Cellular senescence in neuroinflammatory disease: new therapies for old cells?

There is an unmet need for novel therapeutic strategies that can halt neuroinflammatory disorders progressing towards a degenerative phenotype.Accumulating evidence links cellular senescence to a plethora of human diseases.Initial data indicate the presence of cellular senescence in neuroinflammatory disorders, suggesting it as a potential driver of pathogenesis.Senotherapeutics were able to reduce the senescent burden in animal models and, more recently, in humans.Incorporating senotherapeutics in the field of neuroinflammation could improve treatment outcomes. Neuroinflammatory diseases remain a therapeutic challenge, notably when progressing towards neurodegeneration. In this context, multiple sclerosis represents a central nervous system (CNS) disorder that combines pathogenic inflammatory and degenerative processes. Immunosuppression is effective for managing inflammatory activity, but neurodegenerative processes secondary to chronic inflammation are often refractory to contemporary treatments. Recent evidence indicates that pathways involved in chronic neuroinflammation demonstrate features of cellular senescence. These features could provide a framework that could serve as a target for senotherapeutics. In this review, we discuss the unmet need for strategies capable of overcoming the treatment resistance of neuroinflammatory diseases, and we discuss the potential of cellular senescence towards developing these strategies. Neuroinflammatory diseases remain a therapeutic challenge, notably when progressing towards neurodegeneration. In this context, multiple sclerosis represents a central nervous system (CNS) disorder that combines pathogenic inflammatory and degenerative processes. Immunosuppression is effective for managing inflammatory activity, but neurodegenerative processes secondary to chronic inflammation are often refractory to contemporary treatments. Recent evidence indicates that pathways involved in chronic neuroinflammation demonstrate features of cellular senescence. These features could provide a framework that could serve as a target for senotherapeutics. In this review, we discuss the unmet need for strategies capable of overcoming the treatment resistance of neuroinflammatory diseases, and we discuss the potential of cellular senescence towards developing these strategies. The cellular state of senescence is characterized by the inability of a cell to proliferate despite sufficient resources and stimuli [1.Jurk D. et al.Chronic inflammation induces telomere dysfunction and accelerates ageing in mice.Nat. Commun. 2014; 5: 4172Crossref Scopus (444) Google Scholar,2.Di Micco R. et al.Cellular senescence in ageing: from mechanisms to therapeutic opportunities.Nat. Rev. Mol. Cell Biol. 2021; 22: 75-95Crossref PubMed Scopus (239) Google Scholar]. This concept was first described in 1961 and has since attracted considerable scientific interest, particularly over the past 5 years [3.Hayflick L. Moorhead P.S. The serial cultivation of human diploid cell strains.Exp. Cell Res. 1961; 25: 585-621Crossref PubMed Google Scholar]. Indeed, senotherapeutic research has advanced exponentially and demonstrated that targeting cellular senescence (see Glossary) is a promising treatment strategy for otherwise incurable diseases, at least in animal models [4.Kirkland J.L. Tchkonia T. Senolytic drugs: from discovery to translation.J. Intern. Med. 2020; 288: 518-536Crossref PubMed Scopus (197) Google Scholar,5.Raffaele M. Vinciguerra M. The costs and benefits of senotherapeutics for human health.Lancet Healthy Longev. 2022; 3: e67-e77Abstract Full Text Full Text PDF Google Scholar]. For example, pharmacological depletion of senescent cells improved functional outcomes in a murine model of Alzheimer’s disease (AD) [6.Zhang P. et al.Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model.Nat. Neurosci. 2019; 22: 719-728Crossref PubMed Scopus (314) Google Scholar]. Following these results, senotherapies (Box 1) are currently being tested in clinical trials for neurodegenerative diseases such as AD [7.Gonzales M.M. et al.Senolytic therapy to modulate the progression of Alzheimer’s disease (SToMP-AD): a pilot clinical trial.J. Prev. Alzheimers Dis. 2022; 9: 22-29PubMed Google Scholar], as well as for other pathologies (e.g., cardiometabolic or age-associated conditions) [5.Raffaele M. Vinciguerra M. The costs and benefits of senotherapeutics for human health.Lancet Healthy Longev. 2022; 3: e67-e77Abstract Full Text Full Text PDF Google Scholar]. By contrast, research and literature focusing on cellular senescence in the context of neuroinflammation is sparse. Neuroinflammatory diseases are characterized by autoimmunity directed against components of the nervous system. Contemporary treatment options are often able to halt neuroinflammation to a considerable extent [8.University of California, San Francisco MS-EPIC Team et al.Long-term evolution of multiple sclerosis disability in the treatment era.Ann. Neurol. 2016; 80: 499-510Crossref PubMed Scopus (248) Google Scholar]. However, neuroinflammatory disorders that have a degenerative component often respond poorly to therapy and constitute an unmet need for novel therapeutic approaches [9.Rolfes L. et al.Failed, interrupted, or inconclusive trials on immunomodulatory treatment strategies in multiple sclerosis: update 2015–2020.BioDrugs Clin. Immunother. Biopharm. Gene Ther. 2020; 34: 587-610Google Scholar]. This concept is perhaps best exemplified by multiple sclerosis (MS). Immunosuppression may dampen inflammation in relapsing–remitting MS (RRMS), effectively reducing disability progression [8.University of California, San Francisco MS-EPIC Team et al.Long-term evolution of multiple sclerosis disability in the treatment era.Ann. Neurol. 2016; 80: 499-510Crossref PubMed Scopus (248) Google Scholar,10.Cree B.A.C. et al.Secondary progressive multiple sclerosis: new insights.Neurology. 2021; 97: 378-388Crossref PubMed Scopus (19) Google Scholar]. By contrast, once RRMS advances to the secondary progressive course of the disease (SPMS), neurodegeneration and disease progression are often insidious and unresponsive to therapeutic modulation [11.Wallin M.T. et al.Global, regional, and national burden of multiple sclerosis 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet Neurol. 2019; 18: 269-285Abstract Full Text Full Text PDF PubMed Scopus (444) Google Scholar].Box 1SenotherapeuticsSenotherapeutics (from Latin senex = old) aim to reduce the burden of cellular senescence. Senotherapeutic strategies can be broadly divided into two categories (senolytics and senomorphics) based on their mechanism of action. First, senolytics selectively induce cell death in senescent cells. Most senolytics target prosurvival and/or anti-apoptotic cellular pathways such as p53, p21, B cell lymphoma (Bcl-2) family proteins, HSP90, or protein kinase B (Akt). Different senolytic agents target distinct subpopulations of senescent cells, depending on their mechanism of action. Second, senomorphics aim to suppress the senescence-associated secretory phenotype (SASP) without inducing cell death. Most senomorphics target cellular pathways mediating senescent reprogramming, such as nuclear factor κB (NF-κB), mTOR, JAK 1/2 inhibitors, rho-kinase 1 (ROCK1), or p38 MAPK. As the field of senotherapeutics is rapidly evolving, a conclusive definition of therapeutic subgroups is currently lacking. It is worth noting that individual agents often exhibit mechanisms that qualify for one or more subgroups of senotherapy: for example, senolytics might also act as senomorphics and vice versa. An overview of contemporary senotherapeutics is given in Table 1 in main text. Senotherapeutics (from Latin senex = old) aim to reduce the burden of cellular senescence. Senotherapeutic strategies can be broadly divided into two categories (senolytics and senomorphics) based on their mechanism of action. First, senolytics selectively induce cell death in senescent cells. Most senolytics target prosurvival and/or anti-apoptotic cellular pathways such as p53, p21, B cell lymphoma (Bcl-2) family proteins, HSP90, or protein kinase B (Akt). Different senolytic agents target distinct subpopulations of senescent cells, depending on their mechanism of action. Second, senomorphics aim to suppress the senescence-associated secretory phenotype (SASP) without inducing cell death. Most senomorphics target cellular pathways mediating senescent reprogramming, such as nuclear factor κB (NF-κB), mTOR, JAK 1/2 inhibitors, rho-kinase 1 (ROCK1), or p38 MAPK. As the field of senotherapeutics is rapidly evolving, a conclusive definition of therapeutic subgroups is currently lacking. It is worth noting that individual agents often exhibit mechanisms that qualify for one or more subgroups of senotherapy: for example, senolytics might also act as senomorphics and vice versa. An overview of contemporary senotherapeutics is given in Table 1 in main text. Effective strategies to ameliorate secondary degenerative processes following chronic inflammation are yet to be successfully translated into clinical practice. Senotherapies may be a promising approach to improve therapeutic outcomes of neuroinflammatory diseases that have an unsatisfactory response to immunosuppressive treatment alone. In this review, we provide a current overview of the current knowledge on cellular senescence and its role in neuroinflammatory disorders. For the latter, we focus on MS as a neuroinflammatory disease exhibiting neurodegenerative components. However, we also discuss inflammatory pathologies of the peripheral nervous system (PNS) and skeletal muscle, as these areas of research have progressed recently and share common pathogenic traits with CNS disorders. We further demonstrate how senotherapeutics may be used as new treatment strategies to overcome treatment refractoriness in those diseases. Overall, this review intends to stimulate further research in the emerging field of senotherapeutics. Cellular senescence is the consequence of endogenous and exogenous stress. Among other things, these stressors include DNA damage, telomere dysfunction, oncogene activation, and chronic inflammation [1.Jurk D. et al.Chronic inflammation induces telomere dysfunction and accelerates ageing in mice.Nat. Commun. 2014; 5: 4172Crossref Scopus (444) Google Scholar,2.Di Micco R. et al.Cellular senescence in ageing: from mechanisms to therapeutic opportunities.Nat. Rev. Mol. Cell Biol. 2021; 22: 75-95Crossref PubMed Scopus (239) Google Scholar]. Pathways of cellular senescence and apoptosis are intimately linked and mediated, in part, by p53 signaling [12.Mijit M. et al.Role of p53 in the regulation of cellular senescence.Biomolecules. 2020; 10: E420Crossref PubMed Scopus (0) Google Scholar]. However, the factors shaping a cell’s trajectory towards apoptosis or senescence remain to be established [2.Di Micco R. et al.Cellular senescence in ageing: from mechanisms to therapeutic opportunities.Nat. Rev. Mol. Cell Biol. 2021; 22: 75-95Crossref PubMed Scopus (239) Google Scholar,13.Milanovic M. et al.Senescence-associated reprogramming promotes cancer stemness.Nature. 2018; 553: 96-100Crossref PubMed Scopus (421) Google Scholar]. Intriguingly, senescence is not confined to the cell experiencing stress, but exhibits the ability to spread. Xenotransplantation of senescent fibroblasts into skeletal muscle of young mice induces expression of a senescent phenotype in bystander cells [14.da Silva P.F.L. et al.The bystander effect contributes to the accumulation of senescent cells in vivo.Aging Cell. 2019; 18e12848Crossref PubMed Scopus (92) Google Scholar]. These bystander cells included fibroblasts and myofibers. One mechanism that may explain the dissemination of senescence is the secretory phenotype of senescent cells establishing a microenvironment perpetuating cellular senescence. Although subject to variation across tissues, the corresponding senescence-associated secretory phenotype (SASP) is characterized by a set of proinflammatory cytokines, growth factors, and proteases (Figure 1) [15.Nelke C. et al.Skeletal muscle as potential central link between sarcopenia and immune senescence.eBioMedicine. 2019; 49: 381-388Abstract Full Text Full Text PDF PubMed Google Scholar,16.Kirkland J.L. Tchkonia T. Cellular senescence: a translational perspective.eBioMedicine. 2017; 21: 21-28Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar]. The composition of the SASP is heterogeneous, with unique quantitative and qualitative features depending on the corresponding trigger, cell type, and tissue [17.Papadopoulos D. et al.Aging, cellular senescence, and progressive multiple sclerosis.Front. Cell. Neurosci. 2020; 14: 178Crossref PubMed Scopus (21) Google Scholar]. Even within the CNS, SASP profiles diverge between cell types (the phenotypes are discussed in detail by Papadopoulos et al. [17.Papadopoulos D. et al.Aging, cellular senescence, and progressive multiple sclerosis.Front. Cell. Neurosci. 2020; 14: 178Crossref PubMed Scopus (21) Google Scholar]). The senescent secretome includes a range of proinflammatory and immunomodulatory cytokines (e.g., IL-6, IL-7), chemokines [e.g., CC-chemokine ligand 2 (CCL2), CCL8], growth factors [e.g., epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF)], and proteases (e.g., MMP-1/3) [18.Acosta J.C. et al.Chemokine signaling via the CXCR2 receptor reinforces senescence.Cell. 2008; 133: 1006-1018Abstract Full Text Full Text PDF PubMed Scopus (1131) Google Scholar,19.Basisty N. et al.A proteomic atlas of senescence-associated secretomes for aging biomarker development.PLoS Biol. 2020; 18e3000599Crossref PubMed Scopus (282) Google Scholar]. Senescent cells also interact by specific receptors [e.g., intercellular adhesion molecule-1 (ICAM-1), urokinase receptor (uPAR), tumor necrosis factor (TNF) receptors], non-protein molecules [e.g., prostaglandin E2 (PGE2)], insoluble factors (e.g., fibronectin, collagens), exosomes, and ectosomes [20.Gorgoulis V. et al.Cellular senescence: defining a path forward.Cell. 2019; 179: 813-827Abstract Full Text Full Text PDF PubMed Scopus (685) Google Scholar]. Thus, both soluble and insoluble interaction molecules are employed by senescent cells to influence the local microenvironment. The effect of the SASP is highly dynamic. Initially, it is characterized by immunosuppressive and profibrotic effects, preserving or restoring tissue homeostasis [21.Neves J. et al.Of flies, mice, and men: evolutionarily conserved tissue damage responses and aging.Dev. Cell. 2015; 32: 9-18Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar]. However, with accumulation of senescent cells during inflammation and aging, its proinflammatory and potentially detrimental characteristics dominate and result in inflammation, tissue damage, and detrimental growth responses in bystander cells [22.Tchkonia T. et al.Cellular senescence and the senescent secretory phenotype: therapeutic opportunities.J. Clin. Invest. 2013; 123: 966-972Crossref PubMed Scopus (993) Google Scholar, 23.Kuilman T. Peeper D.S. Senescence-messaging secretome: SMS-ing cellular stress.Nat. Rev. Cancer. 2009; 9: 81-94Crossref PubMed Scopus (615) Google Scholar, 24.Acosta J.C. et al.A complex secretory program orchestrated by the inflammasome controls paracrine senescence.Nat. Cell Biol. 2013; 15: 978-990Crossref PubMed Scopus (1047) Google Scholar]. Thus, the SASP is increasingly recognized as a key driver of age-related pathologies, such as chronic inflammation [25.Tominaga K. The emerging role of senescent cells in tissue homeostasis and pathophysiology.Pathobiol. Aging Age Relat. Dis. 2015; 527743PubMed Google Scholar]. Of note, SASP components are effective proinflammatory cytokines capable of attracting and activating immune cells, thereby promoting an inflammatory tissue environment [22.Tchkonia T. et al.Cellular senescence and the senescent secretory phenotype: therapeutic opportunities.J. Clin. Invest. 2013; 123: 966-972Crossref PubMed Scopus (993) Google Scholar, 23.Kuilman T. Peeper D.S. Senescence-messaging secretome: SMS-ing cellular stress.Nat. Rev. Cancer. 2009; 9: 81-94Crossref PubMed Scopus (615) Google Scholar, 24.Acosta J.C. et al.A complex secretory program orchestrated by the inflammasome controls paracrine senescence.Nat. Cell Biol. 2013; 15: 978-990Crossref PubMed Scopus (1047) Google Scholar]. Following this line of argument, cells with a senescent phenotype resistant to apoptosis might provide a proinflammatory microenvironment sustaining the progression of neuroinflammatory diseases, which we discuss in the following subsections. MS is a common autoimmune disease of the CNS resulting in demyelination and axonal degeneration [26.Attfield K.E. et al.The immunology of multiple sclerosis.Nat. Rev. Immunol. 2022; (Published online May 4, 2022)http://doi.org/10.1038/s41577-022-00718-zCrossref PubMed Scopus (1) Google Scholar]. Around 80% of MS patients are first diagnosed as having RRMS. Here, patients experience unpredictable relapses of inflammatory activity, often linked to persisting disability. A substantial proportion of RRMS patients, ranging from 25% to 60% as demonstrated by natural history studies [27.Faissner S. et al.Progressive multiple sclerosis: from pathophysiology to therapeutic strategies.Nat. Rev. Drug Discov. 2019; 18: 905-922Crossref PubMed Scopus (155) Google Scholar,28.Scalfari A. et al.Onset of secondary progressive phase and long-term evolution of multiple sclerosis.J. Neurol. Neurosurg. Psychiatry. 2014; 85: 67-75Crossref PubMed Scopus (175) Google Scholar], advance to a progressive phase of the disease termed SPMS. The remaining 10–20% of MS patients have a primary progressive MS course (PPMS) from disease onset. Both progressive forms of MS are characterized by sustained disability accumulation, with only a minor fluctuation of symptoms [27.Faissner S. et al.Progressive multiple sclerosis: from pathophysiology to therapeutic strategies.Nat. Rev. Drug Discov. 2019; 18: 905-922Crossref PubMed Scopus (155) Google Scholar]. Indeed, a current study on the natural history of MS demonstrated that 75–100% of PPMS patients experience substantial disease worsening as compared to ~55% of RRMS patients [8.University of California, San Francisco MS-EPIC Team et al.Long-term evolution of multiple sclerosis disability in the treatment era.Ann. Neurol. 2016; 80: 499-510Crossref PubMed Scopus (248) Google Scholar]. While clear clinical or pathological criteria defining transition from RRMS to SPMS remain to be defined, the distinction between RRMS and progressive MS is crucial as their pathophysiological mechanisms and therapeutic responses differ [27.Faissner S. et al.Progressive multiple sclerosis: from pathophysiology to therapeutic strategies.Nat. Rev. Drug Discov. 2019; 18: 905-922Crossref PubMed Scopus (155) Google Scholar]. The current viewpoint on progressive MS recognizes chronic inflammation compartmentalized behind a closed blood–brain barrier as a pathogenic hallmark [27.Faissner S. et al.Progressive multiple sclerosis: from pathophysiology to therapeutic strategies.Nat. Rev. Drug Discov. 2019; 18: 905-922Crossref PubMed Scopus (155) Google Scholar]. Persistent activation of immune cells and microglia, as well as mitochondrial damage, leads to neurodegeneration with progredient neuroaxonal cell death. Altered ion-channel function and imbalance of reactive oxygen species (ROS) likely amplify inflammatory conditions [29.Bittner S. et al.Endothelial TWIK-related potassium channel-1 (TREK1) regulates immune-cell trafficking into the CNS.Nat. Med. 2013; 19: 1161-1165Crossref PubMed Scopus (112) Google Scholar, 30.Ruck T. et al.K2P18.1 translates T cell receptor signals into thymic regulatory T cell development.Cell Res. 2022; 32: 72-88Crossref PubMed Scopus (3) Google Scholar, 31.Bittner S. et al.TREK-king the blood–brain-barrier.J. NeuroImmune Pharmacol. 2014; 9: 293-301Crossref PubMed Scopus (0) Google Scholar]. Only a few immunosuppressive drugs have shown limited efficacy in the treatment of progressive MS [9.Rolfes L. et al.Failed, interrupted, or inconclusive trials on immunomodulatory treatment strategies in multiple sclerosis: update 2015–2020.BioDrugs Clin. Immunother. Biopharm. Gene Ther. 2020; 34: 587-610Google Scholar]. Consequently, treatment approaches for progressive MS remain unsatisfactory, as contemporary immunosuppressants are unable to effectively halt neurodegeneration. The challenge of managing progressive MS is highlighted by the (un)availability of treatment agents. While over 15 drugs have been approved for RRMS, only two (siponimod and cladribine) have demonstrated limited efficacy in SPMS and only one (ocrelizumab) in PPMS [10.Cree B.A.C. et al.Secondary progressive multiple sclerosis: new insights.Neurology. 2021; 97: 378-388Crossref PubMed Scopus (19) Google Scholar]. However, the efficacy of approved agents for progressive MS is linked mainly to treating features of acute inflammatory activity [32.Hauser S.L. et al.Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis.N. Engl. J. Med. 2017; 376: 221-234Crossref PubMed Scopus (870) Google Scholar]. However, progression independent of relapse activity (PIRA) recently emerged as a major driver of disability accumulation [33.Kappos L. et al.Contribution of relapse-independent progression vs relapse-associated worsening to overall confirmed disability accumulation in typical relapsing multiple sclerosis in a pooled analysis of 2 randomized clinical trials.JAMA Neurol. 2020; 77: 1132-1140Crossref PubMed Scopus (90) Google Scholar]. Indeed, over a period of 96 weeks, confirmed disability accumulation occurred in 80–90% of RRMS patients as PIRA. By contrast, only ~17% of disability was attributed to clinical relapses [33.Kappos L. et al.Contribution of relapse-independent progression vs relapse-associated worsening to overall confirmed disability accumulation in typical relapsing multiple sclerosis in a pooled analysis of 2 randomized clinical trials.JAMA Neurol. 2020; 77: 1132-1140Crossref PubMed Scopus (90) Google Scholar]. This observation challenges the dichotomy of RRMS and progressive MS and highlights the need for treatment strategies capable of preventing insidious neurodegeneration independent of inflammatory activity. Interestingly, aside from the transition to a progressive form, age at baseline was more frequently associated with negative results for treatment trials of drugs proven to be effective in RRMS [9.Rolfes L. et al.Failed, interrupted, or inconclusive trials on immunomodulatory treatment strategies in multiple sclerosis: update 2015–2020.BioDrugs Clin. Immunother. Biopharm. Gene Ther. 2020; 34: 587-610Google Scholar]. Consequently, evidence for therapeutic efficacy is not available for the majority of established drugs when treating patients over the age of 55 years [9.Rolfes L. et al.Failed, interrupted, or inconclusive trials on immunomodulatory treatment strategies in multiple sclerosis: update 2015–2020.BioDrugs Clin. Immunother. Biopharm. Gene Ther. 2020; 34: 587-610Google Scholar]. Taken together, novel strategies are needed to effectively manage progressive MS. Senotherapeutics are a promising potential solution to this issue. In the following sections, we will discuss the current (albeit preliminary) data on cellular senescence in MS. Chronic inflammation and oxidative stress are pathogenic hallmarks of MS [34.Wiley C.D. et al.Mitochondrial dysfunction induces senescence with a distinct secretory phenotype.Cell Metab. 2016; 23: 303-314Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar, 35.López-Otín C. et al.The hallmarks of aging.Cell. 2013; 153: 1194-1217Abstract Full Text Full Text PDF PubMed Scopus (7049) Google Scholar, 36.Oost W. et al.Targeting senescence to delay progression of multiple sclerosis.J. Mol. Med. (Berl.). 2018; 96: 1153-1166Crossref PubMed Scopus (0) Google Scholar]. Accumulating evidence supports senescent cells as a source of chronic inflammation [20.Gorgoulis V. et al.Cellular senescence: defining a path forward.Cell. 2019; 179: 813-827Abstract Full Text Full Text PDF PubMed Scopus (685) Google Scholar]. Vice versa, data on chronic inflammation promoting cellular senescence are less robust, warranting further research in the bidirectional interplay of senescence and inflammation. Senescent cells promote an inflammatory milieu by secretion of proinflammatory cytokines, chemokines, and ROS [37.Passos J.F. et al.Feedback between p21 and reactive oxygen production is necessary for cell senescence.Mol. Syst. Biol. 2010; 6: 347Crossref PubMed Scopus (560) Google Scholar]. Consequently, DNA damage and telomerase dysfunction lead to cell cycle arrest in adult progenitor cells exceeding the regenerative capacity of the CNS and resulting in dysfunction of resident cell types such as oligodendrocyte precursor cells (OPCs) (Figure 2) [38.Purcell M. et al.Gene expression profiling of replicative and induced senescence.Cell Cycle. 2014; 13: 3927-3937Crossref PubMed Scopus (68) Google Scholar, 39.Koutsoudaki P.N. et al.Cellular senescence and failure of myelin repair in multiple sclerosis.Mech. Ageing Dev. 2020; 192111366Crossref PubMed Scopus (3) Google Scholar, 40.Nicaise A.M. et al.Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis.Proc. Natl. Acad. Sci. U. S. A. 2019; 116: 9030-9039Crossref PubMed Scopus (92) Google Scholar]. Consistent with this, senescent glial cells were detected in the white and gray matter of demyelinating lesions in a murine cuprizone-induced demyelination model of MS [41.Klein B. et al.Age influences microglial activation after cuprizone-induced demyelination.Front. Aging Neurosci. 2018; 10: 278Crossref PubMed Scopus (21) Google Scholar,42.Karamita M. et al.Cellular senescence correlates with demyelination, brain atrophy and motor impairment in a model of multiple sclerosis (P2.405).Neurology. 2018; 90: P2.405Google Scholar]. These cells were identified by β-galactosidase and lipofuscin histochemistry. Senescence of OPCs and other neural progenitor cells is thought to play a role in remyelination failure in MS, thereby promoting transition from nonprogressive to progressive MS [40.Nicaise A.M. et al.Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis.Proc. Natl. Acad. Sci. U. S. A. 2019; 116: 9030-9039Crossref PubMed Scopus (92) Google Scholar,43.Cantuti-Castelvetri L. et al.Defective cholesterol clearance limits remyelination in the aged central nervous system.Science. 2018; 359: 684-688Crossref PubMed Scopus (198) Google Scholar]. Indeed, in aged rodents, OPCs exhibit a senescent phenotype unresponsive to differentiation signals and impaired metabolic homeostasis [44.Neumann B. et al.Metformin restores CNS remyelination capacity by rejuvenating aged stem cells.Cell Stem Cell. 2019; 25: 473-485.e8Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar]. Premature immunosenescence of T cells has been described in MS, as well as in rheumatoid arthritis [45.Thewissen M. et al.Premature immunosenescence in rheumatoid arthritis and multiple sclerosis patients.Ann. N. Y. Acad. Sci. 2005; 1051: 255-262Crossref PubMed Scopus (0) Google Scholar]. Specifically, our group previously demonstrated that premature immune aging, especially in the CD8+ T cell compartment, occurs in young MS patients and may impact disease severity [46.Eschborn M. et al.Evaluation of age-dependent immune signatures in patients with multiple sclerosis.Neurol. Neuroimmunol. Neuroinflamm. 2021; 8e1094Crossref PubMed Scopus (6) Google Scholar]. Moreover, expression of immunoinhibitory molecules was decreased while a premature immune aging signature consisting of KLRG1, LAG3, CTLA-4, and CD226 was identified [46.Eschborn M. et al.Evaluation of age-dependent immune signatures in patients with multiple sclerosis.Neurol. Neuroimmunol. Neuroinflamm. 2021; 8e1094Crossref PubMed Scopus (6) Google Scholar]. Interestingly, the loss of age-dependent regulation was more prominent in PPMS than in RRMS patients and correlated with disease severity [46.Eschborn M. et al.Evaluation of age-dependent immune signatures in patients with multiple sclerosis.Neurol. Neuroimmunol. Neuroinflamm. 2021; 8e1094Crossref PubMed Scopus (6) Google Scholar]. Likewise, there is evidence that premature senescence of B cells promotes inflammation and disease progression in MS [47.Claes N. et al.Age-associated B cells with proinflammatory characteristics are expanded in a proportion of multiple sclerosis patients.J. Immunol. 2016; 197: 4576-4583Crossref PubMed Scopus (84) Google Scholar]. Induced pluripotent stem-cell lines isolated from peripheral-blood mononuclear cells displayed increased markers of cellular senescence as evidenced by β-galactosidase activity in patients with PPMS and RRMS compared with controls [48.Mutukula N. et al.Generation of RRMS and PPMS specific iPSCs as a platform for modeling multiple sclerosis.Stem Cell Res. 2021; 53102319Crossref PubMed Scopus (5) Google Scholar]. Differentiation of this cell line into neural progenitor cells also demonstrated increased expression of senescence markers [48.Mutukula N. et al.Generation of RRMS and PPMS specific iPSCs as a platform for modeling multiple sclerosis.Stem Cell Res. 2021; 53102319Crossref PubMed Scopus (5) Google Scholar]. Further insight into cellular senescence in the CNS might be gained from studying a model of AD (Box 2). In both humans and mice, OPCs surrounding aggregates of amyloid-β exhibit a senescent phenotype characterized by activation of the p16 pathway an