Cellular senescence in migraine – a hypothesis-driven narrative review

Abstract

Background

Migraine may signal early signs of aging-related processes, such as reduced autophagy, increased reactive oxygen and nitrogen species (RONS), and low-grade inflammation in people prone to migraine, without necessarily indicating systemic aging. While migraine is not an age-related condition, brain aging might be accelerated by cellular senescence in neurons and glia, contributing to cognitive decline in migraine patients. Although neurons are postmitotic cells, they can undergo postmitotic cellular senescence, which may contribute to the chronicity of migraine.

Main body

Oxidative stress is a key factor inducing senescence and also plays a role in migraine development, as the brains of migraine sufferers show an over-reliance on mitochondria that produce an excess of RONS. These RONS can lower the threshold for cortical spreading depression and directly activate trigeminovascular nociceptors through RONS-sensitive ion channels, resulting in calcitonin gene-related peptide-dependent migraine pain. Excessive RONS can also damage DNA, and abnormal repair of single-strand DNA breaks caused by migraine-related brain activity may connect migraine with senescence. Defects in autophagy could activate cellular senescence and stabilize senescence-associated secretory phenotype. Impaired autophagy in microglia might trigger secretory autophagy and the release of brain-derived nuclear factor, which could induce autophagy in neurons to eliminate cellular debris caused by oxidative stress. This sequence of events is possible but has not yet been demonstrated in material from migraine patients and animal models.

Conclusion

Cellular senescence may influence migraine through various mechanisms, including oxidative stress, cortical spreading depression, abnormal DNA damage responses, and impaired autophagy. Currently, there is no direct evidence linking cellular senescence to migraine, but it is unclear whether such research has been conducted to date, and we have argued that these studies are warranted.

Introduction

Although the introduction of calcitonin gene-related peptide (CGRP) antagonists and antibodies against CGRP and its receptor has revolutionized migraine prevention, this strategy has been effective in managing and reducing the frequency and severity of attacks, but does not guarantee a definitive cure [1]. Moreover, not all migraine patients respond to anti-CGRP treatment. Subsequent clinical trials with pituitary adenylate cyclase–activating polypeptide (PACAP) for migraine prevention indicate that PACAP blockade is among the most promising next-generation migraine therapies, especially for patients unresponsive to CGRP, although the results thus far remain promising. There are no solid data supporting a rationale for a PACAP-related therapy breakthrough compared to anti-CGRP treatment [2]. In consequence, migraine remains an incurable syndrome. One reason for this condition might be limited understanding of the molecular mechanisms behind migraine development.

Migraine is not classified as a typical neurodegenerative disease, although structural changes are observed in the brains of migraine patients, which alters the perception of migraine as a solely benign condition [3]. Cellular senescence is a state of permanent arrest of the cell cycle and is associated with several changes occurring in the senescent cell and its environment, including neighboring cells [4]. Although this definition suggests that cellular senescence is primarily considered in proliferation-competent cells, there is increasing interest in relating this effect to postmitotic cells, including neurons [5]. Although the causal role of CGRP in migraine has been established, the exact molecular mechanisms remain unknown. Emerging evidence points to a biologically plausible link between CGRP action and cellular senescence across various tissues and conditions [6–8]. However, such a link in migraine is indirect, emerging at the intersection of the CGRP signaling, neuroinflammation, mitochondrial stress, and the senescence‑associated secretory phenotype (SASP), but it has not been experimentally proven [9, 10].

Although oxidative stress is implicated in the pathogenesis of many syndromes, its involvement in mitochondrial dysfunction and energy deficit, cortical spreading depression (CSD), activation and sensitization of the trigeminovascular system, endothelial dysfunction, and neurovascular coupling, as well as neuroinflammation, makes it an important potential player in migraine pathophysiology [11]. On the other hand, oxidative stress can be a strong and multipathway inducer of cellular senescence [12, 13].

Yet another potential link between cellular senescence and migraine may stem from aging. Persistent activation of senescence can contribute to various age-related pathological conditions, and emerging evidence links aging to increased cellular senescence, leading to the accumulation of senescent cells [12]. On the one hand, the role of aging in migraine pathogenesis is not completely clear, but there are rationales to link migraine with accelerated brain aging [14]. Therefore, although there is no direct experimental evidence of a causal link between migraine and cellular senescence, various data and reasonings suggest such a connection. In this hypothesis-driven narrative review, we provide an overview of migraine pathogenesis, including the role of brain aging. Then, we present cellular senescence and SASP and discuss their roles in the functioning of the central nervous system (CNS) and in its pathologies, including migraine. The main goal of this study is to present arguments for conducting experimental research on the role of cellular senescence in migraine development.

Migraine, brain aging, and cellular senescence

Aging in migraine is a complex issue whose role in its pathogenesis has not been fully explained yet. Chronological aging cannot be directly related to migraine, as migraine prevalence peaks at 20–40 years. Moreover, most people do not suffer from migraine during their entire lifetime. On the other side, some migraine patients show impairment in cognitive ability associated with an aging brain [15]. Consequently, migraine could reflect early activation of aging-related pathways, including impaired autophagy, increased level of RONS, and low-grade inflammation without systemic aging in migraine-susceptible individuals. Later in life, hormonal stabilization and reduced cortical excitability may lower attack frequency. Therefore, migraine may represent a condition where aging-like molecular signatures appear early in specific brain regions, driven by metabolic, hormonal, and genetic stress, rather than chronological age. Among several kinds of aging, brain aging seems to be the most relevant to migraine pathogenesis as it can be associated with shrinking of neurons, dendritic degeneration, demyelination, small vessel disease, decreased metabolic rate, microglial activation, gray and white matter volume changes, and white matter lesions (reviewed in [16]). Most of these symptoms were observed in migraine patients [3, 17]. However, other kinds of aging, including metabolic, social, and epigenetic aging, may contribute to migraine pathogenesis (reviewed in [14]).

Cellular senescence is a state characterized by withdrawal from the cell cycle, resulting in irreversible inhibition of cellular division while maintaining metabolic activity. However, cellular senescence is currently understood as a multipathway process that affects not only the senescent cell but also neighboring cells and the extracellular matrix. This is due to the development of SASP, characterized by the overproduction of growth factors, proinflammatory cytokines, and extracellular vesicles, which may act in an autocrine or paracrine manner [4] (Fig. 1). Senescent cells are also characterized by the persistent activation of DNA damage response (DDR) [18]. Moreover, senescent cells display morphological changes, mitochondrial impairment, overproduction of RONS, increased activity of β‑galactosidase (senescence‑associated (SA)-β‑gal) and resistance to apoptosis. The formation of senescence-associated heterochromatin foci and global chromatin remodeling are additional features of senescent cells [19].

Fig. 1.

Cellular senescence and senescence-associated secretory phenotype (SASP). Cellular senescence is characterized by a permanent inhibition of the cell cycle, yet the cell remains metabolically active. It can be induced by telomere erosion (replicative senescence), endoplasmic reticulum (ER) stress associated with an impaired unfolded protein response (UPR), oncogene activation, mitochondrial quality control (mtQC) impairment, changes in chromatin structure, and alterations in the epigenetic profile. DNA damage and reactive oxygen and nitrogen species (RONS) are primary inducers of cellular senescence, and senescent cells are characterized by a permanent activation of DNA damage response (DDR) and increased expression of β‑galactosidase (senescence‑associated (SA) b‑gal). Senescent cells display a senescence-associated secretory phenotype (SASP), characterized by the release of signaling molecules, either directly or in extracellular vesicles. Senescent cells release molecules – cytokines, chemokines, growth factors, RONS that act back on themselves (autocrine senescence) or induce senescence in neighboring, initially non-senescent cells (paracrine senescence). RONS attributed to SASP are marked with a different color than RONS inducing SASP, as they may represent different species depending on specific conditions. Created in https://BioRender.com

As people age, the body’s ability to clear senescent cells diminishes, leading to their buildup and increased secretion of pro-inflammatory SASP factors, which ultimately contribute to the development of age-related diseases [20]. Removing these long-lasting senescent cells improves disease outcomes, highlighting their harmful effect on tissue function [21, 22].

Accumulating human and epidemiological data indicate that migraine chronification is associated with biological processes typically observed in aging, suggesting that chronic migraine (CM) may represent a state of accelerated or stress‑induced brain aging rather than a purely episodic pain disorder [14]. Neuroimaging studies demonstrate that CM is accompanied by structural markers of premature brain aging, including reduced cortical thickness, increased white‑matter hyperintensities, and hippocampal atrophy, changes not typically observed in age‑matched EM patients [23]. Using machine‑learning–derived brain‑age estimates, individuals with CM were shown to have a brain‑age gap approximately 4.16 years older than their chronological age, indicating accelerated neurostructural decline [24]. These alterations correlate with impairments in declarative memory, disruptions of memory‑encoding processes, and higher rates of affective comorbidities, all of which are features commonly associated with aging‑related neurodegeneration. Together, these findings support the notion that CM is accompanied by age‑like neurobiological remodeling, potentially mediated by chronic nociceptive signaling, neuroinflammation, obesity, or hypertension, which exacerbate long‑term neural vulnerability.

Complementing these neuroimaging findings, population‑level epidemiological evidence further links migraine to molecular hallmarks of biological aging. A large NHANES‑based study (n = 6,169) reported that short peripheral blood telomere length, a well‑recognized marker of cellular aging and cumulative oxidative stress, is significantly associated with increased migraine risk among adults aged 20–50 years, with an L‑shaped telomere‑migraine relationship and a striking odds ratio of 9.34 for the shortest telomere category [25]. Notably, this association disappears after age 50, suggesting that migraine in early and mid‑adulthood may be driven in part by accelerated biological aging rather than by chronological aging. Telomere shortening has established mechanistic ties to oxidative stress, mitochondrial dysfunction, and DNA damage pathways already implicated in migraine pathophysiology. In addition, clinical reviews consistently report elevated levels of oxidative stress markers and impaired antioxidant defenses in migraine patients, particularly those with higher attack frequency or CM, further reinforcing that aging‑related oxidative mechanisms track with migraine severity and progression. Together, these converging lines of evidence suggest that migraine chronification is associated with accelerated or stress‑related aging processes at both molecular and systems levels. This framework opens the possibility that biological aging pathways, including oxidative stress, autophagy impairment, mitochondrial dysfunction, genomic instability, and neuroinflammation, may be promising targets for future mechanistic and therapeutic investigations in chronic migraine.

Cellular senescence is increasingly acknowledged as a major factor in brain aging through multiple interconnected processes. Senescent cells are found in the brain, and SASP-related chronic low-grade inflammation disrupts neuronal function and synaptic plasticity, which are important in migraine pathogenesis [26]. Overproduced RONS damage neurons and glia, promoting aging-related cognitive decline [27]. Senescence of neural stem/progenitor cells reduces neurogenesis in the brain, reducing its plasticity and correlating with memory impairment [28]. Reduced levels or impaired function of endothelial progenitor cells (EPCs) indicate endothelial dysfunction, observed in migraine patients, especially those with aura [29]. A decreased number and reduced functionality of circulating EPCs were observed in migraine patients with and without aura compared to subjects without headaches [30]. Functionally, EPCs from migraine patients displayed decreased migratory capacity and increased cellular senescence. A subsequent study showed a reduced level of EPCs in both ictal and interictal phases of episodic migraine [31]. The number of EPCs declined as migraine advanced.

In summary, migraine may be a condition in which molecular signs of aging appear early in specific brain regions, caused by various stresses that lead to adverse effects, including cellular senescence, rather than by chronological aging.

Cellular senescence in sensory neurons and pain

Although neurons are post-mitotic cells, they can acquire a senescence-like phenotype, usually referred to as post-mitotic cellular senescence (PoMiCS) which may contribute to various human pathologies, including neurodegenerative diseases [32]. This state is characterized by persistent DDR, mitochondrial dysfunction, SA-β‑gal, enhanced oxidative stress, activation of the cyclin-dependent kinase inhibitor 2 A (p16/INK4a) and cyclin‑dependent kinase inhibitor 1 A (CDKN1A) pathways, and the acquisition of SASP. Such phenotype was observed in dorsal root ganglion (DRG) in aged organisms and following nerve injury [33]. Although DRG neurons are not central drivers of migraine pathogenesis, they may play secondary or modulatory roles in migraine-related effects, including migraine allodynia, central sensitization, migraine chronification and others. Upper cervical DRG neurons (C1-C3) innervate neck muscles, joints, and occipital skin, and are covered centrally with trigeminal afferents in the trigeminocervical complex (TCC) [34]. This may explain neck pain that occurs before or alongside migraines, occipital pain referring to the frontal or head regions, and the modulation of migraine severity by central pathology [35, 36]. During repeated migraine attacks, spinal (DRG-linked) nociceptive pathways become sensitized after trigeminal neurons, which is clinically manifested as cutaneous allodynia extending beyond the trigeminal territory and increased pain from neck, shoulders, and upper body [37, 38]. DRG neurons may be important for migraine chronification (reviewed in [39]).

A key characteristic of senescent sensory neurons is the development of pro-inflammatory SASP, which is crucial in pain pathophysiology [40]. Key SASP components related to pain include cytokines IL6, IL1B, and tumor necrosis factor alpha (TNFA); chemokines C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 1 (CXCL1); prostaglandins; and matrix-remodeling enzymes [41, 42]. These factors are released locally within the DRG and function in autocrine and paracrine ways, creating a chronically sensitized microenvironment [42]. Senescent nociceptors are not functionally inert. On the contrary, they display increased intrinsic excitability, lower thresholds for action potential firing, and enhanced responsiveness to inflammatory mediators [33, 43, 44]. Electrophysiological profiling shows that senescence-marker–positive dorsal root ganglion neurons primarily exhibit high-frequency firing, lower action-potential thresholds, and nociceptor-like intrinsic excitability, directly linking neuronal senescence to ongoing pain signaling [33].

In general, sensory neurons may become senescent in response to aging-related stress (telomere-independent DNA damage, metabolic stress), peripheral nerve injury (axotomy, compression, diabetic neuropathy), oxidative stress, and inflammation, which stabilize senescence signaling loops [33, 42, 43]. However, single-cell transcriptomic studies have shown that only specific subsets of sensory neurons, not all, undergo senescence, suggesting selective vulnerability. SASP factors released by senescent neurons can activate satellite glial cells and infiltrating immune cells in the DRG. This process enhances local inflammation and oxidative stress and encourages secondary senescence in nearby neurons, known as the bystander effect [40]. This creates a self-perpetuating inflammatory cycle, which helps clarify why pain persists long after the initial injury has healed.

Aging is a major risk factor for chronic pain. Potential cellular mechanisms underlying this relationship arise from the observation that aged DRGs contain significantly more senescent nociceptors, even in the absence of injury. Peripheral injury in older individuals leads to additional accumulation of senescent neurons, lowering the threshold for pain chronification in aging populations. Perhaps the strongest evidence for causality comes from senolytic studies showing that pharmacologically removing senescent cells decreases mechanical allodynia and thermal hypersensitivity while maintaining overall sensory function, indicating selective elimination of dysfunctional neurons [33]. These effects have been shown in various mouse models of nerve injury and aging, strongly indicating that senescent neurons are active contributors to pain rather than just passive markers.

In summary, cellular senescence in sensory neurons contributes to pain by transforming certain nociceptors into chronically overactive, pro-inflammatory cells that enhance nociceptive signaling, sustain neuroinflammation, and raise the risk of chronic pain – especially with aging and nerve injury (Fig. 2). In migraine, cellular senescence in trigeminal nociceptors may promote chronification by converting a subset of pain-sensitive neurons into persistently hyperexcitable, pro-inflammatory cells that amplify CGRP/PACAP-dependent signaling and maintain trigeminovascular inflammation, particularly after repeated attacks, aging, or injury-related stress. Chronic SASP signaling promotes hyperexcitability and central/peripheral sensitization, increasing migraine frequency and severity.

Fig. 2.

Senescent sensory neurons may potentially contribute to migraine. Sensory neurons, including nociceptors in the trigeminal ganglion or dorsal root ganglia, may become senescent in response to aging-related stress, peripheral nerve injury, oxidative stress, and inflammation, which stabilize senescence signaling loops. Senescent neurons may release migraine-related neuropeptides, including calcitonin gene-related peptide (CGRP), substance P, and pituitary adenylate cyclase–activating polypeptide (PACAP). Senescence-sociated secretory phenotype (SASP) factors released by senescent neurons can activate satellite glial cells and infiltrating immune cells in the DRG. This process enhances local inflammation and oxidative stress, creating a self-perpetuating inflammatory cycle that may contribute to migraine and/or its chronification. Created in https://BioRender.com

Oxidative stress and mitochondrial impairment in migraine and cellular senescence

Oxidative stress is among the most potent and multi-pathway drivers of cellular senescence [45]. It is associated with elevated RONS that may damage cellular components, including proteins and nucleic acids. Damage to proteins in the mitochondrial electron transport chain (mtETC) results in RONS overproduction, which may further damage mtETC components, leading to additional RONS production and forming a positive feedback loop (“vicious cycle”). Also, damage to mitochondrial and nuclear DNA (mtDNA and nDNA) may result in the synthesis of faulty mtETC proteins that overproduce RONS. However, mtDNA damage is another independent key driver of cellular senescence [46]. Therefore, there is a strong link between oxidative stress, mitochondrial impairment, and DNA damage on one side and cellular senescence on the other.

A mechanistic pathway linking oxidative stress and migraine has been demonstrated. This pathway involves mitochondrial-derived RONS that activate the trigeminal system and CSD. Migraine-affected brains show impaired mitochondrial oxidative phosphorylation (OXPHOS), especially in the cortex, brainstem, and trigeminal neurons. This leads to reduced ATP production, electron leakage from complexes I and III, and increased mitochondrial RONS production, including superoxide and hydrogen peroxide. These changes create a state of neuronal energy vulnerability. A decreased phosphocreatine concentration and ATP levels were observed in the brains of patients with migraine without aura [47]. These results emphasize the significance of mitochondrial metabolism and, consequently, oxidative stress in migraine pathogenesis. Elevated levels of lipid peroxidation markers, NO stable metabolites (NOx), and thiobarbituric acid reactive substances (TBARS) were demonstrated in the urine of episodic migraine patients during the headache-free period [48]. That study suggests an increased vulnerability to oxidative stress in migraine sufferers.

Although the precise mechanism and role of CSD, a wave of neuronal and glial cell depolarization that travels across the cortex during migraine, are not fully understood, this phenomenon is at least an important feature of migraine aura. However, CSD is not only involved in the aura phase but is also believed to play a critical role in triggering migraine headaches by activating trigeminovascular pathways [49]. Decreased activity of the glucose-based antioxidant system caused significant, sudden, and harmful changes in cellular functions [50]. These changes spread throughout the hippocampus and resulted in long-lasting silencing of synaptic transmission, abnormal oxidation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and reduced flavin adenine dinucleotide (FADH2), increased oxygen consumption, and significant neuronal depolarization. They were linked to a prior buildup of RONS and were largely prevented by applying the antioxidant Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl). Since the observed changes resembled CSD, it was suggested that RONS accumulation might be the main trigger for CSD, as Tempol effectively reduced CSD occurrence in vivo, indicating RONS buildup could be a key mechanism in initiating CSD. Although the hippocampus is not a primary “migraine generator” like the trigeminovascular system, it may play a modulatory role, especially in pain processing, stress response, memory, emotion, and migraine chronification [51]. Another study found that CSD elevated levels of malondialdehyde (MDA), a lipid peroxidation product, in the ipsilateral cerebral cortex and meninges, as well as in both ipsilateral and contralateral trigeminal ganglia in rats [52]. Applying hydrogen peroxide to the meninges temporarily increased electrical spiking activity in the trigeminal nerves, indicating a pro-nociceptive effect of RONS mediated by transient receptor potential cation channel subfamily A member 1 (TRPA1). Additionally, hydrogen peroxide stimulated the release of CGRP. Therefore, CSD may induce oxidative stress that propagates within the trigeminal nociceptive system and may contribute to the link between CSD and the activation of the trigeminovascular system in migraine development.

Oxidative stress activates migraine pain via specific molecular targets in trigeminal neurons. The major mediators of this effect are transient receptor potential (TRP) proteins, expressed in trigeminal neurons and brain regions affected by migraine, which modulate CGRP release [53]. TRPs are targeted by botulinum neurotoxin type A, a drug used in chronic migraine therapy [54]. Transient receptor potential cation channel subfamily V member 1 (TRPV1) plays an important role in meningeal nociception and migraine pain and is likely the most studied potential druggable pain target [55]. Another TRP, TRPA1, colocalizes with TRPV1 in a subset of neurons and is activated by several migraine triggers [56]. TRPA1 is involved in migraine-related effects, including pain transmission, neurogenic inflammation, and vasodilation (reviewed in [57]). RONS and lipid peroxidation products may activate TRPA1 and sensitize TRPV1 in trigeminal neurons [58]. Mechanistically, TRPA1 may detect RONS produced by migraine triggers or excessive energy production and transmit pain signals to sensory neurons, including those in the trigeminal nerve, which are crucial in migraine development. After activation, both TRPV1 and TRPA1 may promote CGRP release from the trigeminal nerve. There is substantial experimental evidence linking TRPV1 with cellular senescence, particularly in the context of vascular and endothelial aging [33, 59, 60]. Although there is no direct experimental evidence that TRPA1 is involved in cellular senescence, growing indirect data hint at such a connection, mainly through pathways central to senescence: oxidative stress, Ca²⁺ signaling, mitochondrial dysfunction, inflammation, and SASP regulation [61]. Indirect evidence comes from cancer and stress tolerance models, where TRPA1 has been shown to promote cell survival under oxidative stress and to activate the key transcription factor regulating the cellular response to oxidative stress, nuclear factor erythroid 2–related factor 2 (NRF2), which in turn activates antioxidant programs [62]. Several clinical trials demonstrated that some antioxidants, including riboflavin, coenzyme Q10, and magnesium, reduced the frequency, duration, and severity of migraine attacks [63–65].

To summarize the connection between oxidative stress in migraine and cellular senescence, current evidence suggests that oxidative stress is a key upstream trigger of cellular senescence through mitochondrial dysfunction, RONS-induced DNA and chromatin damage, and the induction of a pro-inflammatory SASP. This occurs in various tissues, including the brain, where neuronal senescence is increasingly recognized despite neurons being post-mitotic. These neurons exhibit DNA damage, nuclear lamina changes, and SASP-like signaling. In migraine, human and experimental studies consistently report abnormalities in oxidative stress, including increased lipid peroxidation products, fluctuations in nitric oxide during aura, mitochondrial energy deficits, and activation of redox-sensitive nociceptive channels, such as TRPA1. These findings are linked to CSD thresholds, trigeminovascular activation, and central sensitization. Although antioxidant or bioenergetic supplements show preliminary but inconclusive benefits, it is reasonable to speculate that migraine-related oxidative stress likely promotes senescence-like traits in vulnerable neural and glial cells, thereby amplifying neuroinflammation and network hyperexcitability through SASP mediators. Conversely, senescence-associated mitochondrial and lysosomal dysfunction are expected to sustain redox imbalance, lowering attack thresholds and creating a bidirectional feedback loop. Major gaps include: (1) a lack of cell-type-specific, longitudinal human data directly showing senescence markers in migraine brains and their timing related to oxidative surges; (2) absence of standardized multi-marker panels to distinguish neurosenescence/SASP from temporary stress responses in patients; (3) a lack of causal intervention studies testing whether senescence-targeting or antioxidant strategies can change migraine frequency or severity while monitoring validated CNS biomarkers; and (4) insufficient understanding of how CSD and purinergic/CGRP pathways mechanistically interact with senescence regulators in vivo.

In summary, there is solid experimental evidence that oxidative stress is involved in migraine, and very strong experimental evidence that oxidative stress induces cellular senescence (Fig. 3). Mitochondrial oxidative stress lowers the threshold for CSD and directly activates trigeminovascular nociceptors via RONS-sensitive ion channels, e.g., TRPA1, leading to CGRP-dependent migraine pain. However, direct, causally demonstrated links showing oxidative‑stress‑driven cellular senescence as a mechanism in migraine are emerging but still incomplete. The same conclusions concern mitochondrial impairment. Yet, there is a convergent chain of mechanistic evidence from animal models, human biomarker studies, and cellular experiments that strongly supports the involvement of cellular senescence as a mediator of oxidative stress in migraine pathogenesis.

Fig. 3.

Potential of oxidative stress, mitochondrial impairment, and senescence in migraine. Impaired mitochondria overproduce reactive oxygen and nitrogen species (RONS) that may further damage mitochondria. RONS may activate the trigeminal system (TGS) through RONS-sensitive ion channels. Impaired mitochondria may induce cellular senescence through RONS-dependent and -independent mechanisms. Senescence cells acquire a senescence-associated secretory phenotype (SASP), release and may sensitize nociceptors in TGS. The SASP factors lower the threshold for cortical spreading depression (CSD) and stimulate the release of calcitonin gene-related peptide (CGRP), a crucial factor in migraine. Created in https://BioRender.com

DNA damage and repair in cellular senescence and migraine

DNA damage is a primary and universal inducer of cellular senescence [12]. Telomere shortening, which is also a form of DNA damage, occurs in most somatic cells because of the loss of a fragment of telomeric DNA with each cell division – the replication end problem. These cells undergo replicative senescence to prevent damage to genes vital for their homeostasis [66].

Persistent DDR activation is a key characteristic of cellular senescence. Several studies have shown that DDR persists for months or even years after senescence is induced, and the apparent loss of DDR in some cell lineages results from the selective death of heavily damaged cells, rather than the resolution of DNA damage [18, 67, 68]. Senescence can be enforced by chronically active DDR through unrepaired telomere lesions, unresolved replication stress, and oncogene-induced genotoxicity [69]. It should be noted that DDR maintains cellular senescence through DDR signaling rather than by permanent repair of damaged DNA.

The role of DNA damage and repair in migraine remains controversial. There is limited evidence for increased oxidative DNA damage, as indicated by 8-hydroxy-2’-deoxyguanosine (8-oxoG), in the peripheral blood of migraine patients compared to controls [70]. Additionally, variability in the DNA repair genes apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1), X‑ray repair cross‑complementing 3 (XRCC3), excision repair cross‑complementation group 2 (ERCC2), and 8‑oxoguanine DNA glycosylase 1 (hOGG1) was linked to migraine occurrence in a case-control study [71]. These studies might justify examining the role of DNA damage and repair in migraine.

Strong evidence of the crucial role of DNA damage and repair in the CNS came from two 2021 studies, which demonstrated ongoing induction of DNA damage and its repair at specific genomic sites in neuronal genomes [72, 73]. DNA damage observed at these sites was single-strand breaks (SSBs), resulting from the removal of methylated DNA bases in gene enhancers [73]. On the other hand, increased DNA repair efficiency was observed at neuronal genomic sites, thereby protecting the integrity of genes vital to the identity and function of CNS neurons [72]. These effects were considered an important element in regulating gene expression and, consequently, in determining the CNS phenotype. Although the mechanisms by which these effects contribute to specific CNS pathologies remain unknown, this provides a rationale for further investigation of the role of DNA damage and repair in CNS pathophysiology.

We presented further arguments that DNA damage and repair may play a role in the pathogenesis of migraine [74]. Oxidative stress-related RONS may damage DNA, activating DDR. The main DNA damage induced by RONS is oxidative modification of DNA bases, which is converted into SSBs in base excision repair (BER) [75]. SSBs may be targeted by DNA single-strand break repair (SSBR), in which poly(ADP-ribose) polymerase I (PARP1) is a crucial element [76]. Another protein playing a critical role in SSBR is X-ray repair cross-complementing 1 (XRCC1). Overactivation of PARP-1 may couple SSBs to neurological dysfunctions, as increased levels of poly(ADP-ribose) are neurotoxic [77]. This effect may be prevented by XRCC1. Another source of SSBs in the CNS is the aberrant action of the DNA topoisomerase I (TOP1), which induces SSBs but may be unable to seal them [76]. TOP1 was shown to be inhibited in depolarized neurons, suggesting a link with CSD [78]. When a wave of depolarization accompanying CSD reaches cortical neurons in migraine with aura, these neurons may silence their TOP1 via PARylation by PARP1 [74]. Additionally, the TOP1 complex may be stabilized by oxidative stress, leading to the induction of SSBs rather than their sealing.

Transient receptor potential melastatin 2 (TRPM2) is a plasma membrane cation channel that connects oxidative stress to calcium release, ultimately activating NOD-like receptor family, pyrin domain-containing 3 (NLRP3) [79]. It has also been directly implicated in the neurobiology of experimental migraine [80]. Furthermore, TRPM2 can be gated by ADP-ribose [81]. During oxidative stress, TRPM2 acts as a downstream effector of the PARP/poly(ADP-ribose) glycohydrolase pathway, operating through PARP1/2-dependent poly(ADP-ribose) formation.

Although DSBs are the main and well-established DNA damage to induce cellular senescence, it should be considered that SSBs occurring in both DNA strands at many sites are (1) a prerequisite for DSBs if they are close to each other, (2) may induce parthanatos, a kind of programmed cellular death, and (3) can be converted to DSB during replication. Therefore, SSBs may induce cellular senescence by converting into DSBs. However, SSBs can also induce senescence directly. SSBs, especially those that interfere with replication or transcription, produce stretches of single‑stranded DNA coated with RPA. This structure is the canonical activator of the ataxia telangiectasia and Rad3‑related (ATR) kinase, which in turn activates checkpoint kinase I (CHK1). The ATR signaling induces p53 activation, p21 upregulation, and senescence rather than apoptosis when the damage is low but persistent [82, 83]. Another pathway of SSB-induced senescence is associated with NAD+ depletion resulting from PARP1 hyperactivation (metabolic senescence) [84, 85].

As mentioned neuronal enhancers are hotspots for SSBs and rely heavily on PARP1–XRCC1–POLβ repair mechanisms. When this pathway becomes overwhelmed or defective, persistent SSBs accumulate, and neurons exhibit continuous, localized SSBR activity at specific genomic sites, reflecting ongoing DNA breakage during normal activity. If SSBs are not repaired efficiently, they lead to persistent DNA damage signals, which are known triggers of cellular senescence. Unrepaired SSBs alter transcription, chromatin structure, inflammation, and metabolism – all key features of senescence. PARP1 and PARP2 detect SSBs and recruit repair proteins. Continuous PARP1 activation consumes NAD+, leading to metabolic disturbances that can promote senescence. XRCC1 serves as the main scaffold for SSBR, and when XRCC1-dependent repair fails, SSBs accumulate, maintaining DDR signaling. Neuronal DDR activation is linked to neuroinflammation. Neurons repair SSBs mainly at enhancers of activity-regulated genes, such as those induced during intense neuronal firing. Clusters of enhancer SSBs are associated with active DNA demethylation sites, which naturally create abasic sites and SSBs. Persistent SSBs at enhancers can disrupt transcription, lead to R-loop formation, and induce chromatin changes, all of which can trigger senescence. Although studies on DNA repair specific to migraine are limited, the mechanistic basis is strong given the link between neuronal activity and SSB formation. Increased metabolic load increases RONS, thereby directly elevating SSB frequency. Neuronal activity itself causes regulated DNA breaks at the promoters and enhancers of immediate-early genes – a normal process that becomes pathological when repair capacity is exceeded. Inflammation related to migraine may further slow repair processes, pushing neurons toward persistent DDR signaling and senescence. In summary, migraine and hyperexcitable brain states indirectly contribute to the DNA damage-senescence-migraine cycle by increasing SSB formation and impairing repair, making neuronal senescence a key factor in migraine development.

In summary, oxidative stress is associated with elevated levels of RONS, which can damage DNA. Therefore, it may be speculated that migraine may be associated with DNA damage through oxidative stress. SSBs can be continuously induced at specific sites in neuronal genomes and repaired by either BER or SSBR (Fig. 4). Abnormal SSBR activity, resulting mainly from dysfunctional PARP-1 and/or XRCC1, may be a major mechanism underlying pathological, migraine-related brain effects. SSBs, especially those in excess, may induce cellular senescence, mechanistically linking migraine with senescence.

Fig. 4.

DNA damage and cellular senescence may trigger neuroinflammation, potentially contributing to migraine. Oxidative stress-related reactive oxygen and nitrogen species (RONS) can cause DNA single-strand breaks (SSBs) that are repaired by SSB repair (SSBR). Both RONS and DNA damage may induce cellular senescence, characterized by the senescence-associated secretory phenotype (SASP), which involves the release of cytokines, chemokines, and other molecules that can activate the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome. This activation may promote neuroinflammation and contribute to migraine. The key enzymes of SSBR, poly(ADP-ribose) polymerase (PARP), modify themselves and many other proteins, including SSBR proteins, and mediate RONS-induced activation of the transient receptor potential melastatin 2 (TRPM2) channel, which also activates NLRP3. Created in https://BioRender.com

Autophagy in cellular senescence and migraine

Autophagy, a process essential for cellular and organismal homeostasis, removes damaged, dysfunctional, or no longer needed material, invaders, and their remnants from the cell. Material to be removed is degraded and potentially recycled within the cell (degradative or canonical autophagy) or exported from the cell (secretory or non-canonical autophagy).

Autophagy and secretory autophagy both begin with the formation of an isolation membrane, which gradually engulfs the material to be degraded or expelled. Once fully enclosed, this structure becomes autophagosome. In degradative autophagy, the autophagosome fuses with a lysosome, forming an autolysosome in which lysosomal enzymes degrade the cargo. In secretory autophagy, it fuses with the plasma membrane, releasing its contents into the extracellular space. The resulting breakdown products can then be recycled and utilized in cellular metabolism.

When autophagy becomes insufficient or dysfunctional, several cellular stresses accumulate. These stresses – especially proteotoxic stress, mitochondrial dysfunction, and genomic instability – directly activate senescence pathways. When autophagy is impaired, cytoplasmic protein aggregates accumulate, the proteasome becomes overloaded, and unfolded protein response becomes chronically activated [86, 87]. This proteotoxic stress activates p53, p21, and p16INK4a, promoting a stable cell-cycle arrest characteristic of senescence [88]. When degradative autophagy is defective, e.g., due to impaired lysosomal function, cells can redirect autophagosomes to the secretory pathway, thereby increasing the release of SASP factors [89]. As mentioned, impaired degradative autophagy leads to the accumulation of GATA binding protein 4 (GATA4), which increases inflammatory signaling and secretion via secretory autophagy [90]. Therefore, impaired autophagy contributes to senescence partly by rerouting autophagosomes from degradation to secretion, and this mechanism is considered central to integrate autophagy dysfunction, chronic inflammation, and the stability of the senescent state.

Many reports suggest that autophagy might play a key role in migraine pathophysiology (reviewed in [91]). However, these studies are generally limited to autophagy-related proteins, autophagy-like signaling, or regions important for migraine, and there is no direct evidence, such as autophagic flux or the expression of autophagic proteins, demonstrating autophagy’s involvement in migraine pathogenesis. Autophagy has been linked to migraine development in NTG and inflammatory animal models, but its exact mechanisms are largely unknown. Several studies indicate that the primary candidates in the migraine–autophagy link are brain-derived neurotrophic factor (BDNF), and the purinergic receptors P2X 4 (P2X4R), and P2X 7 (P2X7R) [92, 93]. Functionally, this connection may be mediated by various mechanisms, but neuroinflammation is the most consistently reported link [94–100]. Recent animal and computational studies indicate that autophagy regulation is crucial in modulating pain symptoms. This is primarily supported by autophagy’s anti-inflammatory effects. Mechanistically, ATP links BDNF, P2X4R, and P2X7R by activating these receptors and promoting BDNF release from microglia during migraine. Typically, BDNF is secreted from microglial cells through the exocytosis of BDNF-containing granules.

We speculated that secretory autophagy in migraine-affected microglia might also play a role in that process [101]. BDNF levels are found to be elevated during but not between migraine attacks; however, most research on BDNF levels related to migraine has analyzed serum or plasma samples [102–104]. We suggest that BDNF may be released from microglia at higher concentrations during migraine episodes, driven by factors such as increased ATP levels that suppress degradative autophagy and induce secretory autophagy. Since this BDNF needs to interact with neurons to be effective, it would not be detected in peripheral blood. Therefore, animal models, cellular studies, and in silico research indicate that migraine may involve elevated ATP levels that activate purinergic P2X receptors on microglia. This activation inhibits macroautophagy, promotes autolysosomal export, induces membrane pore formation, and increases BDNF release, possibly via secretory autophagy. BDNF then activates macroautophagy in neurons, aiding in the clearance of products generated by RONS during migraine attacks.

Human senescent cells express high levels of NTRK2, supporting their survival and apoptosis resistance, and release the NTRK2 ligand BDNF, which is part of their SASP [105] Therefore, BDNF may link senescence and autophagy in the human brain.

To distinguish migraine-induced abnormalities leading to senescence activation and senescence-mediated autophagic disorders that may potentially exacerbate migraine, we summarized the putative causal relationship between autophagy and senescence in migraine in Table 1.

Table 1.

Side-by-side comparison of logical chains leading from migraine to senescence and vice versa

Causal direction	Starting point	Mechanism	Endpoint
Migraine → Autophagy deficit → Senescence	Migraine attack (CGRP, ATP, CSD, inflammation)	Autophagy adaptors activation, P2X7R impairment of lysosomes, reduced mitophagy	Persistent cellular stress → senescence activation
Senescence → Autophagy dysfunction → Migraine worsening	Pre‑existing or migraine‑induced senescent glia/neurons	Senescence-associated lysosomal/autophagy dysfunction + SASP	Increased neuroinflammation, synaptic dysregulation → migraine exacerbation

In summary, autophagy is a vital process crucial for cellular homeostasis, and its impairment may lead to the accumulation of various cellular stresses, including proteotoxic stress, mitochondrial dysfunction, and genomic instability, which can directly activate senescence pathways. When degradative autophagy is defective, cells may switch to secretory autophagy, but these two pathways can also cooperate. Defects in autophagy may activate cellular senescence and stabilize SASP. Autophagy plays an important role in regulating pain responses, and its proteins have been shown to be associated with migraine phenotype in animal models. Impaired autophagy in microglia may activate secretory autophagy and the release of BDNF, which could induce autophagy in neurons to clear cellular debris produced by oxidative stress – an oxidative response in the brain triggered by migraine-related energy deficits (Fig. 5). However, BDNF may also be secreted by senescent glial cells as a part of their SASP and therefore senescence in glial cells may help neurons to clear cellular debris, being a persistent consequence of migraine.

Fig. 5.

The interaction between degradative and secretory autophagy (DA and SA) might potentially protect brain neurons from the long-term effects of migraine. Increased levels of reactive oxygen and nitrogen species (RONS) caused by oxidative stress in the migraine-affected brain damage neurons and glial cells (represented here by an astrocyte), resulting in the buildup of cellular debris that autophagy may remove. However, migraine could suppress degradative autophagy in microglia, which can be offset by SA, which releases brain-derived neurotrophic factor (BDNF) that activates DA in neurons. Additionally, BDNF might be secreted as part of the senescence-associated secretory phenotype (SASP) of aging glial cells. Created in https://BioRender.com

Discussion, conclusions and perspectives

Senescent cells, especially senescent nociceptors, can promote chronic pain through inflammatory signaling and changes in neuronal excitability. Animal studies, supported by human data, have shown that cellular senescence in dorsal root ganglion and trigeminal ganglion neurons contributes to neuropathic and facial pain. This has potential implications for migraine, as the same trigeminal neuronal populations become hyperexcitable in migraine. This establishes a potential mechanistic link among senescence-related inflammation, inflammaging, and the sensitization of nociceptive pathways implicated in migraine.

Evidence from both theory and preliminary experiments suggests that cellular senescence may affect migraine through mechanisms such as oxidative stress, CSD, mitochondrial dysfunction, DDR, sensory neuron dysfunction, autophagy, and neuroinflammation. If cellular senescence contributes to migraine, it could justify exploring treatments that target senescence. Promising approaches include using senolytics to eliminate senescent cells by disrupting their survival pathways, or employing ‘senomorphics’ to reduce harmful SASP factors [106]. Since the discovery of first-generation senolytics such as dasatinib and quercetin, many other therapies have been identified, and several promising targets are currently under investigation.

Cellular senescence is a stable and long-lasting cellular program, but this stability does not imply that senescence must directly trigger sudden, short-term physiological events such as migraine attacks. Instead, available epidemiological and neurobiological evidence indicates that processes related to senescence might mainly contribute to vulnerability, sensitization, and lowering of attack thresholds, which are characteristic of migraine chronicity. Meanwhile, the immediate initiation of attacks remains driven by traditional triggers such as CSD, CGRP surges, sensory overload, metabolic stress, and neuroimmune activation. This view is strongly supported by human data linking CM to accelerated brain aging, shown by long-term structural changes rather than episodic events. Likewise, studies on telomere length reveal that individuals with shorter telomeres – an established marker of biological aging – have a significantly higher risk of migraine in early and mid-adulthood. Elevated oxidative stress markers, common in migraine patients, especially those with higher attack frequency, further demonstrate that chronic redox imbalance, which drives and amplifies senescence, is more closely linked to migraine severity and progression than to immediate attack initiation.

Migraine may reflect early activation of aging-related pathways, including impaired autophagy, increased levels of RONS, oxidative DNA damage, and low-grade inflammation, even in the absence of systemic aging in migraine-susceptible individuals. All these pathways are linked to cellular senescence, but it remains unclear whether they are causally related.

Although indirect evidence links senescence to migraine, direct confirmation is lacking. Key next steps might include: (1) profiling senescence markers, e.g., p16/INK4a, SA-β-gal, SASP proteins, in human trigeminal ganglion, meninges, and migraine-relevant cortical regions; (2) comparing senescence signatures between migraine patients and healthy controls; (3) resolving how senescent nociceptors affect CGRP and PACAP release, neuroinflammation, CSD, and glial–neuronal interactions; (4) determining whether SASP factors amplify neuronal hyperexcitability that characterizes migraine; (5) clarifying how senescent nociceptors affect CGRP release, neuroinflammation, cortical spreading depression, and glial–neuronal interactions.

At present, there is no direct experimental evidence that DNA damage or autophagy defects induce cellular senescence in any established animal model of migraine or in human migraine tissue. All available data support indirect mechanistic plausibility, but no study to date has demonstrated senescence induction as a causal downstream consequence of DNA damage or autophagy impairment specifically within a migraine model.

Current clinical data do not demonstrate a validated correlation between canonical senescence markers, such as p16/INK4a, SA‑β‑gal, lamin‑B1 loss, SASP factors, and migraine subtype or chronicity. Reviews of oxidative stress and inflammation in migraine consistently show elevated redox imbalance, lipid peroxidation products, NO dysregulation, and mitochondrial defects in patients across episodic and chronic subtypes, but none of these studies include senescence‑specific biomarkers in their clinical sampling or analysis. Likewise, mechanistic reviews of CSD, CGRP‑driven inflammation, and neuroimmune activation in migraine emphasize microglial and neuronal stress responses, but do not report senescence‑associated markers in human samples or patient cohorts, nor do they provide subtype‑stratified (MWA vs. MWoA, episodic vs. chronic) senescence profiling. Meanwhile, senescence research in CNS diseases outside migraine shows clear associations between oxidative stress and senescence‑like states, e.g., mitochondrial dysfunction, RONS‑driven DNA damage, SASP secretion, and chromatin disruption in neurons and glia, but these findings have not yet been translated into migraine‑specific clinical investigations. This gap is explicitly highlighted in broad reviews of oxidative stress‑driven senescence and neuronal senescence, which outline the molecular plausibility but provide no migraine‑focused clinical evidence.

Given the almost complete absence of direct clinical data, future research should prioritize obtaining human biospecimens stratified by migraine subtype and chronicity, ideally during both ictal and interictal phases. The most feasible and informative clinical sampling strategies include: (1) peripheral blood mononuclear cells to assay p16/INK4a, p21, SASP cytokines, and markers of DNA damage, especially because oxidative stress markers are already routinely measured in serum/plasma in migraine studies; (2) saliva or tear fluid, which reliably reflects neurogenic inflammatory signatures and may permit SASP cytokine profiling; and (3) CSF samples in patients undergoing lumbar puncture for clinical indications, allowing detection of central senescence‑like secretory factors, mitochondrial DNA damage markers, and neuronal SASP‑related molecules. On the experimental side, NTG‑induced migraine models, CSD models, and transgenic migraine‑mutation mouse lines provide good platforms: oxidative stress and autophagy disruption are already well-characterized in these systems, but senescence markers have simply never been assayed. An immediately actionable design would involve inducing migraine‑like states (NTG or CSD) and then quantifying p16, p21, SA‑β‑gal activity, γH2AX, lamin‑B1 loss, and SASP cytokine expression in trigeminal ganglion, brainstem nuclei, cortex, and microglia. Parallel pharmacological manipulations, autophagy protein inhibitors, autophagy inducers, PARP inhibitors, or antioxidants, could then determine whether altering stress‑repair pathways modulates both migraine phenotypes and senescence signatures. Such integrated clinical‑experimental frameworks would finally test the long‑hypothesized but yet unproven connection between migraine‑related oxidative stress, DDR impairment, autophagic dysfunction, and cellular senescence.

We want to emphasize that the experimental evidence suggesting a potential link between senescence and migraine, except for the work of Lee et al. [30], relates only to the connection between effects associated with migraine and those related to senescence, not to a direct link between migraine and senescence. For example, reactive oxygen and nitrogen species, such as those produced by a migraine-affected brain, may trigger senescence. However, there remains no direct evidence of senescence induction in migraine-specific human tissues or established migraine models. On the other hand, it is unclear whether anyone has attempted to detect senescent cells in human tissues or animal models. We have not found such research, which is why we argue that such studies are both justified and necessary.

Table 2 summarizes proposed mechanisms, supporting evidence, and knowledge gaps regarding the potential link between cellular senescence and migraine that are most relevant from a clinical standpoint.

Table 2.

Summary of proposed mechanisms, supporting evidence, and knowledge gaps in the hypothetical link between cellular senescence and migraine

Hypothetical Mechanisms	Supporting evidence	Knowledge gaps
Senescence-like changes in trigeminal sensory neurons might increase nociceptor excitability.	Analysis of animal and human datasets reveals senescent features in nociceptors, including those in the trigeminal ganglion.	There are no direct studies in migraine patients examining senescence markers in the trigeminal ganglion or pain-processing pathway.
Senescence-associated secretory phenotype (SASP) might enhance neuroinflammation.	Senescence–neuroinflammation coupling may be a key mechanism in brain aging, with relevance to diseases where inflammatory processes contribute to symptoms (indirectly supporting a migraine connection).	Missing mechanistic data linking SASP neuroinflammatory components to specific migraine phases (prodrome, aura, headache).
Age-related buildup of senescent cells may raise susceptibility to chronic pain conditions, possibly interacting with migraine pathways.	The study reports senescence signatures in trigeminal cells, indicating their relevance to headache disorders associated with trigeminal pathways.	Lack of evidence on whether senolytics or anti‑senescence interventions provide migraine‑specific therapeutic benefits.
Dysregulated immune-neuronal crosstalk driven by senescent glia may contribute to migraines by disrupting inflammatory and pain signaling pathways.	Senescence–neuroinflammation coupling might be a key mechanism in brain aging, especially in conditions where inflammatory cascades worsen symptoms (indirectly supporting a migraine link). CGRP interacts with immune cells, emphasizing neuroimmune pathways that could overlap with senescence-driven inflammation.	Insufficient data on whether senescent glial cells directly influence CGRP-mediated neuronal activity in migraine.
Shared mechanisms between neuropathic/facial pain and migraine, such as senescence signatures in the dorsal root ganglion and the trigeminal ganglion.	Cross-dataset integration (“iPain atlas”) identifies consistent senescence markers in chronic pain models, suggesting relevance for trigeminal pain conditions.	Although senescence signatures have been identified in trigeminal cells, none of the current datasets are from confirmed migraine patients, which limits their direct translational relevance.
It is unclear whether senescence might cause, result from, or influence migraine.

In conclusion, cellular senescence may contribute to migraine development, primarily through this flowchart: oxidative stress/CSD → senescence in trigeminal neurons and endothelium → SASP → neuroinflammation and CGRP activation → trigeminovascular activation → migraine → further senescence. These elements may be underlined by impaired mitochondrial function, abnormal DDR, and compromised autophagy. Although our proposed framework is largely hypothesis-driven, determining how to apply this flowchart to migraine prevention, diagnosis, and treatment is challenging and warrants further research.

Abbreviations

APE1

Apurinic/apyrimidinic endodeoxyribonuclease 1

ATR

Ataxia telangiectasia and Rad3‑related

BBB

Blood-brain barrier

BDNF

Brain-derived neurotrophic factor

BER

Base excision repair

CACNA1A

Calcium voltage-gated channel subunit alpha1

CCL2

C-C motif chemokine ligand 2

CDKN1A/2A

Cyclin‑dependent kinase inhibitor 1 A/2A

cGAS-STING

Cyclic GMP–AMP synthase-stimulator of interferon

CHK1

Checkpoint kinase 1

CGRP

Calcitonin gene-related peptide

CNS

Central nervous system

CSD

Cortical spreading depolarization/depression

CXCL1

C-X-C motif chemokine ligand 1

DDR

DNA damage response

DRG

Dorsal root ganglion

DSB

Double-strand break

EPC

Endothelial progenitor cells

ER

Endoplasmic reticulum

ERCC2

Excision repair cross‑complementation group 2

FADH2

Reduced flavin adenine dinucleotide

GATA binding protein 4

GATA4hOGG1:8‑oxoguanine DNA glycosylase 1

MCP-1

Monocyte chemoattractant protein‑1

mtETC

Mitochondrial electron transport chain

mtDNA

Mitochondrial DNA

mtQC

Mitochondrial quality control

NADPH

Reduced nicotinamide adenine dinucleotide phosphate

nDNA

Nuclear DNA

NLRP3

NOD-like receptor family, pyrin domain-containing 3

OXPHOS

Oxidative phosphorylation

P2 × 4R/7R

Purinergic receptors P2 × 4/P2 × 7

PACAP

Pituitary adenylate cyclase–activating polypeptide

PARP1

Poly(ADP-ribose) polymerase I

PoMiCS

Post-mitotic cellular senescence

RONS

Reactive oxygen and nitrogen species

SA-β-gal

Senescence-associated β‑galactosidase

SASP

Senescence‑associated secretory phenotype

SIRT1

Sirtuin 1

SOD1/2

Superoxide dismutase 1/2

SSB

Single-strand break

SSBR

Single-strand break repair

TBARS

Thiobarbituric acid reactive substances

TCC

Trigeminocervical complex

tempol

4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl

TOP1

DNA topoisomerase I

TRPA1

Transient receptor potential cation channel subfamily A member 1

TRPM2

Transient receptor potential melastatin 2

TRPV1

Transient receptor potential cation channel subfamily V member 1

TTH

Tension-type headaches

XRCC3

X‑ray repair cross‑complementing 3

Author contributions

Conceptualization, J.B., M.F., and M.O.; writing—original draft preparation, J.B., J.K., E.P., J.D., and M.F.; writing—review and editing, J.B. All authors have read and agreed to the submitted version of the manuscript.

Funding

This research was supported by the Ministry of Science and Higher Education, Poland, internal grant PMMH-RI number 2023.2/5/5-GW.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.