Chronic subdural hematoma through the hallmarks of aging: a geroscience framework for the commonest neurosurgical condition of older adults

Abstract

Chronic subdural hematoma (CSDH) is among the commonest cranial neurosurgical conditions of older adults and is projected, on the basis of incidence modeling, to become the most common cranial neurosurgical condition in adults by 2030. Despite this clinical centrality, CSDH has not been formally examined through the conceptual lens of geroscience. This minireview reframes CSDH as a geroscience disease by mapping its pathogenesis onto the twelve hallmarks of aging articulated by López-Otín and colleagues. Two hallmarks have strong direct support in the existing CSDH literature. Chronic inflammation and altered intercellular communication both manifest in the inflammaging fingerprint of hematoma fluid and in the dysregulated paracrine signaling of the outer neomembrane. Cellular senescence is the most fertile moderate-evidence hallmark. The molecular signature of the senescence-associated secretory phenotype overlaps closely with the cytokine, chemokine, and matrix remodeling milieu of the CSDH cavity, but no study has yet demonstrated senescent cells in resected neomembrane tissue. Mitochondrial dysfunction, deregulated nutrient sensing, and loss of proteostasis have weak inferential support. Four hallmarks, namely, genomic instability, telomere attrition, epigenetic alterations, and stem cell exhaustion, are essentially unstudied in CSDH and are framed as research priorities. Disabled macroautophagy and dysbiosis have recently received initial direct measurements but remain only partially addressed. The 2024 randomized trials of middle meningeal artery embolization, the success of atorvastatin in the ATOCH trial, and emerging senolytic clinical translation collectively suggest that CSDH may be a tractable target for future mechanism-directed gerotherapeutic interventions. The most actionable contribution of this framework is to specify which experiments would convert CSDH from a surgical emergency of older adults into an exemplar of clinical geroscience.

Introduction

Chronic subdural hematoma (CSDH) is no longer a sequel of major head trauma. It is a disease of older adults in whom minor or unrecognized injury, brain atrophy, fragile bridging veins, and frequent antithrombotic exposure converge to initiate a subdural collection that is then sustained by a self-perpetuating inflammatory-angiogenic process within the dural border cell layer [1–3]. Population-based data from Japan, Finland, and the USA document a steep rise in incidence in adults over 65 years, with rates approaching 130 per 100,000 in those aged 80 years and over, and an approximately sixfold rise in age-stratified incidence in elderly populations between 2002 and 2015 [4–7]. A mathematical projection by Balser et al., modeling incidence as a function of population age, sex, and comorbidity, forecasts that CSDH will become the most common cranial neurosurgical condition in adults by 2030 [5], while separate US inpatient data project subdural hematoma case volumes rising from approximately 136,000 in 2020 to 208,000 annually by 2040 [7]. Mortality is sobering. Thirty-day mortality reaches 24% in unselected elderly cohorts that include conservatively managed patients [4], whereas mortality at 1 year approaches a third among elderly patients undergoing surgical drainage [5], in both settings reflecting underlying frailty rather than the lesion itself.

The standard of care has shifted decisively. Burr-hole drainage with a subdural drain remains first-line surgical treatment [8, 9]. The 2024 FINISH trial found that omitting intraoperative irrigation produced a higher reoperation rate (18.3% vs 12.6%) and failed to demonstrate noninferiority of drainage without irrigation, supporting continued use of subdural irrigation [10]. Three randomized trials published simultaneously in November 2024, namely, EMBOLISE, STEM, and MAGIC-MT, established adjunctive middle meningeal artery (MMA) embolization as a potent risk reducer in selected patients [11–13], an effect confirmed in two 2025 meta-analyses [14, 15] and codified in the ARISE I consensus statement [16]. Pharmacologic adjuncts have followed an instructive trajectory. Dexamethasone, despite its broad anti-inflammatory profile, reduced reoperation in the Dex-CSDH trial but produced worse functional outcomes in older patients [17]. Dexamethasone monotherapy was inferior to surgery in DECSA [18]. Atorvastatin, by contrast, reduced hematoma volume by 12.55 mL versus placebo in the ATOCH trial and behaved like a pleiotropic anti-inflammatory and antiangiogenic agent [19]. Tranexamic acid attenuates fibrinolysis with promising but not yet definitive effect [20].

What unifies these clinical observations is age. CSDH is a disease in which biological aging supplies the permissive context and the maladaptive response, across the anatomic substrate, the vasculature, the immune system, and the capacity for tissue resolution. Weigel et al. made this argument forcefully in 2022, invoking senescence and a SASP-like neomembrane secretome conceptually within an integrative pathophysiologic framework [2]. The present minireview extends their argument by performing the formal hallmark-by-hallmark mapping that the geroscience literature now demands [21], integrating evidence on dural senescence, age-related meningeal lymphatic decline [22], and the mechanistic reframing implied by the 2024 MMA embolization trials. The novelty here lies less in claiming CSDH is fully explained by aging biology than in showing, with discipline, how little aging biology has actually been measured in this commonest neurosurgical disease of older adults and in specifying the experiments that would close those gaps. CSDH is also unlikely to be a single uniform entity, and the aging mechanisms considered here may apply to differing degrees across its subtypes, for example, traumatic versus spontaneous, subacute versus long-standing, and anticoagulant-associated versus otherwise.

The hallmarks-of-aging framework

The hallmarks-of-aging framework, first articulated by López-Otín et al. in 2013 [23] and expanded in 2023 [21], organizes the molecular, cellular, and systemic processes that drive biological aging into 12 interrelated categories satisfying three criteria. Time-dependent manifestation, experimental acceleration of aging by accentuation, and amelioration of aging phenotypes by therapeutic intervention. The 2023 update grouped the hallmarks into three tiers. Primary hallmarks, namely, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, and disabled macroautophagy, represent unequivocal cellular damage. Antagonistic hallmarks, namely, deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence, are responses that protect young organisms but become detrimental with chronic activation. Integrative hallmarks, namely, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis, emerge when primary and antagonistic hallmarks overwhelm tissue homeostasis [21].

The geroscience hypothesis holds that age-related diseases are amenable to common interventions targeting these hallmarks rather than disease-specific pathways [24]. Statistical analyses of human age-related disease co-occurrence support this position. Diseases linked causally to the same hallmark cluster more tightly than diseases linked to different hallmarks [21]. The framework has been productively applied to neurodegenerative disease, cardiovascular disease, and cancer. However, its application to neurosurgical disease has been minimal. CSDH is an unusually clean test case because it is anatomically circumscribed, surgically accessible, and produces tissue specimens (the resected outer neomembrane) and fluid samples that are routinely available but rarely studied with the molecular tools that aging biology has developed. The aged dural border interface, together with a hallmark-by-hallmark mapping graded by evidence strength, is summarized schematically in Fig. 1. The remainder of this minireview applies the framework category by category, with the evidence base for each detailed in Table 1.

Fig. 1.

Conceptual mapping of CSDH onto the hallmarks of aging. A Schematic of the aged dural border interface as the disease locus, showing the anatomic stack from the skull through the atrophic cortex, the chronic subdural hematoma cavity with its dominant SASP-overlapping cytokine signature (IL-6, IL-8, TNF-α, IL-1β, VEGF, MMP-2/−9, PAI-1, and angiopoietin-1/−2 imbalance), the leaky immature neovasculature in the outer neomembrane, the ruptured fragile bridging vein, and the impaired meningeal lymphatic drainage of the aged host. B The twelve hallmarks of aging mapped to CSDH by evidence strength: two categories (chronic inflammation and altered intercellular communication) have strong evidence; cellular senescence has moderate evidence, reflecting the molecular overlap of the SASP with hematoma fluid biology; loss of proteostasis, deregulated nutrient sensing, and mitochondrial dysfunction have weak evidence, while disabled macroautophagy and dysbiosis have partial evidence; and four categories (genomic instability, telomere attrition, epigenetic alterations, and stem cell exhaustion) have no direct evidence in CSDH and are framed as research priorities (Table 1)

Table 1.

Mapping the 12 hallmarks of aging onto chronic subdural hematoma. Evidence strength is graded on the basis of direct measurements in CSDH tissue or fluid. Six hallmarks are essentially unstudied in CSDH and constitute the principal research priority gaps

Hallmark	Tier	Evidence in CSDH	Key supporting findings or experimental gap	Therapeutic/translational implication
Genomic instability	Primary	None	No DDR, micronuclei, or γH2AX/53BP1 data in CSDH tissue. Archived neomembrane IHC would fill this gap	Could refine recurrence-risk stratification if DDR burden correlates with neomembrane regrowth
Telomere attrition	Primary	None	No telomere length or TIF data in dural fibroblasts or neomembrane endothelium. qFISH on archived tissue is feasible	Telomere length as a frailty comarker may stratify perioperative risk
Epigenetic alterations	Primary	None	No methylome, chromatin-accessibility, or histone-modification data. snATAC-seq or methylome profiling of neomembranes is undone	Epigenetic clocks (GrimAge, DunedinPACE) may stratify systemic biological age and recurrence risk
Loss of proteostasis	Primary	Weak	Sustained collagen synthesis, fibrinogen accumulation, TGF-β1/SMAD signaling. No autophagy flux or UPS data	Generic; no proteostasis-targeting agent currently in CSDH translation
Disabled macroautophagy	Primary	Partial	Osuka 2019: Beclin-1, ATG12, and LC3A/B detected by Western blot and IHC in CSDH outer membranes [54]. Quantitative autophagic flux not measured	Spermidine and rapalog repurposing are conceivable
Deregulated nutrient sensing	Antagonistic	Weak	ATOCH RCT positive; statin pleiotropy implicates AMPK/mTOR. mTOR detected by Osuka 2019 [54]; phospho-mTOR/S6K activation status not measured. IGF-1 data absent	Atorvastatin already in clinical use; ATOCH-II pending. Metformin, rapalogs are theoretical adjuncts
Mitochondrial dysfunction	Antagonistic	Weak	HIF-1α and VEGF mRNA elevation. No respirometry, mtDNA copy number, or EM data on neomembrane mitochondria	NAD + precursors, urolithin A, mitophagy enhancers are speculative
Cellular senescence	Antagonistic	Moderate	Strong SASP-CSDH cytokine overlap (IL-6, IL-8, MMPs, VEGF, and PAI-1). No SA-β-gal, p16^INK4a^, or p21 data on neomembrane	Senolytic (D + Q, fisetin) trial in CSDH is the most testable proof of concept; SASP biomarker panel for recurrence prediction
Stem cell exhaustion	Integrative	None	Dural mesenchymal progenitor behavior in CSDH vs healthy aged dura uncharacterized	Conceptual link to impaired dural repair; no immediate intervention
Altered intercellular communication	Integrative	Strong	TGF-β1/SMAD fibroproliferation, VEGF/Ang-1/2 imbalance, fragile neovasculature, age-related meningeal lymphatic decline	MMA embolization (proposed to interrupt neovascular feed, mechanism uncertain); meningeal-lymphatic-targeted agents are theoretical
Chronic inflammation	Integrative	Strong	100–1000 × elevation of IL-6, IL-8, IL-1β, and TNF-α in hematoma fluid; failed resolution profile	Dexamethasone (mixed; Dex-CSDH); atorvastatin (ATOCH); SASP-targeted agents in development
Dysbiosis	Integrative	Partial	Mohr 2026: 16S rDNA sequencing of 39 outer-capsule specimens detected bacterial DNA exclusively in recurrent CSDH (P = 0.02) [53]. Gut and oral microbiome data absent. Preliminary finding from a small sample, needs replication	Indirect; via systemic inflammaging modulation. Antimicrobial trial in recurrent CSDH conceivable

CSDH chronic subdural hematoma, DDR DNA damage response, D + Q dasatinib plus quercetin, EM electron microscopy, IHC immunohistochemistry, IL interleukin, MMA middle meningeal artery, MMP matrix metalloproteinase, PAI-1 plasminogen activator inhibitor-1, qFISH quantitative fluorescence in situ hybridization, SA-β-gal senescence-associated β-galactosidase, SASP senescence-associated secretory phenotype, snATAC-seq single-nucleus assay for transposase-accessible chromatin sequencing, TIF telomere dysfunction-induced focus, TNF-α tumor necrosis factor α, UPS ubiquitin–proteasome system, VEGF vascular endothelial growth factor

Strong-evidence hallmarks

Chronic inflammation: the inflammaging fingerprint of CSDH

The most reproducible biochemical finding in CSDH is sustained, compartmentalized inflammation within the subdural cavity and the outer neomembrane. Interleukin-6 (IL-6) and IL-8 are elevated several 100-fold in hematoma fluid relative to autologous serum (approximately 480- to 530-fold for IL-6, 200- to 230-fold for IL-8 across the principal cytokine studies), while TNF-α is more modestly elevated and IL-1β shows inconsistent findings, with local synthesis demonstrated in neomembrane macrophages and meningothelial cells [25–28]. The cytokine pattern cosegregates statistically into pro- and anti-inflammatory clusters, with the anti-inflammatory cluster, notably IL-10, inadequately represented relative to the proinflammatory cluster, which is a profile diagnostic of failed resolution [27, 28]. The Dex-CSDH trial confirmed that broad immunosuppression reduces reoperation but worsens functional outcomes [17], establishing that inflammation is mechanistically central yet must be modulated rather than abolished in the elderly host.

This pattern is the defining signature of inflammaging, a chronic, sterile, low-grade inflammatory state characterized by elevated proinflammatory cytokines, immune cell exhaustion, and impaired resolution [29–31]. Plasma IL-6 is itself a predictive biomarker of all-cause mortality in older adults [21], and the systemic inflammaging burden of older patients with CSDH plausibly explains why 30-day mortality and 1-year mortality after evacuation track underlying frailty rather than the volumetric burden of the lesion itself [6]. The CSDH cavity appears to function as a localized amplification chamber for this systemic process, with the unique property that the inflammation is geographically confined to the dural border-arachnoid interface and accessible to direct sampling at surgery. This compartmentalization may make CSDH an unusually tractable human model of inflammaging-driven local pathology, in which interventions targeting the inflammatory cascade can be tested with a degree of anatomic and biochemical precision that is not available in the diffuse, brain-parenchymal inflammaging of dementia or stroke.

Altered intercellular communication: the dural microenvironment

The integrative category of altered intercellular communication, of which inflammaging is one facet, encompasses dysregulated paracrine signaling, extracellular matrix remodeling, and impaired barrier function [21]. In CSDH, the dural border layer, a discontinuous, fluid-prone interface formed of loosely connected cells with sparse extracellular matrix, is the anatomic locus of failure [3, 32]. Trauma or nontraumatic shear cleaves the layer, exposing dural fibroblasts and meningothelial cells to plasma constituents and triggering a cascade of TGF-β1/SMAD-mediated fibroproliferation, VEGF-driven pathological angiogenesis, and matrix metalloproteinase–mediated extracellular matrix remodeling [3, 33–35].

The neovascular endothelium of the outer neomembrane is morphologically immature. Vessels lack basal membrane, pericytes, and intact endothelial junctions. Gap junctions of up to 8 μm have been observed, and fenestrations are abundant [3, 33]. This produces a chronic exudative leak that, combined with recurrent microhemorrhage from these fragile vessels, sustains hematoma volume independently of any antecedent trauma [3, 35]. VEGF, angiopoietin-2, and placental growth factor concentrations in hematoma fluid are markedly elevated, with an angiopoietin-1/−2 imbalance favoring vessel destabilization [33].

A closely related but noncanonical dimension of altered intercellular communication is age-related decline in meningeal lymphatic function. Da Mesquita et al. demonstrated in mice that meningeal lymphatic vessels are essential for clearance of cerebrospinal fluid macromolecules and brain-derived molecules, that their diameter and drainage capacity decline markedly in aged animals (20–24 months), and that pharmacologic or genetic ablation impairs cognitive performance and aggravates amyloid pathology in transgenic models [22]. Critically, the same study showed that adeno-associated virus delivery of vascular endothelial growth factor C (AAV1-mVEGF-C) to old mice restored meningeal lymphatic vessel diameter, increased cerebrospinal fluid tracer drainage to the deep cervical lymph nodes, and improved cognitive performance, establishing that aged meningeal lymphatic dysfunction is reversible and pharmacologically tractable [22]. Trieu and Thomas identify impaired meningeal lymphatic drainage as a likely mechanism for sustained inflammation and incomplete clearance of blood breakdown products in CSDH [3], linking dural pathology mechanistically to broader brain-cerebrospinal fluid aging biology. The MMA embolization trials of 2024 may operate, in part, by interrupting this aged neovascular-lymphatic dysregulation rather than by simple devascularization [11–15]. Whether embolization secondarily alters meningeal lymphatic function in older patients is, to date, an unanswered question that paired pre- and post-procedure imaging studies could address.

Moderate-evidence hallmark: cellular senescence

Of all the antagonistic hallmarks, cellular senescence has the richest conceptual fit with CSDH biology and is, paradoxically, the most undermeasured. The strength of the fit at the level of shared molecules should not be mistaken for evidence that senescent cells are present in the tissue. Senescent cells are defined by stable cell cycle arrest, lysosomal expansion detectable by senescence-associated β-galactosidase, upregulation of p16^INK4a^ and p21, loss of LMNB1, persistent γH2AX foci, and a distinctive senescence-associated secretory phenotype (SASP) [21, 36, 37]. The SASP comprises IL-6, IL-8, IL-1α/β, MMP-1/3/10/12/13/14, VEGF, angiogenin, placental growth factor, plasminogen activator inhibitor-1, TGF-β, and chemokines including CXCL1–3 and CCL2 [36, 37].

The molecular overlap with CSDH neomembrane and hematoma fluid biology is striking but, on its own, inconclusive. IL-6 and IL-8 are the cardinal SASP factors and the dominant cytokines in CSDH fluid [25–27, 37]. MMP-9 and MMP-2 elevation has been documented in CSDH hematoma fluid [34]. VEGF overexpression is the defining angiogenic abnormality of the outer membrane [33, 38]. Causal proof that senescent cells drive degenerative pathology is robust in other tissues. Genetic clearance of p16^INK4a^-positive cells delays multiple aging phenotypes in mice [39, 40]. Bussian et al. showed in the PS19 tauopathy model that p16^INK4a^-positive senescent astrocytes and microglia accumulate in the hippocampus from approximately 4 months of age, preceding neurofibrillary tangle deposition. Their genetic clearance via the INK-ATTAC system prevented gliosis, tau hyperphosphorylation and aggregation, and cognitive decline, with the pharmacologic senolytic navitoclax (ABT263) partially recapitulating the benefit [41]. The fibroproliferative parallel is equally instructive. In idiopathic pulmonary fibrosis, an age-emergent disease of impaired tissue resolution, p16^INK4a^ expression scales with disease severity, the secretome of senescent fibroblasts is itself fibrogenic, and dasatinib plus quercetin replicates the functional benefits of genetic senescent cell ablation in the bleomycin-injury model [46]. The mechanistic resemblance to the dural fibroproliferative response in CSDH, where TGF-β1/SMAD-driven fibroblast activation and a chronic SASP-like secretome maintain the neomembrane, is direct. Cytokine overlap alone cannot establish senescence, because wound healing and other chronic inflammatory states can generate a closely similar secretory signature, and only senescence-specific markers such as SA-β-gal activity or p16^INK4a^ and p21 immunolabeling of CSDH tissue would settle the question.

What is missing in CSDH is direct evidence. Recent transcriptomic work has begun to characterize CSDH cellular and molecular biology. Zhang et al. performed single-cell RNA sequencing of cells suspended in hematoma fluid, rather than neomembrane tissue, and identified expanded M2 macrophage and dendritic cell populations [52]. Mohr et al. performed bulk RNA sequencing of outer membrane specimens, identifying 184 differentially expressed genes between primary and recurrent CSDH including consistent Toll-like receptor 4 upregulation [53]. However, no published study has performed senescence-associated β-galactosidase staining, p16^INK4a^ or p21 immunohistochemistry, persistent DNA damage focus quantification, or single-cell transcriptomics specifically on resected neomembrane tissue. Given that thousands of such specimens are obtained worldwide each year and many institutions bank surgical tissue, this represents the most directly addressable experimental gap in the field. A well-designed study comparing senescent cell burden between CSDH neomembrane, age-matched control dura (such as from elective intracranial procedures), and meningioma capsule could be performed with conventional immunohistochemistry within months and would advance the case for senescence from indirect to direct evidence in this disease. Until senescence-specific markers are demonstrated in neomembrane tissue, senescence in CSDH is best regarded as a reasonable hypothesis rather than an established feature of the disease.

The translational implication is direct. Senolytic drugs, including dasatinib plus quercetin, fisetin, and senescent cell antiapoptotic pathway inhibitors, have entered human trials [42–46]. The SToMP-AD pilot study, the first central nervous system senolytic trial, demonstrated cerebrospinal fluid detectability of dasatinib at clinically relevant levels (CSF-to-plasma ratio 0.4–0.9%) and acceptable safety in older adults with mild Alzheimer disease, supporting feasibility of CNS-targeted senolytic dosing. Cognitive outcomes were exploratory and did not differ significantly from baseline [47]. No senolytic trial has yet been registered in any cerebrovascular or neurosurgical condition. Given that CSDH offers a circumscribed, surgically accessible target with a clean SASP-overlapping cytokine signature in fluid that can be sampled longitudinally, it is a plausible candidate indication for a future proof-of-concept senolytic trial, should preclinical evidence of senescent cell burden in neomembrane tissue first be established.

Weak-evidence hallmarks

Mitochondrial dysfunction

Hypoxia-inducible factor 1α (HIF-1α) and VEGF mRNA are elevated in neomembrane tissue, indicating local hypoxia and metabolic stress [38]. Trieu and Thomas describe metabolic deficits in the dural border layer as a mechanism limiting resolution [3]. A PubMed search through April 2026 identified no published direct measurements of mitochondrial respiration, mitochondrial DNA copy number, oxidative phosphorylation capacity, or electron-microscopic mitochondrial morphology in CSDH tissue. This mapping is therefore plausible but inferential, and the experimental gap is straightforwardly fillable with standard respirometry on dissociated neomembrane cells.

Deregulated nutrient sensing

The strongest case for this category in CSDH is therapeutic, not biochemical. The ATOCH trial demonstrated that 8 weeks of atorvastatin reduced hematoma volume by 12.55 mL versus placebo and roughly halved the proportion progressing to surgical evacuation [19]. Statins exhibit established pleiotropy beyond cholesterol metabolism, including AMPK activation, mTOR-pathway modulation, and antiangiogenic activity [2, 3]. The ATOCH-II trial combining atorvastatin with low-dose dexamethasone is awaited. The success of a metabolically pleiotropic drug in CSDH constitutes indirect evidence that nutrient-sensing adjacent pathways are druggable in this disease. Direct measurements provide partial corroboration. Osuka et al. detected mammalian target of rapamycin (mTOR) by Western blot in CSDH outer membranes, alongside the autophagy-related kinase ULK1 and the regulator GβL [54]. Quantitative measurements of mTOR activation status (phosphorylated S6K1 or 4E-BP1), IGF-1, and insulin-signaling pathway flux in CSDH tissue remain absent.

Loss of proteostasis

Sustained collagen synthesis, fibrinogen and procollagen propeptide accumulation, and TGF-β1/SMAD-driven fibroproliferation in CSDH neomembranes [3, 32] suggest dysregulated protein turnover at the dural-arachnoid interface. No CSDH-specific data exist on autophagic flux, ubiquitin–proteasome system function, or chaperone capacity in dural cells. This mapping is speculative on present evidence.

No-evidence hallmarks: a research agenda

Four categories have no direct evidence in CSDH biology and must be framed honestly as research priorities rather than evidence claims. Two further categories, disabled macroautophagy and dysbiosis, have recently received first direct measurements but remain only partially addressed.

Genomic instability and telomere attrition

No CSDH-specific data exist on DNA damage responses, micronuclei, telomere length, or telomere dysfunction-induced foci in dural fibroblasts, meningothelial cells, or neomembrane endothelium. Retrospective immunohistochemistry on archived neomembrane specimens (γH2AX, 53BP1) and quantitative fluorescence in situ hybridization for telomere length would directly fill this gap.

Epigenetic alterations

No methylation, chromatin accessibility, or histone modification data exist for CSDH tissue. Single-nucleus assay for transposase-accessible chromatin sequencing and methylome profiling of resected neomembranes would establish baselines and could be related to existing epigenetic clock measures of biological age such as GrimAge and DunedinPACE [48, 49].

Disabled macroautophagy

Osuka et al. detected the autophagy markers Beclin-1, ATG12, and LC3A/B by Western blot and immunohistochemistry in CSDH outer membranes, with localization to fibroblasts and the endothelial cells of the immature neovasculature [54]. The expression pattern is consistent with active autophagic machinery in the dural border interface, but quantitative measurements of autophagic flux, such as LC3-II/LC3-I turnover under bafilomycin block, p62 accumulation kinetics, or autolysosome quantification, and comparison to age-matched control dura have not been reported. The 2023 framework addition is therefore partially addressed at the level of marker expression but unaddressed at the level of functional flux.

Stem cell exhaustion

Dural and meningeal mesenchymal progenitor populations have been described, but their behavior in CSDH versus healthy aged dura is uncharacterized. Single-cell transcriptomic comparison would address both this gap and the senescence question simultaneously.

Dysbiosis

Mohr et al. recently performed deep 16S rDNA sequencing of 39 outer capsule specimens from 19 CSDH patients and detected bacterial DNA exclusively in recurrent CSDH (six samples from four patients out of 19) but not in primary specimens (P = 0.02), identifying genera including Staphylococcus, Neisseria, Prevotellamassilia, and Paracoccus [53]. This detection rests on a very small sample and requires replication in larger, prospectively designed cohorts before any mechanistic conclusion about a meningeal microbiome and CSDH recurrence can be drawn. Whether this represents a true meningeal microbiome, contamination, or low-grade subclinical infection contributing to recurrence remains to be clarified. Gut and oral microbiome data in CSDH cohorts have not been reported. Given emerging evidence linking gut microbiome composition to systemic inflammaging [21], dysbiosis represents a partially addressed but largely open question in this disease.

These remaining gaps do not weaken the geroscience framing of CSDH but rather specify it. Each gap names an experiment that, if performed, would either confirm or refute the framework’s prediction in this disease.

Therapeutic implications and a clinical geroscience agenda for CSDH

The geroscience framework reframes existing and emerging CSDH treatments along a continuum from anatomic-mechanical to biology-modifying. Burr-hole drainage and craniotomy address the mass effect [8–10]. MMA embolization is thought to interrupt the pathological neovascular feed, although which mechanism predominates remains uncertain [11–15]. Dexamethasone broadly suppresses inflammation [17, 18]. Atorvastatin acts as a pleiotropic anti-inflammatory and antiangiogenic agent [19]. Tranexamic acid attenuates fibrinolysis [20]. None of these directly targets the cellular machinery of aging, but several, particularly atorvastatin and possibly the mechanism of MMA embolization, may behave like de facto gerotherapeutics by modifying SASP-relevant outputs.

The next decade offers three concrete translational opportunities. Firstly, biomarker stratification of recurrence risk. Recurrence after surgical evacuation occurs in approximately 10–20% of modern series, with a meta-analytic pooled rate of 12%, and is the dominant driver of morbidity, length of stay, and second-procedure complications [50]. Existing risk-stratification tools rely largely on imaging and demographic factors. A focused SASP biomarker panel encompassing the Hickson-measured circulating SASP factors (IL-1α, IL-6, MMP-9, and MMP-12) [43] and the broader plasma proteomic signature of human aging (notably growth/differentiation factor 15 and chemokines from the Tanaka panel) [51] would be directly applicable to CSDH, because most of these proteins are already documented in hematoma fluid. Tissue-level p16^INK4a^ immunohistochemistry on resected neomembrane could provide an additional senescence-load measure. Epigenetic age acceleration metrics could refine systemic frailty stratification [48, 49].

Second, a senolytic proof-of-concept trial. Dasatinib plus quercetin has been administered in pulmonary fibrosis [42], diabetic kidney disease [43], and mild Alzheimer disease [47] with manageable safety profiles, the IPF cohort reporting one serious adverse event among 14 participants and the diabetic kidney disease and Alzheimer cohorts reporting no serious treatment-related events. The Justice 2019 first-in-human study used intermittent oral dosing (dasatinib 100 mg plus quercetin 1250 mg, 3 days per week for three consecutive weeks) [42], and the Hickson 2019 trial showed that even a single 3-day course of dasatinib 100 mg plus quercetin 1000 mg significantly reduced p16^INK4a^- and p21-positive senescent cells in adipose tissue, decreased crown-like structures and tissue macrophages, and lowered circulating IL-1α, IL-6, and matrix metalloproteinase-9 and metalloproteinase-12 within 11 days [43]. This hit-and-run property is decisive for surgical translation. CSDH offers a uniquely tractable target. A circumscribed disease with surgically accessible tissue, a longitudinally sampleable fluid compartment, an established imaging endpoint (hematoma volume), and a clinically relevant outcome (reoperation). A phase 1/2 trial of brief perioperative dasatinib plus quercetin in patients undergoing burr-hole evacuation, with hematoma fluid sampling, neomembrane immunohistochemistry, and recurrence as outcomes, would constitute the first senolytic intervention in any neurosurgical disease and would generate human data on whether senescent cell-derived signaling contributes causally to neomembrane regrowth. Such a trial should be understood as a future research proposal rather than a near-term clinical option and would depend on prior confirmation of senescent cells in the tissue and on careful safety evaluation in a frail, elderly population.

Third, integration with MMA embolization. The MMA embolization trials suggest that interrupting the aged neovascular feed may achieve much of what pharmacologic antiangiogenesis aims for [11–15]. Combination strategies such as embolization plus a SASP-targeting agent, or embolization stratified by senescence-load biomarkers, are obvious next-generation designs. Whether the success of MMA embolization reflects mechanical devascularization, interruption of senescent cell-derived angiogenic signaling, or both, is itself a testable question through paired pre- and post-embolization fluid sampling.

Conclusion

CSDH satisfies the geroscience hypothesis. It is a disease whose incidence rises steeply with chronological age, whose mechanisms map onto the hallmarks of aging at multiple levels, and whose response to perturbation reflects the diminished resilience of the aged host. Two of these categories, namely, chronic inflammation and altered intercellular communication, have strong direct evidence in CSDH. Cellular senescence has compelling indirect support and is the most fertile target for immediate experimental work. Four further categories (genomic instability, telomere attrition, epigenetic alterations, and stem cell exhaustion) remain effectively unmeasured. Disabled macroautophagy and dysbiosis have early direct measurements but remain only partially addressed. The relative weight of individual aging mechanisms is likely to vary across this spectrum of presentations, so the framework is best read as a variable rather than a uniform map of CSDH pathobiology.

Weigel et al. argued in 2022 that aging processes are central to CSDH pathophysiology [2]. The argument made here is the necessary next step. The formal hallmarks framework, with its experimental discipline and translational vocabulary, can convert that observation into a testable research program. The 2024 randomized trials of MMA embolization, the precedent of atorvastatin in ATOCH, and the maturing senolytic translational pipeline collectively identify CSDH as a promising candidate for future clinical geroscience translation rather than as a setting for immediate intervention. The most actionable contribution of this framework is therefore not to claim that aging biology has explained CSDH but to specify the experiments that would test whether it can.

Author contribution

DZD: conceptualization, methodology, formal analysis, investigation, writing—original draft, writing—review and editing, visualization. The author conceived the manuscript, conducted the literature search and evidence synthesis, designed the staged adoption pathway, prepared all figures and tables, and wrote and revised the manuscript.

Funding

No funding was received for the preparation of this manuscript.

Data availability

No datasets were generated or analyzed for this study.

Declarations

Competing interests

The author declares no competing interests.