Telomere-to-telomere genome assembly of Oldenlandia diffusa.

We report the complete telomere-to-telomere genome assembly of Oldenlandia diffusa which renowned in traditional Chinese medicine, comprising 16 chromosomes and spanning 499.7 Mb. The assembly showcases 28 telomeres and minimal gaps, with a total of only five. Repeat sequences constitute 46.41% of the genome, and 49,701 potential protein-coding genes have been predicted. Compared with O. corymbosa, O. diffusa exhibits chromosome duplication and fusion events, diverging 20.34 million years ago. Additionally, a total of 11 clusters of terpene synthase have been identified. The comprehensive genome sequence, gene catalog, and terpene synthase clusters of O. diffusa detailed in this study will significantly contribute to advancing research in this species' genetic, genomic, and pharmacological aspects.

Telomere length as biomarker of nutritional therapy for prevention of type 2 diabetes mellitus development in patients with coronary heart disease: CORDIOPREV randomised controlled trial.

BACKGROUND: Telomere Length (TL), a marker of cellular aging, holds promise as a biomarker to elucidate the molecular mechanism of diabetes. This study aimed to investigate whether shorter telomeres are associated with a higher risk of type 2 diabetes mellitus (T2DM) incidence in patients with coronary heart disease; and to determine whether the most suitable dietary patterns, particularly a Mediterranean diet or a low-fat diet, can mitigate the development of diabetes in these patients after a follow-up period of five years. METHODS: The CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (CORDIOPREV study) was a single-centre, randomised clinical trial done at the Reina Sofia University Hospital in Córdoba, Spain. Patients with established coronary heart disease (aged 20-75 years) were randomly assigned in a 1:1 ratio by the Andalusian School of Public Health to receive two healthy diets. Clinical investigators were masked to treatment assignment; participants were not. Quantitative-PCR was used to assess TL measurements. FINDINGS: 1002 patients (59.5 ± 8.7 years and 82.5% men) were enrolled into Mediterranean diet (n = 502) or a low-fat diet (n = 500) groups. In this analysis, we included all 462 patients who did not have T2DM at baseline. Among them, 107 patients developed T2DM after a median of 60 months. Cox regression analyses showed that patients at risk of short telomeres (TL < percentile 20th) are more likely to experience T2DM than those at no risk of short telomeres (HR 1.65, p-value 0.023). In terms of diet, patients at high risk of short telomeres had a higher risk of T2DM incidence after consuming a low-fat diet compared to patients at no risk of short telomeres (HR 2.43, 95CI% 1.26 to 4.69, p-value 0.008), while no differences were observed in the Mediterranean diet group. CONCLUSION: Patients with shorter TL presented a higher risk of developing T2DM. This association could be mitigated with a specific dietary pattern, in our case a Mediterranean diet, to prevent T2DM in patients with coronary heart disease. TRIAL REGISTRATION: Clinicaltrials.gov number NCT00924937.

Shortened telomere length in peripheral blood leukocytes is associated with cumulative radioactive iodine doses in patients with differentiated thyroid carcinoma.

BACKGROUND: Telomere length is associated with cancer risk and cancer aggressiveness. Radioactive iodine (RAI) therapy for thyroid cancer has raised concerns for second primary malignancy (SPM) in patients with high cumulative doses. The association between RAI dose and peripheral blood leukocyte telomere length was examined. METHODS: A total of 425 patients were included who underwent total thyroidectomy and were followed up for at least 1 year with or without RAI treatment. The relative telomere length (RTL) of the patients was assessed via a quantitative polymerase chain reaction amplification method. RAI doses were divided into five groups on the basis of cumulative dose, and a comparison was made among these groups. RESULTS: The number of patients with RAI treatment was 287 (67.5%), and the cumulative RAI dose was 3.33 GBq (range, 1.11-131.35 GBq). The mean RTL was significantly shorter in the highest RAI group (>22.2 GBq) compared to both the no-RAI and lower dose groups. The association between RAI dose and RTL was positive in the lower RAI group (1.1-3.7 GBq) and negative in the highest RAI group in both univariate and multivariate analyses. We observed 59 (13.9%) SPMs and 20 (4.7%) mortalities, and RTL did not show a significant risk effect for all-cause, thyroid cancer-specific, or SPM-specific mortality. CONCLUSIONS: In patients with thyroid cancer who underwent total thyroidectomy, peripheral blood leukocyte telomere length exhibited a significant association with cumulative RAI dose higher than 22.2 GBq. These results suggest the possibility of telomere length shortening in patients who undergo high-dose RAI treatment.

The function of Bazhen decoction in rescuing progeroid cell senescence via facilitating G-quadruplex resolving and telomere elongation.

ETHNOPHARMACOLOGICAL RELEVANCE: The Bazhen decoction is one of the most extensively used Traditional Chinese medicine (TCM) prescriptions for treatment of aging related diseases. However, due to the complexity of the components, the pharmacological mechanism of Bazhen decoction is still limited. AIM OF THE STUDY: In this study, with the aim of helping the clinical precision medicine of TCM, we try out a systematic analysis for dissecting the molecular mechanism of complicated TCM prescription: Bazhen decoction. We identify the pharmacological mechanism of Bazhen decoction in telomere elongation as revealed by systematic analysis. MATERIALS AND METHODS: By RNA sequencing and transcriptome analysis of Bazhen decoction treated wild type cells, we reveal the transcriptome profile induced by Bazhen decoction. We utilized the cells derived from Werner syndrome (WS) mice, which is known to be dysfunctional in telomere elongation due to the deficiency of DNA helicase Wrn. By Western blot, qPCR, Immunofluorescence, flow cytometry, telomere FISH, and SA-ß-Gal staining, we verify the transcriptome data and confirm the pharmacological function of Bazhen decoction and its drug containing serum in telomere elongation and reversing progeroid cell senescence. RESULTS: We reveal that Bazhen decoction may systematically regulate multiple anti-aging pathways, including stem cell regulation, protein homeostasis, cardiovascular function, neuronal function, anti-inflammation, anti-DNA damage induced stress, DNA helicase activity and telomere lengthening. We find that Bazhen decoction and its drug containing serum could up-regulate multiple DNA helicases and telomere regulating proteins. The increased DNA helicases promote the resolving of G-quadruplex (G4) structures, and facilitate DNA replication and telomere elongation. These improvements also endow the cellular resistance to DNA damages induced by replication stress, and rescue the WS caused cellular senescence. CONCLUSIONS: Together these data suggest that Bazhen decoction up-regulate the expression of DNA helicases, thus facilitate G4 resolving and telomere maintenance, which rescue the progeroid cellular senescence and contribute to its anti-aging properties. Our data reveal a new molecular mechanism of Bazhen decoction in anti-aging related diseases via elongating telomere, this may shed light in the application of Bazhen decoction in multiple degenerative diseases caused by telomere erosion.

Folic acid alleviated oxidative stress-induced telomere attrition and inhibited apoptosis of neurocytes in old rats.

PURPOSE: Oxidative stress has been reported to cause telomere attrition, which triggers cell apoptosis. Apoptosis of neurocytes may play an essential role in the pathogenesis of neurodegenerative diseases. This study hypothesized that folic acid (FA) supplementation decreased neurocyte apoptosis by alleviating oxidative stress-induced telomere attrition in 25-month-old Sprague Dawley (SD) rats. METHODS: Three-month-old male SD rats were randomly divided into four diet groups by different concentrations of folic acid in equal numbers, with intervention for 22 months. Folate, homocysteine (Hcy), reactive oxygen species (ROS) levels, antioxidant activities, and telomere length in the brain tissues were tested at 11, 18, and 22 months of intervention, and 8-hydroxy-deoxyguanosine (8-OHdG) levels, neurocyte apoptosis and telomere length in the cerebral cortex and hippocampal regions were tested during the 22-month intervention. An automated chemiluminescence system, auto-chemistry analyzer, Q-FISH, qPCR, and TUNEL assay were used in this study. RESULTS: The rats had lower folate concentrations and higher Hcy, ROS, and 8-OHdG concentrations in brain tissue with aging. However, FA supplementation increased folate concentrations and antioxidant activities while decreasing Hcy, ROS, and 8-OHdG levels in rat brain tissue after 11, 18, and 22 months of intervention. Furthermore, FA supplementation alleviated telomere length shortening and inhibited neurocyte apoptosis during the 22-month intervention. CONCLUSION: FA supplementation alleviated oxidative stress-induced telomere attrition and inhibited apoptosis of neurocytes in 25-month-old rats.

A novel nutraceutical formulation increases telomere length and activates telomerase activity in middle­aged rats.

Telomeres are major contributors to cell fate and aging through their involvement in cell cycle arrest and senescence. The accelerated attrition of telomeres is associated with aging­related diseases, and agents able to maintain telomere length (TL) through telomerase activation may serve as potential treatment strategies. The aim of the present study was to assess the potency of a novel telomerase activator on TL and telomerase activity in vivo. The administration of a nutraceutical formulation containing Centella asiatica extract, vitamin C, zinc and vitamin D3 in 18­month­old rats for a period of 3 months reduced the telomere shortening rate at the lower supplement dose and increased mean the TL at the higher dose, compared to pre­treatment levels. TL was determined using the Q­FISH method in peripheral blood mononuclear cells collected from the tail vein of the rats and cultured with RPMI­1640 medium. In both cases, TLs were significantly longer compared to the untreated controls (P≤0.001). In addition, telomerase activity was increased in the peripheral blood mononuclear cells of both treatment groups. On the whole, the present study demonstrates that the nutraceutical formulation can maintain or even increase TL and telomerase activity in middle­aged rats, indicating a potential role of this formula in the prevention and treatment of aging­related diseases.

Folic Acid Supplementation during Pregnancy and Its Association with Telomere Length in Children at Four Years: Results from the INMA Birth Cohort Study.

This study examined the association between folic acid supplements (FAs) during different periods of pregnancy and offspring telomere length (TL) at age four in 666 children from the INMA study. FAs were self-reported using food-structured questionnaires during three periods of pregnancy (the first three months of pregnancy, from month fourth onward, and the whole pregnancy). For each period, the average daily dosage of FAs was categorised into (i) <400 µg/d, (ii) ≥400 to 999 µg/d, (iii) ≥1000 to 4999 µg/d, and (iv) ≥5000 µg/d. Leucocyte TL at age four was measured using quantitative PCR methods. Multiple robust linear log-level regression models were used to report the % difference among FA categories. During the first period, and compared with children whose mothers were classified in the reference group (<400 µg/d), children whose mothers took higher dosages of FAs showed shorter TL at age four (≥5000 µg/d). When the first and the second periods were mutually adjusted, children whose mothers self-reported ≥5000 µg/d during the first period of pregnancy had a statistically significant shorter TL than their counterparts (% difference: -7.28% [95% CI: -14.42 to -0.13]). Similar trends were observed for the whole period of pregnancy. When the analysis was stratified by sex, the association was more evident in boys (% difference: -13.5% [95% CI: -23.0 to -4.04]), whereas no association was observed in girls. This study suggests that high dosages of FAs in the first pregnancy period may be associated with a shorter TL in children at age four, particularly among boys. Further studies should confirm these results.

Effects of Vitamin D Supplementation on Telomere Length: An Analysis of Data from the Randomised Controlled D-Health Trial.

OBJECTIVES: Observational studies have suggested that a higher 25-hydroxyvitamin D concentration may be associated with longer telomere length; however, this has not been investigated in randomised controlled trials. We conducted an ancillary study within a randomised, double-blind, placebo-controlled trial of monthly vitamin D (the D-Health Trial) for the prevention of all-cause mortality, conducted from 2014 to 2020, to assess the effect of vitamin D supplementation on telomere length (measured as the telomere to single copy gene (T/S) ratio). DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: Participants were Australians aged 60-84 years and we randomly selected 1,519 D-Health participants (vitamin D: n=744; placebo: n=775) for this analysis. We used quantitative polymerase chain reaction to measure the relative telomere length (T/S ratio) at 4 or 5 years after randomisation. We compared the mean T/S ratio between the vitamin D and placebo groups to assess the effect of vitamin D supplementation on relative telomere length, using a linear regression model with adjustment for age, sex, and state which were used to stratify the randomisation. RESULTS: The mean T/S ratio was 0.70 for both groups (standard deviation 0.18 and 0.16 for the vitamin D and placebo groups respectively). The adjusted mean difference (vitamin D minus placebo) was -0.001 (95% CI -0.02 to 0.02). There was no effect modification by age, sex, body mass index, or predicted baseline 25-hydroxyvitamin D concentration. CONCLUSION: In conclusion, routinely supplementing older adults, who are largely vitamin D replete, with monthly doses of vitamin D is unlikely to influence telomere length.

Blood and liver telomere length, mitochondrial DNA copy number, and hepatic gene expression of mitochondrial dynamics in mid-lactation cows supplemented with l-carnitine under systemic inflammation.

The current study was conducted to examine the effect of l-carnitine (LC) supplementation on telomere length and mitochondrial DNA copy number (mtDNAcn) per cell in mid-lactation cows challenged by lipopolysaccharide (LPS) in blood and liver. The mRNA abundance of 31 genes related to inflammation, oxidative stress, and the corresponding stress response mechanisms, the mitochondrial quality control and the protein import system, as well as the phosphatidylinositol 3-kinase/protein kinase B pathway, were assessed using microfluidics integrated fluidic circuit chips (96.96 dynamic arrays). In addition to comparing the responses in cows with or without LC, our objectives were to characterize the oxidative and inflammatory status by assessing the circulating concentration of lactoferrin (Lf), haptoglobin (Hp), fibrinogen, derivates of reactive oxygen metabolites (dROM), and arylesterase activity (AEA), and to extend the measurement of Lf and Hp to milk. Pluriparous Holstein cows were assigned to either a control group (CON, n = 26) or an LC-supplemented group (CAR; 25 g LC/cow per day; d 42 ante partum to d 126 postpartum (PP), n = 27). On d 111 PP, each cow was injected intravenously with LPS (Escherichia coli O111:B4, 0.5 µg/kg). The mRNA abundance was examined in liver biopsies of d -11 and +1 relative to LPS administration. Plasma and milk samples were frequently collected before and after the challenge. After LPS administration, circulating plasma fibrinogen and serum dROM concentrations increased, whereas AEA decreased. Moreover, serum P4 initially increased by 3 h after LPS administration and declined thereafter irrespective of grouping. The Lf concentrations increased in both groups after LPS administration, with the CAR group showing greater concentrations in serum and milk than the CON group. After LPS administration, telomere length in blood increased, whereas mtDNAcn per cell decreased; however, both remained unaffected in liver. For mitochondrial protein import genes, the hepatic mRNA abundance of the translocase of the mitochondrial inner membrane (TIM)-17B was increased in CAR cows. Moreover, TIM23 increased in both groups after LPS administration. Regarding the mRNA abundance of genes related to stress response mechanisms, 7 out of 14 genes showed group × time interactions, indicating a (local) protective effect due to the dietary LC supplementation against oxidative stress in mid-lactating dairy cows. For mtDNAcn and telomere length, the effects of the LPS-induced inflammation were more pronounced than the dietary supplementation of LC. Dietary LC supplementation affected the response to LPS primarily by altering mitochondrial dynamics. Regarding mRNA abundance of genes related to the mitochondrial protein import system, the inner mitochondrial membrane translocase (TIM complex) seemed to be more sensitive to dietary LC than the outer mitochondrial membrane translocase (TOM complex).

Effect of Traditional Korean Medicine Oncotherapy on the Survival, Quality of Life, and Telomere Length: A Prospective Cohort Study.

A 4-year prospective cohort study on patients with lung, gastric, hepatic, colorectal, breast, uterine, and ovarian cancer was conducted at the East-West Cancer Center (EWCC) of Daejeon Korean Medicine Hospital in Daejeon, Korea. We divided patients into 2 groups based on how long they had been receiving TKM oncotherapy and compared event-free survival (EFS), telomere length change, and quality of life (QoL). The study collected data on 83 patients from October 2016 to June 2020 and discovered no statistical differences in EFS based on the duration of TKM oncotherapy. In the analysis of changes in QoL outcomes, there were no statistically significant group differences between the groups. After controlling for covariates that could affect telomere length, the long-term TKM oncotherapy group had a higher daily telomere attrition rate. The study of the relationship between telomere length and prognostic factors discovered that patients with advanced N stage at the time of diagnosis and who had previously received radiotherapy had shorter telomere length. When examining associations between SNP genotype and percentile score of telomere length, this study was able to confirm an association between telomere length and rs4387287. This study is significant because it is the first to assess the effects of TKM oncotherapy and investigate telomere length-related factors. To assess the effects of TKM oncotherapy on cancer patients' survival and QoL, a longer-term observational study with a larger sample size is required.

Angelica sinensis extract induces telomere dysfunction, cell cycle arrest, and mitochondria-mediated apoptosis in human glioblastoma cells.

Glioblastoma (GB) is one of the most aggressive and malignant tumors of the central nervous system. Conventional treatment for GB requires surgical resection followed by radiotherapy combined with temozolomide chemotherapy; however, the median survival time is only 12-15 months. Angelica sinensis Radix (AS) is commonly used as a traditional medicinal herb or a food/dietary supplement in Asia, Europe, and North America. This study aimed to investigate the effect of AS-acetone extract (AS-A) on the progression of GB and the potential mechanisms underlying its effects. The results indicated that AS-A used in this study showed potency in growth inhibition of GB cells and reduction of telomerase activity. In addition, AS-A blocked the cell cycle at the G0/G1 phase by regulating the expression of p53 and p16. Furthermore, apoptotic morphology, such as chromatin condensation, DNA fragmentation, and apoptotic bodies, was observed in AS-A-treated cells, induced by the activation of the mitochondria-mediated pathway. In an animal study, AS-A reduced tumor volume and prolonged lifespans of mice, with no significant changes in body weight or obvious organ toxicity. This study confirmed the anticancer effects of AS-A by inhibiting cell proliferation, reducing telomerase activity, altering cell cycle progression, and inducing apoptosis. These findings suggest that AS-A has great potential for development as a novel agent or dietary supplement against GB.

UMSBP2 is chromatin remodeler that functions in regulation of gene expression and suppression of antigenic variation in trypanosomes.

Universal Minicircle Sequence binding proteins (UMSBPs) are CCHC-type zinc-finger proteins that bind the single-stranded G-rich UMS sequence, conserved at the replication origins of minicircles in the kinetoplast DNA, the mitochondrial genome of kinetoplastids. Trypanosoma brucei UMSBP2 has been recently shown to colocalize with telomeres and to play an essential role in chromosome end protection. Here we report that TbUMSBP2 decondenses in vitro DNA molecules, which were condensed by core histones H2B, H4 or linker histone H1. DNA decondensation is mediated via protein-protein interactions between TbUMSBP2 and these histones, independently of its previously described DNA binding activity. Silencing of the TbUMSBP2 gene resulted in a significant decrease in the disassembly of nucleosomes in T. brucei chromatin, a phenotype that could be reverted, by supplementing the knockdown cells with TbUMSBP2. Transcriptome analysis revealed that silencing of TbUMSBP2 affects the expression of multiple genes in T. brucei, with a most significant effect on the upregulation of the subtelomeric variant surface glycoproteins (VSG) genes, which mediate the antigenic variation in African trypanosomes. These observations suggest that UMSBP2 is a chromatin remodeling protein that functions in the regulation of gene expression and plays a role in the control of antigenic variation in T. brucei.

Instant Coffee Is Negatively Associated with Telomere Length: Finding from Observational and Mendelian Randomization Analyses of UK Biobank.

Telomere length, as a biomarker of accelerated aging, is closely related to many chronic diseases. We aimed to explore the association between coffee consumption and telomere length. Our study included 468,924 participants from the UK Biobank. Multivariate linear models (observational analyses) were conducted to evaluate the associations of coffee intake, instant coffee intake, and filtered coffee intake with telomere length. In addition, we evaluated the causality of these associations in Mendelian randomization (MR) analyses by four methods (inverse-variance weighted (IVW), MR pleiotropy residual sum and outlier (MR-PRESSO), MR-Egger, and weighted median). Observational analyses indicated that coffee intake and instant coffee intake were negatively correlated with telomere length, which was equal to 0.12 year of age-related decrease in telomere length for each additional cup of coffee intake (p < 0.001), and 0.38 year of age-related decrease in telomere length for each additional cup of instant coffee intake (p < 0.001), respectively. There was no significant correlation between filtered coffee and telomere length (p = 0.862). Mendelian randomization analyses supported the results of observational analyses. Coffee intake was found to have a causal effect on telomere length through weighted median analysis (p = 0.022), and instant coffee intake had a causal effect on telomere length through IVW analysis (p = 0.019) and MR-PRESSO analysis (p = 0.028). No causal relationship was found between filtered coffee intake and telomere length (p > 0.05). Coffee intake, particularly instant coffee, was found to have an important role in shortening telomere length.

Folic acid protects against age-associated apoptosis and telomere attrition of neural stem cells in senescence-accelerated mouse prone 8.

Folic acid (FA) could improve cognitive performance and attenuate brain cell injury in the aging brain; FA supplementation is also associated with inhibiting neural stem cell (NSC) apoptosis. However, its role in age-associated telomere attrition remains unclear. We hypothesized that FA supplementation attenuates age-associated apoptosis of NSCs in mice via alleviating telomere attrition in senescence-accelerated mouse prone 8 (SAMP8). In this study, 4-month-old male SAMP8 mice were assigned equal numbers to four different diet groups (n = 15). Fifteen age-matched senescence-accelerated mouse resistant 1 mice, fed with the FA-normal diet, were used as the standard aging control group. After FA treatment for 6 months, all mice were sacrificed. NSC apoptosis, proliferation, oxidative damage, and telomere length were evaluated by immunofluorescence and Q-fluorescent in situ hybridization. The results showed that FA supplementation inhibited age-associated NSC apoptosis and prevented telomere attrition in the cerebral cortex of SAMP8 mice. Importantly, this effect might be explained by the decreased levels of oxidative damage. In conclusion, we demonstrate it may be one of the mechanisms by which FA inhibits age-associated NSC apoptosis by alleviating telomere length shortening.

Prenatal thyroid hormones accelerate postnatal growth and telomere shortening in wild great tits.

The early-life environment is known to affect later-life health and disease, which could be mediated by the early-life programming of telomere length, a key hallmark of ageing. According to the fetal programming of telomere biology hypothesis, variation in prenatal exposure to hormones is likely to influence telomere length. Yet, the contribution of key metabolic hormones, i.e. thyroid hormones (THs), has been largely ignored. We recently showed that in contrast to predictions, exposure to elevated prenatal THs increased postnatal telomere length in wild collared flycatchers, but the generality of such effect, the underlying proximate mechanisms and consequences for survival have not been investigated. We therefore conducted a comprehensive study evaluating the impact of THs on potential drivers of telomere dynamics (growth, post-natal THs, mitochondria and oxidative stress), telomere length and medium-term survival using wild great tits as a model system. While prenatal THs did not significantly affect telomere length a week after hatching (i.e. day 7), they influenced postnatal telomere shortening (i.e. shorter telomeres at day 14 and the following winter) but not apparent survival. Circulating THs, mitochondrial density or oxidative stress biomarkers were not significantly influenced, whereas the TH-supplemented group showed accelerated growth, which may explain the observed delayed effect on telomeres. We discuss several alternative hypotheses that may explain the contrast with our previous findings in flycatchers. Given that shorter telomeres in early life tend to be carried until adulthood and are often associated with decreased survival prospects, the effects of prenatal THs on telomeres may have long-lasting effects on senescence.

Associations of green tea, coffee, and soft drink consumption with longitudinal changes in leukocyte telomere length.

Whether beverage consumption is associated with longitudinal observation of telomere length remains unclear. We evaluated the association of green tea, coffee, and soft drink consumption with 6-year changes in leukocyte telomere length (LTL). The study included 1952 participants who provided whole blood samples for LTL assays during the baseline (year 2011-2012) and follow-up (year 2017-2018) periods and reported baseline information on consumption of green tea, coffee, and soft drinks. Robust regression analysis was used to analyze the association adjusted for potential confounding variables. In the results, an inverse association between green tea consumption and LTL changes from baseline, which indicate telomere shortening, was found; regression coefficient [95% confidence interval] was - 0.097 [- 0.164, - 0.029] for participants who daily consumed at least 1 cup of green tea compared with non-consumers (p value = 0.006). This association was stronger among women (versus men) and younger participants aged 50-64 years (versus older). However, a positive association between soft drink consumption and LTL shortening was observed among women (p value < 0.05). Coffee consumption was not associated with LTL changes. These findings suggested that green tea consumption may be protective against telomere shortening reflecting biological aging whereas coffee and soft drink consumption may not.

The association between household biomass fuel use and leukocyte telomere length among toddlers in Bhaktapur, Nepal.

BACKGROUND: Biomass fuels are still in use for cooking by many households in resource poor countries such as Nepal and is a major source of household air pollution (HAP). Chronic exposure to HAP has been shown to be associated with shorter telomere length in adults. OBJECTIVES: To measure the association between exposure related to household biomass fuel in infancy and leukocyte telomere length (LTL) at 18-23 months of age among 497 children from Bhaktapur, Nepal. METHODS: In a prospective cohort study design, we have collected information on household cooking fuel use and several clinical, anthropometric, demographic, and socioeconomic variables. We estimated the association between biomass fuel use and the relative LTL in multiple linear regression models. RESULTS: Most of the families (78%) reported liquified petroleum gas (LPG) as the primary cooking fuel, and 18.7% used biomass. The mean relative (SD) LTL was 1.03 (0.19). Children living in households using biomass fuel had on average 0.09 (95% CI: 0.05 to 0.13) units shorter LTL than children in households with no biomass fuel use. The observed association was unaltered after adjusting for relevant confounders. The association between LTL and biomass use was strongest among children from households with ≤2 rooms and without separate kitchen. SIGNIFICANCE: Exposure to biomass fuel use in early life might have consequences for longevity, and risk of chronic illnesses reflected in shortening of the telomeres. Our findings support the ongoing effort to reduce exposure to biomass fuel in low-resource settings. IMPACT STATEMENTS: Biomass for cooking is a leading source of household air pollution in low and middle-income countries, contributing to many chronic diseases and premature deaths. Chronic exposure to biomass fuel through oxidative stress and inflammation has been associated with a shortening of the telomeres, a "biological marker" of longevity. This prospective cohort study describes the association between household biomass fuel use and leukocyte telomere length among 497 toddlers. Leukocyte telomere length was significantly shorter among children living in households with biomass fuel than in children from homes where mainly LPG was used for cooking. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT02272842, registered October 21, 2014, Universal Trial Number: U1111-1161-5187 (September 8, 2014).

Lifelong docosahexaenoic acid intervention ameliorates aging in the telomere-DNA-mitochondria axis in telomerase-deficient mice.

The health benefits of n-3 polyunsaturated fatty acids (PUFAs) in multiple age-related diseases are associated with telomere length. Telomerase is intimately related to inflammation and oxidative stress, but whether the underlying function of n-3 PUFAs on telomere maintenance is based on telomerase activation or related mechanisms remains unclear. Herein, we utilized late-generation (G4) telomerase-deficient (Terc-/-) mice to perform a lifelong docosahexaenoic acid (DHA) intervention to determine the potential of DHA in telomere maintenance and health promotion. Unfortunately, DHA failed to prolong mouse longevity in either intrinsic or premature aging. However, intriguingly, lifelong dietary DHA intervention slowed the aging phenotypes and profoundly attenuated telomere attrition in blood leukocytes and multiple tissues, consistent with decreased ß-galactosidase activity and other senescence hallmarks with no observed sex differences. Notably, DHA intervention alleviated telomere attrition-induced γ-H2AX accumulation dependent on poly (ADP-ribose) polymerase 1 (PARP1) recruitment, and further regulated mitochondrial dysfunction critically involved in the DNA damage response. Together with the improvement of mitochondria function, the blocked reactive oxygen species (ROS) accumulation and suppression of the nuclear factor-κB (NF-κB)/nucleotide-binding domain-like receptor protein 3 (NLRP3)/caspase-1 pathways partially indicated anti-oxidative and anti-inflammatory effects of DHA. These data revealed a regulatory paradigm involving DHA in the telomere-DNA-mitochondria feedback loop mediated by DNA damage response and inflammation in alleviating senescence, which may hold potential as a translatable intervention in telomere-related diseases during aging.

Alternative lengthening of telomeres (ALT) in pediatric high-grade gliomas can occur without ATRX mutation and is enriched in patients with pathogenic germline mismatch repair (MMR) variants.

BACKGROUND: To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available. METHODS: We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n = 40/579) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on pediatric high-grade gliomas (pHGGs) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations. RESULTS: ALT is common in pHGGs (n = 24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ pHGGs and in 30% of ALT- pHGGs. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT. CONCLUSIONS: We demonstrate that ATRX is mutated in only a subset of ALT+ pHGGs, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with the development of ALT in patients with pHGG.