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https://www.sciencedirect.com/science/article/pii/S002228362300181X

Molecular Mechanisms of Cellular Senescence in Neurodegenerative Diseases

Review Article

Molecular Mechanisms of Cellular Senescence in Neurodegenerative Diseases

Author links open overlay panelHe-Jin Lee 1 2, Ye-Seul Yoon 1 2, Seung-Jae Lee 3 4

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Highlights

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  Cellular senescence contributes to aging and neurodegenerative diseases.

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  Protein aggregates can induce cellular senescence in brain cells.

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  Cellular senescence can be targeted for therapy for neurodegenerative diseases.

Abstract

Neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, are characterized by several pathological features, including selective neuronal loss, aggregation of specific proteins, and chronic inflammation. Aging is the most critical risk factor of these disorders. However, the mechanism by which aging contributes to the pathogenesis of neurodegenerative diseases is not clearly understood. Cellular senescence is a cell state or fate in response to stimuli. It is typically associated with a series of changes in cellular phenotypes such as abnormal cellular metabolism and proteostasis, reactive oxygen species (ROS) production, and increased secretion of certain molecules via senescence-associated secretory phenotype (SASP). In this review, we discuss how cellular senescence contributes to brain aging and neurodegenerative diseases, and the relationship between protein aggregation and cellular senescence. Finally, we discuss the potential of senescence modifiers and senolytics in the treatment of neurodegenerative diseases.

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Keywords

cellular senescence

neurodegenerative diseases

protein aggregation

senolytic therapy

senescence-associated secretory phenotype

Introduction

Neurodegenerative diseases (NDs) are characterized by progressive pathological changes, including neuronal death, deposition of abnormal protein aggregates, and chronic inflammation in specific brain regions. In Alzheimer’s disease (AD), pathological protein deposits include amyloid β (Aβ) and hyperphosphorylated tau in senile plaques and neurofibrillary tangles (NFTs), respectively.1 The α-synuclein aggregates are hallmarks of a group of diseases, often referred to as synucleinopathies, including Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB).2, 3, 4, 5 TAR DNA-binding protein 43 aggregates are found in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).6 These protein aggregates are initiated in different brain areas for specific diseases and spread to other areas as the disease progresses.7

Protein aggregates are associated with various intracellular changes, leading to neuronal dysfunction and death. Mitochondrial dysfunction, which triggers impaired energy metabolism and oxidative stress, has been detected in AD, PD, and other neurodegenerative disorders.8, 9, 10, 11 Autophagy-lysosomal and proteasomal degradation pathways are also affected.12, 13 Intracellular trafficking of vesicles and organelles is often disrupted in cells with abnormal protein aggregates.14, 15, 16 Protein aggregates not only affect cells intracellularly, but can also propagate to neighboring neurons and glia, thereby impeding cellular functions and inducing inflammatory responses.17

Aging is a strong risk factor for neurodegenerative diseases, accompanied by central nervous system (CNS) atrophy, accumulation of protein aggregates, and an increased number of senescent cells in the brain.18, 19 Cellular senescence is characterized by irreversible cell cycle arrest and the inhibition of apoptotic death. It is also associated with changes in cellular metabolism and proteostasis, reactive oxygen species (ROS) production, and senescence-associated secretory phenotype (SASP).20 In cellular senescence, morphological changes are also observed where cells become larger and irregular in shape owing to cytoskeletal rearrangements and changes in cell membrane composition.21, 22 Here, we provide a comprehensive review of the current literature linking cellular senescence to the pathogenesis of neurodegenerative diseases.23, 24

Cellular senescence

Cellular senescence can be categorized into acute and chronic types.25 The acute type is a normal biological process that occurs during embryological development or tissue repair. Chronic senescence is induced by prolonged exposure to stresses, thereby generating cellular and tissue alterations (Figure 1).25, 26

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Figure 1. Cellular Senescence. (a) Replicative (RS), oncogene-induced (OIS), and stress-induced senescence (SIS). (b) Staging of cellular senescence. As cells become senescent, several features are observed, including morphological changes, loss of nuclear Lamin B1 and HMGB1, SAHF, SA-β-gal, and SASP. As senescent cells accumulate, the anti-death signals from these cells inhibit clearance by immune cells and become resilient to apoptosis. The Threshhold Theory of Senescent Burden hypothesizes that the accumulation of senescent cells above a certain limit sends enough signals to inhibit clearing by immune cells.40, 41, 42

Cellular senescence was first recognized when primary cells in culture ceased to proliferate after a certain number of passages.27 These cells demonstrated telomere shortening and irreparable DNA damage. This type of senescence is referred to as replicative senescence and is mainly observed in cells cultured in vitro.28 Another cause of cellular senescence may be the overexpression‎ of oncogenes, such as Ras, Akt, E2F1, cyclin E, Mos, and Cdc6, and is known as oncogene-induced senescence.29 Moreover, senescence can be induced by stressful events such as oxidative stress, irradiation, impairment of protein degradation pathways, and mitochondrial dysfunction, which are known to be independent of replication and telomere trimming. This is known as premature (stress-induced) senescence.20, 29

Regardless of the type of senescence, senescent cells share common characteristics. Proliferating cells exhibit stable cell cycle arrest when they become senescent, and this process is regulated by the p16INK4a and p53/pRB pathways.20 Increased p53 expression‎ upregulates p21 and arrests the cell cycle. Activation of p16INK4a leads to stable cell cycle arrest by cyclin-dependent kinase 4 (CDK4) and CDK6 inhibition, which then hypophosphorylates pRB to block S phase entry.30, 31

A typical feature of senescent cells is morphological changes. Cells usually become larger and flattened with irregular shapes. Changes in the cell membrane and cytoskeletal rearrangements appear to be the primary reasons for such morphological differences.21, 32, 33 In addition, an abnormal appearance is observed in the mitochondria, ER, and nucleus.21

Cellular senescence also affects cellular metabolism and organelle function. Altered mitochondrial function leads to elevated ROS generation, changes in carbohydrate metabolism, and transcriptional changes that upregulate senescence-related genes.20 Furthermore, impaired mitophagy results in the accumulation of dysfunctional mitochondria, which are often observed in senescent cells.34 In addition, lysosomal changes lead to elevated levels of senescence-associated β-galactosidase (SA-β-gal) in the cells.35 Nuclear changes demonstrate persistent DNA damage responses with increased double-stranded DNA damage marker (γH2AX), increased senescence-associated heterochromatin formation (SAHF), and downregulation of lamin B1 or HMGB1.36, 37, 38

Senescence-associated secretory phenotype is a crucial feature of cellular senescence, and is characterized by exocytosis of pro-inflammatory cytokines, chemokines, extracellular matrix proteases, bioactive lipids, microRNAs, other non-coding nucleotides, and extracellular vesicles. These molecules have paracrine effects on neighboring cells, affecting cellular metabolism and causing toxicity.24

Senescent cells resist apoptotic death, leading to persistent senescent signals that can be fatal to neighboring cells.39 Senescent cells are cleared by immune cells attracted to pro-inflammatory SASP factors.40 However, the ‘threshold theory of senescent cell burden’ explains that when senescent cells accumulate above the clearing capacity of the immune system, the aging mechanism is accelerated.40, 41, 42 Simply, when senescent cells reach above a threshold burden, they may inhibit the immune system and the clearing mechanism by expressing ‘anti-death’ signals. For example, matrix metalloproteinases (MMPs) secreted from senescent cells through the SASP cleave FAS ligands and other immune cell surface proteins, preventing cell death.42 Senescent cells also trigger fibrosis, which prevents the infiltration of immune cells and traps them within localized foci.40

Some useful markers of cellular senescence have been identified. For example, changes in the levels of SA-β-gal, p16INK4a, and p53/pRB pathways are often measured.20, 30, 43 In addition, nuclear changes in SAHF were detected using trimethylated histone H3 lysine9 (H3K9me3) immunostaining44. The loss of lamin B1 and HMGB1 in the nucleus can also be measured using specific antibodies.36, 38 The secretion of SASP factors, such as pro-inflammatory cytokines and proteases, can be quantified. However, these markers may not be useful for all types of senescent cells and caution is required.

Cellular senescence in the aging brain

Aging is the gradual deterioration of the body from birth to death. When aging organisms accumulate senescent cells, it causes significant damage to tissues and organs, increasing the risk of chronic diseases, geriatric symptoms, and mortality.45

The brain consists of various cell types including neurons, glia (astrocytes, oligodendrocytes, and microglia), and endothelial cells. Aging brain cells share some common cellular senescence characteristics yet display specific features depending on the cell type. The brain is also highly vulnerable to oxidative stress owing to active mitochondria and aerobic metabolism, as it utilizes glucose as the primary energy source.29, 46, 47 Moreover, the brain contains fewer antioxidant enzymes than other organs do.48 Redox homeostasis and energy metabolism are significantly disturbed in aging brain cells owing to mitochondrial dysfunction. This triggers impairment of DNA damage repair, synaptic plasticity, glucose metabolism, abnormal epigenetic modifications, and alteration of heterochromatin, which ultimately leads to cellular senescence.49

Another important feature of the aging brain is that the blood–brain barrier (BBB), a protective barrier against the peripheral environment of the CNS, is often a target of inflammatory and oxidative damage.50 Although BBB disruption is frequently observed in normally aging individuals,51 it is regarded as a key signal for neuroinflammation, a common feature of neurodegenerative diseases. Furthermore, BBB permeability is altered in senescence-induced mouse models, which showed an abnormal increase of plasma proteins in the brain parenchyma.52, 53 Ultimately, cellular senescence in the CNS may contribute to neuroinflammation, impaired neurogenesis, and degeneration of tissue structure and integrity (Figure 2).23

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Figure 2. Cellular Senescence in Aging Brain. Multiple types of brain cells are affected by cellular senescence. Neurons are post-mitotic and go through p21-mediated stress-induced senescence and show characteristics of lipofuscin deposits and persistent DNA damage responses. Astrocytes and microglia proliferate and show replicative senescence-like phenotypes. Increased secretion of SASP factors causes immune responses, including neuroinflammation and BBB disruption. Oligodendrocytes show inhibition of axonal remyelination capacities and reduced proliferation of OPCs.

Senescence phenotypes in neurons

Neurons are different from other brain cells in that they are postmitotic. Aged mouse neurons display typical senescence phenotypes, such as increased double-stranded DNA breaks, SA-β-gal, heterochromatinization, pro-inflammatory cytokines, and senescence gene expression‎.20, 54, 55 In addition, the senescent phenotype of neurons is rescued by knockout of CDKN1A in mice, indicating that p21 mediates senescence in aged neurons.55

Another feature of aged neurons is the accumulation of cytoplasmic deposits such as lipofuscin, a typical characteristic of postmitotic senescent cells.56 Lipofuscin is composed of extremely complex forms of proteins, lipids, and sugars that are highly crosslinked in nature. It is formed when increased levels of lipid peroxidation products attack lipids, proteins, and other susceptible groups. Altered proteostasis and mitochondrial dysfunction appear to be the major causes of lipofuscin formation. Lipofuscin levels increase with normal aging but seem to be accelerated by pathological processes, such as neuronal loss, gliosis, oxidative stress, and mitochondrial and lysosomal dysfunctions.56 Lipofuscin is also found in the neurons of NDs, such as AD, PD, Huntigton’s disease (HD), and FTD. For example, lysosomes become filled with lipofuscin in the early stages of AD and then progress to a vast cytoplasmic accumulation of large lipofuscin deposits.57 Interestingly, lipofuscins are found in the extracellular space after neuronal death and usually colocalize with Aβ plaques, suggesting that lipofuscin may be linked to the formation of senile Aβ plaques in AD.8, 57 In patients with PD, α-synuclein was found in lipofuscin deposits of substantia nigra pars compacta (SNpc) neurons.58 In fact, it appears that there is a similarity in the timeline of lipofuscin formation and protein aggregate deposits in the pathogenesis of NDs.59, 60 It is not clear whether there is a direct interaction between lipofuscin formation and protein aggregates, such as Aβ, α-synuclein, or tau, but studies show that there may be a link with cellular senescence.

Lastly, an intriguing characteristic of neuronal senescence is the active DNA damage response that inhibits cell cycle re-entry and, therefore, apoptotic death.61 The accumulation of severe DNA damage triggers persistent DNA damage responses that lead to the active secretion of pro-inflammatory cytokines, such as IL-6, as well as regulation of p53/p21 downstream pathways for DNA repair, cell cycle arrest, and apoptosis.61, 62 Consequently, surviving neurons with senescent phenotypes may release pro-inflammatory factors for chronic immune responses and constantly influence the extracellular environment that affects other CNS cells.

Senescence phenotypes in astrocytes

Astrocytes are the most abundant glial cells in the CNS and perform complex functions. They are remarkably heterogeneous and are involved in neurogenesis, maintaining extracellular homeostasis, and regulating BBB permeability.63

Astrocytes grown in culture over time display stress-induced, replicative senescence-like features.64, 65, 66 Aged astrocytes exhibited flattened morphology, increased SA-β-gal levels, ROS production, p53, p21CIP1, p16INK4a, SAHF, and expression‎ of astrogliosis markers, such as glial fibrillary acidic protein (GFAP) and S100β.

Most importantly, astrocytes in the aging brain display SASP characteristics with increased secretion of pro-inflammatory cytokines, such as IL-6.67 In addition, neurons co-cultured with senescent astrocytes demonstrated reduced survival compared with that in neurons cultured with non-senescent astrocytes, indicating that senescent astrocytes may affect neuronal survival.65 Neurons co-cultured with senescent astrocytes also showed reduced glutamate release from synapses, where synaptic vesicle pools decreased.68

Perivascular astrocytes, pericytes, and other specialized endothelial cells, sheath cerebral blood vessels through their extended end feet.69 In mouse and rat models, BBB dysfunction is linked to astrogliosis via the secretion of IL-6, monocyte chemoattractant protein-1 (MCP-1; CCL2), and matrix metalloproteinase 9 (MMP9). Such changes in the extracellular environment can affect communication between neighboring neurons and other glial cells.70

Senescence phenotypes in microglia

Microglia are the primary immune cells of the CNS and originate from the mesenchymal cells. They exhibit typical ‘replicative’ senescence with telomere shortening, growth arrest, SA-β-gal elevation, and SAHF formation.71 Microglia from old mice produce high levels of pro-inflammatory cytokines, such as IL-6, IL-1β, and tumor necrosis factor α (TNFα), which are generally upregulated during cellular senescence.72

Senescent microglia have been detected in multiple areas of the aging human brain.73, 74, 75 Senescence affects both the structure and function of microglia. Senescent microglia differ from typical reactive microglia in their morphology, where deramification, beading, and cytoplasmic fragmentation are frequently observed.73 Senescent microglial cells also exhibit reduced motility, affecting their ability to migrate toward the damaged site, where their immune function is required.76 Transcriptome analyses of aged microglia have shown an increase in some genes associated with NDs, including Triggering Receptor Expressed on Myeloid Cells 2 (TREM2).77, 78 Functionally, microglia are crucial for maintaining iron homeostasis in the brain, as iron is taken up and stored in ferritin proteins.79, 80 Iron is a key co-factor in mitochondrial respiration and is therefore critical for energy production.81 However, senescent microglia may lose their capacity to store iron, leading to elevated iron levels and oxidative stress in the brain.

Senescence phenotypes in oligodendrocytes

Oligodendrocytes are post-mitotic cells that myelinate neuronal axons in the CNS. These cells are highly vulnerable to oxidative stress owing to active glycolysis and mitochondrial activity.82, 83 Glycolysis also increases the level of acetyl-CoA, which promotes the synthesis of fatty acids required for myelination. Oxidative DNA damage and elevated SA-β-gal are detected in oligodendrocytes of aging individuals, suggesting that oligodendrocytes may undergo stress-induced cellular senescence.20, 84

Oligodendrocyte progenitor cells (OPCs) are the precursors to mature oligodendrocytes. These cells move to damaged neurons and remyelinate axons during the repair process. Aging decreases the regenerative potential of damaged axons, which correlates with the senescent phenotypes observed in oligodendrocytes and OPCs. Senescent OPCs in culture increased the expression‎ of esophageal cancer-related gene 4 (Ecrg4), which induces senescence by accelerating the proteasome-dependent degradation of the cell cycle genes cyclin D1 and D3.85 Thus, Ecrg4 inhibits further proliferation of OPCs, which leads to a reduction in the OPC population. In addition, senescent OPCs secrete Ecrg4, which can induce senescence in other OPCs. These results suggest that senescent oligodendrocytes and OPCs no longer support neuronal regeneration and energy supply.

Cellular senescence vs. reactive gliosis

Glial cells of the CNS, such as astrocytes and microglia, are known to be activated by injuries or diseases. This reactive gliosis causes cells to proliferate and change shape, and some cells migrate to the injury sites to form glial scars.86 In the case of astrocytes, cells become larger and increase expression‎ of cytoskeletal proteins such as GFAP, vimentin, and nestin.86 Gene expression‎ changes in astrocytes differ significantly depending on the type of injury. Focal ischemic stroke produced by transient MCAO and neuroinflammation induced by lipopolysaccharide (LPS) injection in the mouse brain caused reactive astrogliosis but showed distinct sets of induced genes.87 Activated microglia change from flattened to an amoeboid-like shape and express high levels of immune markers and inflammatory cytokines.88 Reactive astrocytes and microglia release cytokines, chemokines, and proteases to the extracellular space.89

There is a significant overlap between the reactive and the senescent glia, such as inflammatory secretion.90 However, recent studies identified the features that could assist in discriminating between activated vs. senescent glia. For example, reactive astrocytes become hypertrophic with enlarged cell bodies, whereas senescent astrocytes are growth-arrested and show flattened morphology.89, 90 Astrogliosis is accompanied by a high expression‎ of GFAP and other cytoskeletal proteins.89, 90 Senescent astrocytes display markedly increased expression‎ of a different set of genes, such as p16, p21, p53, SA-β-gal, and DNA repair genes.90 In the case of microglia, senescent microglia may also be difficult to distinguish from reactive cells as the common secretory factors, such as TNF-α, IL-1β, and IL-6, overlap, and no specific factors for senescent cells have been discovered yet.91 However, some exclusive features of senescent cells, in general, may be helpful in such discrimination. Senescent microglia are growth-arrested with upregulation of p16 and p21, and exhibit increases in SA-β-gal expression‎ and lipofuscin accumulation. Activated inflammatory microglia are highly proliferative and do not show changes in SA-β-gal or lipofuscin.91

As both glial activation and senescence display a complex spectrum of molecular, cellular, and functional changes responding to various stresses, it is still challenging to distinguish one from the other and to understand exactly how they regulate the immune responses in the brain.

Cellular senescence in neurodegenerative diseases

Recent evidence suggests that pathological changes in neurodegenerative diseases begin long before the symptoms appear.92, 93 These changes include chronic inflammation, the abnormal accumulation of protein aggregates, and neuronal loss. Prolonged exposure to stress, such as increases in ROS production, persistent DNA damage, or impairment of mitochondria and other organelle functions, may induce cellular senescence. These stresses contribute to disease pathogenesis by affecting the metabolism and gene expression‎ and by instigating pro-inflammatory responses through SASP. This section reviews the current literature on cellular senescence in neurodegenerative diseases.

Alzheimer’s disease

Alzheimer’s Disease is the most common neurodegenerative disease, constituting approximately 70% of all dementia cases. It is characterized by memory loss, cognitive impairment, neuronal loss, and accumulation of amyloid plaques and NFTs of hyperphosphorylated tau in the brain.94

Several senescence-like features have been observed in the brains of patients with AD. Increases in cellular senescence markers, such as γH2AX and SA-β-gal, have been observed in the hippocampus, lymphocytes, and plasma samples.95, 96, 97, 98 Changes in the expression‎ of genes related to senescence, such as p53, p21, and p16INK4a, have been reported.99, 100, 101, 102 Furthermore, the upregulation of p38MAPK, a well-known SASP regulator, and the increases in SASP factors, such as pro-inflammatory cytokines IL-6, IL-1, TGF, and TNFα, and extracellular proteinases MMP-1, MMP-3, and MMP-10, are observed in the AD brain.20, 103, 104, 105

Similar senescence phenotypes have been observed in mouse and cell models of AD. Expression‎ of p16INK4a and p21 genes was elevated in 12-month-old APP/PS1 mice.106 Neural stem progenitor cells, isolated from APP/PS1 Tg mice and cultured in the presence of Aβ42 oligomers, showed more senescent cells with increased SA-β-gal and p16INK4a than those isolated from wild-type mice.107 Neurons containing NFT-like tau aggregates exhibited senescence-like phenotypes, showing DNA damage, NF-κB activation, and SASP in four AD Tg mouse models.108

Cellular senescence in the AD brain involves multiple types of cells. Astrocytes play an important role in the pathogenesis and progression of AD because astrogliosis may cause excitotoxic glutamate release, inflammatory cytokine release, ROS production, and BBB breakdown, leading to neuropathological processes.109, 110 Reactive astrogliosis is observed in astrocytes surrounding amyloid plaques in the AD brain, and these cells are positive for IL-6, a key SASP component.111, 112 Astrogliosis is comparable to cellular senescence in that pro-inflammatory factors are secreted and cause neuroinflammation.113, 114 Several senescent phenotypes were noted in the astrocytes of patients with AD. Increased levels of γH2AX, p16INK4a, IL-6, and MMP-1 in astrocytes have been observed in the brains of patients with AD.114, 115, 116 In vitro culture of human astrocytes with conditioned medium from Aβ-producing cells or synthetic Ab42 oligomers showed typical signs of senescence, such as flattened morphology and increased p16 and SA-β-gal expression‎.114 Examining p53 isoforms in patients with AD revealed that Δ133p53 was downregulated while p53β was upregulated, and the same pattern was observed in senescent astrocytes cultured in vitro, suggesting that p53 isoforms are implicated in astrocyte senescence.116

Microglial activation causes high levels of inflammation in the brain and has been implicated in the pathogenesis of neurodegenerative diseases. Chronic microglial activation is commonly observed in patients with AD. These cells often have characteristics similar to cellular senescence, including a flattened morphology, SA-β-gal expression‎, and SASP.79 Microglia in AD have shorter telomeres than those in age-matched controls.117 In addition, cultured microglia isolated from patients with AD undergo replicative senescence with telomere shortening.71 Aged microglia from rats cultured with Aβ oligomers acquired a senescent phenotype.118 Senescent microglia show reduced capacity for phagocytosis and motility, indicating that their function as immune cells is compromised.76

Human AD brains also show senescent oligodendrocyte precursor cells in the inferior parietal lobes near Aβ plaques, and similar observations were made in APP/PS Tg mice.119 These cells showed upregulation of p21, p16INK4a, and SA-β-gal activity, and direct exposure of cultured OPCs to Aβ aggregates accelerated senescence phenotypes.

These results suggest that cellular senescence in the AD brain is an ongoing process involving various cell types and gradually impairs cellular function, leading to a degenerative phenotype.

Parkinson’s disease

Parkinson’s disease is the second most common neurodegenerative disorder that affects motor movements, manifesting motor symptoms such as bradykinesia, rigidity, and resting tremor. Patients with PD also experience non-motor symptoms, such as sleep disorders, psychiatric problems, and autonomic dysfunction. The pathological features of PD include selective degeneration of neurons, particularly dopaminergic neurons in the SNpc of the midbrain, and intraneuronal inclusion bodies known as Lewy bodies and Lewy neurites.120

Postmortem brain tissues of sporadic patients with PD showed increased expression‎ of senescence markers, especially in astrocytes in the SNpc region.121 These cells had increased p16INK4a, IL-6, IL-1α, IL-8, and MMP3 levels and reduced lamin B1 levels in PD brain tissues compared to those in control brains. In addition, exposure of cultured neurons and glial cells to environmental stresses, such as exposure to the herbicide paraquat or to α-synuclein protein aggregates, resulted in the detection of senescence markers, lamin B1, p21, HMBG1, and SA-β-gal.121, 122 Special AT-rich sequence-binding protein 1 (SATB1), a transcription factor that directly represses the expression‎ of p21, is a risk factor for PD. In cultured dopaminergic (DA) neurons, the loss of SATB1 expression‎ led to a premature senescence phenotype with increased SA-β-gal and SASP factors.123 A recent transcriptome analysis using a neuronal cell model showed that α-synuclein expression‎ led to the activation of cellular senescence and DNA damage responses associated with the p53 pathway.124 These studies suggest that PD, as well as in AD, shows cellular senescence in brain cells, which may be closely related to the pathogenesis and progression of the disease.

Other neurodegenerative diseases

Amyotrophic lateral sclerosis (ALS) is a common degenerative motor neuron disease involving the death of the upper and lower motor neurons, which leads to paralysis of the voluntary muscles.24 The symptomatic SOD1G93A Tg rat ALS model displayed increased p16INK4a and reduced lamin B1 expression‎ in microglia of the lumbar spinal cord.125 Furthermore, cultured SOD1G93A microglia showed senescence characteristics, including large and flat morphology, increased expression‎ of senescence markers, SA-β-gal, p16INK4a, p53, and MMP-1, and upregulation of SASP factors. Interestingly, ChAT-positive motor neurons and astrocytes also showed nuclear p16INK4a staining. Differentiated astrocytes from patients with ALS also display SASP characteristics, indicating that multiple cell types are associated with cellular senescence in ALS.126

Multiple sclerosis (MS) is a chronic disorder characterized by inflammatory demyelination, astrogliosis, and neuronal death of the CNS.127 Premature senescence of B cells has been observed, which may promote inflammation and contribute to the progression of MS.128 Senescent glial cells and neurons with lipofuscin-positive phenotypes have been detected in white matter lesions in patients with MS.20 These data suggest that chronic inflammation of immune cells and premature senescence of neurons and glial cells in the CNS may be linked to the pathogenesis of MS.

Cellular senescence and protein aggregation in NDs

The two major pathological hallmarks of NDs are accumulation of abnormal protein aggregates and neuroinflammation. As discussed in previous sections, neuroinflammation is closely linked to the SASP characteristics of cellular senescence and the secretion of several pro-inflammatory factors. Moreover, dynamic regulation to maintain protein homeostasis (proteostasis) in the cell is altered or impaired in NDs.129 The complex proteostasis network involves molecular chaperones, proteolytic machinery, and regulator proteins for protein synthesis, folding, and degradation.129 Impairment of the proteostasis network is considered the major cause of the accumulation of abnormal protein aggregates in cells.

Abnormal protein aggregates can be secreted from neurons and affect the functions of neighboring cells. For example, secreted pathogenic protein aggregates, such as tau, α-synuclein, and huntingtin, are internalized by neighboring cells, activating immune responses in glial cells.130, 131, 132, 133 Furthermore, the secreted protein aggregates could be internalized into the connected and neighboring neurons and subsequently trigger misfolding and aggregation of endogenous proteins, which is considered the basis for the spread of proteinopathies during disease progression. This ‘prion-like’ spreading of pathological changes is widely reported in various NDs, including AD, PD, FTD, and HD.134, 135, 136, 137

The relationship between protein aggregates and cellular senescence in NDs was first observed when Aβ42 oligomers were used to treat neural stem/progenitor cells of the mouse hippocampus in vitro.107 The Aβ42 oligomers induced senescence markers, SA-β-gal and p16INK4a, in cultured cells. In addition, Aβ aggregate-producing APP/PS1 Tg mice showed significantly high levels of SA-β-gal and p16INK4a.107 In the brains of patients with AD and mouse models, Aβ plaque-associated OPCs showed senescence phenotypes with the upregulation of p21, p16INK4a, and SA-β-gal.119 Furthermore, direct exposure of cultured OPCs to aggregated Aβ42 resulted in a higher number of SA-β-gal-positive cells than in the control.

Tauopathies, including AD and FTD, are characterized by cognitive deficits and the deposition of tau aggregates in the brain, mainly in the form of NFTs. Transcriptome analyses of NFT-accumulated neurons microdissected from the postmortem AD brain showed an expression‎ profile consistent with cellular senescence.108 In addition, Tau oligomer-containing astrocytes from AD and FTD brains displayed a senescence-like phenotype, where cells showed elevated levels of p16INK4a, γH2AX, and cytoplasmic HMGB1.138 When senescent astrocytes and glial cells were cleared from tau-expressing MAPTP301SPS19 Tg mice by crossing with INK-ATTAC Tg mice, a significant amount of phosphorylated tau aggregates was reduced.139

The α-synuclein aggregates are found in intracellular inclusion bodies, such as Lewy bodies, of several neurodegenerative diseases referred to as synucleinopathies, including PD, MSA, and DLB.2, 3, 4, 5 These inclusions contain protein aggregates, organelles, and lipids, and are similar to lipofuscin, which is often found in aged cells. Synucleinopathy is found not only in neurons, but also in glial cells, such as oligodendrocytes and astrocytes. The α-synuclein protein levels are high in neurons. However, it is uncertain whether mature human glial cells express α-synuclein at high levels.140, 141 Recent studies have proposed that α-synuclein can be transferred from neurons to glial cells under diseased conditions.120, 137, 142

In mouse primary cultures of neurons, astrocytes, and microglia, adding α-synuclein pre-formed fibrils (PFFs) to the culture medium accelerated cellular senescence, reducing the levels of lamin B1 and HMGB1 but increasing p21.122 Transcriptome analyses of SH-SY5Y neuronal cells expressing high levels of α-synuclein showed activation of the p53 pathway, which led to DNA damage responses and cellular senescence.124 Cellular senescence markers, such as γH2AX, SA-β-gal, and H3K9me3, were elevated compared to those in control cells. Interestingly, these cells showed elevated levels of the DNA double-strand break markers γH2AX and 53BP1, but reduced MRE11, a key component of the double-strand break repair system, indicating that the DNA repair pathway was impaired.

Intriguingly, aberrant proteostasis is a typical phenotype of senescent cells, exhibiting nucleolar dysfunction, autophagy/lysosome anomalies, and ER/UPR stress.26, 143 A recent study showed that TNFα treatment of rodent neurons induced neuronal senescence, and senescent neurons increased α-synuclein secretion through the SASP.144 The increased SASP was mediated by lysosomal exocytosis, indicating that secretory lysosomes were more abundant in senescent neurons than in non-senescent neurons.

Collectively, senescent neurons increase the secretion of α-synuclein, thereby promoting cell-to-cell propagation of this protein. The secreted α-synuclein can induce neuronal senescence, further promoting α-synuclein secretion. This may explain how aggregate propagation is promoted in the aging brain. Furthermore, SASP can trigger the inflammatory microenvironment, further promoting the propagation of protein aggregates.144.

Therefore, senescence may be the central phenomenon that interconnects major neuropathological features such as neuroinflammation and protein aggregation/spreading (Figure 3).

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Figure 3. Cellular Senescence and Protein Aggregation. Aberrant protein aggregate accumulation and neuroinflammation are the major characteristics of neurodegenerative diseases. Neuroinflammation is closely linked to the inflammatory SASP factors of cellular senescence. Abnormal cellular protein deposits in neurodegenerative diseases, induce oxidative and metabolic stresses leading to cellular senescence. Even further, these aggregates may be secreted and affect neighboring cells, which bind to the plasma membrane or are internalized to interfere with normal cellular functions, causing these cells to become senescent. Senescent cells with altered metabolism may induce more protein aggregation continuing the vicious cycle of senescence and protein aggregation, eventually leading to neuronal death.

Targeting cellular senescence for therapy

There have been various attempts to slow down the aging process in early human studies. Dietary interventions such as caloric restriction and intermittent fasting, exercise, metformin, mTOR inhibitor rapamycin, sirtuin agonist resveratrol, SASP inhibitors, and senolytics seemed partially successful in improving healthspan.45 In fact, some of these approaches seem to function by inhibiting cellular senescence. For example, metformin may have anti-aging effects by affecting the SASP, autophagy-related mTOR activity, and mitochondrial function.145 Exercise prevents obesity-induced senescent cell formation in mice.146

One of the devastating characteristics of senescent cells is that they can damage and kill neighboring cells by secreting pro-inflammatory and other pathogenic SASP factors, yet these cells are resilient to cell death. Due to the detrimental effects, much attention has been paid to eliminating toxic senescent cells.

Senolytics are drugs that remove senescent cells by triggering apoptosis. Transcriptome analyses of senescent cells identified several candidates as targets of senolytics, and RNA interference assays showed that disabling such targets leads to apoptotic death.45 Fisetin, quercetin, dasatinib, and now more than 20 other drugs could selectively eliminate senescent cells in mice and humans.42, 45 A senolytic drug combination of dasatinib and quercetin was shown to remove senescent adipocyte progenitor cells and improve metabolic function in obese mice.147 These drugs reduced the number of p16INK4a- and SA-β-gal-positive senescent cells, inflammatory macrophage infiltration, and fibrosis in the abdominal subcutaneous adipose tissue of obese and diabetic humans.148 In addition, the INK-ATTAC Tg mice in the C57BL/6 background, expressing a ‘suicide’ transgene encoding caspase 8 explicitly in senescent cells, showed improvement in bone mass and strength and bone microarchitecture compared to those in vehicle-treated mice at old age (20–22 months).149, 150

With the success of senolytic drugs in various diseases, they are currently being tested for neurodegenerative diseases. The PS19 tau Tg mice crossed with INK-ATTAC Tg mice showed reduced p16INK4a-positive senescent astrocytes and microglia in the hippocampus and cortices.139 In the same study, the senolytic drug ABT263 (navitoclax), a specific inhibitor of BCL-2 proteins, showed similar effects in removing senescent cells. Clearance of senescent cells reduced gliosis, tau hyperphosphorylation, insoluble tau aggregates, and cortical and hippocampal neuronal degenerations. In the APP/PS1 mouse model, dasatinib and quercetin treatment removed senescent oligodendrocyte progenitor cells and ameliorated Aβ plaque-associated inflammation and cognitive deficits, suggesting that senolytic therapy may be effective for AD.119 Based on the favorable outcomes of senolytic treatment in preclinical animal studies, two clinical trials of phase1/2, based on the use of dasatinib and quercetin for patients with early AD, are in progress.151

The anti-senescence approach for pharmacological therapy of patients with PD is currently limited to cell and animal models.152 The P21 inhibitor UC2288 significantly reduces the number of senescent cells, oxidative stress, and inflammation in a SATB1 knockout PD model mice.123 Furthermore, astragaloside IV, derived from a herbal plant with powerful antioxidant, antifibrotic, and anti-inflammatory properties, reduced senescent astrocytes in the SNpc region of the MPTP mouse model. It exerts anti-senescent effects by promoting mitophagy and antioxidant properties.153 Another reagent, GSK-650394, a glucocorticoid-related kinase 1 inhibitor that impedes NF-κB pathways and inflammatory responses, has been shown to reduce neuronal senescence and inflammation by impairing astrocytes and microglial serum/glucocorticoid-related kinase 1 (SGK1).154 Glial inhibition of SGK1 suppresses senescence-related genes, such as NFκB-mediated pro-inflammatory cytokines and p16INK4a, and upregulates genes involved in neuroprotection, such as the glutamate clearance pathway.

Another therapeutic strategy for treating senescent cell-induced diseases is the prevention of senescent cell formation through caloric restriction. A human study with 30% caloric restriction for over 10 years showed that the colonic mucosa had reduced expression‎ of p16INK4a and IL-6.155 The hypocaloric diet in mice reduced the number of senescent cells in intestinal and hepatic tissues.156 It prevented fat deposition and telomere-associated DNA damage foci in hepatocytes.157 The post-mitotic neurons also showed a similar reduction in senescent cells.55 Although the exact mechanisms by which caloric restriction reduces the appearance of senescent cells are unknown, it may involve a reduction in ROS, autophagy activation, increased expression‎ of sirtuins, and triggering of DNA damage repair.158 A recent study of aging-promoting genetic variants in C. elegans with PD phenotypes showed that treatment with the anti-aging agent N-acetylglucosamine enhances lysosomal function and reduces protein aggregate propagation.159

Anti-SASP compounds, which can block SASP and inflammatory responses, are also alternative candidates for anti-senescence therapy.158 The antidiabetic drug metformin was shown to block the SASP in transformed fibroblasts, and its chronic use is associated with extended life and health spans.160, 161 In addition, the autophagy-promoting drug rapamycin inhibits the transcription of several SASP factors.162 JAK-STAT inhibitors with anti-inflammatory properties have shown anti-SASP effects in vitro.163

Perspectives

Much of the focus on developing senescence-related drugs is on eliminating long-lasting senescent cells, which affect neighboring cells in a harmful way. Some senolytic drugs have originally been used to treat diseases unrelated to senescence, and by drug repositioning, these drugs are now being tested for senescence-induced diseases, including neurodegenerative diseases. Although such drugs are quick and valuable, the exact mechanism by which they work has not been clearly defined. Understanding the mechanisms of action of these drugs, as well as the molecular network leading to cellular senescence, will lead to the development of new anti-senescence drugs for neurodegenerative diseases. The recent advancement of single-cell analysis tools will assist in identifying new molecules and pathways critical in cellular senescence. Modifying these pathways with gene editing in cultured cells and animal models will provide mechanistic insights into the precise role of cellular senescence in brain aging and neurodegenerative diseases. Furthermore, senescent cells induced by disease, especially neurodegenerative diseases, may display distinct phenotypes, which have not been fully explored yet. Thus, the characterization of different types of senescent cells is required to help a deeper understanding of the role of cellular senescence in neurodegenerative diseases.These future studies are expected to generate novel targets for drug development to treat neurodegenerative diseases.

CRediT authorship contribution statement

He-Jin Lee: Conceptualization, Writing – original draft, Writing – review & editing, Supervision, Funding acquisition. Ye-Seul Yoon: Writing – original draft, Visualization. Seung-Jae Lee: Conceptualization, Writing – original draft, Writing – review & editing, Funding acquisition.

Acknowledgments

This study was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government (NRF-2021R1A2C1005984, NRF-2016R1A5A2012284 to H.-J.L., NRF-2018R1A5A2025964 to S.-J.L.) The figures were created with BioRender.com and Procreate app.

Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.-J.L. is the founder and CEO of Neuramedy Co., Ltd.

Data availability

No data was used for the research described in the article.

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