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Berkeley
Pharma Tech
Journal of Medicine

Correspondence: 
gabybentolila5@gmail.com 

Keywords:
Cellular senescence 
Neurodegenerative diseases
Neuroinflammation
SASPs (Senescence-Associated 
Secretory Phenotypes)
Senolytics
Senomorphics
tau protein

Submitted July 19, 2024 
Accepted August 19, 2024
Published December 27, 2024

Full Open Access

Creative Commons Attribution 
License 4.0

Abstract
There is strong evidence that cellular senescence is involved in the pathogenesis of 
neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Presence of 
abnormal tau protein in mouse models is implicated in senescence phenotypes leading 
to cognitive decline, while the significance of pro-inflammatory molecules called 
senescence-associated secretory phenotypes (SASPs) in inflammation and 
degeneration highlights its potential importance in disease treatment. Understanding 
the involvement of senescence in disease progression is vital to develop effective 
treatment strategies. Clearance of such cells can be performed through senolytics drugs 
that disturb non-apoptosis pathways. Alternatively, senomorphics involve the 
suppression of senescence burden, rather than elimination through apoptosis, through 
the intervention of SASP factors that elicit neuroinflammation and tau toxicity. Other 
therapeutic approaches involve targeting mitochondrial dysfunction to attenuate 
neuroinflammation and senescence stressors, thereby preventing the formation of a 
feedback loop. This review offers insights into the mechanisms of neuro-degeneration 
driven by cellular senescence in the brain and outlines novel therapeutic strategies to 
reduce the senescence burden and slow disease progression.

Exploring the Role of Senescent Cells in 
Neurodegenerative Pathology: A
Window Into Promising Therapeutic 
Avenues
By: Gabriela Bentolila, Niharika Agrawal, Julie Phung, Linh Van, and Gatik Trivedi



1. Introduction

Cellular senescence is a state of irreversible growth arrest in cells that have
aged and ceased their ability to multiply, yet they avoid undergoing
apoptosis. This process is triggered in response to various stressors such as
DNA damage, telomere shortening, mitochondrial dysfunction, tumor
suppression, oxidative stress, and ionizing radiation (Fig. 1A). While
senescence plays a protective role in development, aiding in wound healing
and limiting tumor progression, its accumulation also leads to harmful
effects associated with aging and age-related diseases. The harmful impact of
senescence is mainly attributed to the release of SASPs. Research comparing
biomarkers of senescence in young and aged mouse brains has shown that
senescent cells increase with age, along with a rise in SASP factor genes.1

Consequently, this contributes to decreased tissue regeneration and
increased neuroinflammation, paving the way for neurodegenerative
diseases like Alzheimer's disease (AD), Parkinson's, and multiple sclerosis.
Furthermore, gene ontology analysis has revealed a strong connection
between senescence-related genes, mild cognitive impairment, and
neurodegenerative diseases.2 Treating senescence has shown promise in
improving cognitive function among patients with neurodegenerative
diseases.

Glial cells are the primary cell type in the brain undergoing senescence,
contributing to neurodegenerative diseases.3 Glial cells play a supportive role
in maintaining neuronal functions, and when compromised through
senescence, they trigger SASP production, neurotoxicity, and
neuroinflammation—common characteristics of neurodegenerative
diseases.4 Astrocytes, which are abundant in the brain and regulate synaptic
signaling, neurotrophic support, and glutamate metabolism, have been
found to be affected by senescence. Likewise, microglia, essential for CNS
homeostasis, experience senescence during aging and are associated with
neuroinflammatory phenotypes and neural impairment when increased in
number.1 Moreover, oligodendrocytes (OLG), derived from
oligodendrocyte progenitor cells (OPCs), are involved in responding to
neuronal injury and demyelination. In areas of the brain of AD patients,
where there is elevated Aβ plaque and neural degeneration and

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inflammation, there is a notable correlation with the presence of senescent
OPC populations.5 Considering the role of senescent glial cells in
aging-related neurodegenerative diseases, targeting these cells has emerged as
a potential therapeutic approach to tackle such conditions effectively. We
may develop strategies to promote healthier aging and reduce the burden of
neurodegenerative diseases.

2. Mechanisms of Senescence-Associated
Neurodegeneration

In the realm of neurodegeneration, the intricate interplay between cellular
senescence and the emergence of pathological hallmarks such as SASPs and
tau pathology has garnered significant attention. These mechanisms not
only shed light on the complex processes underlying aging-related
neurological disorders but also offer insights into potential avenues for
therapeutic interventions.

2.1 SASP

It was previously believed that senescent cells lack function; however, in
reality they simply have altered important morphological functions.6 Many
altered functions fall under SASP, which is a core feature of most senescent
cells.7 SASP is mainly characterized by the production and secretion of
factors like cytokines, chemokines, and other molecules that create an
inflammatory microenvironment.6 The main function of SASP is to recruit
immune cells for tissue damage repair; however, an abundance of senescent
cells has a negative effect on tissue restoration and leads to a chronic,
low-grade inflammation called “inflammaging”.8 Activation of
inflammaging results in decreased clearance of senescent cells, establishing a
positive feedback mechanism that ultimately further fuels inflammaging. In
an autocrine or paracrine manner, senescent cells can secrete SASP factors
that induce neighboring cells to senescence, furthering the accumulation of
senescent cells (Fig. 1B). When this process occurs in the brain, it leads to
the loss of neurons, resulting in the initiation, severity, and progression of
neurodegeneration.9

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Figure 1: Mechanisms Triggering Cellular Senescence. (A) Cellular senescence is
triggered by stressors such as DNA damage, telomere shortening, mitochondrial
dysfunction, tumor suppression, oxidative stress, ionizing radiation, and many other
abnormal factors. (B) Through the release of SASP factors, senescent cells can use autocrine
or paracrine signaling to induce senescence in neighboring cells.

Early SASP is often induced by Transforming Growth Factor-β (TGF-β),
secreted by senescent cells. TGF-β can also help maintain the secretory
phenotype if its target cell is already senescent. If early SASP is upregulated
for an extended period of time, it transforms into late SASP, which is
regulated mainly through transcription factors CCAAT/enhancer-binding
protein β (C/EBP β) and nuclear factor (NF)-κB. C/EBP β regulates the
expression of various SASP factors, such as interleukin (IL)-1β, IL-6, and
IL-8. Late SASP expression is induced when C/EBP β levels increase,
suggesting C/EBP β is a key regulator of the early to late SASP transition.7

However, NF-κB signaling is the main signaling pathway in late SASP
induction. NF-κB activation induces expression of inflammatory mediators
IL-6, IL-8, and IL-1α. In a positive feedback loop, IL-1α contributes to
SASP maintenance by regulating NF-κB and C/EBP β DNA binding
activities to induce further IL-6 and IL-8 transcription. This feedback loop
is regulated by rapamycin-mTOR signaling.8 NF-κB signaling is also
provoked by DNA damage through signaling pathways that include p38
mitogen-activated protein kinase (p38 MAPK) and retinoic acid inducible
gene-1 (RIG-1).10 p38 MAPK acts to stimulate NF-κB through the
activation of MAPK-activated protein kinase 2 (MK2),8 and p38 MAPK

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signaling itself can be induced by environmental stress or chronic
inflammation, such as inflammaging (Fig. 2).10

Persistent NF-κB activation is partially maintained by tumor necrosis factor
(TNF)-α. Upon TNF-α activation, AK kinase is phosphorylated, which
subsequently phosphorylates signal transducers and activators of
transcription 3 (STAT3). These phosphorylated STAT3 molecules then
migrate to the nucleus, contributing to prolonged activation of NF-κB and
increased expression of SASP factors.8 Interestingly, TNF-α itself is a
common cytokine secreted by SASP.4 Thus, its ability to induce SASP
through NF-κB activation presents another positive feedback loop that
serves to maintain SASP. Persistent SASP expression through NF-κB, as well
as other contributing factors, induces proinflammation, which promotes
tissue dysfunction, cellular aging, and other aging-associated issues (Fig. 2).8

Figure 2: SASP Regulation and Neuroinflammation Pathways. Several different
molecules act through the NF-κB pathway to activate and regulate SASP.

Upon acquisition of SASP, the secreted SASP factors promote autonomous
neurotoxicity and disrupt normal function in the brain. In fact, it was
found that treatment of senescent astrocytes with an antibody that
neutralizes IL-6, a SASP-associated cytokine, alleviates neuronal cell death.4

In vitro studies showed that IL-6 production was found to have the most
dramatic increase in senescent astrocytes, matching in vivo findings of IL-6

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at elevated levels in the CNS in AD patients.6 Moreover, in a study with
primary cortical neurons from senescence accelerated mouse prone 8
(SAMP8) mice, SASP factor plasminogen activator inhibitor 1 (PAI-1) was
found to promote neuron apoptosis; however, the exact mechanisms by
which PAI-1 carries out this activity is still unknown.11

Several SASP factors have been linked to axonal and myelin injury.
Activation of SASP in neurons through the lymphotoxin-NF-κB pathway
was found to trigger expression of chemokine CXCL13, which recruited
CD8+ T cells. CD8+ T cells then activated caspase 3 in injured dorsal root
ganglia (DRG), which was found to hinder signaling and lead to the
repression of the neuron’s axonal regeneration capabilities. However, the
same study showed that regenerative failure in DRG could be restored by
the neutralization of chemokine CXCL13 with monoclonal antibodies.12

Similarly, myelin injury and regenerative failure can occur if SASP is
activated in OLGs.13 A study with mice showed that persistent NF-κB
signaling in OLGs led to chronic neuroinflammation and post-mitotic
senescence. NF-κB signaling also promoted white matter degeneration
(WMD) in the brain, a well-known process of aging. WMD often manifests
in myelin loss, which was confirmed by ultrastructural analysis of the mice
that revealed impaired myelin protein expression. Additionally, the mice
exhibited neurological deficits within three weeks following treatment.14

OLGs have also been found to be affected by secretion factor high-mobility
group box-1 (HMGB1) in vivo. When extracellular HMGB1 was released
by senescent progenitor cells, differentiation of OPCs to myelinating OLGs
was prevented, ultimately inhibiting CNS remyelination.15 Moreover,
HMGB1 prevailed at higher levels in the brains of patients with primary
progressive multiple sclerosis (PPMS) compared to healthy controls. More
specifically, HMGB1 was found at high concentrations in white matter
lesions of the brain, and progenitor cells were identified to be the source.16

This highlights the contributing role of SASP factor HMGB1 in the limited
remyelination found in PPMS, as well as potentially other
neurodegenerative diseases.

Examples of other neurotoxic SASP factors include IL-8, IL-1, matrix
metalloproteinases, insulin-like growth factors (IGFs), endothelial growth

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factor (EGF), epidermal growth factor receptor (EGFR), specific miRNAs,
and many other molecules.7

2.2 Biomarkers

Understanding the relationship between cellular senescence and
neurodegenerative conditions is crucial for developing effective therapeutic
strategies. To this end, researchers have focused on identifying biomarkers
that link cellular senescence to neurodegeneration. Several enzymes,
cytokines, chemokines, genes, and other biomarkers have been implicated in
senescence-related processes in the brain. These biomarkers provide valuable
insights into the mechanisms underlying neurodegenerative diseases and
offer potential targets for therapeutic interventions.

Enzymes
● Senescence-Associated Beta-Galactosidase (SA-β-gal): SA-β-gal is one of
the earliest markers identified for the detection of senescent cells in situ
within tissues.7 This hydrolytic enzyme becomes active in senescent cells and
is commonly used as a hallmark to distinguish senescent cells from
non-senescent cells.
● Caspase 3: Caspase 3 is an enzyme involved in apoptosis. It suggests a
potential link between senescence and cell death pathways.18

Cytokines
Cytokines are signaling molecules that play critical roles in inflammation
and immune responses. Certain cytokines have been found to be associated
with the development of neurodegeneration.

● IL27: This cytokine is involved in the activation of Natural killer cells in
the dentate gyrus, which leads to the elimination of neuroblasts and
subsequently contributes to neurodegeneration and cognitive decline.19

● IL-6, IL-8, IL-1β: IL-6, IL-8, and IL-1β are among the cytokines that
mediate tumor suppressor functions. Studies conducted by Bussian et al.
andMusi et al. have identified these cytokines in the brains of mouse models
with tauopathy. They were found to be part of the SASPs observed in these
models.20,21

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Chemokines
Chemokines are small signaling proteins involved in cellular migration and
immune responses. One chemokine that has been linked to
senescence-associated neurodegeneration is CCL2.22

● CCL2: Studies have implicated CCL2 in the development of
neurodegenerative processes. It may contribute to the recruitment of
immune cells, such as microglia, to the site of neurodegeneration, further
promoting inflammation and tissue damage.23 Apart from its role in
immune cell recruitment, CCL2 can also directly influence neuronal
function. It has been suggested that CCL2 might affect synaptic plasticity
and neurotransmission, potentially contributing to cognitive and functional
impairments seen in neurodegenerative diseases.22

Genes
Several genes have been identified as crucial regulators of cellular senescence,
and their dysregulation may contribute to neurodegeneration.

● p16, p21, p53: These genes encode cell cycle inhibitors and repressors and
are essential components of the senescence program. Exposure to tau has
been shown to increase the expression of senescence-associated markers,
including p16INK4a and p21WAF1, in microglia, potentially contributing
to neurodegeneration.24

● CDKN2A and CDKN2D/p19: Neurons expressing CDKN2D/p19, a
gene related to CDKN2A, were found to be more prone to containing tau
aggregates and displaying signs of neurodegeneration, suggesting a potential
role for senescent neurons in the development of tauopathy.25 Additionally,
NFTs (neurofibrillary tangles) have been directly linked to CDKN2A
upregulation.21

Other Biomarkers
Other biomarkers associated with senescent cells and neurodegeneration
have been identified.

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● B2M: B2M is an extracellular epitope of senescent cells and serves as a
membrane marker for MHC class I molecules. Its expression may
contribute to immune responses and inflammation in the context of
senescence.26

● PAI-1: Plasminogen activator inhibitor-1 is a serine protease inhibitor that
increases with aging and has been found to contribute to brain cell
senescence. However, the specific mechanisms linking PAI-1 to
neurodegeneration are still being investigated.11

● HMGB1: High mobility group box 1 serves as a crucial biomarker. This
multifunctional protein plays significant roles within the cell, particularly in
DNA repair and autophagy regulation. Studies conducted by Gaikwad et al.
and Rouilliard et al. have brought to light its potential implications in the
advancement of neurodegenerative diseases. HMGB1's involvement as part
of the SASP is particularly noteworthy, as it contributes to
neuroinflammation and impedes the growth of myelin, which is essential for
nerve fiber insulation. 15,27

● Lamin B1: Lamin B1 is a protein that plays a crucial role in maintaining
the structural integrity of the cell nucleus. It is a component of the nuclear
lamina, a network of proteins that provides support to the nuclear envelope.
Lamin B1 has been implicated in the aging process as its expression levels
decline with age in various tissues.28 Reduced levels of Lamin B1 have been
observed in certain senescent cells, and its loss has been linked to nuclear
envelope disorganization and altered gene expression, contributing to
cellular dysfunction and aging-related changes.28

● Igfbp5: Insulin-like Growth Factor Binding Protein 5 is a member of the
insulin-like growth factor-binding protein family and plays a role in
regulating the bioavailability and activity of insulin-like growth factors
(IGFs). IGFs are essential for cell growth, proliferation, and survival. Igfbp5
modulates the actions of IGFs by binding to them and regulating their
interactions with cell surface receptors.29 Additionally, Igfbp5 has been
found to be involved in processes related to brain development and
function, and its dysregulation may influence neuronal survival and
synaptic plasticity, potentially contributing to neurodegeneration.29

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2.3. Tau Pathology

The tau protein, predominantly located within neurons, plays a vital role in
maintaining the structural integrity of nerve cells by stabilizing
microtubules and facilitating efficient axonal transport.4 In addition to its
structural functions, tau protein is involved in essential cellular processes
such as cell signaling, synaptic plasticity, and the preservation of genomic
stability, and in OLGs cells, it also plays the role of myelination.30,31 When
tau becomes abnormal, it can contribute to the development of
neurodegenerative diseases. Excessive phosphorylation, genetic mutations,
and mis-splicing contribute to the abnormal aggregation of tau protein,
resulting in the formation of either tau oligomers or neurofibrillary tangles
(NFTs).32 Tau oligomers are small aggregates of abnormal tau protein that
form prior to the development of NFTs, which are larger insoluble clumps
of hyperphosphorylated tau protein. Both tau oligomers and NFTs
contribute to pathogenesis of neurodegenerative diseases. Abnormal tau can
be secreted by neurons into extracellular space, which are taken up by
healthy neighboring neuronal and glial cells through endocytosis,
pinocytosis, or phagocytosis means, thereby contributing to the
propagation of tau pathology across interconnected brain regions.27 In
addition, extracellular tau was found to induce human astrocyte senescence,
inflammation, and SASPs. The inflammatory state can cause induction of
senescence in nearby cells in a paracrine-like manner, further propagating
neurodegeneration, which is why overall extracellular tau may be more
neurotoxic than intracellular tau.4 One pathological change caused by
abnormal tau accumulation is the disruption of cell function and the blood
brain barrier (BBB), which is responsible for protecting the CNS from
pathogens and maintaining homeostasis in the microenvironment of the
brain.31 Other tau pathologies include chronic neuroinflammation, DNA
damage, and oxidative stress, which are known stressors of senescence.
These tau-related pathologies contribute to the establishment of a vicious
cycle, where tau pathology triggers senescence, leading to the release of toxic
SASP factors that, in turn, exacerbate the formation of abnormal tau (Fig.
3).

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Neurons
Senescent cells are present in both AD and non-AD brains. However, it has
been determined that the number of senescent cells was significantly higher
in AD brains. Additionally, a subset of senescent cells in AD brains were
neurons that expressed the gene CDKN2D/p19. These neurons also
showed signs of tau neuropathology.25 Moreover, an examination of the
transcriptomic profile of cortical neurons containing neurofibrillary tangles
(NFTs) in AD brains revealed that those neurons displayed a senescence-like
phenotype. This means that the gene expression patterns observed in these
neurons resemble those typically seen in senescent cells, suggesting that AD
neurons undergo a cellular aging process akin to senescence.21

Astrocytes
Tau can be transmitted from neurons to astrocytes, causing the astrocytes to
senesce and produce SASPs. Studies have shown that astrocyte senescence is
detrimental to dendritic and synaptic structure and density. This suggests
that pathogenic soluble tau-induced astrocyte senescence may contribute to
synaptic dysfunction and loss in AD.33 Recent research has highlighted that
tau oligomers play a role in promoting the release of HMGB1 from
astrocytes during inflammation. Notably, the release of HMGB1 not only
leads to inflammation but also drives paracrine senescence in neighboring
cells.27 Moreover, tau oligomers have been specifically implicated in
promoting the aggregation of p53 in AD patients. In the study, this
interaction between tau oligomers and p53 was observed exclusively in AD
brains, compared to control, resulting in the sequestration or aggregation of
p53 outside the nucleus. Consequently, this phenomenon hinders the
ability of p53 to carry out DNA repair processes, leading to DNA damage
and ultimately triggering senescence. The accumulation of senescent cells
further exacerbates the progression of AD.34 One study found that
astrocytes and microglia are the two major types of senescent cells that
accumulate in the dentate gyrus of the hippocampus in AD.20 This was
supported by the laboratory of Human Carcinogenesis, where they found
that astrocytes are the primary type of senescent cells present in patients
with AD, amyotrophic lateral sclerosis (ALS), aged individuals and those
receiving cranial radiation.4 Flow cytometry analysis of PS19 mouse models,
which overexpress human mutant tau, also validated these findings by

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revealing increased expression of senescence-associated genes, including
p16Ink4a, in isolated astrocytes and microglia, while OLGs and neurons did
not exhibit the same upregulation. Furthermore, the study reported that
senescent astrocytes and microglia exhibit inflammatory reactions to
extracellular tau, leading to damaged neurons.20 In the context of neuronal
damage, it has been identified that astrocyte senescence is associated with
the downregulation of glutamate and potassium transporter genes.
Consequently, this impairment of glutamate clearance increased
susceptibility of neurons to glutamate-induced toxicity and ultimately
neuronal cell death (Fig. 3).35

Microglial
In the aged human brain, many microglial cells showmorphological features
indicative of senescence or degeneration rather than activation. This
suggests that microglial senescence and associated loss of neuroprotection
could be involved in aging-related neurodegenerative diseases. In fact, Streit
et al. reports that dystrophic microglial cells are implicated in the
development of AD, associated with severe tau pathology. Investigation of
microglial dysfunction by examining their morphology in the vicinity of
tau-positive structures revealed that microglial degeneration may precede
the onset of NFT pathology, meaning that the loss of microglial structural
integrity contributes to neurodegeneration.36 Karabag et al. conducted a
study demonstrating that exposure to tau can induce microglial senescence.
Specifically, they found that an exposure to 15 nM concentration of tau
resulted in increased levels of cell cycle arrest and a DNA damage marker. It
also led to the loss of nuclear envelope protein lamin B1 and the histone
marker H3K9me3, thereby affecting the clearance of tau and impairing cell
migration (Fig.3). Additionally, this exposure caused alterations in cell
morphology and triggered the formation of a SASP.24

Oligodendrocytes
Tauopathies involving OLGs have been identified in specific dementias,
such as progressive supranuclear palsy (PSP), corticobasal degeneration, and
frontotemporal dementia, which includes Pick's disease and certain cases of
AD.37 Because pathological tau has the ability to propagate from neurons to
other cell types both trans-cellularly and trans-synaptically, it can contribute

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to the spread of neurodegenerative disease.38 However, studies now propose
that OLGs can contribute to the spread of tau without passing through
intra-neuronal transport in a glial-to-glial fashion, playing a further role in
the spreading of tauopathies.39 The spread of tau pathology to OLGs is
closely linked to the loss of high-firing pyramidal neurons, a crucial neuron
type essential for cognitive function. The depletion of these neurons can
lead to cognitive decline, as assessed through various behavioral tests in
mice. In one study, mice injected with human tau aggregates displayed
prolonged search times in locating the platform in the Morris water maze,
reduced visits to the correct arm in the Y -maze, and decreased exploration
time of the novel object compared to control mice.37 The aggregation of tau
in OLGs may be a contributing factor to the development of gait
abnormalities and myelin loss in neurodegenerative diseases (Fig. 3).30 In
fact, Luo et al., found that OLG lineage cells from old donors had lower
myelination potential than OLG lineage cells from younger donors.40

Figure 3: Cellular Morphological Changes in Senescence. Senescent cells undergo
morphological changes, such as altered cell size and structure, that lead to
neurodegeneration. These cellular changes make up a vicious cycle as they contribute to the
propagation of other senescent cells.

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3. Therapeutic Approaches

3.1. Senolytics

Senolytics eliminate senescent cells by inducing apoptosis. This is done by
targeting senescent cell anti-apoptotic pathways (SCAPs) such as p53 and
BCL-2. Through removing senescence, senolytics have the potential to
reduce neuroinflammation, enhance tissue regeneration, and improve
cognitive function. The effects of senolytics are currently mainly tested
through mouse models and cell populations characterized with an
age-related disease.

Dasatinib and Quercetin
The combination of dasatinib and quercetin (D+Q) is one of the most
extensively studied senolytics, shown to be effective in numerous age-related
diseases by selectively targeting senescent cells while maintaining the
viability of non-senescent cells. Dasatinib is a tyrosine kinase inhibitor that
was initially discovered for use in cancer treatments to prevent cancer cell
growth. By targeting pro-survival pathways, dasatinib induces apoptosis to
senescent cells. Quercetin is a natural flavonoid and enhances the
effectiveness of dasatinib with its anti-inflammatory and pro-apoptotic
properties. When used together, their effectiveness as a senolytic increases, as
they are able to target a larger variety of senescent cell types. Beyond
targeting SCAPs, quercetin has also been found to improve cognitive
function in AD patients through activating AMP-activated protein kinase
leading to a reduction in Aβ-induced mitochondrial dysfunction, a main
characteristic in early AD pathogenesis.41 Through clearance of senescent
cells by targeting BCL-2 and other anti-apoptotic proteins, D+Q has shown
to be effective in numerous age-related conditions. By decreasing senescence,
D+Q relieves tissue degeneration, inflammation, and other SASP factors.42

D+Q acts in a dosage-dependent manner positively correlating with
increased senescent cell death in mice with AD, specifically in OLGs. These
mice were also found with reduced levels of Aβ plaque associated
proinflammatory cytokines such as Il-1β5. NFTs are also reduced by D+Q
in tau transgenic mice with effects of improved cerebral blood flow and

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decreased neurodegeneration.21 Intermittent treatment with D+Q on mice
showed improved cognitive function by reducing senescent microglia. Y
oung and aged mice were put through phenotypic, memory, and cognitive
assessments. Assessment results of young mice were unchanged while aged
mice improved significantly in a Stone T-maze following treatment of D+Q
suggesting high effectiveness of D+Q during aging.43 A current clinical trial
of D+Q involving early-stage older AD patients suggests promising results.
The patients were treated intermittently with D+Q for 12 weeks while their
cognitive function and progression of AD were measured. The only
statistically significant changes in safety parameters of D+Q observed was an
increase in total cholesterol, yet this higher total cholesterol remained in a
normal range, and one possibly related adverse event, yet this event was
resolved between 1 to 16 days. Several tests were conducted to test changes
in cognitive function including the Montreal Cognitive Assessment
(MoCA) and the Clinical Dementia Rating Sum of Boxes (CDR SOB).
There was no significant change in the results from these cognitive
assessments from the baseline to post-treatment. MRIs also showed no
significant change from the baseline to post-treatment, suggesting a stable
brain morphology over the treatment period. Plasma and cerebrospinal fluid
(CSF) levels revealed that D was able to penetrate through the BBB while Q
was not able to. Overall, the study’s results are promising in the safety and
potential of D+Q as a senolytic, yet further studies are needed to examine
long-term efficacy.44

Fisetin
With studies of quercetin, a natural flavonoid, being an effective senolytic,
other flavonoids were explored for their senolytic abilities such as fisetin.
Fisetin, present in various fruits and vegetables, was found to possess great
seno-therapeutic qualities.45 It is assumed that with similar chemical
structures, fisetin and quercetin hold similar therapeutic and
anti-inflammatory effects.46 With a fisetin diet, abundance of p16 was
reduced in aged mice and levels of p16 and SASP factors continued to
remain in significantly low levels following treatment. Senescence was
reduced in multiple organs of the mice along with markers of inflammation
and oxidative stress.45 Through blocking mitogen activated protein kinase
(MAPK) and NF-κB signaling pathways, fisetin is able to reduce

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inflammation.46 Specifically, fisetin targets senescence through the SCAP
networks of BCL-xL and HIF-α. Fisetin has also shown to be able to extend
median and maximal lifespan, suggesting promising results for age-related
treatments.47 Fisetin also attacks the P13K/AKT pathway, which promotes
cell survival, to induce apoptosis.48 Human adipose tissue explants treated
with fisetin had a decrease in SA-β-gal positive cells and SASP expression of
IL-6, IL-8, and MCP-1. Similar to D+Q, fisetin was effective in reducing
senescence without affecting proliferating cells.45 Currently, fisetin has
proven to be successful as a senotherapeutic agent, yet further testing is
needed to study its safety for age-related and neurodegenerative
treatments.47

Navitoclax
Navitoclax, also known as ABT263, is another discovered senolytic. Initially
used as an anti-cancer drug, Navitoclax works by inducing apoptosis in
cancer cells. This mechanism is likewise in its role as a senolytic drug,
disrupting BCL-2 and pro-death proteins to induce apoptosis in senescent
cells.49 This disruption is caused by Navitoclax binding to BH3 of BCL-2,
resulting in the displacement of a pro-apoptotic protein, BIM, that causes
cell apoptosis (Fig. 4).50 Aged mice treated with Navitoclax enhanced
neurovascular coupling, regulating cerebral blood flow that is essential for
cognitive function. Examination through a radial arms water maze,
Navitoclax improved on the learning capabilities and memory retention in
aged mice.51 Hippocampal neurogenesis reduced by aging can be restored by
Navitoclax. By targeting senescent cells that impair neural progenitor cells
(NPCs), hippocampal neurons and hippocampus-dependent spatial
memory function was increased following Navitoclax treatment.52 Trails of
Navitoclax were tested on p16 transgenic mice in biweekly cycles. Apoptosis
of senescent cells increased in these mice, yet the possibility of
thrombocytopenia and neutropenia as side effects rose.48

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Figure 4: Navitoclax Mechanism of Action in Senescence. The figure demonstrates
Navitoclax targeting the BCL-2 pathway to release Caspase 3 and cause apoptosis in
senescence.

AP-20187
AP-20187 (AP) is a drug that targets senescence by disrupting SCAPs and
activating a pro-apoptosis protein.53 A study on young and old INK-A
TTAC mice revealed significant effectiveness in clearing senescence during
aging following intermittent treatment of AP. Cognitive impairment was
reduced without affecting the physicality of the mice. Specifically,
aging-induced senescent microglia was reduced in aged mice with AP
treatment.43 In another study, AP increased neuron density and decreased
tau aggregation in PS19 mice, which express models of tauopathy, with
twice-weekly administrations. With treatment, expression of senescent genes
were measured at levels compared to that of control mice. Treatment of AP
was able to mitigate short-term memory loss in novel-scent discrimination
assessments.20

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Limitations
Senolytics is an emerging field and therefore there remains a lack of
information on the exact mechanisms of senolytics in neurodegenerative
diseases and long-term effects. Future studies are necessary to test the safety
and efficacy of senolytics long-term before being able to be used beyond
clinical trials.54 While senolytics have shown to improve lifespan, cognitive
functions, and anti-inflammation, senolytics have the risk of eliminating
benefits of senescence such as wound healing and tissue development. Since
senescent cells are not replaced when removed by senolytics, fibrosis can
occur, resulting in scarring and thickening of tissues.55 As there are other cell
types that are non-senescent yet can have a high p16 expression, some
senolytics such as Navitoclax and AP can have off-target effects and
eliminate non-senescent cells.43,56

3.2. Senomorphics

Senomorphic medications intervene with SASP factors without inducing
apoptosis. Unlike senolytics, the benefit of senomorphic drugs is that they
do not kill functioning senescent cells, which are still important for
anti-tumor cell signaling (Fig. 5). Senomorphic medication mainly targets
signaling pathways: NF-κB, mTOR, IL-1α, p38 MAPK, etc. There are
currently multiple senomorphic drugs being tested to varying levels of
success that will be covered in the following sections.

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Figure 5: Comparison of Senolytic and Senomorphic Mechanism of Action and
Effect. Senolytics eliminate senescent cells, while senomorphics modulate SASP factors to
mitigate inflammation without inducing apoptosis.

Metformin
Metformin has a neuroprotective effect in animal models, and is shown to
reduce inflammation and oxidative stress.57 Metformin is a drug that was
originally approved for the treatment of Type 2 diabetes, but its therapeutic
effects have expanded into age-related disorders and neurodegenerative
diseases. It is effective in suppressing cellular senescence and SASPS; for
example, Metformin reduced cellular SA-β-gal activity and down-regulated
the expression of senescence and SASP factors in human diploid
fibroblasts—cells commonly found in the perivascular spaces, meninges,
and choroid plexus of the brain—among other cells.58,59 Metformin also
increases the lifespan of different model organisms, including mice.60

Despite the fact that Metformin has been tested in detail, its exact
mechanism of action remains unknown, and is an area for further
experimentation and testing. Metformin has been proven to reduce
senescence via transcriptional up-regulation of Nrf2-medicated GPx7 in
human diploid fibroblasts, but it also decreases cellular senescence and
SASPS via the microRNA processing protein DICER1.61,62 Metformin has
been found to influence all hallmarks of aging, which is why understanding
its mechanism of action is so complicated. Its impact has been found in
nutrient signaling pathways, insulin signaling, repairing oxidative damage,
and inhibiting protein synthesis, among others.63 Currently, there is an
ongoing clinical trial (NCT04098666) for Alzheimer’s prevention using
Metformin. At baseline and after study visit at 18 months a brain MRI,
physical exams, plasma tau and amyloid beta levels are being measured to
assess prevention of AD, along with clinical interviews, physical exams, and
brain MRIs. Results are inconclusive as of yet.57

Resveratrol
Resveratrol is an SIRT1 activator that plays an important role in promoting
anti-inflammatory and antioxidant properties in the body, and has an effect
on cellular senescence.8 It also mitigates neuroinflammation by promoting
microglia polarization towards the M2 phenotype it activates, PGC-1α: a
transcription factor involved in the suppression of SASP.64 M2microglia are

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involved in anti-inflammatory responses; they promote tissue repair and
protect neurons from damage; thus, promoting the M2 phenotype will help
reduce neuroinflammation and protect neurons from further damage. In
trials, long term Resveratrol treatment prevented age-dependent decline in
cellular viability and various cell parameters—metabolic, oxidative,
inflammatory, and senescent—in hypothalamic astrocytes from aged rats. It
also increased the expression of genes involved in cellular homeostasis, such
as: Nrf2, HO-1, SIRT1, and PGC-1α.65,66 However, Resveratrol has a
biphasic effect. At low concentrations (below 10 μM), Resveratrol acts as a
senomorphic and prevents cellular senescence and suppresses SASPs. For
example, Resveratrol prevented cellular senescence by activating the
telomerase of endothelial progenitor cells via the P13K-Akt pathway.67 The
drug has also been shown to suppress SASP factors by inhibiting NF-κB and
upregulating Nrf2 pathways in the vascular smooth muscle cells of rhesus
monkeys. However, at higher concentrations (over 25 μM), Resveratrol
triggers growth arrest and induces senescence of apoptotic death in cell lines.
As such, controlling the dosage of Resveratrol is very important for using it
as a senomorphic therapy.

Rapamycin
Rapamycin is also known as sirolimus. While it was originally used as an
immunosuppressive drug for the prevention of organ rejection in kidney
transplantation, studies have shown that rapamycin could reduce cellular
senescence and suppress SASP markers in a variety of mouse and human cell
lines. It is an incredibly well-established senomorphic drug. In multiple
invertebrate models, including yeast, flies, and worms, rapamycin has
increased lifespan, and late-life administration has extended lifespan in male
and female mice. In vivo studies have demonstrated that rapamycin
alleviates age-related dysfunctions, decreases aging rate, and increases
life-span. Further, Rapamycin treatment has reversed the cellular senescence
phenotype in PPMS NPCs, as evidenced by the reduced expression of
senescence markers and increased cellular proliferation. It further enhanced
the PPMS NPC support for OLG maturation, as seen in the increased
expression of OLG differentiation markers and decreased HMGB1
secretion.16 Decreased HMGB1 secretion is important; it is seen that
patients with PMS exhibit higher levels of HMGB1, a senescence marker,

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which inhibits the differentiation of progenitor cells into OLGs. This is
incredibly important for neurodegenerative disease progression, as OLGs
are what produce myelin to protect our neurons.16 Rapamycin has
side-effects, however: metabolic dysregulation and impaired wound healing,
among others. Rapamycin works by inhibiting TORC1 activity in
association with the intracellular protein FKBP12. TORC1, or Target of
Rapamycin Complex 1, is a eukaryotic protein complex related to cell
proliferation.68 The senomorphic and longevity effects of rapamycin relate
to its inhibition of mTOR signaling by reducing the phosphorylation of
S6K and 4E-BP. Other potential or secondary mechanisms by which
rapamycin may regulate senescence and lifespan are being explored—for
example, activating the Nrf2 pathway and decreasing NF-κB activity to
reduce IL-1α production. It is also to be determined whether other mTOR
pathway inhibitors and rapalogues such as everolimus, temsirolimus,
deforolimus, ridaforolimus and zotarolimus may exhibit senomorphic
activities.63

Aspirin
Aspirin has been found to partially prevent Aβ-induced neuronal
senescence and DNA damage by upregulating sirtuin-1 (SIRT1) in a
dosage-dependent manner.23 It also delayed the onset of senescence in
endothelial cells by increasing nitric oxide synthesis and decreasing oxidative
stress, subsequently upregulating telomerase activity.69 However, other
experimental studies indicate that the effects of aspirin on senescence vary
with context, stress type, and dosage.63

Ethyl Pyruvate and Glycyrrhizic Acid
Ethyl Pyruvate and Glycyrrhizic Acid inhibit the release of HMGB1, and
can also inhibit p53 aggregation and prevent tau phosphorylation.27,34This
indicates that the two drugs could have potential benefits in treating
Alzheimer’s. Other areas that are only just being explored include NF-κB
inhibition, p38 MAPK inhibition, The Janus kinase/signal transducer
signaling pathway, mutated Ataxia telangiectasia inhibitors, and statins.63

Overall, senomorphic medications are a very promising area of research for
treatment of neurodegenerative diseases, but there is still a lot of work to be
done and discoveries to be made.

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2.3. Mitochondria-Based Therapies

Mitochondria are the dominant sources of reactive oxygen species (ROS),
which is produced as a by-product of the electron transport chain in
mitochondria. Under normal conditions, ROS is central for organismal
homeostasis, able to promote necessary signal transduction by mediating
redox modifications of specific molecules; however, damaged mitochondria
often result in an overproduction of this superoxide, leading to oxidative
stress, another leading factor of cellular senescence. Imbalances between
ROS production and detoxification of these reactive species, or antioxidant
activity, is toxic to cells. It activates p53, which induces the cyclin-dependent
kinase (CDK) inhibitor p21, causing cell cycle arrest and senescence. In
addition, elevated ROS levels have also been found to be strong modulators
of inflammatory pathways that can accelerate cellular senescence and further
aggravate inflammaging. As a result, dysfunctional mitochondria have
become a hallmark of and contributor to aging and aging-related
neurodegeneration. While the role of dysfunctional mitochondria in aging
and cellular senescence is still being explored, many studies show that
therapies targeting these defects have been effective in alleviating
senescence-associated symptoms.7

NAD+ supplementation
NAD+ supplementation has rapidly become a popular research avenue as a
potential therapy for neurodegenerative diseases with underlying
mitochondrial dysfunction-induced senescence causes. Studies have shown
that NADH improves motor symptoms in Parkinson's disease and NAD+
supplementation can prevent STING-induced senescence in A-T cells and
mice, while promoting mitophagy to remove damaged mitochondria and
prevent senescence and neuroinflammation.70,71 Additionally, the
cGAS-STING pathway has been implicated in attenuating
neuroinflammation, suggesting that boosting NAD+ with nicotinamide
riboside (NR) treatment could serve as a therapeutic approach to mitigate
neurodegeneration.72 These findings highlight the potential of NAD+ as a
therapeutic strategy for addressing senescence-related issues in
neurodegenerative diseases.

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Limitations
Studies have shown that increased NAD+ levels could lead to the
accumulation of potential toxic metabolites and may even contribute to
tumorigenesis.70 Additionally, excessive NAD+ supplementation in young
healthy mice, which already have sufficient NAD+ levels, has been linked to
elevated levels of pro-inflammatory cytokines such as IL1β and IL6,
suggesting unintended consequences on inflammatory pathways.71 These
findings highlight the need for cautious consideration of NAD+
supplementation as a therapeutic approach, with attention to dosage and
potential age-related variations to avoid adverse effects. Further research is
necessary to fully understand the risks and benefits of NAD+
supplementation as a therapy for senescence and neurodegenerative diseases.

MAPKs
Mitogen-activated protein kinase 15 (MAPK15) is another potential target
of mitochondria-based therapies. MAPK15, an atypical mitogen-activated
protein (MAP) kinase, has been found to control the mitophagic process by
stimulating phosphorylation of Unc-51 Like Autophagy Activating Kinase
1 (ULK1)-dependent parkin RBR E3 ubiquitin protein ligase (PRKN)
Ser108, which induces recruitment of damaged mitochondria to lysosomal
compartments for disposal. As such, by effectively getting rid of defective
mitochondria, MAPK15 helps prevent oxidative stress and DNA damage
accumulation, both of which are effective in inducing senescence. In a study
conducted with human Airway Epithelial Cells, it was found that the
downregulation of MAPK15 resulted in reduced cell proliferation,
increased p21 levels, increased SA-β-Gal activity, and increased expression of
SASP cytokines, all of which are associated with senescence.73 The
usefulness of other members of the MAP kinase family is still being
investigated as they have a duality that both helps prevent and promote the
negative effects of senescence. The activation of p38 MAPK has been
observed in senescent cells indicating an involvement in the cellular
senescence process. In an α-synuclein mouse model of Parkinson’s disease it
has been shown to promote mitochondrial fission. Chemical inhibition of
p38 MAP with molecule SB203580 was shown to protect cells from
mitochondrial dysfunction and cell death.74 Additionally, p38MAPK plays

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a crucial role in the secretion of SASP factors. Interestingly, p38MAPK can
induce SASP independently of the DNA damage response (DDR),
suggesting its significance as a separate pathway for SASP activation. Thus,
when p38 MAPK is inhibited, it has been found to effectively suppress the
SASP , potentially offering a promising target for therapeutic interventions
aimed at mitigating the harmful effects associated with cellular senescence.75

Furthermore, it is interesting to note that MAPKs and NF-κB have been
found to regulate the expression of the other in a feedback mechanism,
suggesting inhibition could lead to regulation of SASPs.76,77 Further
research on p38 MAPK's intricate role in senescence and its modulation
may provide valuable insights into aging-related processes and age-associated
diseases. While specific therapies that target MAPKs have not yet been
thoroughly developed, these findings point to the great potential of
MAPK-based treatments.

Limitations
Excessive and constitutive mitophagy may contribute notably to the
progression of neurodegenerative disease. In addition, in vitro studies on
chronic obstructive pulmonary disease (CPOD) epithelial cells found that
cigarette smoke activated MAPK15 signaling and led to oxidative stress,
rather than the opposite, as what has been more commonly discovered in
other studies.78 Hence, patients with neurodegenerative diseases that smoke
may encounter additional barriers to treatment with MAPK15-targeted
therapies.The p38 MAPK has also been linked to oxidative stress, playing a
role in the induction of senescence. Thus caution of these therapies is
essential in order to avoid producing the opposite effect.

4. Future Directions

It is crucial to explore the heterogeneity of senescent cells and their distinct
contributions to neurodegeneration. Understanding the specific factors and
signaling pathways that drive the detrimental effects of different senescent
cells in neurodegenerative diseases will help guide the development of
targeted therapies. One area that could be further explored is the use of
targeted therapies. Some research has been done but needs to be expanded
upon for applications in neurodegenerative diseases. One of those is

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second-generation senolytics: they offer a specific approach to enhance the
effectiveness of existing senolytic drugs while minimizing the side effects. An
example is B2M ADC, an antibody conjugation that increases efficacy and
selectivity when it comes to using senolytics to clear senescent cells.79 Future
research in combining strategies, like using senolytic drugs and
immunotherapy simultaneously promises potential benefits as well. Similar
to how CAR T cell therapy has been used to treat cancers, this therapy can
be applied and engineered to target senescent biomarkers for
neurodegenerative diseases. So far very limited research has been done in this
area but Amor et al. successfully created a senolytic CAR T therapy that
effectively eliminated senescent cells in mouse models and improved
outcomes in liver fibrosis. However, This technique comes with its
limitations. A condition called cytokine release syndrome may arise, in
which an intense storm of T cells causes fever and impacts breathing and
blood pressure.80 In addition, antibodies made to neutralize SASPs are
another promising avenue to take in the path of immunotherapy
treatments. Particularly, intervention of cytokine IL27 as well as the
upregulation of MHC class-I-related molecules, such as RAE1 can be
applied to alleviate senescence burden and interaction between NK cells and
receptor NKG2D, which influences age-related decline in neurogenesis and
cognition.19

Another area of research is in leveraging the lymphatic system, which plays
an imperative role in clearing senescent cells and therefore preventing
neurodegenerative diseases. Such diseases are known to cause chronic
inflammatory cascades that damage hippocampal micro vessels and
therefore lymphatic drainage. This in turn creates a dangerous cycle where
the disease causes lymphatic blockage of senescent cell clearance and
senescent cells clearance accelerates cognitive decline that further damages
hippocampus. A study determined that such drainage is dependent on the
VEGF-C/CCL21 pathway. Leveraging these pathways to improve
lymphatic drainage could prove extremely beneficial in combination with
senolytics like D+Q. One such idea is dispersing Astrocyte VEGF-C into
the CSF promoting lymphangiogenesis, and thus enhancing drainage of
parenchymal waste to the dural lymphatics. Given that studies have
demonstrated the aggravation of pathogenic tau accumulation in AD

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mouse models when AQP4 water channels are pharmacologically inhibited,
there is a need for further research strategies for mitigating the
downregulation of AQP4 water channels in senescent astrocytes. These
channels play a crucial role in facilitating cerebrospinal fluid and interstitial
fluid exchange, thereby regulating glymphatic transport and helping clear
senescent cells.23,35 Overall, further research into second
generation-senolytics, immunotherapy, and lymphatic drainage can pave the
way for improved therapies to alleviate senescence burden and
neurodegenerative disease onset and progression.

5. Conclusion

The field of neurodegenerative diseases is only just beginning to be explored;
the brain is a complicated area of study, and cognitive decline even moreso.
In recent years, many potential avenues have been explored for possible
treatments, including senolytics, senomorphics, and mitochondrial-targeted
therapies. Senescence is a vital part of neurodegenerative diseases, and
understanding its role proposes a powerful avenue of treatment. Constant
stimuli, such as NF-κB signaling, contributes to SASP , reinforcing
inflammaging by its characteristic overproduction of proinflammatory
cytokines and chemokines.8 In addition, it is clear that many factors
function to induce and maintain SASP in a positive feedback manner,
increasing senescent cell accumulation and exacerbating chronic
inflammation. These factors contribute to a neurotoxic environment in
which neuronal cell death occurs, advancing neurodegeneration in affected
patients. Extracellular tau can further cause oxidative stress and DNA
damage, which are known to be associated with induction of senescence.4 In
addition, therapeutic strategies targeting senescence offer promising avenues
for addressing neurodegenerative diseases. Senolytics have shown potential
in reducing neuroinflammation and improving cognitive function, while
senomorphics provide alternatives by modulating SASP factors without
inducing cell death. Similarly, mitochondria-based therapies hold promise in
mitigating oxidative stress and enhancing cellular health. However,
challenges remain in understanding mechanisms, potential side effects, and
disease-specific applications. Collaborative research across disciplines is vital

Berkeley Pharma Tech Journal of Medicine | 68



to fully harness the potential of these approaches and reshape the landscape
of neurodegenerative disease treatment.

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