Potential roles of telomeres and telomerase in neurodegenerative diseases

Wang, Jiequan; Liu, Yaru; Xia, Qingrong; Qin, Xia; Wang, Baoshi; Yang, Chengli; Liang, Jun; Liu, Xinhua

doi:10.1016/j.ijbiomac.2020.07.046

Cited by 28 publications

(12 citation statements)

References 221 publications

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“…Chronic heavy alcohol consumption reduces life expectancy, leads to premature aging worldwide [ 1 – 3 ], and is associated with age-related diseases such as cardiometabolic diseases, cancer and decline in brain function [ 4 – 10 ]. It has been reported that individuals with heavier alcohol use among those with alcohol use disorder (AUD) have more pronounced age-related disease and accelerated biological aging compared to healthy individuals [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Alcohol use disorder is associated with DNA methylation-based shortening of telomere length and regulated by TESPA1: implications for aging

et al. 2022

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Chronic heavy alcohol consumption is associated with increased mortality and morbidity and often leads to premature aging; however, the mechanisms of alcohol-associated cellular aging are not well understood. In this study, we used DNA methylation derived telomere length (DNAmTL) as a novel approach to investigate the role of alcohol use on the aging process. DNAmTL was estimated by 140 cytosine phosphate guanines (CpG) sites in 372 individuals with alcohol use disorder (AUD) and 243 healthy controls (HC) and assessed using various endophenotypes and clinical biomarkers. Validation in an independent sample of DNAmTL on alcohol consumption was performed (N = 4219). Exploratory genome-wide association studies (GWAS) on DNAmTL were also performed to identify genetic variants contributing to DNAmTL shortening. Top GWAS findings were analyzed using in-silico expression quantitative trait loci analyses and related to structural MRI hippocampus volumes of individuals with AUD. DNAmTL was 0.11-kilobases shorter per year in AUD compared to HC after adjustment for age, sex, race, and blood cell composition (p = 4.0 × 10−12). This association was partially attenuated but remained significant after additionally adjusting for BMI, and smoking status (0.06 kilobases shorter per year, p = 0.002). DNAmTL shortening was strongly associated with chronic heavy alcohol use (ps < 0.001), elevated gamma-glutamyl transferase (GGT), and aspartate aminotransferase (AST) (ps < 0.004). Comparison of DNAmTL with PCR-based methods of assessing TL revealed positive correlations (R = 0.3, p = 2.2 × 10−5), highlighting the accuracy of DNAmTL as a biomarker. The GWAS meta-analysis identified a single nucleotide polymorphism (SNP), rs4374022 and 18 imputed ones in Thymocyte Expressed, Positive Selection Associated 1(TESPA1), at the genome-wide level (p = 3.75 × 10−8). The allele C of rs4374022 was associated with DNAmTL shortening, lower hippocampus volume (p < 0.01), and decreased mRNA expression in hippocampus tissue (p = 0.04). Our study demonstrates DNAmTL-related aging acceleration in AUD and suggests a functional role for TESPA1 in regulating DNAmTL length, possibly via the immune system with subsequent biological effects on brain regions negatively affected by alcohol and implicated in aging.

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Section: Introductionmentioning

confidence: 99%

Alcohol use disorder is associated with DNA methylation-based shortening of telomere length and regulated by TESPA1: implications for aging

et al. 2022

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“…Telomere shortening is a hallmark of cell senescence [ 32 ]. However, accelerated telomere shortening and cell senescence in brain cells has been associated with several neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases [ 33 , 34 , 35 ]. Investigating the effect of MeHg on the telomere length of brain cells may provide a basis for the prevention of neurological diseases.…”

Section: Discussionmentioning

confidence: 99%

Subchronic Low-Dose Methylmercury Exposure Accelerated Cerebral Telomere Shortening in Relevant with Declined Urinary aMT6s Level in Rats

Tao

et al. 2023

Toxics

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Methylmercury (MeHg) is a global pollutant with established toxic effects on the central nervous system (CNS). However, early events and early-warning biomarkers of CNS damage following exposure to low-dose MeHg are still lacking. This study aimed to investigate whether subchronic low-dose MeHg exposure had adverse effects on the cerebral telomere length, as well as serum melatonin and its urinary metabolite 6-sulfatoxymelatonin (aMT6s) in rats. Sixteen male Sprague Dawley rats were divided into two groups. Group I was the control group. In group II, rats were exposed to MeHg by gavage at a dose of 0.1 mg/kg/day for 3 months. This study revealed that MeHg exposure resulted in impairment of learning and memory ability, a slightly reduced number of neurons and an irregular arrangement of neurons in the hippocampus. It also significantly accelerated telomere shortening in the cerebral cortex, hippocampus and hypothalamus. Moreover, MeHg exposure decreased the levels of melatonin in serum and aMT6s in urine, partly by suppressing the synthesis of 5-hydroxytryptamine (5-HT) in the brain but promoted the expression of melatonin-catalyzing AANAT and ASMT. Importantly, cerebral telomere length was positively correlated with MT and aMT6s after MeHg exposure. These results suggested that the shortened telomere length in the brain may be an early event in MeHg-induced CNS toxicity, and the level of aMT6s in urine may serve as an early-warning biomarker for MeHg-induced CNS damage.

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“…Furthermore, telomere length shortening can also happen in various neurodegenerative disorders. 8 These findings suggest that people with shorter telomere lengths are more vulnerable to neurodegenerative disorders, whereas people with longer telomere lengths might be more resistant to such disorders. Results of many studies support this hypothesis.…”

Section: Intrtoductionmentioning

confidence: 95%

Is Telomere Length Shortening a Risk Factor for Neurodegenerative Disorders?

Koh

2022

Dement Neurocogn Disord

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Telomeres are located at the end of chromosomes. They are known to protect chromosomes and prevent cellular senescence. Telomere length shortening has been considered an important marker of aging. Many studies have reported this concept in connection with neurodegenerative disorders. Considering the role of telomeres, it seems that longer telomeres are beneficial while shorter telomeres are detrimental in preventing neurodegenerative disorders. However, several studies have shown that people with longer telomeres might also be vulnerable to neurodegenerative disorders. Before these conflicting results can be explained through large-scale longitudinal clinical studies on the role of telomere length in neurodegenerative disorders, it would be beneficial to simultaneously review these opposing results. Understanding these conflicting results might help us plan future studies to reveal the role of telomere length in neurodegenerative disorders. In this review, these contradictory findings are thoroughly discussed, with the aim to better understand the role of telomere length in neurodegenerative disorders.

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Potential roles of telomeres and telomerase in neurodegenerative diseases

Cited by 28 publications

References 221 publications

Alcohol use disorder is associated with DNA methylation-based shortening of telomere length and regulated by TESPA1: implications for aging

Alcohol use disorder is associated with DNA methylation-based shortening of telomere length and regulated by TESPA1: implications for aging

Subchronic Low-Dose Methylmercury Exposure Accelerated Cerebral Telomere Shortening in Relevant with Declined Urinary aMT6s Level in Rats

Is Telomere Length Shortening a Risk Factor for Neurodegenerative Disorders?

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