Age-Related Alterations in Immune Function and Inflammation: Focus on Ischemic Stroke

Abstract

1. Introduction

Stroke is the leading cause of mortality and disability [1]. Most cases are ischemic stroke, in which blood flow to the brain is reduced or interrupted by arterial occlusion, which is usually caused by emboli originating from the heart or large arteries, localized thrombosis, arterial dissection, or vasculitis [2]. Ischemic stroke therapy aims to promptly restore cerebral blood flow; however, few patients are eligible for this treatment [3]. Numerous studies have demonstrated that when cerebral blood flow is interrupted, a cascade of detrimental events occurs in the brain, including neurotoxicity, microvascular thrombosis, and inflammation, resulting in ischemic stroke outcomes irrespective of reperfusion treatment [4]. Moreover, 80% of strokes occur in people over 65 years of age, and the incidence of stroke doubles every decade after the age of 55. In addition to the higher incidence observed in older patients, they also present higher mortality rates, experience more severe deficits, and recover more slowly than younger patients [5].

Age-related degeneration of the central nervous system (CNS) depends on various mechanisms associated with chronic inflammation and a subsequent decrease in the immune response [6]. Additionally, dysregulation of molecular mechanisms of the immune system with aging accelerates neurodegeneration and plays a vital role in determining outcomes, including for stroke. Immunosenescence and inflammation are subclinical processes that underlie age-related conditions [7]. Immunosenescence is a condition in which the immune system deteriorates, and the immune response becomes dysregulated due to cellular senescence; thus, older persons are more vulnerable to the associated effects [8]. Although inflammation effectively eliminates pathogenic microorganisms and toxic substances from the body, the low-grade chronic inflammation (inflammaging) associated with aging increases the risk of stroke [9]. Inflammaging is characterized by elevated blood levels of acute-phase proteins (e.g., C-reactive protein) and proinflammatory substances (e.g., tumor necrosis factor-alpha [TNF-α], interleukin-1β [IL-1β], and IL-6) [10]. This suggests that the balance between pro- and anti-inflammatory molecules is lost with age and that the inflammatory state predominates, resulting in various levels of damage to the entire organism [9]. An in-depth investigation of immunosenescence and inflammaging at the cellular and molecular levels may aid in clinical decision-making and improve the prognosis of older patients who experienced stroke. Therefore, the effects of aging on other known biological systems, such as the immune system, should be further investigated to comprehensively understand the risk factors, pathology, and recovery process of stroke (Table 1).

Here, we summarize the recent advancements in aging-induced dysregulation of the immune system in stroke and changes in transcriptional amplitude, with an emphasis on functional analyses of aging immune cells and their potential impact on stroke. In addition, we briefly discuss the molecular mechanisms and biomarkers of stroke-related cellular senescence, including telomere attrition, DNA repair, genomic instability, mitochondrial dysfunction, epigenetic alterations, and impaired autophagy. Finally, we discuss preventive or therapeutic ideas that may delay or reduce aging and thereby prevent stroke onset.

2. Role of Aging in the Pathophysiology of Stroke

Risk factors for stroke include sex, age, diet, lifestyle, smoking, and glucose abnormalities, and age is the most potent and reliable [25]. Age-related increases in stroke risk have been observed in both men and women, particularly those over the age of 55 [26]. Youth enhances resistance to ischemia and positively affects recovery after ischemic damage [27]. Younger patients who experienced stroke have a better functional prognosis when adjusted for stroke severity at baseline, whereas older patients have an increased risk of stroke and worsened functional outcomes, including immune system deficiencies, vascular dysfunction, and increased risk of infection [27, 28]. Notably, aging is another adverse prognostic factor for ischemic brain tissue, and ischemic but viable tissue is more likely to develop into infarction in the penumbra region and the overall size of ischemic lesions are more likely to increase in the elderly population [29]. Advances in penumbra imaging may enable the noninvasive preservation of salvageable tissue. Recent studies have demonstrated that neuroimmune-targeted therapy is an effective strategy because the therapeutic window of expected efficacy is extended, and fewer hemorrhagic complications are observed [30].

Similar to the nervous system, the immune system also undergoes aging. These age-related changes determine susceptibility to infectious disease, elevate the risk of cancer and cardio-cerebrovascular disease, and decrease vaccination efficacy [31, 32]. The senescence cascade response of the immune system may exacerbate the alterations caused by brain aging and age-related neurological damage or disease [33]. Specifically, the architecture of lymphoid organs, where immune cells mature, develop, and reside, and the composition and function of cell subsets change with age [34]. Immunosenescence, which amplifies neuroinflammation, progressively alters and deteriorates the immune system over time and eventually causes negative consequences in older individuals, such as stroke [35].

The three main barriers in a healthy brain that protect the parenchyma from foreign pathogens are the blood-brain barrier (BBB), choroid plexus (CP), and meninges. Under normal environmental conditions, immune cells circulate freely in the blood and a few lymphocytes perform immune surveillance in the cerebrospinal fluid (CSF). The disrupted environment after ischemic stroke triggers a series of pathological cascade responses through the immune system and neuroinflammation. However, aging further exacerbates these responses, as detailed in Section IV.

The BBB, which protects the brain from pathogens and restricts the entry of circulating substances, primarily consists of brain endothelial cells (BECs). The aging phenotype of BECs develops in the brain microvasculature and includes microvascular thinning, proinflammatory changes, vasodilatory dysfunction, and BBB disruption [36]. Senescent BECs promote neurovascular uncoupling by deregulating angiogenesis and vascular endothelial growth factor (VEGF) or by increasing the reactive oxygen species (ROS)/reduced nitric oxide (NO) axis [37]. Dysregulation of neurovascular coupling leads to a loss of astrocyte endfoot coverage, disrupts communication between neurons and endothelial cells, and exacerbates neurodegeneration [37]. In age-related cerebrovascular diseases, proinflammatory senescence-associated secretory phenotype (SASP) mediators (IL-6 and IL-1β) induce a leaky BBB, which contributes to peripheral immune cell infiltration [38]. Senescent plasma upregulates vascular cell adhesion molecule 1 (VCAM1) in BECs, which boosts the capacity of immune cells to infiltrate the CNS in response to vascular damage, thereby impairing neural precursor cell activity and increasing microglial reactivity (Fig. 1) [39]. For example, Chen et al. found that the infusion of young plasma into aged mice produced a rejuvenating effect on BECs [40]. Additionally, short-term infusion of aged plasma into young mice upregulated innate immune and oxidative stress response pathways [40]. These results further confirm that BECs in the BBB are a possible target for treating age-related diseases.

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Figure 1.

Age-related changes in cerebral ischemia stroke. Aged microglia became activated, upregulated phagocytic phenotype and proinflammatory factors, reduced the proportion of microglia M1/M2, showed more downregulated genes and less upregulated genes, and IFN-I may be involved in the transcriptional response of genes. Disruption of the BBB and loss of tight junction proteins enable leukocytes to roll and adhere to the luminal side of the vessel and subsequently move from the vascular lumen to the brain parenchyma. Moreover, leukocytes are transferred to the brain parenchyma through the blood-membrane and blood-cerebrospinal fluid barriers. C1q, C3a, and C3b hyperactivate microglia phagocytosis and exacerbate synaptic function through a C3aR-dependent mechanism. Aged microglia stimulate the conversion of astrocytes into neurotoxic responsive astrocytes A1. IFN-I, induced type-I interferon; BBB, blood-brain barrier

The CP is an epithelial monolayer that forms the blood-CSF barrier and produces CSF. After ischemic stroke, monocyte-derived macrophages (MDMs) enter the CSF via the CP (Fig. 1) [41]. Aging-induced type-I interferon (IFN-I) signaling in the CP impairs brain function [42]. Although IFN-I was initially identified because of its antiviral properties, it has a vital role in reducing inflammation within and outside the CNS. CP and BECs are important factors in preventing or promoting peripheral inflammatory signals, such as IFN-1 and MDMs.

Neutrophils have been found in the extraluminal sites of soft meningeal vessels within hours after stroke in mice and humans, suggesting a strong correlation between neutrophils and soft meningeal vessels (Fig. 1) [43, 44]. Age-related meningeal lymphatic vessel (MLV) dysfunction has also been observed in aged mice [45]. Specifically, CSF perfusion is impaired in aged mice, which is accompanied by a reduction in the coverage and diameter of the MLVs and a decrease in CSF drainage to the deep cervical lymph nodes. Meningeal lymphatic endothelial cell (LEC) gene expression analysis also confirmed significant downregulation of lymphangiogenic growth factor signaling in LEC during aging [45]. Using magnetic resonance imaging, Zhou et al. identified a strong relationship among the glymphatic pathway, MLV, and aging [46] and showed that the transport capacity of the glymphatic pathway and MLV is significantly impaired in the aging human brain, which hinders the clearance of senescent cells and interstitial waste. They also found that MLVs were located downstream of the glymphatic route.

Although the leukocyte immune response in the brain parenchyma has been clarified, whether meningeal neutrophils continue to infiltrate areas of ischemia has not been clarified and how inflammatory responses change in the meninges of the ischemic aging brain has not been revealed [47]. Therefore, future studies should precisely subcategorize the individual meningeal layers to assess their unique structural and functional properties separately to identify and clarify the utility of immune cells associated with the aging brain and boundary compartments (meninges) during stroke. Moreover, new therapeutic strategies targeting age-related MLVs, and the intracerebral lymphatic system may aid in delaying the onset and progression of stroke [48].

3. Aging Alters the Magnitude of Transcription Post-Stroke

Although gene expression studies in animals with stroke using microarrays and RNA sequencing (scRNA-seq) have provided great insights into the pathophysiology of ischemic stroke [49, 50], only a few studies have examined gene expression in aging animals with stroke.

Androvic et al. investigated the effects of ischemia in aged mice and identified 400 upregulated genes that increase the neuroinflammatory milieu. This upregulation is followed by the secretion of proinflammatory cytokines, activation and infiltration of peripheral immune cells, and activation of signaling pathways (IFN-I, ERK/MAPK, and cAMP/cGMP) that contribute to secondary injury [5]. Moreover, aged mice exhibit gene downregulation after stroke, thus leading to the dysregulation of axonal and synaptic maintenance genetic programs, which affects functional recovery after stroke [5]. IFN levels have been proposed to correlate with the severity of the injury, with low levels beneficial for mild ischemic preconditioning and high levels detrimental for severe stroke. This finding is consistent with the fact that older animals, which present greater gene upregulation, generally experience more severe strokes.

Bolte et al. studied the transcriptional response of meninges to traumatic brain injury (TBI) in young and aging mice using single-cell RNA sequencing (scRNA-seq) and showed that TBI leads to the upregulation of IFN-I signature genes in aged meningeal macrophages and controls the upregulation of inflammation-related genes in fibroblasts and adaptive immune cell populations [51]. These findings revealed that ischemic stroke and aging have an effect on the meningeal transcriptome. Further transcriptomic analysis confirmed that an aging immune system might increase the risk of potentially harmful proinflammatory and autoreactive responses after stroke [52]. Recent studies have used RNA-Seq to analyze the transcriptome of human neural stem cells (hNSC) after transplantation into aged mice with stroke. The expression of genes encoding TNF receptors (Tnfrsf1b, Tnfrsf1a, and Tnfrsf10b), adhesion and leukocyte extravasation molecules (Esam, Icam1, Icam2, Mcam1, and Pecam1), apoptotic factors (Casp8 and Fas), proinflammatory factors (Il6ra, Il1r1, Ccl2, and Il6), and Toll-like receptors (TLRs) (Tlr1, Tlr13, Tlr7, and Tlr8) were downregulated in the brains of aged stroke mice after hNSC transplantation compared to those without hNSC transplantation. Furthermore, hNSC transplantation reduces infarct size and proinflammatory factor (TNF-α, IL-6, and IL-1β), matrix metalloproteinase-9 (MMP-9), and MMP-3 expression in aged stroke mice [53].

Transcriptomic data are usually interpreted via correlation, and over-interpreting the results should be avoided. To establish a causal relationship between changes in expression and altered immune cell function in animal studies of aging stroke, further mechanistic studies must be performed and validated in vivo. Multi-omics and single-cell technologies will lead to a better understanding of the transcriptional and cellular changes in aging-associated neurodegenerative diseases (Table 2) [5].

4. Aging-Related Immune System Alterations in Stroke

During the initial stages of ischemic injury (acute phase), the brain rapidly undergoes impairment of the ion pump (energy failure), disruption of membrane integrity, excessive accumulation of sodium and calcium ions, and necrosis and death of neuronal cells. Immune responses are initiated after cellular injury, and damage-associated molecular patterns (DAMPs; e.g., high-mobility group box 1 and heat shock proteins 60) and cytokines (ROS and proinflammatory substances) produced by injured and dying neuronal cells are diverted through the disrupted BBB or CSF lymphatic pathway to the systemic circulation (Fig. 1) [44]. The lymphoid organs are affected by circulating DAMPs and cytokines that cause inflammatory reactions. DAMPs can directly recruit immune cells by interacting with pattern recognition receptors (PRRs) in the periphery. PRRs recognize the released self-molecules (DAMPs) and non-self viral and bacterial products (pathogen-associated molecular patterns, PAMPs). Moreover, innate immune components use PRRs to recognize and alert organisms to attacks by microbes, transformed cells, or damaged cells. PRRs include TLRs, NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs). TLRs act through intracellular signaling pathways, thus leading to the activation of nuclear factor kappa B (NF-κB) and production of various mediators, whereas NLRs can stimulate the inflammasome complex, thus leading to the production of IL-1β and IL-18. RLRs act through IFN-responsive components. Adaptive immunity encompasses humoral and cellular immunity, and this system recognizes and responds to specific pathogens. Moreover, T and B cells, which are among the most cells in the adaptive immune system, infiltrate the brain differently and persist for weeks or months at 1-3 days after ischemia [63].

The number of both PAMPs and DAMPs increases with age. Aging brains show worse functional outcomes and significant increases in activated microglia, neutrophils, dendritic cells (DCs), and inflammatory macrophages, which can lead to greater behavioral deficits and mortality. Tsai et al. analyzed the short- and long-term peripheral immune responses in patients (63.3 ± 17.4 years) after stroke using mass spectrometry flow cytometry [64]. In the acute phase (day 2 after stroke), the rapid activation of pSTAT3 (increased IL-6 levels) in innate immune cell subsets was associated with poorer cognitive performance. In the chronic phase (day 90 after stroke), several sustained immune responses were observed, including a higher frequency of neutrophils and active Th1 cells and DCs. Furthermore, reducing the circulation of lymphocyte invasion by blocking anti-CD49d, which is a key adhesion molecule, improved functional outcomes in patients who experienced stroke in the acute phase but failed to show efficacy in the chronic phase [65]. Consistent with this, Heindl et al. validated the long-term accumulation and local aggregation of T lymphocytes during the chronic phase of stroke in human and animal brains [66]. Moreover, in a 1-year follow-up assessment of blood biomarkers in patients who experienced stroke (64.5 ± 9.5 years), higher TNF-α and IL-1β levels were associated with poor outcomes at 1-year post-stroke [67].

Notably, converting healthy immune cells to an alternative phenotype during the chronic phase of stroke may provide neuroprotective effects by regressing inflammation. This process mainly involves eliminating dead cells, forming an anti-inflammatory environment, and generating favorable factors that promote tissue repair, thereby partially reestablishing neurological function in patients who experienced stroke. However, in the microenvironment of the pathological state, senescence, chronic immunosenescence and inflammaging impair neurogenesis and functional recovery in elderly patients who experienced stroke through the persistent and unresolved production of proinflammatory mediators, impaired recruitment and infiltration of leukocytes, and delays in inflammatory regression, which lead to further neurodegeneration and tissue loss [28]. Next, we examined how aging influences the pathological effects of ischemic brain injury, including identifying multicellular interactions that may determine the evolution of BBB damage, neuronal cell death, glial responses, and immune cell infiltration (Fig. 1, Table 1).

5. Molecular Regulators of Cellular Senescence in Stroke

In this section, we discuss the molecular mechanisms that drive aging under pathological conditions, including telomere attrition, DNA repair, genomic instability, mitochondrial dysfunction, epigenetic alterations, and impaired autophagy. Although their relevance to stroke has been previously discussed, their causal relationship with age-dependent stroke impairment requires further investigation (Fig. 2).

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Figure 2.

Molecular regulators of cellular senescence. Mechanisms that drive cellular senescence include telomere attrition, DNA repair and genomic instability, mitochondrial dysfunction, epigenetic alterations, and impaired autophagy.

6. Biomarkers of Cellular Senescence in Stroke

Strong evidence exists that brain cell senescence influences the pathogenesis of neurodegeneration [203]. However, the possibility that senescent cells are involved in the causative mechanism of stroke-induced brain injury has recently been explored. Therefore, biomarkers of multifactorial processes must be identified to accurately assess cellular senescence linked to stroke.

6.3. Cell-cycle arrest markers (p21, p53, and p16)

The primary pathways that regulate permanent cell cycle arrest are p53/p21^CIP1 and p16 INK4a/retinoblastoma (RB), which are extensively used as biomarkers for identifying cellular senescence in vivo and in vitro. Although the respective contributions of the two effector routes to the initial growth arrest may differ depending on the type of stress, both may eventually be involved in senescence. Specific cyclin-dependent kinases (CDKs; CDK4, CDK6, and CDK2) phosphorylate RB1 and its family members, including RBL1 and RBL2 (Fig. 3).

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Figure 3.

The pathways that regulate cell cycle arrest. Various cell-intrinsic and -extrinsic stressors can activate the cellular senescence process. These stressors involve multiple cellular signaling cascades, eventually activating p53 and p16 INK4a. The kinase cascades involving the apical kinases ataxia telangiectasia mutated and ATR and the downstream kinases CHK2 and CHK1 activate p53 and promote p21 activation, which induces temporary cell cycle arrest by inhibiting the cell cycle protein CDK2. p16 INK4a suppresses cell cycle progression by targeting the CDK4 and CDK6 complexes. Both p21 and p16 INK4a function by inhibiting RB inactivation, which maintains the repression of E2F target genes needed for the onset of the S-phase. RB, retinoblastoma.

Baixauli-Martín et al. demonstrated that the ischemic hemisphere showed considerably increased transcript expression of cell cycle arrest markers, including Cdk2a/ p16 INK4a, Cdkn1a/p21CIP1, and T/p53, compared to the non-ischemic hemisphere [205]. Similarly, p16 INK4a immunostaining showed that MCAO induced brain senescence in rats [207]. Torres-Querol et al. performed immunohistochemistry staining on postmortem brain samples from stroke donors with left middle cerebral artery infarction and found positive immunoreactivity for p16 and p21 in the adjacent ischemic core region [208]. Additionally, a significant increase in the number of p16-positive cells was observed in the infarcted region [208]. One of the best-studied biomarkers for senescence is p16, whereas other CDKISs, such as p21, p27, and p15, also accumulate in senescent cells and are crucial for preserving cell cycle arrest [211]. However, in other cell cycle arrest events, p53 is activated [212], and some nonsenescent cells express p16INK4A [213]. Therefore, various factors and traits must be quantified to identify cell cycle arrest linked to senescence in cerebral ischemic disorders.

7. Interventions to Target Senescence in Stroke

Immunosenescence research shows potential in preventing and treating stroke and improving the health of aging populations (Table 3). Senescent cells cause immune cell dysfunction through increased DDRs, excessive ROS production, and SASP expression, which require potential strategies for drug treatment, including senolytics (eliminating senescent cells) or senostatics (suppressing the senescent phenotype) [221].

A new senolytic agent, navitoclax (ABT-263), causes apoptosis in senescent cells rather than in non-senescent cells by inhibiting the activity of anti-apoptotic BCL-2 family members [222]. Lim et al. demonstrated that the intravenous administration of ABT-263 effectively eliminated senescent cells in MCAO rats with brain IR injury, dramatically decreased infarct size, and improved neurological function [207]. Furthermore, ABT263 reduces the development of atherosclerosis in Ldlr^-/- mice by removing senescent foamy macrophages [215]. Tarantini et al. found that navitoclax treatment improved functional hyperemia in aged mice [223].

Quercetin (Q) is a flavonol that induces apoptosis in senescent cells by increasing the expression of SIRT1 and inhibits PI3K/mTOR signaling. Dasatinib (D), which is a tyrosine kinase inhibitor, induces senescent cell apoptosis by inhibiting the interaction of ephrin ligands with ephrin receptors [224]. Recent studies have demonstrated that quercetin reduces brain infarct size, neurological impairment, and BBB permeability by increasing the SIRT1 signaling pathway both in vivo and in vitro in tMCAO models [225]. However, senescent cell formation is a dynamic and ongoing process, and intermittent treatment with D+Q appears to be more effective than a single-dose treatment. Roos et al. found that combined intermittent D+Q treatment reduced the expression of senescent cell markers (TAF+ cells) in hyper-cholesterolemic mice and improved vasodilatory function in both senescent and atherosclerotic mice [216]. Similarly, D+Q treatment restores tight junction protein function in the brain microvascular endothelial cells and protects the brain barrier from age-related dysfunction [217]. Interestingly, another study revealed that the D+Q combination modulated intestinal aging and inflammation in aged mice [226].

Cells become senescent when both p53 and mTOR are activated; conversely, cells become quiescent when p53 is activated and mTOR is inhibited because mTOR regulates the selection between senescence and quiescence [227]. A microdose of rapamycin has been demonstrated to prolong senescence and limit neuronal death through cytoprotective activity, which reduces the area of acute ischemia-induced cerebral infarction and significantly extends the area in mice [218]. Celastrol is a plant-derived triterpene with neuroprotective properties against several types of brain injury [219]. Celastrol dramatically suppresses the mTOR signaling pathway, thereby reducing Ang II-induced intracellular ROS production and cellular senescence by activating autophagy, which contributes to the prevention and treatment of atherosclerosis [228]. Metformin, which is a frequently used diabetic therapy, also affects lifespan via AMPK activation [229]. Furthermore, metformin reduces brain infarct size and neuronal apoptosis via the AMPK signaling pathway in an ischemic rat model [230]. Metformin exerts protective effects against ischemic stroke by alleviating oxidative stress-mediated inflammation, promoting neurogenesis, and activating the PI3K/Akt1/JNK3/c-Jun pathway [231].

Novel mechanisms of inflammaging are likely to emerge in the near future, and such work will likely lead to potential therapeutic targets for age-related disorders. Therefore, swift and multidimensional interventions using novel preventative and therapeutic techniques are crucial.

8. Conclusion and Future Directions

Immunosenescence and inflammaging are rapidly becoming recognized as potential causes of stroke pathophysiology. Over time, the immune system undergoes dysregulation of complex molecular and cellular mechanisms that ultimately lead to altered functions and phenotypes. Therefore, understanding how individual cellular senescence types contribute to disease phenotypes will assist in developing more tailored and beneficial medicines to delay or prevent age-related disorders, such as stroke.

Although preclinical studies have demonstrated the effectiveness of age-specific interventions, clinical translation of these studies has been slow and even failed. Possible problems include the application of findings from studies in young mice to the treatment of older patients, which may obscure the potential of age-dependent candidate therapies. Moreover, most laboratory mice used for biomedical research are raised in clean and hygienic environments and thus are free of specific pathogens, resulting in an immune system that closely resembles the immune profile of newborn humans. In addition, aging patients who experienced stroke frequently have comorbidities, including hypertension, diabetes, cardiovascular disease, and atherosclerosis. Consequently, preclinical studies should consider the impact of these comorbidities on functional prognosis. With breakthroughs in genomics, transcriptomics, metabolomics, and other multi-omics studies, additional opportunities to fill these gaps will occur in the near future. First, the rise in transcriptomics has provided large amounts of data on the functional changes in age-associated immune cells after stroke, both in the acute and non-acute phases. Notably, non-enzymatic dissociation that occurs with transcriptional and translational inhibitors or at low temperatures minimizes the in vitro confounding (artifacts) of cell isolation techniques. Second, genetic ablation and pharmacological inhibition methods to remove senescent cells may help prevent and treat age-related diseases. Furthermore, distinguishing immunosenescence biomarkers, quantifying immunity, and setting normal reference ranges of immune cells among people of different ages must be performed to aid in the screening, prevention, and treatment of diseases, even at the subclinical stage.

Thus, future research should include prospective longitudinal studies in elderly patients who experienced stroke starting from the onset through symptom development to the recovery phase to characterize the exact contribution of changes in immune function. The long-term trajectory of changes influences the longitudinal recovery of homeostasis within the brain. Data from these elderly patients will serve as a basis for basic studies that can further elucidate the causality between age-related immune alterations and stroke pathophysiology. Moreover, the potential regulatory function of non-classical immune cells may have the same age-specific immunomodulatory role as immune cells. Understanding the complex interplay between immunosenescence and inflammaging enhances the targeting of new therapies to reduce the harmful effects of aging, maximizes the beneficial effects of the therapies, and may improve longevity.

Acknowledgments

Funding Statement

We acknowledge funding from the National Natural Science Foundation of China (82174477), the Outstanding Cultivation Fund of Heilongjiang University of Traditional Chinese Medicine (No. 2019JC03), and the Guidance Category of Key R&D Plans in Heilongjiang Province (GZ20210141).

Footnotes

References