Neuroglial Senescence, α-Synucleinopathy, And The Therapeutic Potential Of Senolytics in Parkinson's Disease Part 3

Concerning PD pathology, activated caspase-1 cleaves αsynuclein into a truncated form that is highly prone to forming the insoluble aggregates characteristic of Lewy bodies (Wang et al., 2016). 

As they age, many people find that their memory begins to decline. This can lead to a range of problems, including forgotten appointments, names of close family members, and even important birthdays. However, recent research suggests that pathological changes associated with PD (Parkinson's disease) may have a positive impact on memory.

PD is a neurodegenerative disease that causes the death of neurons in a specific area of the brain. Death in this area may have consequences for many aspects of cognitive function, especially memory. However, the pathological changes of PD may have some positive effects on memory.

In PD research, a substance in the brain called "Lewy bodies" has been discovered, which are small structures formed by abnormal aggregation of proteins. These small bodies mainly appear in the brains of PD patients but are not directly related to the memory problems that occur in the early and middle stages of PD.

Recent research suggests that Lewy bodies in the brains of PD patients may protect their memory to some extent. Especially in terms of visuospatial memory, PD patients may have some protective effects. This is because these bodies activate and improve specific areas of memory function. Although this research is still in its preliminary stages, it is clear that there is a link between PD pathology and memory.

Overall, although PD patients may face many challenging cognitive and life problems, research suggests that the presence of Lewy bodies in the brains of PD patients may have a positive impact on visuospatial memory. Although this study is still in its exploratory stage, it provides a good starting point for future research to understand the impact of PD pathology on human cognition. It also shows that we should remain optimistic and that although PD may adversely affect our lives, we should not give up our memory or any other cognitive ability. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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There is robust in vitro evidence that inflammasome-activated, caspase-1-induced α-synucleinopathy is cytotoxic (Wang et al., 2016; Ma et al., 2018). Caspase-1 has also been shown to truncate α-synuclein at the C-terminal end in the proteolipid protein α-synuclein (PLP-SYN) transgenic mouse model of MSA, which promoted α-synuclein aggregation, motor deficits, and a reduction in tyrosine hydroxylase-positive neurons in the substantia nigra (Bassil et al., 2016). 

Furthermore, the caspase-1 inhibitor VX-765 is neuroprotective in the PLPSYN mouse model (Bassil et al., 2016). Caspase-like truncation of the C-terminal end of α-synuclein has been discovered and characterized in other PD models of transgenic mice, cell culture, and recombinant adeno-associated virus injected rats (Li et al., 2005; Liu et al., 2005; Ulusoy et al., 2010). 

Truncated α-synuclein as well as full-length α-synuclein have been widely observed in post-mortem brains from PD patients and patients with Dementia with Lewy bodies (Suzuki et al., 2018). 

Therefore, when microglia and astrocytes are exposed to age-related chronic oxidative stress, they progress to releasing the pro-inflammatory SASP and convert WT α-synuclein into a PD-related toxic species. Senescent neuroglia prime neurons for neurodegeneration and contribute to early pathology. For example, when healthy neurons are co-cultured with senescent neuroglia, they experience a reduction in function, synapse maturation, synaptic plasticity, synaptic vesicle size, and disrupted neuronal homeostasis (Bussian et al., 2018; Han et al., 2020; Limbad et al., 2020; Sheeler et al., 2020). 

The factors involved in senescent neuroglial-mediated neuronal detriment include proinflammatory secretion, reduced neurotrophic factor secretion, reduced glutathione secretion, and the reduced ability to clear extracellular α-synuclein (Rodriguez et al., 2015; Burtscher and Millet, 2021). 

Furthermore, it has been shown that removing senescent neuroglia from models of neurodegeneration mitigates reactive gliosis and neuronal death while preserving normal organismal physiology (Chinta et al., 2018; Salas et al., 2020). 

The degeneration of dopaminergic neurons in PD can initiate a self-propagating cycle of oxidative stress, neuroinflammation, neuroglial senescence, neuroglial activation, and neuronal death. The injured, degenerative dopaminergic neurons in PD release insoluble α-synuclein fibrils, ATP, MMP-3, and neuromelanin into the extracellular space (He et al., 2021). 

To maintain brain homeostasis, microglia, and astrocytes are prompted to take up the cellular debris from degenerating neurons and initiate the subsequent inflammatory and oxidative stress responses. 

Although these actions of neuroglia are necessary and beneficial in a non-pathologic state, when they can no longer combat the tide of degeneration, the cycle becomes self-amplifying and destructive. 

The Effects of Neuroglial Uptake of α-Synuclein and Activation by α-Synuclein

Neurons secrete α-synuclein into the extracellular space through an exosomal and calcium-dependent manner (Emmanouilidou et al., 2010). The rate of α-synuclein secretion from neurons and neuroblastomas into the extracellular space, as well as the concentration of secreted insoluble α-synuclein aggregates, increases under cellular stress-induced protein misfolding and damage (Jang et al., 2010). 

The damaged, aberrant αsynuclein is secreted into the extracellular space under stress through exocytosis rather than in exosomes (Jang et al., 2010). Extracellular wild-type and mutant α-synuclein can be taken up by neurons or glia via endocytosis and transmitted between glia and neurons, even in aggregated form, leading to the spread of Lewy bodies (Lee et al., 2011, 2014). 

Extracellular non-mutated α-synuclein oligomers elicit an inflammation response from microglia via paracrine activation of Toll-like receptor 2 (TLR2) (Kim et al., 2013; Lee et al., 2014). Moreover, extracellular α-synuclein can act as damage-associated molecular patterns (DAMPs) to activate other microglial receptors and intracellular pathways, such as the Fc gamma receptor IIB (FcγRIIB) and the NF-κB pathway (Kam et al., 2020). 

The activation of these receptors and pathways leads to reduced microglial phagocytosis, an upregulated inflammation response, α-synuclein nitration, and increased release of ROS (Zhang et al., 2007; Kam et al., 2020; Mavroeidi and Xilouri, 2021). 

A robust debate over whether activated microglia are harmful or beneficial spans back more than 20 years (Streit et al., 1999). In PD, chronically activated microglia increase neuronal susceptibility to neurodegeneration. 

Permanently senescent microglia differ from the transiently activated microglia. Microglia become transiently activated in response to brain injury and upregulate both pro-inflammatory and anti-inflammatory genes simultaneously (Osman et al., 2020). 

However, the chronically activated microglia that are commonly observed in neurodegeneration seem to significantly differ from senescent microglia in semantics only (Lull and Block, 2010; Woodburn et al., 2021). Naturally, there are slight differences between senescent and chronically activated microglia, but they seem to be functionally very similar in PD. 

We hypothesize that the senescent, chronically activated, or transiently activated fates reflect the heterogeneity of microglial populations and the effects of individual microglial microenvironments (Masuda et al., 2020; Tan et al., 2020). Operating under this hypothesis, some senescent microglia may adopt a chronically activated phenotype due to an early neurodegenerative milieu and contribute to the further development of neurodegeneration in a chronic manner (Masuda et al., 2020). 

Chronically activated microglia contribute to the early development of PD in response to interacting with α-synuclein and remain chronically activated as long as α-synuclein is present. For example, an in vivo mouse model that overexpressed full-length, wild-type, human α-synuclein under the murine Thy-1 promoter experienced lifelong activation of microglia (Chesselet et al., 2012). 

Activated microglia first appeared in the striata at 1 month old and in the SNpc at about 5 months old, before neuronal damage was observed (Chesselet et al., 2012). People with idiopathic rapid-eye-movement sleep behavior (IRBD) serve as an interesting population for studying the preclinical hallmarks of PD. Nine out of ten people with IRBD receive a PD diagnosis within 14 years of receiving an IRBD diagnosis (Iranzo et al., 2016). 

The pathology is strikingly similar between the two diseases. For example, striatal 18F-DOPA is reduced in 90% of IRBD patients, coupled with unilateral microglia activation in the SNpc, consistent with early PD (Ouchi, 2017). 

These observations correlate with the notion that inflammation due to chronically activated microglia facilitates the change from IRBP to PD over time. Indeed, postmortem PD brains have substantial quantities of pro-inflammatory microglia and astrocytes in the same areas affected by α-synucleinopathy (Freund et al., 2012; Chinta et al., 2018; Brás et al., 2020; Harms et al., 2021). 

Extracellular α-synuclein endocytosed by astrocytes causes the release of proinflammatory and neuroinhibitory secretions, such as GFAP, cytokines, chemokines, and chondroitin sulfate proteoglycan (Vieira et al., 2020). However, there is some evidence that α-synuclein uptake by astrocytes follows α-synuclein binding to astrocyte receptors to stimulate proinflammatory secretions (Vieira et al., 2020). 

Endocytosed αsynuclein in astrocytes causes disrupted Ca2+ and mitochondrial homeostasis, oxidative stress, and elevated levels of glutathione peroxidase (Mavroeidi and Xilouri, 2021). Astrocytes can harbor insoluble α-synuclein aggregates (Lee et al., 2010). 

The uptake of α-synuclein aggregates by astrocytes is initially a protection mechanism that aims to clear the toxic protein (Booth et al., 2017). However, the pathological inclusion can cause lysosomal dysfunction, can remain in astrocytes, and therefore, accumulate and cause cellular damage (Booth et al., 2017). Astrocytes have a unique susceptibility to becoming senescent in response to cellular stress. 

In response to oxidative stress, astrocytes become senescent before fibroblasts, neurons, and possibly microglia (Bitto et al., 2010; Chinta et al., 2018). In postmortem PD SNpc tissue, the only monitored cell type to have a reduction in nuclear lamin B1 compared to control SNpc tissue were astrocytes (Chinta et al., 2018). Reduced lamin B1 levels are a long-standing biomarker of cellular senescence (Freund et al., 2012). 

However, microglia are the first line of defense in response to injury and oxidative stress. They exhibit fast migration to the injured area to initiate phagocytosis and quickly become activated. Soon afterward, microglia recruit astrocytes to become activated, release pro-inflammatory factors, and promote glutamate-induced excitotoxicity (Liddelow et al., 2017; Iovino et al., 2020; Liu et al., 2020; Matejuk and Ransohoff, 2020). 

If this same pattern is seen in neurodegeneration-related chronic neuroglial activation, then microglia would become "senescent" first. Even if astrocytes become senescent before their cellular neighbors do, the bystander effect ensures the spread of senescence to other cell types (Nelson et al., 2012).

The Effects of Neuroglial Exposure to Preformed α-Synuclein Fibrils

There are three morphological species of α-synuclein. From smallest to largest, they are monomers, oligomers, and fibrils. The major pathological components of Lewy Bodies are αsynuclein fibrils. Artificially synthesized "preformed α-synuclein fibrils" (PFFs) can be injected into animal models of PD to study the spatiotemporal dynamics of α-synuclein movement, inflammation, oxidative stress, and neurodegeneration. 

In response to the presence of α-synuclein fibrils, neuroglia generate superoxide (O2-), ROS, and cytotoxic factors (He et al., 2021). PFFs also exert a strong response in dopaminergic neurons. 

For example, dopaminergic neurons that are treated with synthesized PFFs experience elevated levels of serine 129 phosphorylated α-synuclein, increased α-synuclein aggregation, reduced levels of presynaptic protein, axonal transport protein disruption, and reduced dopaminergic survival (Tapias et al., 2017). These results are attributed to PFF-induced mitochondrial dysfunction, increased O2- production, increased nitric oxide (NO) production, levels of protein nitration, and inflammation (Tapias et al., 2017). 

In a recent study, PFFs were injected into the striata of healthy, young adult, wild-type (C57BL/6) male mice, which initially caused an inflammation response in both astrocytes and microglia (Lai et al., 2021). The inflammatory state peaked at 7 days post-injection (dpi). Aggregates of α-synuclein then increased in concentration and propagation after fourteen dpi and peaked between thirty and ninety dpi (Lai et al., 2021). 

Finally, striatal dopaminergic neuron loss and motor dysfunction were observed (Lai et al., 2021). Similar results were seen in male Fischer 344 rats that received unilateral intrastriatal injections of PFFs (Duffy et al., 2018). 

Microglial activation and associated inflammation were the initial responses to PFF injection in the rats (Duffy et al., 2018). Microglial activation in response to the PFF lasted for at least the 3 months before SNpc neuronal degeneration occurred and persisted throughout the degenerative process, indicating that the microglia were chronically activated (Duffy et al., 2018). 

In another recent study described here, PFF gave rise to activated neuroglia, senescent neuroglia, and neuronal death (Verma et al., 2021). MPP+ or PFF treatment of cultured dopaminergic rat N27 cells caused the cells to express senescence markers, such as reduced levels of Lamin B1 and HMGB1 and increased levels of p16 and p21. 

PFF treatment of cultured primary astrocytes and microglia from C57BL/6 wild-type mice also leads to senescence, as evidenced by decreased Lamnin B1, HMGB1, AT-rich sequence-binding protein 1 (SATB1), and p16 levels, but elevated p21. Interestingly, there was simultaneous production of senescent and reactive astroglia in response to primary culture PFF treatment. 

This observation might reflect the different subpopulations of astrocytes (Miller, 2018). Mice that received brain PFF injections through the cannula demonstrated the same changes in senescent markers. For example, the ventral midbrain and SNpc of these mice experienced reduced levels of Lamnin B1, HMGB1, and p16 levels and increased levels of p21. Increased levels of GFAP and Iba-1 were also seen, indicative of reactive astroglia and microglia respectively. Moreover, there was evidence of neuronal death by reduced levels of β-IIItubulin. 

Finally, SNpc tissue from postmortem PD patients confirmed the involvement of cellular senescence by western blot analysis. Lamnin B1, HMGB1, and SATB1 were reduced, p21 levels were increased and p16 levels remained unchanged in postmortem PD brains compared to control midbrain tissues. The experimental results from Verma et al. (2021) highlight how pathologic α-synuclein instigates simultaneous neuroglial senescence and neuroglial activation that eventually lead to PD-relevant neuronal death.

SENOLYTICS AS A THERAPEUTIC AVENUE FOR PARKINSON'S DISEASE

Senescent cells contribute to a variety of age-related diseases. Conversely, their removal mitigates their associated pathological effects and increases the health span. Reduced activity of the SATB1 protein in dopaminergic neurons has recently been identified as a risk factor for PD (Brichta et al., 2015; Chang et al., 2017; Nalls et al., 2019; Riessland, 2020). 

Furthermore, genetic knockout of Satb1 leads to cellular senescence and increased expression of p21 and CDKN1A in human embryonic stem cells that have differentiated into dopaminergic neurons (Riessland et al., 2019). Riessland et al. (2019) also showed this phenomenon in the midbrains of mice by using a stereotactic adeno-associated virus 1 injection expressing shRNA (AAV1-shRNA) to downregulate Satb1, which subsequently increased p21 expression and neuronal senescence. 

Eventually, treatment with AAV1-shRNA eliminated tyrosine hydroxylase-expressing neurons, reduced the number of mitochondria, upregulated Cdkn1a, and prompted an immune response (Riessland et al., 2019). Additionally, postmortem SNpc tissue from PD patients has elevated p21 expression and decreased regulatory function of SATB1 (Brichta et al., 2015; Riessland et al., 2019; Riessland, 2020). Inhibition of p21 in SATB1 knockout human dopaminergic neurons via the p21 inhibitor UC2288 significantly reduced the effects of senescence without producing proliferation (Riessland et al., 2019). 

Furthermore, treatment of SATB1 knockout human dopaminergic neurons with CDKN1A short hairpin RNA (shRNA) dramatically reduced p21 levels and other senescence hallmarks (Riessland et al., 2019). Additionally, UC2288 has recently been shown to reduce senescence markers such as oxidative stress and inflammation in the MPTP mouse model of PD (Im et al., 2020). Therefore, UC2288 might be a viable anti-senescent agent for PD. 

Astragaloside IV (AS-IV) is an active pharmacological agent derived from the herbal plant Astragalus membranaceus. ASIV has a long history in Chinese herbal medicine due to its many beneficial properties, such as being a powerful antioxidant, antifibrotic, and anti-inflammatory agent (Li et al., 2017). AS-IV is neuroprotective in primary dopaminergic nigral cell culture exposed to 6-hydroxydopamine (Chan et al., 2009). 

Mice treated with chronic MPTP and probenecid injections experience a significant loss of dopaminergic neurons in the SNpc and suffer from loss of muscle strength and balance (Xia et al., 2020). However, when receiving co-treatment with AS-IV, dopaminergic neurons and motor deficits in MPTP and probenecid-treated mice have significant protection without altering MPTP metabolism (Xia et al., 2020). 

An important finding from the Xia et al. (2020) study was that AS-IV treatment reduced the SNpc concentration of senescent astrocytes in the MPTP mouse model and improved many markers of cellular senescence, such as elevated p16 levels and reduced levels of lamin B1 in the cellular nucleus. Furthermore, natural age-related senescence and premature senescence due to MPP + treatment in primary astrocyte culture from mice were shown to be inhibited by the AS-IV treatment (Xia et al., 2020). 

AS-IV was shown to exert its anti-senescent effect by promoting mitophagy and its antioxidant properties (Xia et al., 2020). It has recently been shown that astrocyte and microglia senescence in PD can be mitigated by senolytic treatment with the serum and glucocorticoid-related kinase 1 (SGK1) inhibitor GSK-650394 (Kwon et al., 2021). NF-kB transcription factors are responsible for transcribing pro-inflammatory genes, including those for cytokines and chemokines (Liu et al., 2017). 

Through phosphorylation, SGK1 activates NF-kB pathways and promotes inflammatory responses (Lang and Voelkl, 2013). GSK650394 reduces cytokine levels and SGK1 overexpression boosted cytokine levels in cultured mice astrocytes and microglia from the cortex and ventral midbrain (Kwon et al., 2021). Furthermore, Nurr1 and Foxa2 downregulate Sgk1 in the mouse-cultured glia, as shown in microarray and RNA-seq data (Kwon et al., 2021). Seven out of the top ten genes that were downregulated by GSK-650394 had immune-related ontologies (Kwon et al., 2021). 

Therefore, the anti-inflammatory effects of Nurr1 and Foxa2 in glia are due to inhibitory action on Sgk1. It has also been shown that SGK1 inhibition suppresses inflammation pathways associated with the NLRP3 inflammasome and CGAS-STING, upregulates glutamate clearance from glia and prevents glial mitochondrial damage (Kwon et al., 2021). 

Finally, SGK1 inhibition reduced glial senescent markers such as SA-β-gal, downregulated genes associated with SASP, reduced pro-senescent protein levels, reduced reactive oxygen species production, and downregulated pro-oxidant genes (Kwon et al., 2021). Importantly, mouse midbrain dopaminergic neurons that overexpressed human α-synuclein were co-cultured with mouse ventral midbrain astrocytes and microglia. 

These cultures were treated with PFFs. Culture treatment with GSK-650394 or SGK1 knockdown in the glia reduced α-synuclein pathology in neurons including α-synuclein neuron-to-neuron transfer, provided they were co-cultured with the ventral midbrain glia (Kwon et al., 2021). Furthermore, SGK1 inhibition in mouse ventral midbrain astrocytes and microglia co-cultured with mouse midbrain dopaminergic neurons protected the neurons from toxic insults from H2O2. 

Finally, SGK1 genetic silencing or GSK650394-mediated inhibition in the MPTP mouse model of PD protected against behavioral deficits, midbrain dopaminergic neuron loss, and suppressed SNpc inflammation and senescence (Kwon et al., 2021). B-cell lymphoma-extra large (Bcl-xL) is a member of the Bcl-2 protein family and resides in mitochondrial membranes. Bcl-xL has anti-apoptotic properties mediated through its inhibition of mitochondrial cytochrome c release (D'Aguanno and Del Bufalo, 2020). 

Furthermore, Bcl-xL also has pro-senescent properties. For example, it is hypothesized that damaged cells otherwise destined for apoptosis can instead become senescent through the overexpression of Bcl-xL (Mas-Bargues et al., 2021). Bcl-xL also enhances mitochondrial metabolism and increases the efficiency of ATP synthesis, both of which are necessary to metabolically support the increased SASP production of senescent cells (Herranz and Gil, 2018; Mas-Bargues et al., 2021). 

In postmortem brain samples from PD patients, it was shown that Bcl-xL expression in mesencephalon dopaminergic neurons was close to twice as high as in the controls (Hartmann et al., 2002). Interestingly, Bcl-xL is likely involved in sporadic PD through pro-senescence and anti-Parkin activity. Under normal conditions, the PINK1 protein cooperates with the protein Parkin to translocate to polarized mitochondria and induce mitophagy. However, mutated E3 ubiquitin ligase Parkin and pathological mitochondrial bioenergetics are implicated in autosomal recessive familial PD (Dawson and Dawson, 2010). It has been shown that Bcl-xL antagonizes the ability of PINK1 and Parkin to stimulate mitophagy (Mas-Bargues et al., 2021). 

Disrupted midbrain mitophagy is a foundational pathological feature common in both PD patients and PD animal models (Liu et al., 2019). Therefore, it seems likely that Bcl-xL inhibitors, such as A1331852 and A1155463, could be effective therapeutic agents in PD by promoting mitophagy (Zhu et al., 2017). The relationship between PD pathology and Bcl-xL is complicated. Like cellular senescence, Bcl-xL seems to have the capacity in PD for neuroprotection, as well as exacerbating pathology. 

For example, SH-SY5Y cells transfected with a dopamine transporter were resistant to MPP+ when treated with Bcl-xL (Dietz et al., 2008). SH-SY5Y cells overexpressing Bcl-xL were also resistant to 6-hydroxydopamine-induced death (Jordán et al., 2004). Additionally, SH-SY5Y cells overexpressing Bcl-xL preserved mitochondrial dynamics through anti-oxidative stress mechanisms when LRRK2 was pharmacologically inhibited by GSK2578215A (Saez-Atienzar et al., 2016). Furthermore, Bcl-xL treatment was shown to be neuroprotective in the MPTP mouse model of PD (Dietz et al., 2008). 

Finally, Bcl-xL is necessary for CNS synapse formation, synaptic vesicle membrane dynamics, and neurite outgrowth, all of which become disrupted during neurodegeneration (Li et al., 2008, 2013; Park et al., 2015). Although these results were only demonstrated in cell culture and imperfect mouse models of PD, they do raise some hesitancy for pursuing senolytic Bcl-xL antagonists as a therapeutic avenue. 

Despite the potential dual role of Bcl-xL in PD, perhaps the different effects can be parsed and capitalized on. The Bcl-xL protein can be cleaved at its N-terminus by caspase-dependent mechanisms to produce 1N-Bcl-xL fragments. Bcl-xL fragmentation is increased during glutamate-induced neuroexitotoxicity, which commonly occurs in many neurodegenerative diseases, including PD (Park and Jonas, 2017; Iovino et al., 2020). 

Accumulation of 1N-Bcl-xL fragments induces mitochondrial injury, such as elevated membrane conductance and increased cytochrome c release, eventually leading to neuronal death (Park and Jonas, 2017). The senolytic ABT-737 binds to both Bcl-xL and 1N-Bcl-xL, prevents 1N-Bcl-xL from damaging mitochondria, and prevents the Bcl-xL from forming 1N-Bcl-xL fragments (Park and Jonas, 2017). 

Furthermore, it has been shown that the effects of Bcl-xL senolytics are concentration-dependent. For example, high concentrations of ABT-737 (1 µM) and WEHI-539 (5 µM) exacerbated neurotoxicity from glutamate, disrupted mitochondria membrane potential, and reduced the cellular concentration of ATP (Park et al., 2017). Conversely, a low concentration of ABT-737 (10 ηM) and WEHI-539 (10 ηM) was neuroprotective against glutamate-induced cell death by protecting mitochondrial membrane potential and preserving ATP loss (Park et al., 2017). 

Together, the evidence seems to suggest that Bcl-xL still holds promise as a target in the anti-senescence treatment of PD, but the concentration of Bcl-xL specific senolytics and Bcl-xL fragmentation potential needs to be taken into consideration. Since Bcl-xL fragmentation occurs in response to glutamate neurotoxicity, perhaps Bcl-xL-specific senolytics would have more effect before disease onset. Anti-senescent or senescent cell removal strategies seem like a possible new avenue of pharmacological therapy for PD patients. However, the majority of evidence is currently limited and restricted to cell and animal models as described in Table 1. Indeed, the majority of therapeutic studies of senolytics are preclinical (Romashkan et al., 2021). 

However, the first open-label, single-arm clinical trial of senolytics in human patients was published in 2019 (Justice et al., 2019; Song et al., 2020). This study showed that short-term (3 weeks) treatment of senolytic cells in patients with idiopathic pulmonary fibrosis with dasatinib and quercetin (D + Q) improved symptoms and function (Justice et al., 2019; Song et al., 2020). Since then, D + Q has also been shown to be effective at decreasing senescent cells in diabetic kidney disease patients (Hickson et al., 2019). 

There has been a rapid increase in the number and scope of clinical trials centered on senolytics just during this past year (Kirkland and Tchkonia, 2020; Song et al., 2020; Wissler Gerdes et al., 2020). Concurrently, there has also been a rapid rise in pharmaceutical companies and capitalist investments focused exclusively on developing senolytics over the last handful of years (Dolgin, 2020). There are fourteen clinical studies currently listed at ClinicalTrials.gov that result from searching "senolytic" in the "other" search field. 

Four trials target osteoarthritis, four are focused on mitigating COVID-19, and the rest center on femoroacetabular impingement, frailty in adult survivors of childhood cancer, chronic kidney disease, and improving the skeletal health of healthy older adults. In a variety of combinations and dosings, the senolytics D, Q, and fisetin are included as drug interventions in all of these clinical trials. One of the osteoarthritis trials includes fisetin and also the antihypertensive drug losartan. 

Another current osteoarthritis trial includes Q, fisetin, and also glycyrrhizin as interventions. Glycyrrhizin has anti-inflammatory and antiviral properties. Previous or planned senolytic-focused clinical trials have employed their use in the treatment of hyperoxia-induced reactive airway disease, insulin resistance, diabetes, preeclampsia, fatty liver disease, obesity, macular degeneration, and diabetic chronic kidney disease (Kirkland and Tchkonia, 2020; Song et al., 2020).

Out of the fourteen results, only two trials focus on neurodegeneration: a pilot and phase II trial of the SToMPAD study (Senolytic Therapy to Modulate the Progression of Alzheimer's Disease). The pilot study (ClinicalTrials.gov Identifier: NCT04063124) focuses on the use of D + Q for five patients with early-stage Alzheimer's disease over 12 weeks (Gonzales et al., 2022). 

The Phase II SToMPAD study is currently recruiting and plans to include both patients with Alzheimer's disease and Mild Cognitive Impairment (ClinicalTrials.gov Identifier: NCT04685590). It is fully expected that effective senolytic-based therapy for PD patients and their families will be a reality in the not-too-distant future.

CONCLUSION

Parkinson's disease is the most common movement disorder and the second most common neurodegenerative disorder. However, the complex pathology is not yet fully understood nor is there a cure available. The study of PD has largely focused on neurons since the disease is marked by progressive neurodegeneration. PD research has also largely centered on aggregated α-synuclein since they are the key molecular hallmark of the disease. However, neuroglia account for a large portion of the brain and are responsible for a myriad of critical functions in the CNS. 

The roles of neuroglia in neurodegenerative diseases are underappreciated. Targeting senescent neuroglia in PD is an exciting possible therapeutic avenue. Clinical trials of anti-senescent drugs have very recently started to get underway and hold much promise.

AUTHOR CONTRIBUTIONS

All authors contributed to the writing of the manuscript, have reviewed the manuscript, and approve of its current form. RL oversaw the scope and progress of the manuscript, wrote the final draft, and made the final figures.

FUNDING

This work was funded by the Eastern Nazarene College Instructional and Professional Development Committee and by Pluripotent Diagnostics.

ACKNOWLEDGMENTS

We would like to thank all team members at Pluripotent Diagnostics and the Biology Department at Eastern Nazarene College for their input and fruitful conversations. We would like to also thank the Pluripotent Diagnostics Scientific Advisory Board for their theoretical contributions and continued support.

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