Temporal lobe epilepsy as a model of accelerated brain aging: Roles of biological aging markers and microRNA dysregulation

Abstract

Temporal lobe epilepsy (TLE) is characterized by recurrent seizures; however, growing evidence suggests that it may represent a progressive neurological disorder, sharing key features with accelerated brain aging. Patients with chronic TLE frequently exhibit early cognitive decline, hippocampal atrophy, neuroinflammation, and neurodegenerative changes that exceed those expected for chronological age. These observations suggest that recurrent seizures and persistent network hyperexcitability may promote premature activation of biological aging pathways in the epileptic brain. This mini-review emphasizes the concept of TLE as a model of accelerated brain aging. We highlight major aging hallmarks implicated in TLE, including oxidative stress and mitochondrial dysfunction, chronic neuroinflammation (“inflammaging”), cellular senescence, impaired proteostasis, and dysregulated autophagy. Particular emphasis is placed on epigenetic aging mechanisms, with microRNAs (miRNAs) emerging as key regulators linking epileptogenesis, neuronal aging, and disease progression. Several miRNAs implicated in aging biology, such as miR-34a, miR-146a, miR-132, miR-124, and miR-21, are consistently dysregulated in TLE and may contribute to neurodegeneration, synaptic dysfunction, and drug resistance. We further discuss the clinical and translational relevance of aging markers and miRNAs as potential biomarkers for disease severity, cognitive decline, and therapeutic response. Framing TLE within the context of biological aging provides a novel perspective that may facilitate biomarker discovery and support the development of disease-modifying strategies beyond seizure suppression in TLE.

Key Words: Temporal lobe epilepsy; Biological aging markers; Epigenetics; MicroRNAs; Epileptogenesis

Core Tip: Temporal lobe epilepsy (TLE) is considered as a seizure disorder, but evidence indicates it is a progressive condition resembling accelerated brain aging. Patients with chronic TLE show early cognitive decline, hippocampal atrophy, neuroinflammation, and neurodegenerative changes beyond age expectations. This mini-review highlights key aging hallmarks in TLE, including oxidative stress, mitochondrial dysfunction, chronic inflammation (“inflammaging”), impaired proteostasis, and autophagy dysregulation, and emphasizes microRNAs as epigenetic regulators linking epileptogenesis to neuronal aging. Elucidating the underlying mechanisms of TLE may facilitate the identification of robust biomarkers and inform the development of disease-modifying interventions that extend beyond symptomatic seizure management.

INTRODUCTION

Temporal lobe epilepsy (TLE) is the most prevalent form of focal epilepsy in adults and is commonly associated with mesial temporal sclerosis, pharmacoresistance, and long-term cognitive impairment[1-3]. Traditionally considered a disorder defined by recurrent seizures arising from aberrant neuronal excitability, temporal lobe epilepsy (TLE) is now increasingly recognized as a chronic, progressive neurological condition characterized by persistent structural, functional, and molecular alterations that extend beyond ictal events[4,5]. Longitudinal neuroimaging studies have demonstrated progressive hippocampal atrophy, cortical thinning, and widespread white-matter disruption in patients with TLE, even in the absence of frequent seizures[6-8]. Recent advances in machine-learning-based brain-age prediction models further reveal that individuals with TLE exhibit brains that appear biologically older than those of age-matched healthy controls, indicating premature or accelerated brain aging[9-11]. Importantly, these aging-like neuroimaging signatures correlate strongly with cognitive impairment, particularly in memory and executive domains[12,13].

Clinically, individuals with temporal lobe epilepsy (TLE) often exhibit early and progressive cognitive impairment, which cannot be fully accounted for by seizure frequency, disease duration, or exposure to antiseizure medications alone[5-9,13]. Neuropathological evidence further demonstrates shared features between TLE and age-related neurodegeneration, including hippocampal neuronal loss, reactive gliosis, and abnormal tau accumulation, reinforcing the conceptual overlap between epilepsy and biological brain aging[5,14]. Notably, a recent longitudinal study in refractory TLE reported progressive contralateral hippocampal hypertrophy both before and after surgical resection, reflecting compensatory neuroplastic remodeling in response to ongoing cognitive deficits, particularly in visuospatial memory[15]. This supports current concepts that TLE induces dynamic structural reorganization, where the non-epileptogenic hippocampus adapts to mitigate cognitive disruption. Such changes highlight the interplay between epileptic pathology, network-level alterations, and the brain’s intrinsic capacity for plasticity, emphasizing that structural adaptation in TLE is a distributed, compensatory process influencing cognitive outcomes and recovery after surgery. Recent advances in genetic and epigenetic research have expanded the understanding of epilepsy pathogenesis. Mutations in ion channels (e.g., SCN1A, SCN2A), neurotransmitter receptors (e.g., GABRA1), and synaptic proteins (e.g., SYNGAP1, KCNQ2) have been identified, along with epigenetic regulators including DNA methylation, histone modifications, and microRNAs (miRNAs), which modulate neuronal excitability and plasticity. These discoveries underpin precision medicine approaches and inform potential therapeutic interventions for drug-refractory TLE[16].

Biological aging is increasingly understood as a regulated process driven by cumulative molecular damage, mitochondrial dysfunction, impaired proteostasis, epigenetic dysregulation, and chronic low-grade inflammation rather than chronological age alone[17-19]. However, many of these hallmarks are also central to the pathophysiology of TLE, including oxidative stress, neuroinflammation, and mitochondrial dysfunction[20-24]. Antiseizure medications effectively control seizures but do not prohibit progressive neurodegeneration or prevent cognitive decline, highlighting the critical need for disease-modifying therapeutic interventions[25,26].

Among molecular regulators linking epileptogenesis and aging, miRNAs have emerged as key epigenetic modulators of neuronal survival, synaptic plasticity, inflammatory signaling, and cellular stress responses[27,28]. Dysregulation of specific miRNAs, including miR-132, miR-146a, miR-34a, and miR-134, has been consistently reported in human TLE tissue, experimental epilepsy models, and peripheral circulation, with demonstrated roles in neuroinflammation, apoptosis, and synaptic remodeling[29-33]. Importantly, these miRNAs overlap with regulatory networks implicated in brain aging and neurodegenerative disorders, suggesting a mechanistic convergence between epilepsy and accelerated biological aging. TLE shares several biological hallmarks of brain aging, including oxidative stress, chronic neuroinflammation, impaired proteostasis, cellular senescence, and synaptic dysfunction, with accumulating evidence implicating miRNA dysregulation as a key regulatory mechanism underlying these processes (Table 1). The objective of this mini-review is to evaluate the emerging evidence supporting the conceptualization of TLE as a disorder of accelerated biological brain aging, with particular emphasis on shared aging hallmarks and miRNA-mediated epigenetic regulation. By integrating clinical, neuroimaging, molecular, and epigenetic perspectives, we propose that recurrent seizures, persistent neuroinflammation, mitochondrial dysfunction, and miRNA dysregulation converge to drive accelerated brain aging in TLE (Figure 1). This paradigm shift provides a mechanistic rationale for biomarker discovery and the development of disease-modifying therapeutic strategies that extend beyond seizure suppression[26,27].

Figure 1 Recurrent seizures and persistent network hyperexcitability in temporal lobe epilepsy impose chronic metabolic stress, calcium dysregulation, and excitotoxic injury, leading to excessive reactive oxygen species generation and mitochondrial dysfunction. These processes trigger sustained neuroinflammation (“inflammaging”), impaired proteostasis, dysregulated autophagy, and cellular senescence. Epigenetic alterations, particularly microRNA dysregulation, integrate these aging hallmarks by modulating inflammatory signaling, synaptic plasticity, apoptosis, and neuronal survival. The convergence of these mechanisms results in progressive hippocampal and cortical degeneration, early cognitive decline, and treatment resistance, thereby positioning temporal lobe epilepsy as a disorder of accelerated biological brain aging rather than a purely seizure-based condition. IL-1β: Interleukin-1 beta; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; ROS: Reactive oxygen species; SASP: Senescence-associated secretory phenotype; miRNA: MicroRNA.

Table 1 Biological aging hallmarks implicated in temporal lobe epilepsy and their associated dysregulated microRNAs.

Ref.	Biological aging hallmark	Key pathological features in TLE	Representative dysregulated miRNAs	Functional implications
Waldbaum et al[20], 2010; Fabisiak et al[21], 2022; Sano et al[30], 2012	Oxidative stress and mitochondrial dysfunction	Excess ROS generation during seizures; mitochondrial DNA damage; impaired ATP production	miR-34a	Promotes neuronal apoptosis, mitochondrial dysfunction, and energetic failure
Parsons et al[22], 2022; Fan et al[31], 2020; Huang et al[45], 2019	Chronic neuroinflammation (inflammaging)	Persistent microglial and astrocytic activation; elevated IL-1β, TNF-α, IL-6	miR-146a, miR-132	Sustains inflammatory signaling, synaptic dysfunction, and network instability
Tai et al[5], 2018; López-Otín et al[17], 2013; Horvath et al[28], 2018	Cellular senescence	Senescent neurons and glia; secretion of pro-inflammatory SASP factors	miR-34a	Drives irreversible growth arrest, neuroinflammation, and neurodegeneration
Toscano et al[14], 2023; López-Otín et al[17], 2013; Jimenez-Mateos et al[29], 2011	Impaired proteostasis	Protein misfolding; ER stress; defective ubiquitin-proteasome system; tau accumulation	miR-132	Disrupts protein homeostasis and accelerates neurodegeneration
Fabisiak et al[21], 2022; Henshall et al[27], 2016; Jimenez-Mateos et al[29], 2011	Dysregulated autophagy	Impaired autophagic flux; accumulation of damaged organelles	miR-132, miR-34a	Reduces neuronal survival and promotes epileptogenesis
Chang et al[12]; Henshall et al[27], 2016; 2012; Jimenez-Mateos et al[29], 2011,	Synaptic dysfunction and cognitive decline	Loss of synaptic plasticity; memory and executive impairment	miR-132, miR-134	Alters synaptic remodeling, learning, and memory circuits
Zeng et al[24], 2022; Löscher et al[26], 2021; Fan et al[31], 2020; Wang et al[43], 2021	Gliosis and drug resistance	Astrocytic hypertrophy; altered neurotransmitter homeostasis; increased drug transporter expression	miR-146a, miR-21	Contributes to pharmacoresistance and progressive network dysfunction

TLE: Temporal lobe epilepsy; ROS: Reactive oxygen species; ATP: Adenosine triphosphate; miRNA: MicroRNA; IL-1β: Interleukin-1 beta; TNF-α: Tumor necrosis factor-alpha; IL-6: Interleukin-6; SASP: Senescence-associated secretory phenotype; ER: Endoplasmic reticulum.

TLE AS A MODEL OF ACCELERATED BRAIN AGING

Neuroimaging and clinical evidence of premature aging

Structural and functional neuroimaging studies demonstrate that TLE is associated with patterns resembling premature brain aging. Magnetic resonance imaging and diffusion tensor imaging analyses reveal accelerated gray-matter loss and white-matter degeneration, particularly in patients with mesial TLE and hippocampal sclerosis[6,9]. Brain-age modeling approaches further indicate increased brain-age gaps across epilepsy syndromes, including TLE, suggesting widespread neurobiological aging beyond focal temporal pathology[4,5,10,11,34,35]. Large-scale multicenter studies demonstrate that structural abnormalities in epilepsy extend across distributed cortical and subcortical networks connected to the hippocampus, reflecting system-level degeneration rather than localized damage[8,36].

Hippocampal sclerosis and network degeneration

Hippocampal sclerosis, the pathological hallmark of mesial TLE, is characterized by selective neuronal loss, gliosis, and synaptic reorganization-features that closely resemble age-related neurodegenerative changes[2,3]. Both neuropathological and neuroimaging evidence indicate that degeneration extends beyond the hippocampus to involve temporoparietal and limbic networks, resulting in widespread network disintegration[5,37]. These observations support the classification of TLE as a progressive network disorder analogous to aging-related brain degeneration.

Early cognitive decline as an aging phenotype

Cognitive impairment in TLE often manifests early in the disease course and progresses independently of seizure burden. Longitudinal studies demonstrate accelerated decline in memory and executive function in patients with hippocampal sclerosis, paralleling cognitive trajectories observed in aging populations[12,13]. Neuropathological studies further reveal associations between tau pathology, hippocampal degeneration, and cognitive impairment in TLE, strengthening parallels with age-related neurodegenerative disorders[14].

HALLMARKS OF BIOLOGICAL AGING IN TLE

Recurrent seizures impose substantial metabolic and excitotoxic stress on neurons, leading to calcium dysregulation, oxidative stress, and mitochondrial dysfunction, core mechanisms shared by epilepsy and brain aging[20,21,38,39]. Chronic seizure activity also sustains a pro-inflammatory brain milieu characterized by persistent microglial and astrocytic activation, closely resembling the phenomenon of “inflammaging” described in aging brains[22,31]. Genetic and inflammatory mechanisms are increasingly recognized as contributors to epileptogenesis and drug response. In a North Indian cohort, polymorphisms in the promoter regions of interleukin-1 beta (IL-1β), tumor necrosis factor alpha, and IL-6 genes were investigated for their role in seizure susceptibility and therapeutic outcomes. While IL-1β-511C>T and tumor necrosis factor alpha-308G>A did not influence epilepsy risk, IL-6-174G>C was significantly associated with seizure frequency and drug-refractory epilepsy, highlighting the role of specific inflammatory gene variants in modulating treatment response[40].

Genomic instability and DNA damage

Genomic instability is a fundamental hallmark of biological aging and is increasingly recognized in epilepsy-related neurodegeneration. Recurrent seizures induce oxidative stress, excitotoxicity, and metabolic overload, leading to cumulative DNA damage in neurons and glial cells[20,21]. Experimental models of epilepsy demonstrate increased markers of DNA strand breaks and impaired DNA repair pathways within the hippocampus, which parallel age-related neuronal vulnerability[22,38]. Persistent genomic instability may therefore contribute to irreversible neuronal loss and cognitive decline observed in chronic TLE[22,34].

Mitochondrial dysfunction and energetic failure

Mitochondrial dysfunction is a central driver of both aging and epileptogenesis. In TLE, repeated seizures disrupt mitochondrial bioenergetics, increase reactive oxygen species production, and impair calcium buffering capacity, leading to neuronal metabolic exhaustion[20,21]. Emerging evidence suggests that antioxidant-based modulation of mitochondrial dysfunction may attenuate seizure-induced neuronal injury, further implicating mitochondrial resilience as a therapeutic intersection between epilepsy and brain aging[39]. Similar mitochondrial alterations are observed during normal brain aging, suggesting that seizure-induced mitochondrial stress accelerates aging-like processes in the epileptic brain[17].

Loss of proteostasis and protein aggregation

The maintenance of proteostasis declines with age and is further compromised in TLE. Seizure activity disrupts protein folding, autophagy, and ubiquitin-proteasome system function, resulting in the accumulation of misfolded and aggregated proteins[17,22]. Neuropathological studies in TLE have identified abnormal accumulation of hyperphosphorylated tau and other aggregation-prone proteins, linking epileptic neurodegeneration to aging-related proteinopathies[5,14,41].

Neuroinflammation and inflammaging

Chronic neuroinflammation is a shared hallmark of aging and epilepsy. In TLE, persistent activation of microglia and astrocytes leads to sustained release of pro-inflammatory cytokines and chemokines, promoting synaptic dysfunction and neuronal loss[22,31]. This inflammatory milieu closely resembles “inflammaging”, a phenomenon characterized by low-grade chronic inflammation that drives age-related neurodegeneration. The convergence of seizure-induced inflammation and aging-related immune dysregulation likely accelerates brain aging in TLE[17].

MICRORNA NETWORKS LINKING EPILEPTOGENESIS AND BRAIN AGING

miRNAs as epigenetic regulators of aging and epilepsy

miRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally and play critical roles in neuronal development, synaptic plasticity, inflammation, and stress responses (Table 1). Age-related changes in miRNA expression have been implicated in cognitive decline and neurodegeneration[28]. Similarly, extensive dysregulation of miRNA profiles has been observed in experimental models of epilepsy and human TLE tissue[27,42-44].

Pro-inflammatory and pro-apoptotic miRNAs in TLE

Several miRNAs implicated in aging-associated inflammation and apoptosis are consistently dysregulated in TLE. miR-146a, a key regulator of innate immune signaling, is upregulated in epileptic hippocampi and contributes to chronic neuroinflammation[30,31,45,46]. miR-34a, a well-established aging-associated miRNA, promotes neuronal apoptosis and is elevated in both epilepsy models and aging brains[28,29]. These shared miRNA signatures provide molecular evidence linking TLE to accelerated biological aging.

Synaptic and plasticity-related miRNAs

miR-132 and miR-134 are activity-dependent miRNAs involved in synaptic remodeling and plasticity. Experimental silencing of miR-132 has been shown to reduce spontaneous recurrent seizures and neuronal hyperexcitability in acquired epilepsy models, further supporting its causal role in epileptogenesis and activity-dependent synaptic remodeling[47]. Aberrant expression of these miRNAs in TLE disrupts dendritic spine morphology, synaptic transmission, and memory-related circuits[27,29,48,49]. Given that synaptic dysfunction is a defining feature of brain aging, dysregulation of plasticity-related miRNAs may represent a key mechanism by which recurrent seizures accelerate aging-like synaptic decline.

Circulating miRNAs as biomarkers of accelerated brain aging

Recent studies have identified circulating miRNAs associated with epilepsy severity, cognitive impairment, and neuroinflammation, suggesting their potential utility as minimally invasive biomarkers[32,50-52]. Systematic profiling studies further reveal that circulating microRNA signatures vary across epilepsy subtypes and disease severity, supporting their utility as pan-epilepsy biomarkers with potential relevance to systemic biological aging[52]. Overlap between circulating miRNA signatures in epilepsy and aging further supports the concept of systemic epigenetic aging in TLE[17,28].

CLINICAL IMPLICATIONS OF ACCELERATED BRAIN AGING IN TLE

Cognitive decline and functional outcomes

Recognition of TLE as a disorder of accelerated brain aging has significant clinical implications. Cognitive impairment, particularly in memory and executive function, emerges early and progresses over time, diminishing quality of life and functional independence[12,13,53]. Clinical management of TLE often relies on antiseizure medications; however, their impact on long-term cognitive and functional outcomes is variable. In a cross-sectional study of 486 patients, monotherapy was associated with better seizure control and higher quality of life compared to polytherapy, with non-responders experiencing higher seizure frequency and lower quality of life scores[54]. These findings emphasize the need to optimize antiseizure medication strategies while addressing underlying neurodegenerative mechanisms. Early identification of aging-related biomarkers may enable risk stratification and personalized therapeutic interventions. The trajectory of cognitive decline observed in TLE mirrors patterns described in normative and pathological cognitive aging, suggesting that epilepsy may shift individuals onto an accelerated aging continuum rather than representing a purely seizure-driven cognitive disorder[53].

Limitations of current antiseizure therapies

While antiseizure medications effectively reduce seizure frequency, they do not address underlying neurodegenerative and aging-related mechanisms[25,26]. Consequently, seizure control alone may be insufficient to prevent cognitive decline and structural brain aging, underscoring the need for disease-modifying strategies targeting inflammation, mitochondrial dysfunction, and epigenetic dysregulation.

Therapeutic targeting of aging pathways

Targeting shared aging pathways such as oxidative stress, neuroinflammation, mitochondrial dysfunction, and miRNA-mediated gene regulation represents a promising therapeutic avenue. Recent mechanistic studies further demonstrate that specific miRNAs regulate seizure-associated neuronal death through ferroptosis and oxidative stress pathways, highlighting miRNA-driven redox imbalance as a novel therapeutic target in epilepsy-related neurodegeneration[55]. Preclinical evidence suggests that modulation of specific miRNAs may attenuate seizure-induced neurodegeneration and improve cognitive outcomes[27,55,56]. Integrating anti-aging strategies into epilepsy management may therefore offer novel approaches to preserving brain health in TLE.

FUTURE DIRECTIONS AND CONCLUSIONS

Future research should prioritize longitudinal studies integrating neuroimaging, molecular biomarkers, and cognitive assessments to delineate the temporal dynamics of accelerated brain aging in TLE. The application of brain-age prediction models, combined with miRNA profiling, may facilitate early detection of individuals at high risk for progressive neurodegeneration[10]. Mechanistic studies are needed to elucidate causal links between seizure activity, miRNA dysregulation, and aging hallmarks, as well as to determine whether targeting aging pathways can alter disease trajectory. Large-scale, multi-center studies will be essential to validate miRNAs and other aging-related biomarkers across diverse epilepsy populations.

In conclusion, accumulating evidence supports the concept of TLE as a model of accelerated brain aging, characterized by convergent structural, molecular, and epigenetic alterations. Recognizing epilepsy as an aging-related brain disorder has profound implications for diagnosis, prognosis, and therapy, and may pave the way for disease-modifying interventions that extend beyond seizure suppression. TLE should be reconceptualized as a disorder of accelerated brain aging, driven by recurrent seizures, chronic neuroinflammation, and epigenetic dysregulation. Recognizing shared aging mechanisms offers a paradigm shift toward disease modification, with broad implications for epilepsy research, biomarker discovery, and therapeutic innovation.