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NEURAL REGENERATION RESEARCH｜Vol 21｜No. 7｜July 2026｜3055NEURAL REGENERATION RESEARCHwww.nrronline.orgResearch Art i cleTelomere length as a predict i ve marker for long-term cognit i ve funct i on in a mouse model of subarachnoid hemorrhageAbstract Subarachnoid hemorrhage is a subtype of stroke that causes severe neurological damage and is associated with poor long-term prognosis. Cognitive impairment is a major manifestation of long-term neurological dysfunction in patients with subarachnoid hemorrhage. However, there is notable absence of biological markers to predict long-term prognosis in this patient population. Given the aging-like neurocognitive phenomena associated with subarachnoid hemorrhage, this study postulates that telomere length, a recognized biomarker for aging, could be used as a prognostic indicator for subarachnoid hemorrhage. A left internal carotid artery intravascular puncture mouse model was used to simulate subarachnoid hemorrhage. Comprehensive neurological test scores were obtained through neurobehavioral assessments conducted at one-month intervals. Concurrently, the relative telomere length was analyzed by quantitative polymerase chain reaction, which was performed using DNA extracted from ear notch and brain tissue after each assessment. Furthermore, proteomic analysis was employed to investigate differential protein expression in hippocampal tissue. Subarachnoid hemorrhage mice exhibited persistent neurocognitive impairment over a prolonged period of time. There was a significant positive correlation between telomere length and neurological test scores, confirming the usefulness of telomere length as a prognostic indicator in subarachnoid hemorrhage. Hippocampal tissue from subarachnoid hemorrhage mice showed reduced expression of acetyl-coenzyme A synthetase-2 and abnormalities in the expression of proteins related to ribosomes, energy metabolism, and cellular signal transduction. This study confirmed telomere shortening in the brain and metabolic disturbances in the hippocampi of subarachnoid hemorrhage mice. Thus, telomere length is a predictive marker for long-term impairment of cognitive function in mice following experimental subarachnoid hemorrhage. Key Words: acetyl-coenzyme A synthetase-2; brain aging; DNA damage response; long-term prognosis; subarachnoid hemorrhage; telomere length ht t ps://doi.org/10.4103/NRR.NRR-D-24-01150Date of submission: September 26, 2024 Date of decision: February 6, 2025 Date of acceptance: March 19, 2025 Date of web publicat i on: June 19, 2025 Introduct i on Subarachnoid hemorrhage (SAH), a subtype of stroke, accounted for 9.7% of all pat i ents with stroke in 2019, making it the third most common stroke type. The poor prognosis of pat i ents with SAH represents a substant i al burden on the global economy (GBD 2019 Stroke Collaborators, 2021). The direct toxic ef f ect of heme on nerve cells in SAH induces iron death, oxidat i ve stress, inf l ammatory react i on, cerebral vasospasm (CVS), delayed cerebral ischemia (DCI), and other complicat i ons, which seriously impair nerve funct i on in patients and lead to poor long-term prognosis. Patients with SAH exhibit impaired funct i on, struggle with self-care, experience long-term immobility, and may even face coma or death (Claassen and Park, 2022). Recovery of neurological function after SAH is a dynamic process. Studies have demonstrated that, within a period of 6 months to 1 year following discharge, only 22.6% of patients with SAH exhibit neurological function improvement, as measured by the modif i ed Rankin scale (mRS) score, and pat i ents with an mRS score greater than 3 rarely improve (Hammer et al., 2020). These fi ndings suggest that, part i cularly for pat i ents with SAH with severe symptoms, the damage to their neurological funct i on is long-term and enduring, making it challenging to achieve improvement through rehabilitat i on. Pat i ents with a poor long-term prognosis exhibit not only impaired autonomous function, but also cognit i ve impairment. This impairment manifests in various ways, such as memory decline, anxiety, depression, and other neuropsychological changes (Danala et al., 2022). A follow-up study has demonstrated that an increasing proport i on of pat i ents exhibits cognit i ve impairment, as assessed by the Montreal Cognit i ve Assessment Scale (MoCA) criteria, from 3 months to 1 year af t er SAH (Danala et al., 2022). Whether the long-term cognit i ve impairment of pat i ents with SAH represents persistent neurological impairment af t er the acute stage of SAH and the mechanism underlying this phenomenon require further invest i gat i on.Telomeres are repetitive, non-coding DNA sequences located at the terminal regions of linear eukaryotic chromosomes (Revy et al., 2023; Ying et al., 2025). They serve as biomarkers that are closely associated with aging (Rossiello et al., 2022), and play four crucial funct i ons within cells. First, they safeguard vital genet i c informat i on from erosion during DNA replication. Second, they shield DNA strands from damage that could trigger apoptosis. Third, they bind and recruit proteins essent i al for DNA repair processes. Finally, they serve as a mitot i c clock, providing insight into the proliferat i on history of individual cells (Eitan et al., 2014). Maintaining optimal telomere length requires a delicate and intricate balance between telomere elongat i on mechanisms and telomere shortening processes (Revy et al., 2023). Telomeres can undergo shortening not only through cell division and replicat i on, but also in response to a variety of other 1 Department of Neurosurgery, The Fourth Af f i liated Hospital of School of Medicine, and Internat i onal School of Medicine, Internat i onal Inst i tutes of Medicine, Zhejiang University, Yiwu, Zhejiang Province, China; 2 Department of Neurosurgery, The Second Af f i liated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; 3 Department of Neurosurgery, First Af f i liated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China*Correspondence to: Jianmin Zhang, MD, zjm135@zju.edu.cn; Jun Mo, MD, mojun@zju.edu.cn.ht t ps://orcid.org/0000-0002-3184-1502 (Jianmin Zhang); ht t ps://orcid.org/0000-0002-0389-7453 (Jun Mo)#Both authors contributed equally to this work and share fi rst authorship.Funding: This study was supported by the Nat i onal Natural Science Foundat i on of China, No. 81901336 (to JM).How to cite this article: Zhang Q, Xu C, Fan J, Lou C, Chen J, Zhang J, Mo J (2026) Telomere length as a predict i ve marker for long-term cognit i ve funct i on in a mouse model of subarachnoid hemorrhage. Neural Regen Res 21(7):3055-3062. Graphical AbstractMechanistic insights into SAH-induced telomere shorteningFrom the ContentsIntroductionMethods ResultsDiscussionConclusionQia Zhang 1, 2, # , Chaoran Xu 1, 3, # , Jiayong Fan 1 , Chengjian Lou 1 , Jiarui Chen 2 , Jianmin Zhang 1, 2, * , Jun Mo 1, *