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Frontiers in Aging Neuroscience 01 frontiersin.org
Cellular senescence in brain aging
and cognitive decline
AreezShafqat
1*†, SaifullahKhan
2†, MohamedH.Omer
3,
MahnoorNiaz
2, IbrahemAlbalkhi
1, KhaledAlKattan
1,
AhmedYaqinuddin
1, TamaraTchkonia
4, JamesL.Kirkland
4 and
ShahrukhK.Hashmi
5,6, 7
1 College of Medicine, Alfaisal University, Riyadh, Saudi Arabia, 2 Medical College, Aga Khan University,
Karachi, Pakistan, 3 School of Medicine, Cardi University, Cardi, United Kingdom, 4 Robert and Arlene
Kogod Center on Aging, Mayo Clinic, Rochester, MN, United States, 5 Department of Internal Medicine,
Mayo Clinic, Rochester, MN, United States, 6 Clinical Aairs, Khalifa University, Abu Dhabi, United Arab
Emirates, 7 Department of Medicine, SSMC, Abu Dhabi, United Arab Emirates
Cellular senescence is a biological aging hallmark that plays a key role in the
development of neurodegenerative diseases. Clinical trials are currently underway
to evaluate the eectiveness of senotherapies for these diseases. However, the
impact of senescence on brain aging and cognitive decline in the absence of
neurodegeneration remains uncertain. Moreover, patient populations like cancer
survivors, traumatic brain injury survivors, obese individuals, obstructive sleep
apnea patients, and chronic kidney disease patients can suer age-related brain
changes like cognitive decline prematurely, suggesting that they may suer
accelerated senescence in the brain. Understanding the role of senescence in
neurocognitive deficits linked to these conditions is crucial, especially considering
the rapidly evolving field of senotherapeutics. Such treatments could help alleviate
early brain aging in these patients, significantly reducing patient morbidity and
healthcare costs. This review provides a translational perspective on how cellular
senescence plays a role in brain aging and age-related cognitive decline. Wealso
discuss important caveats surrounding mainstream senotherapies like senolytics
and senomorphics, and present emerging evidence of hyperbaric oxygen therapy
and immune-directed therapies as viable modalities for reducing senescent cell
burden.
KEYWORDS
cellular senescence, aging, cognitive decline, therapy-induced senescence (TIS),
obesity, traumatic brain injury, microglia senescence, astrocyte senescence
Introduction
Increasing life expectancy and a declining birth rate, especially in the West, have led to an
aging population at higher risk of age-related chronic diseases that incur signicant morbidity,
mortality, and healthcare expenditures (Cutler etal., 1990). Consequently, medical research on
promoting healthy aging has become an essential area of investigation carrying signicant public
health and economic implications (Ferrucci etal., 2020).
The mechanisms underlying brain aging have garnered significant attention due to the
significant number of patients suffering from dementia and Alzheimer’s disease (AD). The
cost of managing these patients exceeds that of cancer and cardiovascular disease patients
OPEN ACCESS
EDITED BY
Kristine Freude,
University of Copenhagen, Denmark
REVIEWED BY
Mariana Toricelli,
Association for Research Incentive Fund (AFIP),
Brazil
Ádám Nyúl-Tóth,
University of Oklahoma Health Sciences
Center, UnitedStates
*CORRESPONDENCE
Areez Shafqat
ashafqat@alfaisal.edu
†These authors share first authorship
RECEIVED 22 August 2023
ACCEPTED 01 November 2023
PUBLISHED 23 November 2023
CITATION
Shafqat A, Khan S, Omer MH, Niaz M, Albalkhi I,
AlKattan K, Yaqinuddin A, Tchkonia T,
Kirkland JL and Hashmi SK (2023) Cellular
senescence in brain aging and cognitive
decline.
Front. Aging Neurosci. 15:1281581.
doi: 10.3389/fnagi.2023.1281581
COPYRIGHT
© 2023 Shafqat, Khan, Omer, Niaz, Albalkhi,
AlKattan, Yaqinuddin, Tchkonia, Kirkland and
Hashmi. This is an open-access article
distributed under the terms of the Creative
Commons Attribution License (CC BY). The
use, distribution or reproduction in other
forums is permitted, provided the original
author(s) and the copyright owner(s) are
credited and that the original publication in this
journal is cited, in accordance with accepted
academic practice. No use, distribution or
reproduction is permitted which does not
comply with these terms.
TYPE Review
PUBLISHED 23 November 2023
DOI 10.3389/fnagi.2023.1281581
Shafqat et al. 10.3389/fnagi.2023.1281581
Frontiers in Aging Neuroscience 02 frontiersin.org
combined (Kukull etal., 2002; Hebert etal., 2013). Importantly,
however, cognitive decline is observable in individuals without
AD or overt neurodegenerative changes (Gonzales etal., 2022).
Age-related mild cognitive impairment (MCI) and late-onset
AD can be mechanistically explained by processes governing
biological aging. Currently, 12 biological aging hallmarks have been
identied: genomic instability, telomere attrition, epigenetic
alterations, loss of proteostasis, altered nutrient sensing,
mitochondrial dysfunction, stem cell exhaustion, altered intracellular
communication, cellular senescence, disabled macroautophagy,
chronic inammation (i.e., inammaging), and gut microbiome
dysbiosis (López-Otín etal., 2013, 2023). e geroscience hypothesis
posits that age-related diseases arise from the cumulative eects of
these biological aging hallmarks and that targeting them
constitutes an avenue to ameliorate age-related diseases (Kennedy
etal., 2014).
Cellular senescence describes a state of cell cycle arrest
accompanied by characteristic morphological, cellular, and molecular
changes (Zhang L. et al., 2022). Studies using pharmacological
targeting of senescent cells (SCs), transplanting SCs, and transgenic
mouse models have demonstrated a causal relationship between SC
accumulation and age-related tissue dysfunction, with addition of SCs
being shown to accelerate aging phenotypes on the one hand and
clearance being shown to alleviate them on the other (Xu etal., 2015;
Tchkonia and Kirkland, 2018; Xu etal., 2018; Kirkland and Tchkonia,
2020; Wang etal., 2020a; Xu etal., 2021; Chaib etal., 2022; Sun etal.,
2022; Zhang etal., 2023). In the brain, SCs become more abundant
with aging in mice, which is associated with cognitive decline, and
their depletion mitigates neuroinammation and delays cognitive
decline (Ogrodnik etal., 2021; Zhang X. etal., 2022).
is review explores the association between cellular senescence
and age-related cognitive decline. We also discuss how cellular
senescence may underlie cognitive decline in dierent patient
populations that exhibit a premature brain aging phenotype. ese
patients include cancer survivors, traumatic brain injury (TBI)
patients, obese individuals, obstructive sleep apnea (OSA) patients,
and chronic kidney disease (CKD) patients. Understanding the role
of senescence in cognitive decline is essential, especially considering
the rapidly evolving eld of senotherapeutics. Targeting SCs could
mitigate early brain aging and reduce a signicant burden on patients,
healthcare systems, and society.
Cellular senescence and
senotherapies
Cellular senescence is a state of cell cycle arrest originally
described in 1961 by Hayick and Moorehead when they observed
that cultured human broblasts stopped dividing aer 40–60 serial
cell divisions (Hayick and Moorhead, 1961). is phenomenon was
due to telomere shortening, which triggered a DNA damage response
(DDR) and induced replicative senescence (Olovnikov, 1973;
Olovnikov, 1996). Senescence induction has now been linked to
various other stimuli, including epigenetic alterations, oxidative stress,
mitochondrial dysfunction, inactivation of tumor suppressor genes,
mechanical or shear stress, pathogens, and activation of oncogenes
(Figure 1; Tchkonia et al., 2013; Gorgoulis et al., 2019; Tripathi
etal., 2021a).
Senescence induction in response to these various stimuli is
orchestrated by the p53/p21
Cip1/Waf1
axis, p16
Ink4a
/Rb axis, and other
mechanisms. e proteins involved in these pathways can serve as
markers of senescence. Other features of SCs can bestructural changes
(attened and enlarged cellular morphology), DNA and nuclear
changes (DDR foci and decreased Lamin-B1 expression), elevated
lysosomal enzyme senescence-associated β-galactosidase (SA β-gal)
active at pH 6, mitochondrial changes [impaired membrane integrity,
increased reactive oxygen species (ROS) production], upregulation of
senescence-associated anti-apoptotic pathways (SCAPs), and
elaboration of a senescence-associated secretory phenotype (SASP)
that can comprise cytokines, chemokines, growth factors, proteases,
bioactive small molecules, and nucleotides (e.g., microRNAs and
mitochondrial DNA) (Figure1; Gorgoulis etal., 2019; Iske etal., 2020;
Tripathi etal., 2021b; Zhang etal., 2021; Nunes etal., 2022). While
these changes can beused to identify SCs, no single specic marker of
SCs is currently agreed upon, and more sensitive and specic markers
of SC burden are needed. To this end, a gene set of 125 senescence-
associated genes called SenMayo was recently used to identify SCs
across multiple tissues in both bulk and single-cell RNA sequencing
(scRNA-seq) data. e genes comprising SenMayo were shown to
increase with aging and beresponsive to SC clearance in transgenic
mice (Saul etal., 2022).
Senescence in aging
Cellular senescence is a double-edged sword. It induces growth
arrest in potentially tumorigenic cells (Schosserer etal., 2017). It also
plays essential roles in normal embryogenesis (Storer etal., 2013; Lorda-
Diez etal., 2015) and wound healing (Demaria etal., 2014; Da Silva-
Álvarez etal., 2020). However, the chronic accumulation of SCs in
tissues leads to tissue dysfunction and chronic disease (Biran etal., 2017;
Xu etal., 2017). To explain this, SCs utilize their SASP to exert cell-
autonomous eects, reinforcing their own senescent phenotype through
autocrine eects, and non-cell-autonomous eects, inducing senescence
in neighboring as well as distant cells (Acosta etal., 2013; Xu etal.,
2018). Additionally, the spillover of SASP factors into the circulation
fosters a chronic low-grade inammatory response that promotes
age-related phenotypes (Figure1; Acosta etal., 2013; Xu etal., 2018).
ese pro-aging eects of SCs are made apparent when
transplanting SCs into healthy mice, which accelerates the aging
process and results in early death (Baker etal., 2011; Xu etal., 2018).
Abbreviations: AD, Alzheimer’s disease; Aβ, amyloid-beta; NFT, neurofibrillary
tangles; TBI, traumatic brain injury; CKD, chronic kidney disease; PD, Parkinson’s
disease; OPCs, oligodendrocyte progenitor cells; OSA, obstructive sleep apnea;
CIH, chronic intermittent hypoxia; SCs, senescent cells; DDR, DNA damage
response; SA β-gal, senescence-associated β-galactosidase; ROS, reactive oxygen
species; SCAPs, senescence-associated anti-apoptotic pathways; SASP,
senescence-associated secretory phenotype; SIPS, stress-induced premature
senescence; CICI, chemotherapy-related cognitive impairment; TIS, therapy-
induced senescence; NSCs, neuronal stem cells; TREM2, triggering receptor
expressed on myeloid cells 2; DAM, disease-associated microglia; ApoE4,
apolipoprotein-E4; REST, repressor element-1-silencing transcription factor;
GWAS, genome-wide association study; EAA, epigenetic age acceleration; HDAC,
histone deacetylase; HFD, high-fat diet; HBOT, hyperbaric oxygen therapy.
Shafqat et al. 10.3389/fnagi.2023.1281581
Frontiers in Aging Neuroscience 03 frontiersin.org
SCs are also physically present at sites of chronic diseases, such as
osteoarthritis, idiopathic pulmonary brosis (IPF), cataracts,
age-related macular degeneration, atherosclerosis, sarcopenia, renal
dysfunction, dementias, and organ transplant dysfunction (Chaib
etal., 2022). Mouse models in which highly p16
Ink4a
-or p21
Cip1/Waf1
-
expressing cells can besystemically depleted upon administration of
agents that have little to no eects in wild-type mice have been
developed (Wang etal., 2021; Chandra etal., 2022). ese models have
been utilized to systemically deplete SCs and have helped to establish
a causal relationship between senescence and age-related chronic
diseases (Baker et al., 2011; Demaria et al., 2014; Kirkland and
Tchkonia, 2017).
Senolytics
A pioneering study by Zhu et al. (2015) leveraged the
observation that SCs upregulate SCAPs to suggest a senolytic
approach. is involves using drugs that inhibit SCAPs to selectively
induce apoptosis in SCs (i.e., senolysis). Dasatinib, a
chemotherapeutic agent, and quercetin, a naturally occurring
avonoid, were the rst discovered senolytics. ese drugs
selectively depleted SCs by targeting SCAPs and reduced senescence
markers in the leg muscle and inguinal fat of irradiated mice,
thereby restoring exercise capacity and endurance to levels
comparable to control non-irradiated mice (Zhu et al., 2015).
Fiscetin is also a naturally occurring avonoid closely related to
quercetin that has senolytic properties (Yousefzadeh etal., 2018).
Navitoclax (ABT-263) is an inhibitor of BCL-2, conferring to it its
senolytic eect. However, unlike dasatinib and quercetin, navitoclax
targets a specic SCAP and not SCs specically, leading to o-target
side eects like thrombocytopenia that are dose-limiting (Chang
et al., 2016; Zhu et al., 2016). ese four drugs were the rst-
generation senolytics. Subsequent studies identied numerous
senolytics through the original hypothesis-driven SCAP-targeting
approach, serendipity, and conventional high-throughput library
screens (Chang etal., 2016; Fuhrmann-Stroissnigg etal., 2017; Zhu
et al., 2017; Fuhrmann-Stroissnigg etal., 2019; Xu et al., 2021;
Samakkarnthai etal., 2023). UBX1235 like navitoclax is an anti-BCL
senolytic, but is tailored to targeting senescence-related disorders
FIGURE1
Cellular senescence is classically secondary to telomere shortening and DNA damage, but can also result from other cellular stressors. Hallmarks of
senescence include elevated SA-β-gal activity, reduced lamin-B1 expression, mitochondrial dysfunction and elevated ROS production, apoptosis
resistance by upregulation of SCAPs, and elaboration of a SASP composed of cytokines, chemokines, and growth factors. The SASP mediates the
non-cell autonomous eects of senescence, including senescence-spreading and activating innate and adaptive immune cells to foster chronic
low-grade inflammation. Figure was created using BioRender.com.
Shafqat et al. 10.3389/fnagi.2023.1281581
Frontiers in Aging Neuroscience 04 frontiersin.org
in the eye and shown tolerability and encouraging ecacy in phase
I and II clinical studies on age-related macular degeneration
(Hassan and Bhatwadekar, 2022) (NCT05275205). A major
advantage of senolytic drugs is their “hit-and-run” principle of
administration, whereby intermittent administration is as eective
as continuous administration, since senescence induction takes
time and SCs are present only in small numbers in tissues (Kirkland
etal., 2017). e timeline of senolytic drug discovery, i.e., their
evolution from benchwork to clinical trials, has recently been
reviewed (see Chaib etal., 2022).
A recent phase I, single-blinded, single-center, randomized,
placebo-controlled study showed that the combination of dasatinib
and quercetin was generally tolerable and safe in 12 idiopathic
pulmonary brosis (IPF) patients (Nambiar etal., 2023). Mild side
eects were higher in the treatment group and were generally those
associated with the chemotherapeutic drug dasatinib, such as nausea,
weakness, headache, feeling unwell and sleep disturbances (Nambiar
etal., 2023).
There are several ongoing trials to investigate the role of
senolytics in the prevention or progression modulation of
neurodegenerative diseases. These trials include ALSENLITE
(NCT04785300) and SToMP-AD (NCT04063124; NCT04685590).
Preliminary reports from the Phase ISToMP-AD trial of five
participants exploring the use of dasatinib + quercetin, as a
potential treatment for AD were recently reported (Orr etal.,
2023). Blood levels of the compounds increased in all participants
with detectable levels in the cerebrospinal fluid (CSF), and no
reported adverse events. While cognitive and neuroimaging
measures did not significantly change post-treatment, CSF levels
of certain SASP-typical cytokines/chemokines (IL-17E, IL-21,
IL-23, IL-17A/F, IL-17D, IL-10, VEGF, IL-31, MCP-2, MIP-1β,
and MIP-1α) were significantly decreased in treated patients
(Gonzales etal., 2023; Orr etal., 2023).
Senomorphics
Also known as senostatics, senomorphic drugs modulate
senescence markers or attenuate SASP components to achieve
effects similar to senolytics, but without causing apoptotic cell
death (Lagoumtzi and Chondrogianni, 2021). Some of these
agents act on transcriptional regulators of the SASP, such as the
ATM, mTOR, JAK/STAT, and FOXO (Zhang etal., 2023). Among
senomorphic drugs are rapamycin, metformin, and resveratrol
(Zhang etal., 2023). Other compounds, such as procyanidin C1
or intravenous zoledronic acid, can exhibit both senomorphic
and senolytic properties (Xu etal., 2021; Samakkarnthai etal.,
2023). Preclinical research indicates that some senomorphic
drugs can prolong healthspan of mice and decrease the incidence
of various age-related pathologies, including cancers,
cardiovascular diseases, metabolic disorders, cognitive decline,
and neurodegenerative diseases (Zhang etal., 2023).
Cellular senescence in the aging brain
Biologically, the accumulation of SCs in the brain has three main
consequences: neuroinammation, impaired neurogenesis, and
synaptic dysfunction due to astrocyte senescence (Figure2).
Neuroinflammation
An important feature of SCs is their ability to secrete a composite
of pro-inammatory cytokines and chemokines. ese mediators
foster a chronic low-grade inammatory response called
inammaging, which is causally linked to the aging process in the
brain—termed neuro-inammaging (Franceschi et al., 2000;
Franceschi and Campisi, 2014). In general, neuro-inammaging
involves the skewing of the immune system towards activation of
innate immunity and T-helper 2 (TH
2
) responses (Giunta etal.,
2008; Hu etal., 2019). Diseases like multiple sclerosis and AD
accentuate this trend toward non-TH
1
cytokines (Hu etal., 2019). In
the CSF, levels of several cytokines (e.g., IL-1β, IL-4, IL-6, IL-8,
IFNγ, G-CSF, and GM-CSF) are negatively associated with
AD-related progression of cognitive decline, suggesting a protective
function of these factors (Taipa etal., 2019; Albrecht etal., 2021).
Peripheral inammaging features elevations in mediators like IL-1β,
IL-6, TNFα, and CRP, have been linked to the progression of
age-related cognitive decline and the progression of
neurodegenerative disease-related dementia (Feng etal., 2023). A
dierent set of circulating inammatory proteins like IFNγ and
IL-12, which are hallmarks of a TH
1
response, are seemingly
protective against cognitive decline (Yang etal., 2022).
e mediators of neuro-inammaging are thought to bederived
from glial cells such as astrocytes and microglia (Allen etal., 2023).
is is coupled with aging-related blood–brain barrier (BBB)
disruption from dysfunction of the cerebral microvasculature, which
further propagates neuroinammation by making the normally
immune-privileged brain more susceptible to peripheral immune cell
inltration as well as the circulating inammaging mediators
(Watanabe etal., 2020). Studies have demonstrated that age-related
senescence in astrocytes and microglia results in the elaboration of a
pro-inammatory SASP (Chinta etal., 2015; Sikora etal., 2021; Zhang
X. etal., 2022), while endothelial cell and pericyte senescence of the
cerebral microvasculature has been linked to BBB disruption
(Yamazaki et al., 2016; Iwao etal., 2023). Cellular senescence thus
emerges as a key hypothesis that underlies neuro-inammaging,
central to age-related cognitive deterioration with or without
neurodegeneration (Scheiblich etal., 2020).
Regarding vascular senescence, in naturally aged 28-month-old
C57BL/6 mice (roughly equivalent to a 75-year-old human), the
proportion of senescent brain microvascular endothelial cells is 10%
higher compared to 3-month-old mice (Kiss etal., 2020). In genetically
modied BubR1-hypomorphic (BubR1
H/H
) mice, which are progeroid
models displaying accelerated aging phenotypes, endothelial cells and
pericytes of the cerebral vasculature display increased SA β-gal and
p16
Ink4a
activity, which is associated with reduced gap junction
coverage in cerebral micro-vessels and increased BBB permeability
(Yamazaki etal., 2016). Endothelin-1 (ET1)—a potent vasoconstrictor
that is upregulated with aging (Donato etal., 2009)—binds the ET-A
receptor on brain microvascular endothelial cells, leading to an
upregulation of senescence markers and a downregulation of the
adherens junction protein VE-cadherin (Abdul et al., 2022).
Senescence induction in serially passaged pericytes or those isolated
from aged rat brains increase permeability of in vitro BBB models
composed of intact BMECs (Iwao etal., 2023). However, causal links
between vascular senescence and age-related cognitive decline require
assessing whether genetic or pharmacologic modulation of senescence
in endothelial cells or pericytes mitigates this phenotype.
Shafqat et al. 10.3389/fnagi.2023.1281581
Frontiers in Aging Neuroscience 05 frontiersin.org
Regarding astrocytes, Clarke et al. (2018) carried out
transcriptional proling of astrocytes through the mouse lifespan
and observed an age-dependent skewing of astrocyte transcriptome
towards a pro-inammatory state, likely under the inuence of
microglia-derived pro-inammatory signals like IL-1, TNF-α, and
C1q. Senescence markers like SA β-gal-positivity, lamin-B1
downregulation, mitochondrial dysfunction, and increased ROS
production are upregulated in aged astrocytes, associated with the
elaboration of a pro-inammatory SASP reminiscent of neurotoxic/
proinammatory (formerly called A1) astrocytes (Liddelow etal.,
2017; Matias etal., 2022). Human astrocytes made senescent by
serial replication elaborate a SASP composed of IL-8, GM-CSF,
angiogenin, MMP-3, MMP-10 and TIMP-2, while the production
of anti-inammatory cytokines like IL-10 is reduced (Lye etal.,
2019). On a molecular level, senescent astrocytes display a
signicant dysregulation in their expression of proteins involved in
splicing of mRNA transcripts, which may allow them to alter their
proteome with respect to the SASP (Lye etal., 2019). Importantly,
mRNA transcripts (e.g., p14
ARF
, GFAP-α, and TAU3) upregulated by
senescent astrocytes have been associated with cognitive decline in
an aging population (Lye et al., 2019). What triggers astrocyte
senescence in the aging brain was recently investigated. Serum
FIGURE2
Senescence contributes to brain aging through three main mechanisms: synaptic dysfunction, neuroinflammation, and impaired neurogenesis.
Synaptic dysfunction can bedue to senescence of astrocytes, which decrease neurotransmitter uptake and display decreased neuroprotective
capacity. Neuroinflammation stems from senescence of astrocytes and microglia, skewing them towards pro-inflammatory phenotypes. Senescence
of cerebrovascular endothelial cells and pericytes may contribute to BBB disruption and consequent leakage of factors like TGF-β, which can induce
astrocyte senescence. Senescence of neuroblasts/neuronal stem cells can activate neurotoxic NK cell functions which, in turn, eliminate neuroblasts,
thereby impairing neurogenesis. Figure was created using BioRender.com.
Shafqat et al. 10.3389/fnagi.2023.1281581
Frontiers in Aging Neuroscience 06 frontiersin.org
albumin leaks into the brain parenchyma due to age-related BBB
dysfunction, activates the TGF-β receptor-II on astrocytes, and
induces senescence both in vitro and in vivo (Preininger etal.,
2023). TGF-β-induced senescent hippocampal astrocytes exhibit
increased mRNA levels of SASP components such as TGF-β1,
IL-1β, IL-6, CXCL10, MCP-1, and CCL5 (RANTES), which is
preventable by genetic knockdown or pharmacologic blockade of
the astrocyte TGF-β receptor (Preininger etal., 2023). Whether
modulation of TGF-β-related astrocyte senescence can inuence
cognitive health remains investigational.
Regarding microglia, there is no age-associated brain-wide shi
in their phenotype towards inammation, but subsets of inammatory
microglia do appear in the aged mouse brain, likely driven by local
cues like BBB disruption or microinfarcts (Hammond etal., 2019a).
e hippocampi of aged mice show an accumulation of senescent
p16
Ink4a
-positive microglia and oligodendrocyte progenitor cells
(OPCs) (Ogrodnik etal., 2021). Single-cell analysis of the senescent
microglial population demonstrates increased expression of IGF-1,
MIF, IL-1β, and TIMP-2 (Ogrodnik etal., 2021). Notably, the dentate
gyrus of female mice shows a stronger presence of senescent microglia
and macrophages compared to male. e presence of these senescent
myeloid cells in the dentate gyrus coincides with the downregulation
of mediators of synaptic transmission and inltration of T-cells and
B-cells (Zhang X. etal., 2022). Whole-body clearance of SCs either
genetically (AP20187 in INK-ATTAC mice) or pharmacologically
(dasatinib + quercetin) signicantly alleviated age-associated cognitive
function in naturally aged 25–29-month-old mice (Ogrodnik etal.,
2021). Furthermore, SC depletion with these strategies signicantly
reduced microglial activation and decreased peripheral T-cell presence
into the aged hippocampus (Ogrodnik etal., 2021; Zhang X. etal.,
2022). Hence, clearing SCs in the aged brain may rejuvenate the
immune landscape of the hippocampus and ameliorate age-related
cognitive decline.
Impaired neurogenesis
Neurogenesis is the process of generating new neurons in the
brain and is a relatively recent discovery in humans (Eriksson etal.,
1998). e dentate gyrus of the hippocampus and lateral subventricular
zone (SVZ) act as the neurogenic niches in the adult animal brain.
Neurogenesis in the SVZ is linked to olfaction, while neurogenesis in
the dentate gyrus contributes to learning and memory (Kumar
etal., 2019).
With aging, lamin-B1 is downregulated in the outer granule cell
layer of the dentate gyrus, which is mainly composed of neurons
involved in the consolidation of memory (Matias et al., 2022).
Furthermore, senescence in neuroblasts of the dentate gyrus in aged
humans and mice results in the elaboration of a pro-inammatory
SASP that recruits and activates natural killer (NK) cells, which, in
turn, eliminate neuroblasts (Jin etal., 2021). Attenuation of NK cell
accumulation preserves neurogenesis and improved cognitive
function in aged mice (Jin et al., 2021). Apart from neuronal
senescence, Miranda etal. showed that inoculating neuronal stem cells
(NSCs) with conditioned media of aged astrocytes (isolated from
13-month-old mice) reduces their proliferation compared to
conditioned media of young astrocytes isolated from 3-month-old
mice (Miranda etal., 2012).
Synaptic dysfunction
Synaptic dysfunction is fundamental to brain aging with or
without neurodegeneration. Peri-synaptic processes of astrocytes
enwrap synaptic structures to regulate many aspects of inter-neuronal
communication, including synaptogenesis, synapse maintenance, and
synapse elimination (Sofroniew and Vinters, 2010). ese peri-
synaptic processes of astrocytes particularly cover excitatory synapses,
where they take up glutamate in the synaptic cle via transporters like
GLT-1 and GLAST to prevent excitotoxicity. Glutamate is then
converted to glutamine and supplied to neurons (Tani etal., 2014).
Astrocytes are reported to undergo senescence prematurely in
response to ionizing radiation and hydrogen peroxide (H
2
O
2
)—
termed stress-induced premature senescence (SIPS) (Cohen and
Torres, 2019). SIPS astrocytes downregulate glutamate transporters
and promote excitotoxicity (Limbad etal., 2020). It is important to
state that the inducing stimulus has a profound impact on the specic
phenotype of SCs. Hence, this section discusses the impact of aged/
senescent astrocytes on synaptic function and not the consequences
of SIPS astrocytes (for more detail on SIPS astrocytes see Cohen and
Torres, 2019; Matias etal., 2022).
Astrocytes cultured in vitro to replicative senescence or isolated
from senescence-accelerated mouse models demonstrate a decrease
in their synaptogenic and neuroprotective capacity (Pertusa etal.,
2007; García-Matas etal., 2008; Clarke etal., 2018; Matias etal., 2022).
Indeed, co-culturing neurons with aged astrocytes that upregulate
senescence markers is associated with increased neuron death (Pertusa
et al., 2007; García-Matas etal., 2008). Furthermore, inoculating
hippocampal neurons with replicative senescent astrocyte attenuates
the release of the neurotransmitter glutamate from their presynaptic
terminals, reecting a decreased pool of synaptic vesicles (Kawano
etal., 2012). However, how age-related astrocyte senescence impacts
excitatory neurotransmission is conicting. Studies have demonstrated
both an increase and decrease in glutamate uptake in cortical and
hippocampal senescent astrocytes of aged mice (García-Matas etal.,
2008; Cao etal., 2019; Roalf etal., 2020; Matias etal., 2023). Similarly,
expression levels of glutamate transporters in senescent astrocytes
have been shown to increase and decrease (Lalo etal., 2011; Matias
etal., 2023).
ese diverging phenotypes may be determined by the
senescence-inducing stimulus. Indeed, SIPS astrocytes downregulate
glutamate transporters and promote excitotoxicity (Bitto etal., 2010;
Limbad et al., 2020), whereas senescent astrocytes in the
physiologically aged mouse hippocampus increase glutamate uptake
possibly as a protective mechanism against excitotoxicity (Matias
et al., 2023). Studying the age-related changes in astrocyte
morphology and physiology without the pretext of cellular
senescence, an elegant study compared the morphology and
physiology of astrocytes derived from the CA1 region of the
hippocampus of young (3–4-month-old), adult (9–12-month-old),
and old (20–24-month-old) mice (Popov etal., 2021). As astrocytes
age, their ne processes which enwrap synaptic structures become
atrophic. is is associated with a reduction in the uptake of
extracellular potassium and glutamate with the latter consequently
binding extra-synaptic NMDA receptors, thereby impairing long-
term potentiation (LTP) in the hippocampus—a process underlying
synaptic plasticity responsible for learning and memory (Popov
etal., 2021).
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It is important to identify the specic triggers and mechanisms
that drive aged astrocytes to seemingly divergent phenotypes
regarding glutamate homeostasis, and whether these trajectories can
betherapeutically manipulated to ameliorate age-related cognitive
impairment. Whether cellular senescence gures in this process is also
important to determine. Currently, despite cellular senescence being
well-characterized in the context of SIPS astrocytes, its relevance in
the aging process in the context of synaptic dysfunction is unclear.
Glial heterogeneity and senescence
Cellular heterogeneity at the metabolomic, epigenomic,
transcriptomic, and proteomic levels is being increasingly appreciated in
astrocytes and microglia (Shafqat etal., 2023). Current consensus from
the scientic community advocates moving away from the binary
classication of astrocytes and microglia into pro-inammatory (A1 or
M1) and anti-inammatory (A2 or M2) in favor of a spectrum of glial cell
reactivity that ranges between the extremes of pro-inammatory/
neurotoxic and anti-inammatory/neuroprotective phenotypes (Escartin
etal., 2021; Paolicelli etal., 2022). For instance, the functions of the
so-called A1 and A2 genes in astrocytes are mostly unknown, most
astrocytes with aging and disease exhibit a mixed A1/A2 phenotype
(Clarke etal., 2018; Grubman etal., 2019; Al-Dalahmah etal., 2020), and
both pathological and protective clusters of astrocytes can co-exist in CNS
diseases like multiple sclerosis and AD (Wheeler and Quintana, 2019;
Jiwaji etal., 2022). Where astrocytes exist on this reactivity spectrum in
dierent CNS disease states was recently shown to bedetermined by a
core set of 61 transcriptional regulators (Burda etal., 2022), so it would
beworth exploring how age-related astrocyte senescence alters these
transcription factors to modulate astrocyte reactivity.
e binary classication of microglia into M1 and M2 is an in
vitro classication based on the observation that microglia adopt
diverging phenotypes when stimulated by lipopolysaccharide/
interferon-γ and IL-4, respectively. However, this is not reective of
the in vivo reality in the healthy and diseased CNS, which contain a
mixture of M1- and M2-promoting factors that are spatiotemporally
dynamic (Ransoho, 2016). Accordingly, microglia exhibit
tremendous transcriptional heterogeneity, which is contingent upon
their location in the brain and local environmental signals such as
molecules released by astrocytes or BBB disruption in the context of
aging (Zheng etal., 2021; Masuda etal., 2022). In healthy and disease
CNS states, microglia exhibit a mixed M1/M2 gene signature
(Morganti etal., 2016; Masuda etal., 2019), likely determined with
their micro-environment that creates a spectrum of microglial
activation (Xue etal., 2014). With aging, transcriptional microglial
diversity decreases, but region-specic signatures are retained
(Masuda etal., 2019). Gender also plays a key role in determining
microglial state (Guneykaya etal., 2018; Lynch, 2022). With data
showing that senescence in the aging brain is region-and gender-
specic (Zhang X. et al., 2022), whether baseline microglial
heterogeneity contributes to dierential senescence susceptibility and/
or senescence phenotypes based on gender or location in the brain is
an outstanding question. Distinct microglial states appear with aging
like lipid droplet-accumulating microglia (LDAMs) (Marschallinger
etal., 2020) and white matter-associated microglia (WAMs) (Safaiyan
etal., 2021), but whether age-associated senescent microglia constitute
a distinct subset entirely or are a part of one of these other subsets
remains to bedetermined. Furthermore, when considering senescence
in myeloid cells, it is also not known whether senescence aects the
CNS-associated macrophages (CAMs) [also called border-associated
macrophages (BAMs)] that inhabit the perivasculature, choroid
plexus, and meninges.
Genetics of brain aging and cellular
senescence
Brain aging is incredibly heterogenous and its consequences with
respect to cognitive decline and neurodegeneration are not
experienced uniformly. From a biological viewpoint, this may indicate
that the susceptibility of the brain to cellular senescence may dier
between individuals.
Between-individual dierences in susceptibility to aging and
neurodegenerative disease may beunderpinned by the presence or
absence of certain genetic variants. For example, the International
Genomics of Alzheimer’s Disease Project conducted a meta-analysis
of genome-wide association studies to extend the list of genetic
variants associated with AD to more than 25 loci (Kunkle etal., 2019;
Andrews etal., 2020). Genome-wide association studies have also
identied several genetic variants associated with brain aging,
highlighting that brain aging is inuenced by the interaction of
multiple genes with varying functionalities (Hammond etal., 2019b;
McQuade and Blurton-Jones, 2019; Kim etal., 2023).
TREM2
Many genetic variants associated with cognitive decline and AD
are expressed in microglia, such as triggering receptor expressed on
myeloid cells-2 (TREM2) (Jonsson etal., 2013). TREM2 appears to
facilitate the pro-inammatory disease-associated microglia (DAM)
phenotype that appears in various CNS disease states (Keren-Shaul
et al., 2017). It was recently shown that TREM2-expressing
senescent microglia accumulate in aged and AD mouse brains,
which share signicant transcriptomic overlap with ‘highly
activated microglia’, a subset that uniquely appears in the brains of
aged mice and may trigger neuroinammatory responses
(Rachmian et al., 2023). Depleting TREM2-positive senescent
microglia in 5xFAD mice (which are models of accelerated Aβ
accumulation and AD) signicantly improved cognitive status and
decreased levels of inammatory cytokines in the brain (Rachmian
etal., 2023).
Apolipoprotein-E4
e apolipoprotein-E4 (ApoE4) allele is the most well-known
genetic variant associated with AD risk (Saeh etal., 2019). ApoE4 is
associated with neuro-inammaging, a decrease in proteins involved
in synaptic plasticity and function, and BBB disruption particularly in
the hippocampus (Halliday etal., 2016; Dai etal., 2018; Montagne
etal., 2020). Broadly speaking, these changes are the same as those
seen in the aging process. e well-established link between ApoE4
and neuro-inammaging is reviewed elsewhere (Kloske and Wilcock,
2020). In terms of biological aging, ApoE4 expression is both a cause
and consequence of mitochondrial dysfunction in the brain (Area-
Gomez etal., 2020; Junxiang etal., 2020; Schmukler et al., 2020;
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Wynne etal., 2023), which is implicated in AD pathogenesis and in
cellular senescence (Misrani etal., 2021; Miwa etal., 2022).
At the cellular level, ApoE4 exaggerates microglial
pro-inammatory responses to Aβ in AD mouse models (Kloske etal.,
2021; Serrano-Pozo etal., 2021). ApoE4 leads to an enrichment of a
specic microglial subset in normally aged mouse brains without AD/
neurodegeneration (Lee etal., 2023). ese ‘cluster 6 microglia (Mi_6)’
display a striking transcriptomic similarity to pro-inammatory
DAMs that appear in neurodegenerative disease (Keren-Shaul etal.,
2017; Victor etal., 2022; Lee etal., 2023). ApoE, irrespective of variant,
is believed to play a role in microglial ‘priming’ in early-stage AD by
directing their activation towards a DAM phenotype that phagocytose
tau-expressing neurons, which, in turn, induces senescence and type
IIFN production that is toxic to synapses (Lau etal., 2023). Hence,
ApoE4 may indirectly accelerate microglial senescence.
Separate from microglia, ApoE4 was recently found to decrease
acetyl-CoA levels in hippocampal neurons of elderly ApoE4 mice,
resulting in cellular senescence (Lv etal., 2023). Supplying glycerol
triacetate (GTA) to increase acetyl-CoA levels to ApoE4 elderly mice
decreased cellular senescence in neurons and increased expression of
proteins related to synaptic plasticity.
Repressor element-1-silencing
transcription factor
Repressor element-1-silencing transcription factor (REST)
expression in the brain is associated cognitively healthy brain aging
but is lost in mild cognitive impairment and neurodegeneration (Lu
etal., 2014; Zullo etal., 2019). Functionally, REST appears to protect
neurons from oxidative stress and Aβ-related neurotoxicity and
repress genes associated with AD (Lu etal., 2014). In animals and
humans with extended longevity, REST is upregulated and
downregulates neuronal excitability in the cerebral cortex (Zullo
etal., 2019).
Recently, a GWAS implicated REST and its extended gene
network with cognitive decline (Wang etal., 2023), indicating that
perhaps genetic variations of REST could account for the between-
individual variability in the brain aging phenotype. An obvious area
of mechanistic exploration would be how REST inuences
biological aging hallmarks such as cellular senescence. Neurons
isolated from REST-knockout mice demonstrate impaired
autophagy, loss of proteostasis, higher oxidative stress,
mitochondrial dysfunction and cellular senescence (Rocchi etal.,
2021). Notably, restoring autophagy by treating neurons from
REST-depleted mice with rapamycin reverses the senescence
induction as well as its cellular hallmarks (Rocchi etal., 2021).
ese ndings suggest that REST protects against neuronal
senescence by maintaining autophagic ux in neurons.
Epigenetics of brain aging and cellular
senescence
Epigenetic modications like DNA methylation, histone tail
modications, and microRNAs regulate gene expression without
changing the genome sequence (Bonasio etal., 2010). e epigenome
of humans is incredibly dynamic and undergoes consistent changes in
response to environmental exposures as well as the aging process. In
the brain, age-related epigenetic changes regulate the expression of
genes involved in synaptic plasticity, learning and memory, and
neurogenesis (Miller etal., 2010; Barter and Foster, 2018). is topic
has been reviewed in detail elsewhere (Barter and Foster, 2018;
Harman and Martín, 2020; Bacon and Brinton, 2021).
e consistent nature of DNA methylation alterations in whole
blood and tissues has enabled the development of epigenetic clocks
that leverage these patterns to precisely calculate an individual’s
chronological and/or biological age (Horvath and Raj, 2018). e
Horvath and Hannum clocks predict chronological age (Hannum
etal., 2013; Horvath, 2013), the PhenoAge clock predicts phenotypic
age and GrimAge is predictive of lifespan and mortality risk (Levine
et al., 2018; Lu et al., 2019). e observation that tissues exhibit
dierential susceptibility to epigenetic aging has led studies to create
clocks trained on methylation signatures of a specic tissue. For
instance, a cortical clock trained on DNA methylation data from the
human cortex spanning ages 1–108 years accurately predicted cortical
age in a validation dataset (Shireby etal., 2020). A higher biological
compared to chronological age as measured by epigenetic clocks has
been termed epigenetic age acceleration (EAA) (Horvath and Raj,
2018). Epigenetic age and EAA are signicantly more accurate than
chronological age at predicting age-related atrophic changes of several
regions of the cerebral cortex (Proskovec etal., 2020; Cheong etal.,
2022; Hoare etal., 2022), rationalizing the use of epigenetic clocks as
potential biomarkers of accelerated cortical aging and cognitive
decline risk.
e observation that cellular senescence is associated with
drastic changes in chromatin organization and transcriptomic and
proteomic identity of a cell has led studies to characterize the
epigenome of SCs. A detailed discussion on the broad epigenetic
modications displayed by SCs is beyond the scope of this review
and have been detailed elsewhere (Zhu etal., 2021; Crouch etal.,
2022). Suce it to say that the specic epigenetic alterations seen
in senescent cells are context-dependent, i.e., based on the type of
senescent-inducing stimulus (e.g., replicative senescence vs. SIPS)
(Shock et al., 2011; Chandra et al., 2012; Sakaki et al., 2017).
Accordingly, not all types of cellular senescence are associated with
epigenetic aging as measured by the aforementioned clocks; while
replicative and oncogene-induced SCs are accompanied by
epigenetic aging as measured by the Horvath clock, radiation-
induced SIPS is not (Lowe etal., 2016).
Epigenetic alterations in SCs are particularly important for the
expression of the SASP. Expression of high-mobility group box-2
(HMGB2) in SCs prevents the association of SASP genes into
heterochromatin (Aird et al., 2016). Activating histone tail
modication marks like acetylation and methylation are increased at
key SASP genes in SCs (Capell etal., 2016; Tasdemir etal., 2016). At
the same time, the activity of NAD-dependent histone deacetylase
(HDAC) sirtuin-1, which can deacetylate and thereby decrease the
expression of SASP genes, is decreased in SCs (Hayakawa etal., 2015;
Wiley etal., 2016). KDM4, a histone deacetylase is activated in SCs
secondary to genotoxic stressors like cancer therapy, leading to
signicant chromatin reorganization with increased expression of
SASP proteins (Zhang etal., 2021). Targeting KDM4in SCs attenuates
the SASP without aecting cell-autonomous senescence, improving
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response to chemotherapy, and increasing survival in animals (Zhang
etal., 2021). Given the essential nature of cellular senescence in wound
healing and repair, maintaining cell cycle arrest in tumor cells, and
embryogenesis, it may bemore favorable to target the SASP rather
than cell-autonomous senescent phenotype itself. However,
epigenome alterations in the context of senescence in the aging brain
are largely unexplored.
Nativio etal. (2018) showed that cognitively healthy elderly
individuals age dierently at the epigenetic level than patients
suering from neurodegenerative diseases like AD. e histone
acetylation mark H4K16ac shows a genome-wide increase in the
brain of elderly individuals who are cognitive normal, whereas it
decreases in those with AD. e specic regions of DNA that show
H4K16ac alterations in AD patients overlap signicantly with
known genetic variants that confer an increased risk of AD on
GWAS (Nativio etal., 2018). Other studies have shown that an
increase in H3K16ac marks is related to senescence induction and
increased expression of proteins involved in the senescent
phenotype (Dang etal., 2009; Rai etal., 2014). By this way, normal
brain aging and cellular senescence seem to overlap in their
epigenetic changes. Indeed, clustering specic genes showing
H4K16ac changes during cognitively normal aging are also shown
to bealtered in SCs (Nativio etal., 2018). At the same time, AD
appears to not bea consequence of normal aging and age-related
senescence but rather a feature of dysregulated molecular aging.
ese ndings also indicate that cellular senescence in the brain is
not a ubiquitously pathological process that leads to
neurodegenerative disease but rather a process of normal
brain aging.
An example of how histone PTMs in the brain are potentially
modiable by environmental exposure and may be related to
senescence is the neurotoxin paraquat, a risk factor for Parkinson’s
disease (PD). In terms of its mechanism of action, paraquat
increases histone acetylation and decreases activity of HDAC4
(Song etal., 2011). Exposing astrocytes to paraquat in vitro leads to
HDAC4 inhibition-dependent senescence (Chinta etal., 2018).
Furthermore, the burden of senescent astrocytes is increased in
post-mortem brain tissue of PD patients, suggesting that epigenetic
modications in the brain are modiable by environmental factors,
which may then exert their downstream eects through
cellular senescence.
Cellular senescence in early brain
aging
Accelerated aging-like states are a well-established phenomenon
in several patient populations. ese individuals prematurely develop
age-related diseases including cognitive impairment, hinting toward
the acceleration of biological aging processes such as cellular
senescence in the brains of these patients. Evidence for accelerated
brain aging in these patients is presented in Table1, while Table2 links
the premature brain aging phenotype in these patients to cellular
senescence. e direct role of senescence in CKD-and OSA-associated
accelerated brain aging has not been demonstrated, hence wehave
restricted Table 2 to important studies on TBI, cancer therapy,
and obesity.
Traumatic brain injury
Mild TBIs, including concussions or other minor sub-concussive
head trauma, are common in the general population. All forms of TBI
regardless of severity confer a higher long-term risk of dementia
(Gardner etal., 2014). TBI is also associated with an increased long-
term risk of developing early-onset AD, PD, and chronic traumatic
encephalopathy (Nambiar etal., 2023).
Senescence markers like SA-β-gal, reduced lamin-B1,
γ-H2AX, and SASP components IL-1β, IL-6, CXCL1, and CCL8
are elevated in the brains of repeated TBI mouse models
displaying cognitive deficits and in post-mortem brain samples
of individuals with a history of repeated concussions (Tominaga
et al., 2019; Schwab etal., 2019a,b; Mester etal., 2021). TBI
acutely induces oxidative stress and DDRs in the brain (Singh
etal., 2006; Czarny etal., 2015; Halstrom etal., 2017). Indeed,
markers of DDR are significantly elevated 24 h after injury, while
gene expression profiles at 7 and 14 days post-injury are
consistent with cellular senescence and the production of a
pro-inflammatory SASP (Schwab etal., 2021). Aged mice display
worse motor and cognitive outcomes post-TBI than younger
mice, associated with a higher senescence burden in the cortex
and in microglia at baseline that is significantly exacerbated by
the traumatic insult (Ritzel et al., 2019). This microglial
phenotype of aged mice exhibits diminished homeostatic
functions and skewing towards inflammation, which may explain
why aged mice develop more pronounced neuroinflammation
post-TBI (Ritzel etal., 2019). These findings suggest that a higher
burden of SCs may explain why older age is a poor prognostic
factor for TBI.
Abnormal protein accumulation is a pathologic hallmark of
TBI. Like AD, TBI features Aβ accumulation, which has been
found to trigger senescence in astrocytes (Bhat etal., 2012; Shang
etal., 2020), microglia (Flanary etal., 2007), and NSCs (Wei etal.,
2016; Scopa etal., 2020; Ohline etal., 2022). Depleting senescent
OPCs with the senolytic cocktail of dasatinib and quercetin
reduces Aβ load, alleviates neuroinflammation, and improves
cognitive function (Zhang etal., 2019). TBI also promotes the
intracellular accumulation of hyperphosphorylated tau in
neurofibrillary tangles (NFTs) in neurons (Katsumoto etal., 2019;
Edwards etal., 2020). In AD, NFT-containing neurons upregulate
p16
Ink4a
and pro-inflammatory SASP, associated with cerebral
atrophy and cognitive decline (Musi etal., 2018). The senolytic
cocktail of dasatinib and quercetin significantly reduces the
burden NFT-containing cortical neurons, decreasing cerebral
atrophy and suppressing pro-inflammatory SASP expression
(Musi et al., 2018). Senescent astrocytes and microglia also
accumulate in mouse models of tauopathy, promoting cortical
degeneration and cognitive dysfunction (Bussian etal., 2018).
Tau-induced senescent astrocytes contribute to cognitive decline
via HMGB1 and NLRP3 inflammasome activation (Gaikwad
etal., 2021). Admittedly however, prominent distinctions between
the pathophysiology of AD and TBI are evident (Katsumoto etal.,
2019). For instance, cellular senescence appears to bean acute
consequence of TBI which precedes pathologic protein, but is a
consequence of Aβ and hyperphosphorylated tau in AD (Schwab
etal., 2021).
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Repeated mild TBI is also associated with the emergence of senescent
astrocytes and neurons in the cortex and hippocampus (Schwab etal.,
2022). Single-cell RNA-sequencing of neurons revealed several
transcriptionally distinct neuronal clusters all of which upregulate core
features of cellular senescence including p16Ink4a/p21Cip1/Waf1, SCAPs, and
a pro-inammatory SASP. e transcriptome of astrocytes indicated the
production of a pro-inammatory SASP and dysregulated glutamate
neurotransmission with downstream excitotoxicity, indicating the TBI
serves as a type of SIPS stimulus in astrocytes with downregulation of
glutamate transporters (Schwab et al., 2022). Administration of the
senolytic ABT263 signicantly decreases p21
Cip1/Waf1
expression and
improves memory and executive function in male mouse models of
repeated mild-TBI (Schwab etal., 2022).
Cancer survivors and therapy-induced
senescence
Adult and childhood cancer survivors experience accelerated
aging manifested in the premature onset of frailty, sarcopenia,
osteoporosis, osteoarthritis, second cancers, endocrinopathies, and
other chronic diseases earlier than age-matched healthy controls (Ness
etal., 2015; Cupit-Link etal., 2017; Shafqat etal., 2022).
Cancer treatment-related cognitive impairment is well-
documented and aects patients regardless of cancer type and location
(Lange etal., 2019; Országhová etal., 2021; Table1). Cancer treatments
such as chemotherapy, radiotherapy, hormonal therapy, and
immunotherapy induce senescence in tumor cells but also in normal
cells, known as therapy-induced senescence (TIS) (Wang et al.,
2020b). Radiotherapy exposure triggers a DDR that promotes
apoptosis or senescence, both of which would arrest tumor growth.
However, this phenomenon occurring in non-tumor cells leads to
systemic SC accumulation and subsequent tissue aging (Wang
etal., 2020b).
Radiation-induced brain injury is a major risk factor for long-
term neurocognitive dysfunction in cancer survivors (Greene-
Schloesser et al., 2012). One-year-old mice exposed to full-body
radiation exhibit a signicantly higher burden of senescent neurons
in the hippocampus comparable to levels in two-year-old mice, which
is associated with cognitive decline (Fielder etal., 2022). Similarly,
the irradiated brain tissue of cancer patients exhibits a signicantly
higher burden of p16
Ink4a
-positive senescent astrocytes than
age-matched controls and patients with the same cancer type who did
not receive radiation (Greene-Schloesser etal., 2012; Turnquist etal.,
2019), although whether the irradiated cancer group demonstrated a
greater burden of neurocognitive decits was not determined.
TABLE1 Evidence on early brain aging in certain patient populations.
Patient population Evidence about premature brain aging
Cancer survivors
Cancer survivors overall and survivors of cancer for ≥5 years before cognitive testing, respectively, were signicantly more likely than their
co-twin to develop cognitive dysfunction (OR = 2.10, 95% CI = 1.36 to 3.24; p< 0.001) and (OR = 2.71, 95% CI = 1.47 to 5.01; p< 0.001)
(Hein etal., 2005).
At a mean of 12 years aer treatment for low-grade gliomas, patients who received radiotherapy had signicantly worse attention decits—
even supposed safe fraction doses (≤2 Gy)—than those who did not receive radiotherapy (Douw etal., 2009).
Traumatic brain injury
TBI is associated with increased dementia risk (hazard ratio (HR) = 1.46; 95% CI = 1.41–1.52). Moderate/severe TBI increased risk of
dementia across all ages (age 55–64: HR = 1.72; 95% CI 1.40–2.10 vs. age 65–74: HR = 1.46; 95% CI 1.30–1.64), whereas mild TBI may
bemore detrimental with increasing age (age 55–64 HR = 1.11; 95% CI 0.80–1.53 vs. age 65–74 HR = 1.25; 95% CI 1.04–1.51) (Gardner etal.,
2014).
A recent study examined the impact of mild TBIs on brain aging in 133 participants aged 20–83 years using T1-weighted magnetic
resonance (MRI) imaging findings taken within 7 days and 6 months after TBI. This study showed that mild TBI ages the brain of
older adults (>60 years old) by approximately 10 years. Biologically, hallmarks of CNS aging such as neuroinflammation, glial cell
reactivity, excitotoxicity, and abnormal protein accumulation—tau and amyloid-beta (Aβ)—have been observed in TBI brains
(Halstrom etal., 2017).
Obesity
Obesity increases the risk of mild cognitive impairment, independent of age and cardiovascular risk factors. Obesity in middle-aged adults
increases risk of dementia by 1.5–2 times up to the age of 65 (Dahl et al., 2013; Hassing et al., 2010; Whitmer et al., 2008).
Obesity has been shown to double the risk of Alzheimer’s disease (Anstey etal., 2011; Pedditzi etal., 2016), with postmortem studies of obese
elderly individuals showing increased concentrations of amyloid-beta and hyperphosphorylated tau, which were associated with
hippocampal atrophy (Mrak, 2009).
Obstructive sleep apnea
Compared to controls, patients with moderate–severe OSA performed worse on the Rey Auditory-Verbal Learning test (immediate and
delayed recall), Stroop test, and Digit span backward scores. Patients with moderate–severe OSA had a lower volume of cortical gray matter
(GM), right hippocampus, and the right and le caudate (Torelli etal., 2011).
Greater OSA severity, as indicated by a higher AHI score and lower oxygen saturation during sleep, is directly correlated with the promotion
of several biological aging hallmarks in patients younger than 50 years old, including altered cellular communication, dysregulated nutrient
sensing, mitochondrial dysfunction, and genomic instability (Pinilla etal., 2021).
Chronic kidney disease
A meta-analysis of cross-sectional and longitudinal studies, respectively, of 54, 779 CKD patients demonstrated that patients with CKD were
signicantly more likely to suer cognitive decline than patients without CKD (OR 1.65, 95% CI 1.32–2.05; p< 0.001 and OR 1.39, 95% CI
1.15–1.68; p< 0.001, respectively) (Etgen etal., 2012).
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Irradiated human senescent astrocytes downregulate glutamate
transporters that lead to excitotoxicity (Limbad et al., 2020).
Furthermore, co-culturing NSCs with irradiated human senescent
astrocytes decreases NSC viability and increases their apoptosis,
mediated by astrocyte-derived IL-6 (Turnquist etal., 2019). Reversing
astrocyte senescence attenuates astrocyte-mediated
neuroinammation, indicated by reduced IL-6 production, and
increases mRNA expression of the neurotrophic factor IGF-1
(Turnquist etal., 2019). Administering senolytic drugs (navitoclax or
dasatinib+quercetin) or senomorphic drugs (metformin) to
sub-lethally irradiated mice eectively prevents frailty progression,
improves muscle and liver function, and improves short-term
memory, although the exact brain cell types targeted by these
medications which resulted in improved memory were not
determined (Fielder etal., 2022). Nevertheless, emerging evidence
suggests that cellular senescence could bea novel therapeutic target
for preventing radiotherapy-related cognitive decits in
cancer survivors.
Chemotherapy-induced cognitive impairment (CICI) is a well-
known phenomenon that aects long-term outcomes of cancer
survivors, encompassing decits in memory, executive function,
attention, processing speed, and psychomotor dysfunction (Ossorio-
Salazar and D’Hooge, 2023). With respect to chemotherapy, Demaria
et al. reported that doxorubicin-treated mice have systemic
upregulation of senescence markers and SASP components like IL-1,
IL-6, MMP-3/9, CXCL1, CXCL10, and CCL20 (Demaria etal., 2017).
It is remarkable that depleting SCs almost entirely prevents
doxorubicin-induced cardiomyopathy and signicantly increases the
nocturnal running time of mice (Demaria etal., 2017). Similarly, the
targeted apoptosis of SCs mitigates doxorubicin-induced
hepatotoxicity and improves tness, fur density, and renal function of
prematurely aged and normally aged mice (Baar etal., 2017).
Paclitaxel is a notorious chemotherapeutic agent known to cause
CICI (Ahire etal., 2023). Treating transgenic p16-3MR mice with
paclitaxel for 10 days resulted in cerebrovascular endothelial cell
senescence (SA-β gal-positivity), which was associated with decits in
spatial memory cognitive performance, a decrease in microvascular
density, and an increase in BBB permeability and neuroinammation.
Importantly, genetically (ganciclovir) or pharmacologically (senolytic
anti-BCL2 agent ABT263) depleting senescent endothelial cells in
p16-3MR mice restored BBB integrity, decreased neuroinammation,
improved microvascular density, and improved cognitive performance
(Ahire etal., 2023). ese results, for the rst time, made a strong case
that senescence of cerebrovascular endothelial cells is involved in the
pathogenesis of CICI and that senolytic treatment may be a novel
intervention for ameliorating CICI.
Obesity
Obesity negatively impacts cognition independent of its
cardiovascular comorbidities and increases the lifetime risk of
Alzheimer’s disease and dementia (Beydoun et al., 2008).
Neuroimaging studies in obese patients have shown reduced cortical
volume, particularly in areas mediating cognition such as the
hippocampus (Ward etal., 2005; Raji etal., 2010; Table1).
TABLE2 Evidence of cellular senescence in early brain aging.
Patient population Evidence of cellular senescence in early brain aging
Traumatic brain injury
Subjecting young (12-week-old) and aged (18-month-old) male C57BL/6 mice to controlled cortical impact (CCI) results in more severe
decits in forelimb grip strength, balance, motor coordination, spontaneous locomotor activity, and anxiety-like behavior in the aged group.
Aged mice showed higher number of peripheral leukocyte inltration post-TBI. Microglia of aged mice showed signicantly higher senescent
markers (BCL-2, p16Ink4a, p21Cip1/Waf1, and H2AX) at baseline and aer CCI, associated with impairment in phagocytosis and higher IL-1β
production (Ritzel etal., 2019).
Mild-repeated TBI (mrTBI) in C57BL/6 mice results in behavioral disinhibition and cognitive impairment. Examination of the brain 1-week
post-TBI reveals upregulation of DNA damage, the cytosolic DNA sensor cGAS/STING, and cellular senescence. ScRNA-seq revealed distinct
neuronal clusters, astrocytes, OPCs, immune cells, and vascular cells showing features of cell cycle arrest, SCAP upregulation, and SASP
signaling. Treating mrTBI mice with navitoclax decreased senescence markers in male mice but not female mice. Navitoclax treatment
improved cognitive performance on the Morris water maze test in male mice (Schwab etal., 2021, 2022).
Cancer survivors
Brain tissues of irradiated cancer patients show an upregulation of p16Ink4a-positive astrocytes compared to age-matched controls and
untreated cancer patients. Irradiated astrocytes in vitro downregulate glutamate transporters and produce IL-6. In human astrocytes, Δ133p53
prevents radiation-induced senescence and ameliorates astrocyte-mediated neuroinammation and neurotoxicity (Turnquist etal., 2019;
Limbad etal., 2020).
Paclitaxel (PTX) induces senescence (SA β-gal) in cebromicrovascular capillary endothelial cells of transgenic p16-3MR mice. PTX treatment-
related senescence is associated with reduced indices of cerebrovascular density, decits in neurovascular coupling responses, greater
transcellular permeability between cerebromicrovascular endothelial cells, and signicant impairments in cognitive function and spatial
memory. Ganciclovir-or ABT263-mediated clearance of SCs in PTX-treated pmice signicantly improved cognitive function, neurovascular
coupling, and BBB integrity (Ahire etal., 2023).
Obesity
HFD in C57BL/6 mice leads to anxiety-like behavior. Genetic clearance of SCs by AP20187in INK-ATTAC or dasatinib + quercetin in leptin
receptor-decient obese mice both reduced anxiety-like behavior. SCs accumulated in the amygdala and hypothalamus (but not in the cortex
or hippocampus), which was signicantly decreased by AP20187. HFD increased accumulation of lipid droplets in senescent astrocytes and
microglia in periventricular regions, skewing them toward inammation with higher CXCL1 and IL-6 production. Obese mice displayed
signicant reductions in the numbers of NSCs, immature neurons, and CD133+ ependymal cells in the lateral SVZ, indicating impaired
neurogenesis. AP20187 signicantly increased stem cell and astrocyte numbers in the SVZ, indicating increased neuronal plasticity post-
treatment (Ogrodnik etal., 2019).
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Frontiers in Aging Neuroscience 12 frontiersin.org
Mechanistically, obesity accelerates numerous biological aging
processes, including inammaging, oxidative stress, telomere attrition,
epigenetic alterations, mitochondrial dysfunction, and cellular
senescence (Nunan et al., 2022). A higher SC burden has been
observed in adipose tissue in obesity, aecting preadipocytes,
adipocytes, endothelial cells, and adipose tissue-resident macrophages
(Smith etal., 2021). Furthermore, SCs accumulate in the kidneys of
HFD-obese mice, which is associated with renal dysfunction (Kim
etal., 2019). e livers of obese mice also display a higher SC burden,
linked to hepatic steatosis and non-alcoholic fatty liver disease
(Aravinthan etal., 2013; Ogrodnik etal., 2017).
However, evidence directly implicating senescence as a
mechanism of obesity-related brain aging is currently limited.
Ogrodnik etal. (2019) documented senescence in glial cells in the
amygdala and hypothalamus in obese INK-ATTAC transgenic mice
and leptin receptor-decient obese mice, linked to anxiety-like
behavior. Depleting SCs in obese INK-ATTAC transgenic mice
decreased SC burden in the amygdala and hypothalamus and relieved
anxiety-related behaviors. Obesity also leads to a decrease in the
population of NSCs in the SVZ, which could bepartially recovered by
AP20187 treatment in INK-ATTAC mice (Ogrodnik et al., 2019).
ese results indicate that obesity-related senescence preferentially
aects areas of the brain responsible for anxiety and fear like the
amygdala, but not the hippocampus, which is responsible for learning
and memory. Modulation of senescence may therefore hold
therapeutic value in treating neuropsychiatric disorders in
obese individuals.
Obstructive sleep apnea
OSA is an increasingly prevalent sleep breathing disorder that
results in apnea or hypopnea due to episodic partial or complete
airway obstruction during sleep. Common symptoms of OSA include
loud snoring, gasping, or choking during sleep, nighttime awakenings,
daytime sleepiness, and fatigue (Young et al., 2004; Madani and
Madani, 2009; Rundo, 2019). OSA patients, particularly those with
moderate-to-severe disease, face an increased risk of cognitive
impairment compared to age-matched healthy controls (Torelli etal.,
2011). OSA patients also tend to develop chronic diseases earlier than
healthy controls, including cardiovascular disease, metabolic
disorders, cancer, and neurodegeneration (Veasey and Rosen, 2019).
Biologically, OSA is independently linked to higher burdens of
oxidative stress and inammaging (Lavie, 2015; Liberale and Camici,
2020), prompting consideration of OSA as an accelerated aging
phenotype (Gaspar etal., 2017).
OSA leads to chronic intermittent hypoxia (CIH) and sleep
fragmentation (Gaspar etal., 2017). Sleep disturbance in OSA has
been shown to accelerate telomere attrition, leading to replicative
senescence (Tempaku etal., 2015; Turkiewicz etal., 2021). Exosomes
derived from the blood of OSA patients can induce endothelial cell
senescence and vascular dysfunction, which is partially reversible with
continuous positive airway pressure (CPAP) therapy (Khalyfa etal.,
2020). CIH has recently been demonstrated to induce senescence in
multiple tissues, including preadipocytes, kidneys, vasculature, and
heart (Polonis etal., 2020; Badran etal., 2021; Wei etal., 2022). In the
brain, CIH increases markers of oxidative stress, DNA damage, and
inammation in several regions associated with early-stage AD and
PD (the entorhinal cortex and substantia nigra, respectively). While
this study did not evaluate markers of senescence, such an
environment is known to induce senescence (Martínez-Cué and
Rueda, 2020). However, no study so far has directly investigated the
role of senescence in OSA-related brain changes.
Chronic kidney disease
CKD aects about 15% of US adults and incurs signicant
morbidity, mortality, and health expenditures (Hoerger etal., 2015;
Kovesdy, 2022). Chiu etal. (2019) demonstrated that non-demented
end-stage kidney disease patients receiving dialysis exhibit structural
and cognitive changes associated with normal aging. CKD patients are
also susceptible to systemic early aging-related conditions, including
osteoporosis and pathologic fractures (Pimentel etal., 2017; Hsu etal.,
2020), hypogonadism (Skiba etal., 2020), impaired wound healing
(Maroz and Simman, 2013), insulin resistance (Spoto etal., 2016),
cardiovascular disease (Jankowski et al., 2021), cerebrovascular
disease (Vanent etal., 2022), cognitive impairment (Etgen etal., 2012),
immunosenescence (Crépin etal., 2020), and sarcopenia (Stenvinkel
and Larsson, 2013).
Mouse models of CKD exhibit increased microglial activation,
which correlates with incidence of cerebral microhemorrhages (Fang
etal., 2023). Uremic toxins that accumulate in CKD, such as indoxyl
sulfate, p-cresyl sulfate, trimethylamine-N-oxide (TMAO), and urea,
increase BBB permeability (Lau etal., 2020; Fang etal., 2023). ese
changes—BBB leakiness, microglial activation, and
neuroinammation—are also observed in the aged brain (Sierra etal.,
2007; Koellhoer etal., 2017; Marschallinger etal., 2020; Paul etal.,
2021; Connolly et al., 2022; Iwao et al., 2023). us, CKD may
precipitate a premature aging phenotype by accelerating fundamental
aging processes (Huang etal., 2022; Arabi etal., 2023).
Cellular senescence in CKD involves multiple mechanisms.
Hyperphosphatemia induces senescence in endothelial cells,
myoblasts, and vascular smooth muscle cells, contributing to vascular
aging (Troyano etal., 2015; Yamada etal., 2015; Sosa etal., 2018; Liu
etal., 2021). Uremic toxins in the bloodstream of CKD patients can
induce senescence by imposing oxidative stress and consequent DNA
damage (Vaziri, 2004; Han etal., 2018; Lee etal., 2018). For example,
indoxyl sulfate and TMAO promote ROS-dependent senescence in
the aorta, associated with endothelial dysfunction, vascular
calcication, and wall stiening—all indicators of vascular aging (Ke
etal., 2018; Brunt etal., 2020, 2021; Lau etal., 2020). Indoxyl sulfate
also induces senescence in CD34+ hematopoietic stem cells and curbs
their dierentiation into mature erythrocytes, possibly contributing
to the normocytic normochromic anemia observed in CKD patients
(Duangchan et al., 2022). P-cresyl sulfate promotes senescence
features—ROS production, DDR, and proinammatory SASP—in
mouse adipocytes, promoting adipose tissue inammation and insulin
resistance (Koppe etal., 2013; Tanaka etal., 2020).
In the brain, indoxyl sulfate activates the aryl hydrocarbon
receptor (AhR) on astrocytes and microglia, increasing oxidative
stress and neuroinammation and accelerating cognitive impairment
(Adesso etal., 2017, 2018; Bobot et al., 2020). TMAO-dependent
astrocyte reactivity is implicated in aging-related cognitive decline
(Clarke etal., 2018; Csipo etal., 2020; Brunt etal., 2021). TMAO has
been shown to induce senescence in hippocampal neurons, decreasing
Shafqat et al. 10.3389/fnagi.2023.1281581
Frontiers in Aging Neuroscience 13 frontiersin.org
their expression of synaptic plasticity-related proteins (Li etal., 2018).
DMB, which is an enzyme that decreases TMAO levels, mitigates
cognitive decline in mouse models of accelerated cellular senescence
(Lanz etal., 2022), potentially reecting a reduction in SC burden in
the brain of treated mice.
The future of senotherapies
e remarkable evolution of senolytics and senomorphics from
bench to bedside has resulted in much hype surrounding these drugs
as so-called anti-aging agents. However, several unanswered questions
must rst beaddressed to eectively translate these agents into clinical
practice (Shafqat etal., 2022). Firstly, senescence induction plays
essential roles in wound healing, embryogenesis, and tumor
suppression, underscoring the importance of delineating potential
contraindications. Secondly, the long-term eects of removing or
altering SCs are unknown. In the context of brain aging, it is crucial
to consider the possible long-term consequences on CNS function of
depleting senescent neurons incapable of renewal. ere is also no
agreed-upon senescence biomarker, a composite score of markers, or
a way to gauge the eectiveness of senolytics or senomorphics in
humans other than observable phenotypic/functional improvement.
Lastly, as of 2023, most data on senolytics and senomorphics come
from preclinical animal studies. Data from ongoing clinical trials
studying these drugs in larger and longer cohorts will provide more
information on the ecacy and, more importantly, the safety of
these medications.
Other senescence-targeting strategies, such as immune-direct
strategies and hyperbaric oxygen therapy (HBOT) are currently under
study and may provide an alternative to the SCAP-targeting senolytics
or SASP-targeting senomorphics. Gene therapy and epigenetic
reprogramming may also befeasible approaches to combat cellular
senescence in aging and have been recently reviewed (Zhang etal.,
2020; Wang etal., 2022; Yu etal., 2023).
Immune-mediated SC clearance
'Senescence surveillance’ was introduced by Kang and colleagues
when they observed that senescent pre-malignant hepatocytes
secreted a SASP that recruited CD4+ T-cells, which cleared these SCs
(Kang etal., 2011). Mechanistically, macrophages can upregulate class
IMHC and antigen-processing machinery in senescent tumor cells,
facilitating their recognition by CD8+ T-cells (Reimann etal., 2021;
Sturmlechner etal., 2021; Chen etal., 2023; Marin etal., 2023). SCs
also transfer antigenic peptides to dendritic cells, which, in turn,
activate CD4+ T-cells (Chandra etal., 2012; Prata etal., 2018). e SC
peptidome is signicantly dierent from their parental non-senescent
cells and can act as a target for cell-mediated (T-cell) and humoral
(B-cell) immune responses (Frescas etal., 2017; Suda etal., 2021). One
such protein termed a ‘seno-antigen’, glycoprotein nonmetastatic
melanoma protein B (GPNMB), was formulated into a senolytic
vaccine and injected into progeroid mice, eectively reducing SC
burden, alleviating pathological eects of obesity and atherosclerosis,
and extending lifespan (Suda etal., 2021). Amor et al. developed
chimeric antigen receptor (CAR) T cells targeting urokinase-type
plasminogen activator receptor to deplete SCs in mouse models of
lung cancer and hepatic brosis (Amor et al., 2020). Given this
apparent immunogenicity of SCs, it is curious why SCs accumulate in
aged tissues and are not cleared by the immune system. An aging
functionally declining immune system may not beas eective in
clearing SCs (Prata etal., 2018), or SCs may upregulate certain surface
proteins like PD-L1, which allow them to evade immune surveillance
(Onorati et al., 2022; Wang et al., 2022). How immune-directed
senolytic strategies can berepurposed to target SCs in the brain is
unchartered territory.
Hyperbaric oxygen therapy
Hyperbaric oxygen therapy (HBOT) involves breathing pure
oxygen at a heightened atmospheric pressure to increase partial
pressure of oxygen in the bloodstream and improve oxygen delivery
to tissues. Oxygen has a dual relationship with aging (Hopf etal.,
2005; de Wolde etal., 2022; Fu etal., 2022). It is the source of ROS
that induce lipid peroxidation, DNA damage, and protein
dysfunction. However, repeated exposures to high oxygen pressures,
such as in HBOT, can augment antioxidant responses and
angiogenesis and reduce inammation (Hopf etal., 2005; de Wolde
etal., 2022; Fu etal., 2022). ese eects of HBOT are evident in
tissue rejuvenation strategies, such as ischemic wound healing and
recovery aer muscle injury, where it decreases inammation and
apoptosis to promote healing (Zhang and Gould, 2014; Oyaizu
etal., 2018).
As a senescence-alleviating treatment modality, HBOT can reduce
the number of SA-β gal-positive cardiomyocytes in aging pre-diabetic
rats (Bo-Htay etal., 2021). A prospective clinical trial with a cohort of
70 healthy participants (mean age = 68.07 years) receiving HBOT for
3 months reported a signicant increase in collagen density, elastic
ber length, and vascularity in serial skin biopsies in treated
individuals (Hachmo etal., 2021). Tissue SCs were also signicantly
decreased in the treated group, indicated by reduced lipofuscin
expression (Hachmo etal., 2021). Other studies have documented a
decrease in the levels of cytokines, chemokines, and MMPs aer
HBOT in the context of aging, indicating that this therapeutic
modality can attenuate SASP production (De Wolde etal., 2021; Fu
etal., 2022). Telomere elongation appears to beone of the primary
mechanisms by which HBOT attenuates cellular senescence (i.e.,
replicative senescence). A study on deep sea divers and a prospective
clinical trial of 35 old adults (>65 years old) receiving HBOT both
documented signicantly increased telomere length in peripheral
blood mononuclear cells aer the treatment (Shlush et al., 2011;
Hachmo etal., 2020).
HBOT has also been applied to the context of cognitive decline. Chen
and colleagues intraperitoneally injected -galactose into mice to mimic
age-related cognitive impairment and simultaneously administered
HBOT, which signicantly reversed -galactose-induced learning and
memory impairment and decreased p16
Ink4a
, p21
Cip1/Waf1
, and p53
expression in the hippocampus (Chen etal., 2016). Similarly, HBOT
restores cognitive function in -galactose and obese aged rats, associated
with a decrease in SA-β-gal positive cells in the hippocampus (Shwe etal.,
2021). HBOT also improves the cognitive function of TBI survivors
(Biggs et al., 2021; Chen et al., 2022; Harch, 2022), at least partly
Shafqat et al. 10.3389/fnagi.2023.1281581
Frontiers in Aging Neuroscience 14 frontiersin.org
underpinned by reduced neuroinammation and MMP production,
which may reect an attenuated SASP (Vlodavsky etal., 2006).
Conclusion and outlook
Emerging research underscores the critical involvement of cellular
senescence in the process of brain aging. ere is also mounting
evidence from animal models that cellular senescence plays a
signicant role in the pathogenesis of premature brain aging.
Cancer survivors who have received chemotherapy or
radiotherapy—a population which is increasing annually as well as
getting older—are at an ever-increasing risk of morbidity related to
cognitive decline. erefore, increasing their representation in
senotherapeutic clinical trials will be crucial. However, despite
encouraging safety and tolerability results in phase 1 clinical trials,
their ecacy in a host of chronic diseases must beevaluated before
testing these drugs in frail and vulnerable populations like
cancer survivors.
From a mechanistic viewpoint, weare still confronted with several
gaps in our understanding. e upstream biological cues that regulate
senescence of the aging brain, for instance, require further study.
Secondly, to address why individual brains age at dierent rates,
studies must directly investigate genetic and epigenetic regulation of
senescence in the brain and its relationship to aging and cognition.
irdly, understanding the specic mechanisms through which
senescent brain cells contribute to neuropathology is still in its initial
stages. Current strategies for modulating SCs in mouse models are
systemic and lack specicity; to illustrate this, using AP20187in
INK-ATTAC transgenic mice systemically depletes all p16
Ink4a
-
expressing cells, but not all cells expressing p16Ink4a are senescent and
not all p16Ink4a -positive SCs are present in the brain. e question of
whether the observed improvements in cognitive function and
neuroinammation aer genetic or senolytic-mediated SC elimination
in mice can beattributed to a reduction in senescent brain cells as
opposed to peripheral eects is a critical distinction. Ogrodnik etal.
(2019) addressed this issue by transplanting SCs peripherally in mice
and evaluating whether this recapitulated senescence-related anxiety-
like behaviors in obese mice. ey also evaluated whether inhibiting
circulating SASP factors implicated in neuropathology and depleting
SCs in the brain achieve similar therapeutic benets with respect to
neurobehavioral outcomes. Nevertheless, experiments utilizing
transgenic mice that allow selective depletion of SCs in the brain
would berequired to causally link senescence in specic brain cells to
aging-related brain changes and better comprehend the
neuroinammatory dynamics in the aging brain.
Future research focusing on this pivotal area has the potential to
uncover transformative therapeutic targets and strategies for
alleviating brain aging. In doing so, wecould dramatically lessen the
substantial impact on patients, healthcare systems, and society at large.
Author contributions
AS: Conceptualization, Writing – original dra, Writing – review
& editing. SK: Writing – original dra. MO: Writing – original dra,
Writing – review & editing. MN: Writing – original dra. IA: Writing
– original dra, Writing – review & editing. KA: Writing – review &
editing. AY: Writing – review & editing. TT: Writing – review &
editing, Supervision. JK: Writing – review & editing, Supervision. SH:
Conceptualization, Writing – review & editing.
Funding
e author(s) declare that no nancial support was received for
the research, authorship, and/or publication of this article.
Acknowledgments
Figures were created using BioRender.com. Part of Figure2 was
adapted from “Endothelial Junctions in the Blood Brain barrier”
template and “Adult neurogenesis in the dentate gyrus” template by
“Alessia Caramello” by BioRender.com (2023). Retrieved from https://
app.biorender.com/biorender-templates/gures.
Conflict of interest
TT and JK have a nancial interest related to this research,
including patents and pending patients covering senolytic drugs and
their uses that are held by Mayo Clinic. SH received Honoraria from
Pzer, Novartis, Janssen, erakos Mallinckrodt, and Sanoand Roche.
e remaining authors declare that the research was conducted in
the absence of any commercial or nancial relationships that could
beconstrued as a potential conict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their aliated organizations,
or those of the publisher, the editors and the reviewers. Any product
that may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher.
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