Chronic insomnia disorder is defined by the International Classification of Sleep Disorders diagnostic manual, 3rd edition (ICSD-3), as a complaint of trouble falling asleep, staying asleep, or waking up excessively early with related daytime consequences, even with adequate opportunities and conditions for sleep [1].

Chronic insomnia disorder describes a persistent state of insomnia that lasts longer than 3 months and is defined by symptoms that appear more than 3 nights per week [2]. The clinical features of insomnia include trouble falling asleep, poor sleep maintenance, early awakenings, worse sleep quality, and shorter overall sleep duration along with associated fatigue, mood disorders, and decline in cognitive function. Approximately 30–35% of people globally report having signs of insomnia [3], and comparable prevalence figures are seen in epidemiological research conducted in other nations.

Information about the physiology of insomnia has been attained through several approaches, including investigating genetic, molecular, and cellular processes; brain circuitry; physiologic causes; sleep behaviors; and self-reporting. These findings have resulted in multiple models of insomnia. Sleep-wake characteristics, including the length and timing of sleep, are inherited and controlled by several genes. Research on humans and animals has also linked genetic processes to insomnia [4]. Aging has attracted the attention of both researchers and the general public. A cross-sectional study of the Canadian Longitudinal Study on Aging has shown that insomnia disorder may increase the risk of further cognitive decline [5]. Anxiety and sadness are directly linked to insomnia, and those who struggle with insomnia experience various mental health issues, such as concentration, attention, or memory deficits, which are often reported as the first symptom to a doctor [6]. Multiple investigations have linked sleeplessness to cognitive decline and the potential to accelerate aging [7, 8, 9]. The variability in biological aging across individuals influences the vulnerability to sleeplessness.

Findings from the Women’s Health Initiative Study showed that greater levels of late-differentiated CD8+ T cells as well as a higher epigenetic age of blood tissue were linked to insomnia symptoms [10]. Signs of insomnia are linked to accelerated aging, and inadequate sleep has been linked to a decrease in the number of naïve T cells [10].

The telomere, a unique DNA-protein composite structure at the end of each chromosome that contains the repeated nucleotide sequence “TTAGGG”, is essential for maintaining the integrity and stability of the chromosomal end [11]. Telomere length represents one of the most recognized markers of cell senescence because telomeres shorten with age, resulting in chromosome instability and cell senescence or apoptosis [12]. The attrition rate of telomeres has been an attractive study topic because it more accurately reflects a person’s physiological and functional state than their chronological age. Moreover, new research has unequivocally shown that telomere shortening is associated with age-related disorders, such as cardiovascular diseases [13], cancer [14], and Alzheimer’s disease [15]. In a study of 925 individual questionnaires [16], individuals were categorized as short (less than 6 hours), average (6 to 8 hours), and long (more than 8 hours) sleepers based on their reported the length of sleep. This study suggested that only insomnia disorder, insomnia disorder total sleep time 360 minutes, and long sleepers were associated with short telomeres. Nevertheless, alterations in the telomere attrition rate in patients with chronic insomnia problems have received minimal attention to date.

YKL-40 is a lectin that binds to chitin and is a member of the glycosyl hydrolase family 18. It is also known as chitinase 3-like protein 1 or human cartilage glycoprotein 39 [17]. The 1997 discovery of the human gene encoding YKL-40 led to its location on chromosome 1q31-q32 [18]. The protein lacks enzymatic function and it’s specific biological role is unknown. Many different types of cells, such as macrophages, neutrophils, synoviocytes, chondrocytes, fibroblast-like cells, smooth muscle cells, and tumor cells, produce and release YKL-40. It is crucial for tissue damage, inflammation, tissue regeneration, and remodeling reactions [19]. Sleep loss elevates inflammation and microglial activation [20]. In bipolar disorder, mean YLK-40 levels are much greater compared with those of controls [21]. Recent researchhas suggested that elevated brain, cerebrospinal fluid, and serum levels of YKL-40 are linked to cognitive impairment and dementias [22, 23]. YKL-40 is associated with cell age, which means that it may be involved in the process of aging [24]. At present, research on telomeres, YKL-40, insomnia, and aging is attracting much attention, and the relationships between YKL-40, sleep, and cognition are worth exploring.

We therefore aimed to further assess the correlation between YKL-40 level and telomere length, and difficulty initiating sleep (DIS), early morning awakening (EMA), difficulty maintaining sleep (DMS), and mixed symptoms (MS) in a case-control research design. We also explored the effects of sleep upon the correlation between YKL-40 and telomere length in patients, cognitive impairment in patients with different subtypes of insomnia, and YKL-40 level and telomere length as potential biomarkers of insomnia disorder.

Our findings in this case-control study demonstrated a significant correlation, irrespective of other risk factors including anxiety and depression, between shorter leukocyte telomere length (LTL) and the risk for trouble falling asleep and mixed symptoms. Moreover, cognitive impairment appeared to be associated with difficulty initiating sleep and mixed symptoms. There was no discernible variation within telomere length across early morning awakening/difficulty maintaining and controls. Together, these results suggest that telomere shortening plays diverse and important functions in age-related illnesses.

It has long been believed that telomere length serves as a reliable predictor of age. Shorter telomere length has been associated with insomnia in those 70–88 years old, but not in younger adults. This finding raises the possibility that clinically severe sleep disruptions accelerate cellular aging, particularly in later life [35]. A study of 925 individuals with self-reported sleep duration suggested that total sleep time 360 minutes and long sleepers were associated with short telomeres [16]. According to a study of 5268 participants, telomere length was strongly and inversely correlated with morning sleepiness [36]; these outcomes diverge from the results of the present study. Study of mice and humans has shown that insomnia is associated with more telomere shortening and telomere-specific DNA damage [37]. A systematic review demonstrated that less shortening of telomeres has been linked to optimal sleep habits [38]. Shorter sleep duration and lower SE have been linked to shorter LTL [39, 40, 41, 42].

Because telomeres contain a lot of guanine, they are vulnerable to oxidative damage. This may be demonstrated by the production of 8-hydroxy-2-deoxyguanosine (8-oxodG), a crucial indicator of oxidative stress that accelerates telomere shortening [43]. Oxidative stress could lead to DNA damage, as shown by the presence of 8-oxodG and a decrease of telomeric-repeat binding factor 1 (TRF1) and telomeric-repeat binding factor 2 (TRF2), which play a role in proper telomere replication as well as T-loop formation, resulting in excessively shortened telomere lengths [44]. For a possible link between insomnia and telomere length, one study showed that insomnia might lead to increased levels of oxidation, which might shorten telomere length [45]. In addition, the hypothalamic-pituitary-adrenal axis is disrupted by chronic sleep deprivation and abnormal cortisol secretion, which decreases telomerase activity, shortening the telomere [46, 47].

YKL-40 is a novel indicator of inflammation and produced by macrophages, neutrophils, synoviocytes, chondrocytes, fibroblast-like cells, smooth muscle cells, and tumor cells [19]. It was demonstrated that both cultured macrophages and astrocytes under neuroinflammatory conditions expressed this protein abundantly. Previous studies of neurodegenerative dementias diseases, such as Creutzfeldt-Jakob disease, Alzheimer’s disease, dementia with Lewy bodies, vascular dementia, and Parkinson’s disease, showed that YKL-40 constitutes a disease-specific indicator of neuroinflammation [20, 23, 48, 49, 50]. However, there has been very little research on sleep and YKL-40. So far, there have been no studies on the different clinical symptoms of insomnia and YKL-40. Our findings in the present study indicated a favorable correlation across higher YKL-40 levels and early morning awakening and mixed symptoms. Considering that sleep deficiency may cause the activation of microglia and astrocytes, and the stimulation and release of many pro-inflammatory factors such as interleukin and tumor necrosis factor [51, 52]. A possible explanation is that insomnia triggers neuroinflammation accompanied by elevated YKL-40 levels.

In the present study, the well-known association between age and telomere length (r = –0.814, p-values 0.001), and YKL-40 concentration (r = 0.816, p-values 0.001) was replicated, indicating that telomere length and YKL-40 levels are a sign of aging. Research has indicated that sleep disturbances could increase cellular aging [53]. Based on the conclusion of the current study, it is reasonable to consider that sleep disturbances accelerate aging, and YKL-40 may play a mediating role (perhaps related to nervous system inflammation); however, the specific mechanism needs further elucidation.

Studies have shown that low SE, sleep disruption, and insufficient sleep may cause poor cognitive function [54, 55, 56, 57], and a meta-analysis showed that longer LTL is connected to higher brain volume and higher global cognition by [58].

Consistently, in the present study, we found that cognitive impairment was statistically significantly related to difficulty initiating sleep and mixed symptoms.

Treatment for insomnia may slow down the aging process as it can lead to cognitive impairment and dementia, both of which can accelerate biological aging [7, 8, 9, 59]. Moreover, telomere length and YKL-40 concentration have been shown to be biomarkers of aging [12, 24]. We therefore studied the relationship between cognitive impairment, insomnia disorder, and biomarkers of aging, i.e., telomere length and YKL-40 level. Larger samples are needed in the future to investigate the underlying mechanisms. Since telomere length is continuously shortened as cells divide, shortened telomere length may reflected active cell proliferation, which may be induced by oxidative stress and chronic inflammation. There is evidence that amyloid plaques in the brain are accompanied by neuroinflammatory states characterized by the activation of astrocytes and microglia and release of pro-inflammatory mediators. Patients with cognitive dysfunction show activation of peripheral immune states associated with this inflammation of the brain; thus, shortened telomere length may also be an indicator of cognitive dysfunction [60]. Insomnia may disrupt the inflammatory cascade and increase oxidative stress, thereby increasing the levels of inflammatory cytokines and oxides [44], which could cause DNA damage, ultimately leading to telomere shortening [61].

In this case-control study, telomere length decreased with age and YKL-40 level increased with age. Telomere length within patients suffering difficulty initiating sleep and mixed symptoms was significantly shortened. The level of YKL-40 within sufferers with early morning awakening and mixed symptoms was significantly increased. Cognitive impairment was associated with difficulty initiating sleep and mixed symptoms.

All data generated or analyzed during this study are included in this published article.

MZ contributed to the study conception and design, drafting of the manuscript. JL contributed to analysis of data and critical revision of the manuscript. PPL, YW and CYR contributed to experimental design, data statistics and manuscript revision. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This program has been approved by The First Affiliated Hospital of Anhui University of Science and Technology (First People’s Hospital of Huainan) Ethics Committee (approval number: 2021-KY-214-001). Written informed consent was obtained from all patients or their families/legal guardians for the publication of any potentially identifiable images or data included in this article. We confirm that we have read the journal’s position on ethical publishing issues and confirm that this report is consistent with these guidelines. None of the patient’s information was leaked and the patient gave full informed consent.

We are grateful to the technicians and staff of the Genetics Laboratory in Huainan City for the data collected and management.

Anhui University of Science and Technology university-level project (QN2019124) and Anhui University of Science and Technology medical special cultivation project (YZ2023H1A002).

The authors declare no conflict of interest.