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.

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.

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.

Potential Antiaging and Hepatoprotective Effects of Acanthopanax senticosus Extracts in Adult Rat Models.

Data regarding plant extracts with antiaging properties, particularly through the biological process involving telomeres and telomerase, are limited. Thus, this study aimed to investigate the effects of Acanthopanax senticosus extract (ASE) supplementation on leukocyte telomere length (LTL), telomerase, and inflammatory and metabolic markers in adult animal models. A freeze-dried product of ethanol extracts was prepared using a mixture product of stem and root ASE. In a 24-week experiment that included 24-week-old Sprague Dawley male rats, experimental rats (n = 10) were administrated with 7 mg/day of ASE dissolved in saline and control rats (n = 10) with saline. All rats had access to chow and tap water ad libitum. Their LTL and plasma levels of telomerase and inflammatory and metabolic markers were assayed and compared between the two groups. The experimental rats showed significantly longer LTL (p < 0.05) and lower plasma levels of alanine aminotransferase (p < 0.05) and aspartate aminotransferase (p = 0.08) compared with the control. In addition, LTL was correlated with the aforementioned biochemical parameters of liver function test among experimental rats only. No significant differences in plasma levels of telomerase and inflammatory and metabolic markers were observed. These findings indicate that ASE supplementation may attenuate LTL shortening and reduce liver biochemical parameters, indicating its potential antiaging and hepatoprotective effects without any adverse metabolic response.

In Vitro Determination of the Skin Anti-Aging Potential of Four-Component Plant-Based Ingredient.

The beauty industry is actively searching for solutions to prevent skin aging. Some of the crucial elements protecting cells from the aging process are telomere shortening, telomerase expression, cell senescence, and homeostasis of the redox system. Modification of these factors using natural antioxidants is an appealing way to support healthy skin aging. Therefore, in this study, we sought to investigate the antiaging efficacy of a specific combination of four botanical extracts (pomegranate, sweet orange, Cistanche and Centella asiatica) with proven antioxidant properties. To this end, normal human dermal fibroblasts were used as a cell model and the following studies were performed: cell proliferation was established by means of the MTT assay and the intracellular ROS levels in stress-induced premature senescence fibroblasts; telomere length measurement was performed under standard cell culture conditions using qPCR and under oxidative stress conditions using a variation of the Q-FISH technique; telomerase activity was examined by means of Q-TRAP; and AGE quantification was completed by means of ELISA assay in UV-irradiated fibroblasts. As a result, the botanical blend significantly reversed the H2O2-induced decrease in cell viability and reduced H2O2-induced ROS. Additionally, the presence of the botanical ingredient reduced the telomere shortening rate in both stressed and non-stressed replicating fibroblasts, and under oxidative stress conditions, the fibroblasts presented a higher median and 20th percentile telomere length, as well as a lower percentage of short telomeres (<3 Kbp) compared with untreated fibroblasts. Furthermore, the ingredient transiently increased relative telomerase activity after 24 h and prevented the accumulation of UVR-induced glycated species. The results support the potential use of this four-component plant-based ingredient as an antiaging agent.

Zbtb34 promotes embryonic stem cell proliferation by elongating telomere length.

Zbtb34 is a novel zinc finger protein, which is revealed by biological software analysis to have 3 zinc fingers, but its functions remain unknown. In this study, mouse Zbtb34 cDNA was amplified by PCR and inserted into the plasmid pEGFP-N1 to generate Zbtb34-EGFP fusion protein. The upregulation of Zbtb34 in mouse embryonic stem cells promoted telomere elongation and increased cell proliferation. In order to understand the above phenomena, the telomere co-immunoprecipitation technique was employed to investigate the relationship between Zbtb34 and telomeres. The results indicated that Zbtb34 could bind to the DNA sequences of the telomeres. Alanine substitution of the third zinc finger abolished such binding. Since Pot1 is the only protein binding to the single-stranded DNA at the end of the telomeres, we further investigated the relationship between Zbtb34 and Pot1. The results revealed that the upregulation of Zbtb34 decreased the binding of Pot1b to the telomeres. Through the upregulation of Pot1b, the binding of Zbtb34 to the telomeres was also reduced. In conclusion, we showed that the main biological function of Zbtb34 was to bind telomere DNA via its third ZnF, competing with Pot1b for the binding sites, resulting in telomere elongation and cell proliferation.

Early Life Stage Folic Acid Deficiency Delays the Neurobehavioral Development and Cognitive Function of Rat Offspring by Hindering De Novo Telomere Synthesis.

Early life stage folate status may influence neurodevelopment in offspring. The developmental origin of health and disease highlights the importance of the period of the first 1000 days (from conception to 2 years) of life. This study aimed to evaluate the effect of early life stage folic acid deficiency on de novo telomere synthesis, neurobehavioral development, and the cognitive function of offspring rats. The rats were divided into three diet treatment groups: folate-deficient, folate-normal, and folate-supplemented. They were fed the corresponding diet from 5 weeks of age to the end of the lactation period. After weaning, the offspring rats were still fed with the corresponding diet for up to 100 days. Neurobehavioral tests, folic acid and homocysteine (Hcy) levels, relative telomere length in brain tissue, and uracil incorporation in telomere in offspring were measured at different time points. The results showed that folic acid deficiency decreased the level of folic acid, increased the level of Hcy of brain tissue in offspring, increased the wrong incorporation of uracil into telomeres, and hindered de novo telomere synthesis. However, folic acid supplementation increased the level of folic acid, reduced the level of Hcy of brain tissue in offspring, reduced the wrong incorporation of uracil into telomeres, and protected de novo telomere synthesis of offspring, which was beneficial to the development of early sensory-motor function, spatial learning, and memory in adolescence and adulthood. In conclusion, early life stage folic acid deficiency had long-term inhibiting effects on neurodevelopment and cognitive function in offspring.

Updated Understanding of the Causes of Cancer, and a New Theoretical Perspective of Combinational Cancer Therapies, a Hypothesis.

We present an integrative understanding of cancer as a metabolic multifactorial, multistage disease. We focus on underlying genetics-environmental interactions, evidenced by telomere changes. A range of genetic and epigenetic factors, including physical agents and predisposing factors such as diet and lifestyle are included. We present a structured model of the causes of cancer, methods of investigations, approaches to cancer prevention, and polypharmaceutical multidisciplinary complex treatment within a framework of personalized medicine. We searched PubMed, National Cancer Institute online, and other databases for publications regarding causes of cancer, reports of novel mitochondrial reprogramming, epigenetic, and telomerase therapies and state-of-the-art investigations. We focused on multistep treatment protocols to enhance early detection of cancer, and elimination or neutralization of the causes and factors associated with cancer formation and progression. Our aim is to suggest a model therapeutic protocol that incorporates the patient's genome, metabolism, and immune system status; stage of tumor development; and comorbidity(ies), if any. Investigation and treatment of cancer is a challenge that requires further holistic studies that improve the quality of life and survival rates, but are most likely to aid prevention.

Alleviating Oxidative Damage-Induced Telomere Attrition: a Potential Mechanism for Inhibition by Folic Acid of Apoptosis in Neural Stem Cells.

DNA oxidative damage can cause telomere attrition or dysfunction that triggers cell senescence and apoptosis. The hypothesis of this study is that folic acid decreases apoptosis in neural stem cells (NSCs) by preventing oxidative stress-induced telomere attrition. Primary cultures of NSCs were incubated for 9 days with various concentrations of folic acid (0-40 µM) and then incubated for 24 h with a combination of folic acid and an oxidant (100-µM hydrogen peroxide, H2O2), antioxidant (10-mM N-acetyl-L-cysteine, NAC), or vehicle. Intracellular folate concentration, apoptosis rate, cell proliferative capacity, telomere length, telomeric DNA oxidative damage, telomerase activity, intracellular reactive oxygen species (ROS) levels, cellular oxidative damage, and intracellular antioxidant enzyme activities were determined. The results showed that folic acid deficiency in NSCs decreased intracellular folate concentration, cell proliferation, telomere length, and telomerase activity but increased apoptosis, telomeric DNA oxidative damage, and intracellular ROS levels. In contrast, folic acid supplementation dose-dependently increased intracellular folate concentration, cell proliferative capacity, telomere length, and telomerase activity but decreased apoptosis, telomeric DNA oxidative damage, and intracellular ROS levels. Exposure to H2O2 aggravated telomere attrition and oxidative damage, whereas NAC alleviated the latter. High doses of folic acid prevented telomere attrition and telomeric DNA oxidative damage by H2O2. In conclusion, inhibition of telomeric DNA oxidative damage and telomere attrition in NSCs may be potential mechanisms of inhibiting NSC apoptosis by folic acid.

Telomere and Telomerase: Biological Markers of Organic Vital Force State and Homeopathic Treatment Effectiveness.

BACKGROUND: Philosophical-scientific correlations described in previous studies suggest that the genome can be the biological representation of the vital force, whilst the disease-promoting epigenetic alterations would be the biological representation of the chronic miasmas. In this study, we expand the functional correlation between vital force and chromosomes, describing the mechanism of action of the telomere-telomerase complex in the context of physiological balance. AIMS: The aim of the work is to study the role of the telomere-telomerase complex in cell vitality, biological aging, and the health-disease process, with the goal of proposing the use of telomere length as a biomarker of the vital force state and the effectiveness of homeopathic treatment. RESULTS: Similar to the vital force, telomere length and telomerase enzyme activity play an important role in maintaining cellular vitality, biological longevity, and physiological homeostasis. Telomere shortening functions as a biomarker of vital imbalance and is associated with numerous diseases and health disorders. On the other hand, health-promotion practices neutralize the pathological shortening of the telomeres, acting therapeutically in diseases or age-dependent health disorders. CONCLUSIONS: As a hypothetical biomarker of the vital force state, an intra-individual analysis of the mean leukocyte telomere length before, during, and after homeopathic treatment can be used as a biomarker of therapeutic effectiveness.

Bovine Colostrum, Telomeres, and Skin Aging.

BACKGROUND: Applied topically, growth factors, cytokines, and other components in bovine colostrum are known to affect collagen biosynthesis, thus offering promise as a therapeutic modality in wound healing, delay in skin aging, and skin rejuvenation. OBJECTIVE: To demonstrate the protective effect that liposomal bovine colostrum exerts on skin aging using telomere length as an aging biomarker. METHODS: Human fibroblasts were cultured for 8 weeks with colostrum at three concentrations (0.125%, 0.25%, 0.50%). Cells were cultured and assayed both under standard conditions, as well as with H2O2 added as an agent of oxidative stress. Alterations in proliferation rates, telomere lengths, and telomere shortening rates (TSRs) were determined in each treatment group and compared. RESULTS: Colostrum increased the proliferation rate of the fibroblast control cells and the addition of H2O2(without colostrum) decreased the proliferation rates of the fibroblast control cells. Under standard culture conditions, telomeres shortened progressively over 8 weeks and the addition of colostrum reduced the rate of telomere shortening. Under oxidative stress conditions (H2O2 – induced) the TSR increased; however, treatment with colostrum appeared to attenuate this increase. CONCLUSIONS: Under normal culture conditions and after both 4 weeks and 8 weeks of treatment, liposomal bovine colostrum appears to exert a protective effect on telomere length erosion. Under culture conditions of oxidative stress and after 8 weeks of treatment, colostrum appears to exert a protective effect on telomere length erosion. These results suggest that topical treatment of the liposomal bovine colostrum formulation would enhance skin health as the skin ages. J Drugs Dermatol. 20(5):538-545. doi:10.36849/JDD.5851.

Telomerase: A Target for Therapeutic Effects of Curcumin in Cancer.

Telomerases are attractive targets for development of new anticancer agents. Most tumors express the enzyme telomerase that maintains telomere length and thus ensures indefinite cell proliferation, a hallmark of cancer. Curcumin has been shown to be effective against several types of malignancies and has also been shown to have inhibitory effects on telomerase activity. Hence, the aim of this chapter is to review the available investigations of curcumin on telomerase activity. Based on the findings obtained from the different studies here, we conclude that the telomerase inhibitory effects of curcumin are integral to its anticancer activity, and thus curcumin may be useful therapeutically in the cancer field.

The role of telomerase and viruses interaction in cancer development, and telomerase-dependent therapeutic approaches.

Human telomerase reverse transcriptase (hTERT) is an enzyme that is critically involved in elongating and maintaining telomeres length to control cell life span and replicative potential. Telomerase activity is continuously expressed in human germ-line cells and most cancer cells, whereas it is suppressed in most somatic cells. In normal cells, by reducing telomerase activity and progressively shortening the telomeres, the cells progress to the senescence or apoptosis process. However, in cancer cells, telomere lengths remain constant due to telomerase's reactivation, and cells continue to proliferate and inhibit apoptosis, and ultimately lead to cancer development and human death due to metastasis. Studies demonstrated that several DNA and RNA oncoviruses could interact with telomerase by integrating their genome sequence within the host cell telomeres specifically. Through the activation of the hTERT promoter and lengthening the telomere, these cells contributes to cancer development. Since oncoviruses can activate telomerase and increase hTERT expression, there are several therapeutic strategies based on targeting the telomerase of cancer cells like telomerase-targeted peptide vaccines, hTERT-targeting dendritic cells (DCs), hTERT-targeting gene therapy, and hTERT-targeting CRISPR/Cas9 system that can overcome tumor-mediated toleration mechanisms and specifically apoptosis in cancer cells. This study reviews available data on the molecular structure of telomerase and the role of oncoviruses and telomerase interaction in cancer development and telomerase-dependent therapeutic approaches to conquest the cancer cells.

Association of telomere length and telomerase methylation with n-3 fatty acids in preschool children with obesity.

BACKGROUND: Telomeres play a crucial role in cellular survival and its length is a predictor for onset of chronic non-communicable diseases. Studies on association between telomeres and obesity in children have brought discrepant results and the underlying mechanisms and influential factors are to be elucidated. This study aimed to investigate changes in telomere length and telomerase reverse transcriptase (TERT) DNA methylation, and further to determine their correlation with n-3 polyunsaturated fatty acids (PUFAs) in preschool children with obesity. METHODS: Forty-six preschool children with obesity aged 3 to 4 years were included in the study, with equal numbers of age- and gender-matched children with normal weight as control. Leukocyte telomere length was determined by the ratio of telomeric product and single copy gene obtained using real-time qPCR. DNA methylation of TERT promoter was analyzed by bisulfite sequencing. Fatty acids in erythrocytes were measured by gas chromatography with a total of 15 fatty acids analyzed. The total saturated fatty acids (SFAs), total n-6 PUFAs, total n-3 PUFAs, and the ratio of arachidonic acid (AA) to docosahexaenoic acid (DHA) were calculated. Then the correlation between leukocyte telomere length, TERT promoter methylation and fatty acids was determined. RESULTS: In preschool children with obesity, leukocyte telomeres were shortened and had a negative association with the body mass index. The methylated fractions in 13 of 25 CpG sites in the TERT promoter were increased by approximately 3 to 35% in the children with obesity compared to the normal weight children. Erythrocyte lauric acid and total SFAs, lenoleic acid and total n-6 PUFAs were higher, and DHA was lower in the children with obesity than those in the children with normal weight. Correlative analysis showed that leukocyte telomere length had a positive association with total SFAs and DHA, and a negative association with the AA/DHA ratio. However, no association between erythrocyte DHA and the TERT promoter methylation was found. CONCLUSION: These data indicate that the reduced body DHA content and increased AA/DHA ratio may be associated with shortened leukocyte telomeres in child obesity, which is probably not involved in the TERT promoter methylation.

The Relationship Between Vitamin D and Telomere/Telomerase: A Comprehensive Review.

Telomeres are repetitive nucleotide sequences that together with the associated sheltrin complex protect the ends of chromosomes and maintain genomic stability. Evidences from various organisms suggests that several factors influence telomere length regulation, such as telomere binding proteins, telomere capping proteins, telomerase, and DNA replication enzymes. Recent studies suggest that micronutrients, such as vitamin D, folate and vitamin B12, are involved in telomere biology and cellular aging. In particular, vitamin D is important for a range of vital cellular processes including cellular differentiation, proliferation and apoptosis. As a result of the multiple functions of vitamin D it has been speculated that vitamin D might play a role in telomere biology and genomic stability. In this study, our main goal is investigating the relationship between telomerase enzyme and vitamin D. Findings of this study suggest that higher vitamin D concentrations, which are easily modifiable through nutritional supplementation, are associated with longer LTL, which underscores the potentially beneficial effects of this hormone on aging and age-related diseases. Vitamin D may reduce telomere shortening through anti-inflammatory and anti-cell proliferation mechanisms. Significant Low levels of telomerase activity create short telomeres, which in turn signal exit from the cell cycle resulting in cell senescence and apoptosis. In follow-up examination, the patients who remained vitamin D deficient tended to have shorter telomeres than those patients whose 25-hydroxyvitamin D levels were depleted. Increasing 25-hydroxyvitamin D levels in patients with SLE may be beneficial in maintaining telomere length and preventing cellular aging. Moreover, anti-telomere antibody levels may be a promising biomarker of SLE status and disease activity.

Vitamin D Supplementation Improves Cognitive Function Through Reducing Oxidative Stress Regulated by Telomere Length in Older Adults with Mild Cognitive Impairment: A 12-Month Randomized Controlled Trial.

BACKGROUND: Cognitive decline in older adults is a serious public health problem today. Association between vitamin D supplementation and cognition remains controversial. OBJECTIVE: To determine whether a 12-month vitamin D supplementation improves cognitive function in elderly subjects with mild cognitive impairment (MCI), and whether it is mediated through the mechanism in which telomere length (TL) regulate oxidative stress. METHODS: This was a double-blind, randomized, placebo-controlled trial in Tianjin, China. Participants were all native Chinese speakers aged 65 years and older with MCI. 183 subjects were randomized to an intervention group (vitamin D 800 IU/day, n = 93) or a placebo group (the matching starch granules, n = 90), and followed up for 12 months. Tests of cognitive function and mechanism-related biomarkers were evaluated at baseline, 6 months, and 12 months. RESULTS: Repeated-measures ANOVA showed substantial improvements in the full scale intelligence quotient (FSIQ), information, digit span, vocabulary, block design, and picture arrangement scores in the vitamin D group over the placebo group (p < 0.001). Leukocyte TL was significantly higher, while serum 8-OXO-dG, OGG1mRNA, and P16INK4amRNA revealed greater decreases in the vitamin D group over the placebo group (p < 0.001). According to mixed-model repeated-measures ANOVA analysis, vitamin D group showed a significant enhancement in the FSIQ score for 12 months compared with the control (estimate value = 5.132, p < 0.001). CONCLUSION: Vitamin D supplementation for 12 months appears to improve cognitive function through reducing oxidative stress regulated by increased TL in order adults with MCI. Vitamin D may be a promising public health strategy to prevent cognitive decline.

Replication stress conferred by POT1 dysfunction promotes telomere relocalization to the nuclear pore.

Mutations in the telomere-binding protein POT1 are associated with solid tumors and leukemias. POT1 alterations cause rapid telomere elongation, ATR kinase activation, telomere fragility, and accelerated tumor development. Here, we define the impact of mutant POT1 alleles through complementary genetic and proteomic approaches based on CRISPR interference and biotin-based proximity labeling, respectively. These screens reveal that replication stress is a major vulnerability in cells expressing mutant POT1, which manifests as increased telomere mitotic DNA synthesis at telomeres. Our study also unveils a role for the nuclear pore complex in resolving replication defects at telomeres. Depletion of nuclear pore complex subunits in the context of POT1 dysfunction increases DNA damage signaling, telomere fragility and sister chromatid exchanges. Furthermore, we observed telomere repositioning to the nuclear periphery driven by nuclear F-actin polymerization in cells with POT1 mutations. In conclusion, our study establishes that relocalization of dysfunctional telomeres to the nuclear periphery is critical to preserve telomere repeat integrity.

Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction.

Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.