into the developing nervous system, where they pro- predominantly localized in neurodegenerative regions,15
liferate and establish a self‐renewing population within such as the substantia nigra (SN) in Parkinson's disease
the CNS.4 (PD)16 and the hippocampus in Alzheimer's disease
A common pathological hallmark of NDDs is protein (AD).17 This selective regional distribution suggests a
misfolding, with each disease being associated with potential link between microglial senescence and the
specific misfolded proteins serving as pathognomonic spatial manifestation of neurodegenerative pathologies.
biomarkers.5 Although many NDDs exhibit overlapping The spatial distribution of senescent microglia in
pathologies,6 the aggregation of misfolded proteins is degenerative brain regions suggests a connection
widely regarded as a primary driver of neurodegeneration. between cellular aging within microglia and the specific

F I G U R E 1 Schematic representation of key pathogenic proteins: amyloid‐beta (Aβ), microtubule‐associated protein (tau) alpha‐synuclein
(α‐syn), and TAR‐DNA‐binding protein 43 (TDP‐43), implicated in neurodegenerative proteinopathies through their misfolded conformations.
These misfolded proteins contribute to the induction of microglial senescence across various age‐related neurodegenerative diseases. Specific
markers of microglial senescence observed in these conditions include senescence‐associated secretory phenotype and intracellular ferritin
accumulation. Illustration generated using BioRender.com. SASP, senescence‐associated secretory phenotype.
MICROGLIAL SENESCENCE IN AGING | 3

anatomical sites of NDD pathology. Furthermore, This reliance on self‐renewal via cell division is a
studies have demonstrated that microglia engaged in key factor in the susceptibility of microglial cells to
the phagocytosis of tau‐laden neurons subsequently senescence. Repeated rounds of cell division, com-
exhibit a senescent phenotype.18 For instance, bined with exposure to environmental factors and
Karabag et al.19 characterized microglial senescence in stressors such as misfolded proteins, contribute to
the context of tauopathy by exposing primary microglia aging‐related changes within microglia, ultimately
to 5 and 15 nmol/L of monomeric tau for 18 h, followed leading to senescence. Throughout the history of mi-
by a 48‐h recovery period. Their analysis of senes- croglia research, their morphology has been a critical
cence markers revealed that exposure to 15 nmol/L of indicator of the brain's physiological and pathological
tau induced cell cycle arrest, morphological alterations, states, leading to the development of terminology
and SASP release.19 This research underscores the that describes their functional states. Traditionally,
role of tau in driving microglial senescence, suggesting microglia have been categorized as either “resting”,
that senescent microglia are associated with the accu- characterized by a ramified morphology, or “activated”,
mulation of misfolded proteins commonly observed in characterized by an amoeboid morphology. Amoeboid
advanced stages of NDDs among older adults. Thus, microglia, distinguished by their phagocytic activity
microglia are implicated as key contributors to neuro- and few unramified processes, were considered
degenerative pathophysiology, particularly in response activated. However, the term “resting” has become
to pathological conditions such as iron dysregulation—a outdated as the functions of ramified microglia in syn-
characteristic feature of senescent microglia. This aptic surveillance, pruning, neurogenesis, myelination,
review aimed to provide a comprehensive update on and vasculogenesis have been elucidated.23,26 Rami-
microglial senescence in NDDs, current methodologies fied microglia secrete neurotrophic factors, such as
for identifying senescent microglia, and potential thera- insulin‐like growth factor 1, brain‐derived neurotrophic
peutic strategies, including the use of iron chelators and factor, and nerve growth factor, to modulate inflam-
senolytic agents for the treatment of age‐related NDDs. mation and enhance synaptic plasticity.27,28 Thus,
A systematic search of the PubMed and Medline the term “homeostatic” microglia is now preferred to
databases was conducted in January 2024 to identify describe ramified microglia under normal physiological
studies investigating microglial senescence and its conditions.29
contributions to various NDDs in both human and
animal models. References from the selected literature
were systematically reviewed to identify additional 3 | MICROGLIAL ACTIVATION
relevant studies. IN NEURODEGENERATION
Microglial activation is a complex, multifaceted process
2 | M I C R O G L I A L MO R P H O L O G Y triggered by various forms of neuronal injury, playing a
AND STATES: PAS T AND FUTU R E critical role in disrupting CNS homeostasis. Upon CNS
insult, microglia undergo a morphological transition to an
Microglia were first identified as a distinct cellular amoeboid state, a process known as microgliosis,
entity within the CNS by del Rio‐Hortega in 1919.20 characterized by reactive proliferation in response to
However, their ontogeny remained unclear until 1939 pathological conditions.30 Following injury, microglia
when John Kershman observed their infiltration into clones reorganize through cell migration and apoptosis,
the CNS during embryonic development from the as observed in the facial nucleus post‐facial nerve
mesodermal layer of the yolk sac.21 Subsequent axotomy. In this context, microglia near the lesion
research on microglia remained limited for several may undergo apoptosis or migrate, contributing to the
decades until 1986 when Georg Kreutzberg rekindled restoration of microglial homeostasis.31 Recent ad-
interest in the field. Kreutzberg's team introduced vancements, such as single‐cell RNA sequencing, have
a pioneering model in the 1960s and 1970s to study revealed that reactive microglia upregulate genes
microglial activation independent of peripheral associated with immune responses, neuronal apoptosis,
monocytes. They observed that following peripheral and migration while downregulating homeostatic mark-
facial nerve injury, microglial in the facial nucleus ers such as transmembrane protein 119, purinergeric
became activated and participated in synaptic receptor P2Y 12/13, C‐X3‐C motif chemokine receptor 1
remodeling, a process termed “synaptic stripping”.22 (CX3CR1), colony‐stimulating factor‐1 receptor, trans-
In recent years, microglia have been recognized as forming growth factor‐beta, and C‐C motif chemokine
highly dynamic cells, continuously surveilling their en- receptor 3.32,33 Despite these insights, the precise
vironment and interacting with immune cells, other glial mechanisms driving excessive microglial migration and
cells, neural stem cells, and neurons.23 It is now under- cell death due to clonal expansion in damaged regions
stood that microglia originate from yolk‐sac‐derived remain unclear.
macrophage precursors and possess distinct genetic Aged microglia exhibit an altered surveillance
profiles, compared with circulating monocytes.3 Unlike phenotype, marked by reduced dendritic branching,
other macrophages that infiltrate the CNS during neu- decreased process motility, and prolonged inflamma-
roinflammation,24 microglia do not undergo continuous tory responses to injury,34 suggesting a diminished
renewal from myeloid progenitors but instead maintain neuroprotective capacity. The activation of microglia
their population through local proliferation.25 varies across different proteinopathies,35 however, it is
4 | OLAJIDE ET AL.

well‐established that in NDDs, microglia rapidly responses in living organisms.53 Furthermore, the identi-
respond to neuronal death induced by protein ag- fication of DAM has led to the recognition of a new
gregates by producing an array of inflammatory media- phenotype, senescent microglia, which represent a sub-
tors, including nitric oxide, interleukin‐6 (IL‐6), IL‐1β, and set of DAM12,54,55 and are implicated in the pathogenesis
tumor necrosis factor‐alpha.36,37 Additionally, activated of various brain pathologies.
microglia secrete chemokines that recruit homeostatic
microglia to sites of injury.38,39 Neuronal damage can
also trigger the release of fractalkine (CX3CL1), which 4 | SENESCENT MICROGLIA
binds to its receptor CX3CR1, promoting the release of
inflammatory factors and initiating an inflammatory Over a century ago, the term “senescence” was intro-
cascade.40 The CX3CL1–CX3CR1 axis is crucial for duced to describe the final phase of cell differentiation,
microglia‐neuron communication, facilitating the rapid culminating in cell death.56 Currently, it remains unclear
recruitment of microglia to damaged neurons, indicative whether “senescent” and “dystrophic” refer to the same
of a coordinated microglia‐neuron response to injury. state or represent distinct entities, as these terms
Studies have shown that CX3CR1 knockout reduces are often used interchangeably. Angelova and Brown
microglial migration and adhesion, thus offering en- delineated the differences between these terms, noting
hanced neuroprotection.41 However, CX3CR1 defi- that “cellular senescence”, a concept originating in
ciency can dysregulate microglial responses, leading to cancer research, denotes a loss of proliferative
increased neurotoxicity in lipopolysaccharide‐induced capacity. In contrast, “dystrophic cells” refer to mor-
neuroinflammation models, as well as in models of PD phological changes associated with senescence,11
and amyotrophic lateral sclerosis (ALS).42 Moreover, including deramification, process shortening, gnarling,
recent research using a cuprizone‐induced demyelina- beading, spheroid formation, and cytoplasmic frag-
tion model revealed that administering CX3CL1 signifi- mentation. Streit et al.57 posited that dystrophy reflects
cantly promoted oligodendrocyte precursor cell‐ an increased propensity for senescence, particularly
mediated remyelination in the corpus callosum and observed in microglia during aging and in response to
cortical gray matter via interactions with microglia.43 neuropathological conditions. Studies have also used
These findings underscore the critical role of the “dystrophy” to describe age‐related changes in micro-
CX3CL1–CX3CR1 axis in NDDs, highlighting the need glia's secretory profile, or the SASP.58,59 A defining
for further exploration of therapeutic strategies targeting feature of senescent microglia is the SASP, which
this pathway. includes a variety of signaling molecules such as
Microglia can also activate peripheral T cells through growth factors, proteases, reactive oxygen species
antigen presentation, contributing to CNS damage.44,45 (ROS), chemokines, and pro‐inflammatory cytokines.
Conversely, neuronal injury may be exacerbated by the Senescent microglia secrete elevated levels of pro‐
cytotoxic factors produced by activated microglia. In inflammatory cytokines like tumor necrosis factor, IL‐6,
the early stages of AD, microglia exert neuroprotective and IL‐8, driven by the activation of the p38/mitogen‐
effects by phagocytosing amyloid‐beta (Aβ). However, activated protein kinase and nuclear factor‐kappa B
with aging and disease progression, microglia become pathways. These cells can also induce senescence‐like
increasingly activated and proliferative, clustering phenotypes in neighboring cells through paracrine
around neurons. Despite this increased activity, the signaling,60,61 contributing to inflammation and poten-
efficiency of Aβ clearance diminishes, and elevated tially increasing the risk for NDDs.
levels of inflammatory cytokines further contribute to Recent studies have identified senescent microglia
Aβ accumulation,46,47 demonstrating the complex and as a subset of DAM,12,54,55 characterized by iron
evolving role of microglia in AD pathogenesis. overload.62 The phenomenon of iron accumulation in
To better understand microglial activation, re- aged microglia is intriguing, especially because micro-
searchers have employed the M1/M2 paradigm in vitro. In glia are not the primary iron‐storing cells in the brain.
this framework, M1 microglia exhibit pro‐inflammatory, Iron enters the brain through the blood–brain and
neurotoxic characteristics, while M2 microglia promote blood–cerebrospinal fluid barriers via transferrin‐
anti‐inflammatory responses.48,49 This classification con- mediated endocytosis.63,64 Research has shown that
veys the dichotomy of microglia roles, with M1 associated iron accumulation in brain tissue, induced by treat-
with detrimental effects and M2 with beneficial ones, ments, such as ferric citrate, can promote cerebral
depending on the microenvironment and pathophysiolo- endothelial senescence.65 In vitro studies have also
gical conditions.50 However, recent genome‐wide tran- linked iron overload to cellular senescence.66,67 How-
scriptomic analyses of microglial under various disease ever, whether peripheral iron overload directly induces
conditions have identified a new subpopulation termed microglial senescence remains unexplored. Although
DAM.15,51,52 These studies challenged the classical the broader mechanisms of iron homeostasis are well
view of microglia polarization states as strictly pro‐ understood, the specific roles of iron metabolism within
inflammatory M1 (classical activation) and immuno- the brain, including its uptake, intracellular handling,
suppressive M2 (alternative activation), suggesting that export, and distribution, remain unclear.68
these phenotypes represent extremes within a continuum Telomere shortening, a hallmark of aging observed
of microglia states. In vivo, microglia exhibit a spectrum across species, has been documented in aged rat
of functional states that cannot be fully replicated in vitro, microglia, particularly those associated with dystrophic
emphasizing the complexity and diversity of microglial microglia.69 Telomere shortening occurs due to the
MICROGLIAL SENESCENCE IN AGING | 5

inability to fully replicate chromosome ends during cell microglia in both the healthy aged population and in
division.70,71 The role of telomere dysfunction in NDDs aged‐related NDDs.12,86
and brain aging is still debated, with some studies
suggesting a link between telomere shortening and
age‐related NDDs.72 Another study found that telomere 5 | M A R K E R S OF M I C R OGL IAL
dysfunction correlates with reduced microglia popula- SENESCENCE
tions without fully inducing an aging phenotype,73 high-
lighting the need for further investigation into the rela- Several markers have been associated with cellular
tionship between telomere shortening and senescent senescence in brain cells, including nuclear alterations
microglia. Senescent microglia also exhibit decreased such as the sustained presence of DNA damage
phagocytic activity. For instance, Triggering receptor response proteins, such as gamma‐H2AX,87 and the
expressed on myeloid cells 2 (TREM2), a gene identified reduction of the nuclear lamina protein, lamin B1.88,89
as a risk factor for AD through genome‐wide association Additional markers of brain aging include elevated
studies, is implicated in this process.74,75 Research β‐galactosidase (SA‐β‐gal) activity within the lysosomal
has revealed a correlation between the expression of compartment,90 increased expression of cyclin‐dependent
senescence markers and TREM2 levels, as observed in kinase inhibitors, such as cyclin‐dependent kinase inhibi-
AD mouse models lacking TREM2.75 Rachmian et al.76 tor 2A/p16Ink4a and cyclin‐dependent kinase inhibitor
found reduced levels of senescent microglia in TREM2‐ 1 A/p21CIP1/wildtype p53‐activated fragment 1, which
deficient AD mice compared with those with intact induce stable cell cycle arrest,91 and heightened lipofuscin
TREM2. This finding aligns with the work of Keren‐Shaul accumulation.92 The identification of specific markers for
et al.,77 who concluded that the pro‐inflammatory DAM microglial senescence has recently garnered attention.
phenotype observed in various CNS diseases appears Among these, ferritin protein accumulation has emerged
to be facilitated by TREM2. Although recent studies as a promising indicator of microglial senescence in age‐
using the 5×FAD mouse model of amyloidosis have related NDDs.12
shown that senescent microglia expressing high levels Dystrophic microglia, commonly observed in aging
of TREM2 exhibit a distinct signature different from and NDDs, such as PD and AD, exhibit elevated ferritin
TREM2‐dependent DAM, research indicates that levels.86,93,94 One of the protective roles of microglia is
senescent microglia may indeed be subsets of DAM.78 to prevent iron‐mediated oxidative damage to neurons
Jay et al.79 discovered that TREM2 loss in AD mouse by sequestering free iron within ferritin molecules.
models ameliorates early amyloid pathology but Although this activity benefits neurons, it may adversely
worsens later stages, revealing TREM2's distinct func- affect microglia, potentially leading to oxidative damage
tional roles at different phases of AD. They demon- within these cells.95,96 The accumulation of neuro-
strated that TREM2 impairment reduces myeloid cell fibrillary tangles, neuritic plaques, and age‐related
internalization of amyloid throughout the pathology and oxidative damage to neurons is often exacerbated by
decreases plaque‐associated myeloid cell accumulation free iron's capacity to generate highly reactive oxygen
by lowering cell proliferation, particularly in the late stage radicals via Fenton chemistry.97 A study by Neumann
of AD.79
The characterization of “aged” microglia en-
compasses various distinct phenotypes, and the term
currently lacks precision and clarity, as noted by
Koellhoffer et al.75 The term “senescent” might not
fully capture all forms of “aged” microglia, suggesting
a potential distinction between these microglia and
other DAM, which may simply become more prevalent
with age.54,80 Additionally, senescent cells exhibit
certain morphological and biochemical traits over-
lapping with quiescent cells, complicating their dis-
tinction.81 This complexity is further compounded by
the absence of specific markers exclusive to senes-
cent cells, as no uniform features or biomarkers are
common to all senescent cells. The identification
of senescent cells depends on factors such as the
specific cell or tissue under examination, nature of
the stress stimulus, and mechanism through which
senescence is induced.82 Several factors that can
lead to cellular senescence have been identified, F I G U R E 2 Overview of characteristic features of senescent
including telomere shortening,70 DNA damage,83 microglia: expression of senescence‐associated secretory phenotype,
oncogene activation,84 and metabolic dysfunction.85 morphological deramification, mitotic arrest (loss of proliferative
capacity), intracellular iron overload, and increased cell body
Therefore, the significance of distinguishing senes-
hypertrophy. Cellular senescence markers, such as senescence‐
cent microglial cells remains to be fully determined. associated β‐galactosidase (SA‐β‐gal) activity, and lipofuscin
Currently, the SASP and elevated ferritin levels are accumulation, are also depicted. IL, interleukin; SASP, senescence‐
the only widely accepted phenotypes for senescent associated secretory phenotype; TNF, tumor necrosis factor.
6 | OLAJIDE ET AL.

et al.12 elucidated that not all dystrophic microglia manner. Lau et al.102 proposed that the accumulation
express ferritin. Using immunofluorescence, their of senescent microglia perpetuates and exacerbates
research demonstrated that ferritin‐rich dystrophic AD pathologies, contributing to glial aging and subse-
microglia were found in the hippocampus, adjacent quent senescence.
entorhinal cortex, and brainstem regions near the SN or Pathologically, iron is predominantly sequestered
locus coeruleus in aged human brains. They concluded within ferritin in both amyloid plaques and neurofibrillary
that dystrophic microglia do not display common tangles.104 However, whether this iron sequestration
markers of cellular senescence, such as SA‐β‐gal and may induce iron deficiency in adjacent brain regions
lipofuscin, suggesting that microglial dystrophy may not remains unclear. It has been observed that Aβ 1–42
fully represent a senescent state. This finding empha- facilitates the reduction of redox‐inactive ferric iron
sizes the necessity of distinguishing between “senes- (Fe3+), present as ferrihydrite, into redox‐active ferrous
cent” and “dystrophic” microglia or considering the iron (Fe2+).105 This ferrous iron can subsequently
possibility that progressive iron accumulation in dys- catalyze the Fenton reaction, generating harmful free
trophic microglia may eventually lead to senescence. radicals that may exacerbate neuroinflammation.106
Currently, recognized markers for microglia exhibiting Neuroinflammation plays a critical role in AD, leading to
a senescence phenotype include the presence of increased intracellular ferritin content in activated mi-
the SASP and ferritin, alongside other senescence croglia, primarily in the form of L‐ferritin, which ultimately
markers such as SA‐β‐gal and lipofuscin (Figure 2). contributes to a senescent microglia phenotype.68
Substantial evidence links elevated brain iron levels
with increased lipid peroxidation in patients with AD.
6 | MICROGLIAL SENESCENCE Apart from other forms of cell death, such as necrosis,
IN NDDs pyroptosis, and autophagy, ferroptosis has been pro-
posed as a primary mechanism driving neuronal death
NDDs frequently exhibit overlapping pathological fea- in AD and other NDDs.107–109 Similar to the prion‐like
tures,6 with patients often presenting with multiple co- propagation of misfolded proteins such as Aβ,110,111
existing proteinopathies, and a single proteinopathy may ferroptosis may also spread rapidly from one cell to
be implicated in various disorders. For instance, AD is neighboring cells.112 Furthermore, a study by Kenkhuis
characterized by senile plaques composed of Aβ protein et al.113 identified a subset of microglia in patients with
and neurofibrillary tangles of hyperphosphorylated tau, AD with elevated expression of the iron storage protein
whereas PD is distinguished by Lewy bodies containing ferritin light chain. These microglia exhibited increased
aggregated α‐synuclein. These disorders, collectively ionized calcium binding adaptor molecule 1 (IBA‐1) ex-
classified as proteinopathies, are marked by the abnor- pression but reduced transmembrane protein 119 and
mal accumulation of misfolded proteins, contributing to purinergic receptor P2Y 12 expression, indicative of
neuronal dysfunction and apoptosis.5 Despite these iron accumulation. This subset of activated microglia
overlapping pathologies, senescent microglia have been displayed a morphologically dystrophic appearance,
observed across multiple NDDs. Understanding the role suggestive of a senescent phenotype.113 Collectively,
of microglial senescence in these diseases could yield these findings suggest that microglia iron uptake signif-
critical insights into the pathophysiological mechanisms icantly influences their functional behavior. Moreover,
underlying neurodegeneration and inform the develop- a recent comprehensive review systematically empha-
ment of targeted therapeutic interventions. Although sized the link between microglial senescence and
tau protein is a key misfolded protein implicated in AD, proposing that microglial senescence, associated
the accumulation of senescent microglia,19,98 further with aging and accelerated by neurodegeneration,
research is needed to elucidate the specific pathways constitutes a significant mechanism contributing to the
through which monomeric tau induces microglial pathogenesis of AD.86
senescence.

6.2 | PD
6.1 | AD
PD is the second most common NDD after AD.114
AD, the most prevalent form of dementia, is a progres- Motor symptoms, including muscle rigidity, resting
sive neurodegenerative disorder characterized by the tremor, bradykinesia, and postural instability, are
accumulation of amyloid‐beta plaques and neuro- characteristic features of PD.115,116 Additionally, non-
fibrillary tangles composed of hyperphosphorylated motor symptoms, such as sleep disturbances, halluci-
tau.99 As AD progresses, extensive neurodegeneration nations, autonomic dysfunction, olfactory deficits,
occurs throughout the cerebral cortex, significantly dementia, and depression, can manifest preclinically,
impacting the medial temporal lobe structures, including often preceding the onset of motor symptoms.117
the hippocampal formation and entorhinal cortex.100,101 A hallmark feature of PD is the progressive loss of
Recent studies have underscored the pivotal role of dopaminergic neurons in the SN pars compacta (SNpc)
microglial senescence in the pathogenesis of AD.102,103 of the ventral midbrain.118 In PD, the SN exhibits
Tau protein aggregation, leading to the formation of a higher iron concentration, compared with other
neurofibrillary tangles, has been implicated in inducing brain regions, such as the cortex, globus pallidus, and
microglial senescence in a concentration‐dependent red nucleus, which have lower iron concentrations.
MICROGLIAL SENESCENCE IN AGING | 7

Notably, the total iron content in the SN increases produces a mutant form of huntingtin protein (mHTT),
with disease progression and correlates with the with an expanded polyglutamine tract. This single
severity of motor impairment.119 A key histopatholog- alteration in the huntingtin protein leads to the full
ical feature of PD is the presence of Lewy bodies, spectrum of clinical manifestations associated with
which are intraneuronal inclusions composed of HD.129 The primary pathogenesis of HD is attributed to
aggregated α‐synuclein. Studies have identified iron the toxic effects of mHTT, though the exact molecular
within Lewy bodies, with this iron being redox‐ mechanisms underlying this toxicity remain elusive and
active.120,121 Detection of redox‐active iron in situ has are believed to involve multiple interconnected path-
shown strong labeling of Lewy bodies in SNpc neurons, ways,130 presenting challenges for therapeutic targeting.
suggesting that the sequestration of iron within Lewy One promising area of research involves exploring the
bodies may serve as a protective mechanism rather role of senescent microglia in HD. Dysregulated brain
than contributing to neurodegeneration. Elevated iron iron metabolism, resulting in elevated iron accumulation
levels in the SNpc of patients with PD are associated in the caudate, putamen, and cortex, has been docu-
with increased ferritin and neuromelanin iron load- mented in individuals with HD,131 suggesting a signifi-
ing.122,123 Complementary studies over recent decades cant role of iron in the mHTT‐induced pathological cas-
have observed an accumulation of ferritin‐loaded cade. However, this view contrasts with the findings
microglia in the SN of patients with PD.124,125 A study of van den Bogaard et al.,132 who reported no evidence
by Jiang et al.126 provided insights into the molecular of early iron accumulation as a contributing factor to HD
mechanisms underlying excessive iron accumulation in onset, though they did confirm the presence of excess
PD, highlighting increased activation of divalent metal iron in the brains of patients with HD. The first study to
transporter‐1 (DMT1) as a possible factor, although the report increased brain ferritin and iron levels in an HD
specific triggers for DMT1 activation in regions such as model was conducted by Simmons et al.133 in 2007.
the SN remain unclear. Inflammation is thought to play This research, which included both R6/2 mice and
a role in the upregulation of DMT1 in dopaminergic human patients with HD, demonstrated elevated ferritin
neurons, with recent findings identifying high mobility immunostaining in the striatum, cortex, and hippocam-
group protein B1 as a critical early mediator of pus, with ferritin‐labeled microglia also exhibiting dys-
inflammation‐induced iron accumulation in PD.127 trophic features in the R6/2 mice. These findings offer
Given that aging is the most significant risk factor for novel insights into microglial senescence and its
PD, Shaerzadeh et al. conducted stereological analy- involvement in HD pathogenesis.133 In mammals,
ses on microglia and dopaminergic neurons in the cellular iron homeostasis is primarily regulated post‐
SNpc and ventral tegmental area (VTA) of C57BL/J6 transcriptionally by two cytoplasmic iron regulatory pro-
mice at different ages (1, 6, 9, 18, and 24 months).16 teins, iron regulatory protein (IRP) 1 and IRP2. These
Using double‐stained sections for tyrosine hydroxylase RNA‐binding proteins respond to intracellular iron levels
and IBA‐1, they observed an age‐related increase in by binding to iron‐responsive elements within the mRNA
microglia in both regions, whereas the number of encoding ferritin and transferrin receptors.134 Research
tyrosine hydroxylase neurons remained relatively sta- on N171‐82Q HD transgenic mice has shown increased
ble after 9 months in SNpc and 6 months in the VTA. iron levels in the striatum and cortex, with evidence
Morphometric analyses revealed a decline in microglial suggesting that mHTT may upregulate the expression of
complexity and projection area with aging, accompa- iron regulatory proteins, such as IRP1, transferrin, and
nied by increased cell body size. Furthermore, they its receptor, potentially contributing to the observed iron
found that contact sites between microglia and dopa- accumulation in HD.135 Reactive gliosis, characterized
minergic neurons increased with age, suggesting en- by reactive astrocytosis and microglia activation, is
hanced support and monitoring of dopaminergic neu- consistently observed in the striatum of patients with
rons by microglia. This observation implies that intrinsic HD.136 Positron emission tomography studies have
biological mechanisms within microglia compensate for confirmed significant microglial activation in affected
the age‐related decline in morphological complexity, or brain regions, particularly during advanced stages of the
senescence, thereby maintaining support for neurons disease.137 To date, the only study linking microglial
in the SNpc and VTA.16 activation to ferritin overload in HD was conducted
by Simmons et al.133 in 2007. Consequently, further
research focusing on the relationship between microglial
7 | HUNTINGTON'S DISEASE senescence and HD is needed to deepen our under-
standing of this aspect in HD pathophysiology.
Huntington's disease (HD) is a fatal, autosomal domi-
nant neurodegenerative disorder characterized by
involuntary choreiform movements, cognitive decline, 7.1 | ALS
and behavioral disturbances. These symptoms result
from the expansion of a cytosine‐adenine‐guanine tri- ALS, also known as Lou Gehrig's disease, is a pro-
nucleotide repeat in the gene encoding the huntingtin gressive neurodegenerative disorder characterized
protein on chromosome 4, as confirmed by genetic by the degeneration of both upper and lower motor
testing.128 The huntingtin protein is considered “normal” neurons.138 Although traditionally classified as a neuro-
when it contains 15 – 25 cytosine‐adenine‐guanine muscular disorder, recent imaging and neuropathological
repeats; however, when this repetition exceeds 36, it evidence indicate that ALS also affects nonmotor regions
8 | OLAJIDE ET AL.

of the neuraxis.139 The hallmark pathological feature has been documented across various animal mod-
of ALS is the accumulation of inclusion bodies, or Bunina els,154–158 underscoring the potential deleterious ef-
body‐like protein aggregates, in the cytoplasm of fects of metal exposure in NDDs. In 1991, McLachlan
motor neurons. In approximately 97% of ALS cases, conducted a pivotal study demonstrating that the iron
the primary protein component of these inclusions is chelator deferoxamine significantly attenuated the
TAR‐DNA‐binding protein 43 (TDP‐43).140 However, behavioral and cognitive decline observed in patients
in patients with mutations in superoxide dismutase type 1 with AD.159 Despite the groundbreaking nature of this
(SOD1) or fused in sarcoma, the inclusion bodies pre- research, the exploration of iron chelators as thera-
dominantly contain SOD1 or fused in sarcoma proteins, peutic agents for AD and other NDDs has only recently
respectively.141,142 regained momentum. Researchers are now expanding
Elevated ferritin levels in serum and cerebrospinal fluid upon McLachlan's initial findings to evaluate the effi-
have been reported in patients with ALS, suggesting cacy of iron chelation therapy in managing symptoms
a potential role for ferritin as a biomarker for the dis- and disease progression across various NDDs as
ease.143–145 Microglia, the resident immune cells of the shown in Table 1. Iron chelation therapy has emerged
CNS, are activated in both the motor cortex and spinal as a potential treatment strategy for NDDs due to the
cord in sporadic and familial ALS cases.146 In a study by increasing evidence implicating iron in the patho-
Trais et al.,147 the SOD1G93A transgenic rat model of ALS genesis of these disorders.165,166 In one study, patients
exhibited reduced lamin B1 expression in the lumbar with PD treated with the iron chelator deferiprone over
spinal cord and increased p16Ink4a expression in micro- a 6‐month period exhibited reduced iron levels in the
glia. Additionally, cultured SOD1G93A microglia displayed SN and significant improvements in motor symptoms.
characteristics of cellular senescence, including a large, However, upon cessation of treatment, iron accumu-
flattened morphology, upregulated expression of senes- lation recurred, indicating a return to the pathological
cence markers (p16Ink4a, p53, matrix metallopeptidase state.160 Devos et al.161 conducted a clinical trial
1, and SA‐β‐gal), and overexpression of SASP factors.147 involving newly diagnosed patients with PD who had
These findings suggest a strong link between microglial not yet taken levodopa. Their findings suggested that
senescence and the inflammation and motor neuron loss deferiprone while lowering iron levels, was associated
observed after the onset of paralysis in SOD1G93A rats, with worse parkinsonism scores as measured by the
indicating that cellular senescence may play a critical role Unified PD Rating Scale.161 These contradictory results
in ALS pathogenesis. TDP‐43, an RNA‐binding protein imply that deferiprone should be considered as an
with multiple roles in RNA metabolism, is the most com- adjunct therapy for NDDs, with careful consideration of
mon protein found in ALS inclusion bodies. Various patient characteristics, disease stage, and treatment
mechanisms have been proposed regarding the patho- duration.
genic role of aggregated TDP‐43 in ALS.148–150 It has Research on iron chelation in HD is limited.
been observed that both wild‐type and mutant TDP‐43 However, studies utilizing clioquinol and deferoxamine
can induce cytokine production in primary mouse micro- have shown potential in alleviating symptoms in the
glia.151 TDP‐43 has also been implicated in microglial R6/2 HD mouse model. These effects are thought to
phagocytosis, as demonstrated by Paolicelli et al.,152 who arise from the suppression of oxidative activity by mHtt
showed that microglial‐specific knockout of TARDBP (the and the reduction of iron‐reduced oxidative stress in
gene encoding TDP‐43) enhanced amyloid clearance and endosomal and lysosomal compartments.167,168
reduced synaptic loss in an AD mouse model. Recent M30, a versatile iron chelator identified as 5‐(N‐
studies have reported a marked increase in microglial methyl‐N‐propargylaminomethyl)‐8‐hydroxyquinoline,
CD68 and high expression of L‐ferritin in the motor cortex has emerged as a potent agent, demonstrating
of patients with ALS, with both markers significantly cor- strong inhibition of monoamine oxidases A and B and
relating with phosphorylated TDP‐43 pathology in the ALS iron‐dependent lipid peroxidation.162 Studies have
brain.153 Although phosphorylated TDP‐43 load was confirmed M30's effectiveness in inhibiting lipid per-
notably elevated in both the motor cortex and hippocam- oxidation, showing a higher half maximal inhibitory
pus of patients with ALS, only the motor cortex showed concentration value than does deferiprone.169 M30
increased microglial density and astrogliosis. This evi- has shown therapeutic potential in treating conditions
dence suggests that microglia are initially phagocytic such as AD, age‐related cognitive decline, and ALS,
during the early stages of ALS but become dysfunctional enhancing neuroprotective and adaptive mechanisms
as the disease progresses, driven by the accumulation of by activating pro‐survival signaling pathways in the
phosphorylated TDP‐43. brain.163,164 Additionally, bioactive constituents in
green tea and red wine have demonstrated neuro-
protective, antioxidant, anti‐inflammatory, and iron‐
8 | IRON CHELATION AND chelating properties, potentially addressing NDDs at
SENOLYTICS FO R NDDs the cellular level by reducing microglia activation,
mitigating ROS‐induced damage, chelating iron, and
Although the precise etiologies of numerous NDDs promoting cellular growth.170
remain elusive, accumulating evidence suggests that In addition to iron chelation, senolytic drugs have
exposure to metals, such as lead, nickel, mercury, shown promise in treating aged‐related NDDs,171 as
cadmium, and iron, significantly contributes to the senescent cells accumulate in aging brains and neuro-
pathogenesis of these conditions. This phenomenon degenerative conditions. Senolytics, which selectively
MICROGLIAL SENESCENCE IN AGING | 9

TABLE 1 Studies evaluating the use of iron chelators on the incidence and progression of neurodegenerative diseases.
Iron chelator for neurodegenerative
diseases Functions References

Deferoxamine Mitigates behavioral and cognitive deterioration observed McLachlan et al.,159

in AD

Deferiprone Chelates iron in the substantia nigra, leading to Devos et al.,160 Devos et al.,161
improvements in motor symptoms in patients with PD; not
effective in patients newly diagnosed with PD

5‐(N‐methyl‐N‐propargylaminomethyl)‐8‐ Inhibits monoamine oxidase‐A and B and iron‐dependent Weinreb et al.,162 Youdim163
hydroxyquinoline lipid peroxidation, showing potential in treating AD, PD, age‐ Kupershmidt and Youdim164
related cognitive decline, and amyotrophic lateral sclerosis

Abbreviations: AD, Alzheimer's disease; PD, Parkinson's disease.

TABLE 2 Senolytics approaches for the management of neurodegenerative diseases.

Senolytic drugs
for NDDs Functions References

Dasatinib and Quercetin Effectively alleviate pathology in neurodegenerative Zhang et al.,173 Chaib
diseases in both mouse and human studies et al.,174

ABT263 (navitoclax) Reduces p16Ink4a‐positive senescent astrocytes and Bussian et al.,175

microglia, leading to improved memory function Ng et al.,176

Metformin Impedes cellular senescence in Alzheimer's disease and Ou et al.,177 Katila et al.,178
Parkinson's disease by activating microRNA‐processing
proteins

Abbreviation: NDDs, neurodegenerative diseases.

induce apoptosis in senescent cells,172 could mitigate across various NDDs. This review underscores pre-
the detrimental effects of cellular senescence in NDDs vious research on microglial senescence, highlighting
(Table 2). Dasatinib and quercetin, two senolytic agents, its distinct role in NDDs. Despite the challenges in
have been successfully used to reduce pathology in identifying a definitive senescent microglia pheno-
mouse models of NDDs.173 For instance, in a mouse type, especially given its presence in both healthy
model of tau‐dependent NDD marked by the accumu- aging and age‐related NDDs, progress has been
lation of senescent microglia and astrocytes in the cortex hindered by the absence of specific markers.
and hippocampus, the senolytic agent ABT263 (navito- Currently, the increase in the SASP combined with
clax), a B cell lyphoma 2 protein inhibitor, significantly elevated ferritin levels is considered indicative of
reduced p16Ink4a‐positive senescent astrocytes and senescent microglia. However, reliance solely on
microglia, leading to improvements in memory.175 The SASP can be problematic, as several SASP compo-
success of senolytic treatments in animal models has nents may stem from the inflammatory milieu of
spurred clinical trials investigating the use of dasatinib non‐senescent microglia. Ferritin, an iron storage
and quercetin in patients with early AD.174 These trials protein within microglia, presents as a promising
aim to determine whether senolytic therapy can elim- marker. It sequesters iron, preventing its involvement
inate both senescent cells and the associated SASP, in harmful Fenton chemistry that generates ROS. The
which may have beneficial effects on NDDs.176 More- accumulation of misfolded proteins in NDDs is asso-
over, metformin, a common antidiabetic drug, has been ciated with increased ferritin levels within microglia,
shown to inhibit cellular senescence in AD and PD by suggesting a potential role of “ferroptosis” in neuronal
activating microRNA‐processing proteins, preventing cell death. The source of this increased
amyloid plaque deposition in AD, and suppressing ferritin–whether due to iron overload from misfolded
α‐synuclein phosphorylation in PD.177,178 Collectively, proteins or peripheral circulation via the blood‐brain
these findings, along with the therapeutic potential of barrier through astrocytes–remains unclear. None-
iron chelators (as detailed in Table 1) and senolytic theless, promising therapeutic strategies for mana-
drugs, present promising and innovative strategies for ging age‐related NDDs include the use of iron chela-
addressing the underlying pathophysiology of NDDs. tors like deferoxamine and senolytic drugs as adjunct
therapies. In conclusion, investigating microglial
phenotypes, particularly senescence offers a com-
9 | CONCLUSION pelling avenue for understanding the pathophysiology
of NDDs. Further research is essential to explore this
The role of microglia in neurodegeneration has aspect, potentially unlocking new insights into the
been extensively investigated, focusing on identifying etiologies of neurodegeneration and paving the way
diverse microglia phenotypes and their activation for innovative therapeutic approaches.
10 | OLAJIDE ET AL.

AUTHOR CONTRIBUTIONS 5. Gandhi J, Antonelli AC, Afridi A, et al. Protein misfolding and
Tobiloba Samuel Olajide: Conceptualization (lead); aggregation in neurodegenerative diseases: a review of pa-
Visualization (lead); Writing—original draft (lead); thogeneses, novel detection strategies, and potential ther-
apeutics. Rev Neurosci. 2019;30(4):339‐358. doi:10.1515/
Writing—review and editing (equal). Toheeb O. revneuro-2016-0035
Oyerinde: Visualization (lead); Writing—original draft 6. Das S, Zhang Z, Ang LC. Clinicopathological overlap of
(equal). Omolabake I. Omotosho: Writing—original neurodegenerative diseases: a comprehensive review. J Clin
draft (equal). Oritoke M. Okeowo: Supervision (equal); Neurosci. 2020;78:30‐33. doi:10.1016/j.jocn.2020.04.088
7. York EM, Bernier LP, MacVicar BA. Microglial modulation of
Writing—review and editing (supporting). Olayemi J.
neuronal activity in the healthy brain. Dev Neurobiol. 2018;
Olajide: Supervision (equal); Writing—review and 78(6):593‐603. doi:10.1002/dneu.22571
editing (equal). Omamuyouwi M. Ijomone: Funding 8. Huang P‐S, Tsai P‐Y, Yang L‐Y, et al. 3, 6′‐dithiopomalidomide
acquisition (lead); Supervision (lead); Visualization ameliorates hippocampal neurodegeneration, microgliosis and
(equal); Writing—review and editing (lead). astrogliosis and improves cognitive behaviors in rats with a
moderate traumatic brain injury. Int J Mol Sci. 2021;22(15):8276.
doi:10.3390/ijms22158276
ACKNOWLEDGMENTS 9. Cohen J, Torres C. Astrocyte senescence: evidence and sig-
We acknowledge all whose work has contributed to the nificance. Aging cell. 2019;18(3):e12937. doi:10.1111/acel.
knowledge reviewed here. Omamuyouwi M. Ijomone 12937
receives funding support through the NIH‐FIC 10. Stojiljkovic MR, Ain Q, Bondeva T, Heller R, Schmeer C,
K43TW011920 for career development and research Witte OW. Phenotypic and functional differences between
senescent and aged murine microglia. Neurobiol Aging.
protected towards the writing and review of this man- 2019;74:56‐69. doi:10.1016/j.neurobiolaging.2018.10.007
uscript. The content is solely the responsibility of the 11. Angelova DM, Brown DR. Microglia and the aging brain: are
authors and does not necessarily represent the official senescent microglia the key to neurodegeneration? J Neurochem.
views of the Fogarty International Center or the 2019;151(6):676‐688. doi:10.1111/jnc.14860
12. Neumann P, Lenz DE, Streit WJ, Bechmann I. Is microglial
National Institutes of Health.
dystrophy a form of cellular senescence? an analysis of
senescence markers in the aged human brain. GLIA. 2023;
CONFLICT OF INTEREST STATEMENT 71(2):377‐390. doi:10.1002/glia.24282
The authors declare no conflict of interest. 13. Lopes‐Paciencia S, Saint‐Germain E, Rowell MC, Ruiz AF,
Kalegari P, Ferbeyre G. The senescence‐associated secretory
DATA AVAILABILITY STATEMENT phenotype and its regulation. Cytokine. 2019;117:15‐22.
doi:10.1016/j.cyto.2019.01.013
The data that support the findings of this study are 14. Kumari R, Jat P. Mechanisms of cellular senescence: cell cycle
available from the corresponding author upon reason- arrest and senescence associated secretory phenotype. Front
able request. Cell Dev Biol. 2021;9:645593. doi:10.3389/fcell.2021.645593
15. Deczkowska A, Keren‐Shaul H, Weiner A, Colonna M,
ETHICS STATEMENT Schwartz M, Amit I. Disease‐Associated microglia: a universal
immune sensor of neurodegeneration. Cell. 2018;173(5):
Not applicable. 1073‐1081. doi:10.1016/j.cell.2018.05.003
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ORCID occurs in both substantia nigra and ventral tegmental area.
Tobiloba Samuel Olajide http://orcid.org/0000-0001- GLIA. 2020;68(11):2228‐2245. doi:10.1002/glia.23834
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Toheeb O. Oyerinde http://orcid.org/0000-0002- mouse hippocampus: implications for Alzheimer's disease.
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Omolabake I. Omotosho http://orcid.org/0009-0005- 023-02870-2
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Oritoke M. Okeowo http://orcid.org/0000-0002- hypofunctional and release metalloproteases and tau
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