Telomere shortening follows a developmentally regulated process that leads to replicative senescence of dividing cells. However, whether telomere changes are involved in postmitotic cell function and aging remains elusive. In this study, we discovered that the level of the TRF2 protein, a key telomere‐capping protein, declines in human skeletal muscle over lifetime. In cultured human myotubes, TRF2 downregulation did not trigger telomere dysfunction, but suppressed expression of the mitochondrial Sirtuin 3 gene (SIRT3) leading to mitochondrial respiration dysfunction and increased levels of reactive oxygen species. Importantly, restoring the Sirt3 level in TRF2‐compromised myotubes fully rescued mitochondrial functions. Finally, targeted ablation of the Terf2 gene in mouse skeletal muscle leads to mitochondrial dysfunction and sirt3 downregulation similarly to those of TRF2‐compromised human myotubes. Altogether, these results reveal a TRF2‐SIRT3 axis controlling muscle mitochondrial function. We propose that this axis connects developmentally regulated telomere changes to muscle redox metabolism.
Shelterin forms the core complex of telomere proteins and plays critical roles in protecting telomeres against unwanted activation of the DNA damage response and in maintaining telomere length homeostasis. Although shelterin expression is believed to be ubiquitous for stabilization of chromosomal ends. Evidences suggest that some shelterin subunits have tissue-specific functions. However, very little is known regarding how shelterin subunit gene expression is regulated during development and aging. Using two different animal models, the mouse and zebrafish, we reveal herein that shelterin subunits exhibit distinct spatial and temporal expression patterns that do not correlate with the proliferative status of the organ systems examined. Together, this work shows that the shelterin subunits exhibit distinct spatiotemporal expression patterns, suggesting important tissue-specific functions during development and aging.
The increased level of chromosome instability in cancer cells, leading to aneuploidy and gross chromosomal rearrangements, is not only a driving force for oncogenesis but also can be the Achille's heel of the disease since many chemotherapies (CT) kill cells by inducing a non-tolerable rate of DNA damage. A wealth of published evidence showed that telomere stability can be more affected than the bulk of the genome by several conventional antineoplasic drugs. These results raise the interesting possibility that CT with genotoxic drugs preferentially target telomeres. In agreement with this view, accelerated shortening of telomere length has been described in blood lineage cells following high-dose CT (stem cell transplantation) or non-myeloablative CT. However, almost nothing is known on the consequences of this shortening in terms of telomere stability, senescence and on the development of second cancers or post-treatment aging-like syndromes in cancer survivors (cognitive defect, fertility impairment, etc.). In this article, we propose: (1) telomeres of cancer cells are preferential genomic targets of chemotherapies altering chromosome maintenance; (2) telomere functional parameters can be a surrogate marker of chemotherapy sensitivity and toxicity; (3) the use of anti-telomere molecule could greatly enhance the sensitivity to standards chemotherapies.
Academic stress (AS) is one of the most important health problems experienced by students, but no biomarker of the potential psychological or physical problems associated with AS has yet been identified. As several cross-sectional studies have shown that psychiatric conditions accelerate aging and shorten telomere length (TL), we explored whether AS affected TL.Between June 2014 and July 2014, we recruited 200 junior high school students with imminent final examinations for participation in this study. The students were divided into three subgroups (mild, moderate, and severe anxiety) using the Sarason Test Anxiety Scale (TAS). Saliva samples were collected for TL measurement via quantitative polymerase chain reaction (qPCR).Students from both a specialized and a general school suffered from anxiety (p > 0.05). A total 35% had severe anxiety (score: 26.093.87), 33% had moderate anxiety (16.982.64), and 32% had mild anxiety (7.891.92). The TAS values differed significantly (p < 0.05) among the three subgroups, but the TLs of saliva cells differed only slightly (p > 0.05): 1.140.46 for those with severe anxiety, 1.020.40 for those with moderate anxiety, and 1.120.45 for those with mild anxiety.Previous reports have found that AS is very common in Asian adolescents. We found no immediate telomere shortening in adolescents with AS. Longitudinal observations are required to determine if TL is affected by AS.
Objective: China launched a health care reform policy due to the aging population and rapid urbanization. However, emergency overcrowding is not improved. We assessed the laboratory efficiency of emergency department (ED) in Shanghai hospitals. Methods: We recorded the turn around times for processing laboratory biomarkers to assess laboratory efficiency at 17 EDs in national/regional hospitals. We compared TAT between national and regional hospitals and between central and ED laboratories to analyze the relationship between the laboratory efficiency and the ED overcrowding. Results: All the participating hospitals have an emergency laboratory. The median TAT for c-TNT was 61 min (46-76 min) at regional EDs compared with 64 min (46-87 min) at national EDs; therefore, the TAT at regional EDs were more efficient (P < 0.05). The TAT were longer (65 min (53-85 min)) at ED labs than (60 min (42-83 min)) at central labs (P < 0.05), independent of the hospital tier and working period. We discovered that only 9% of investigated samples at Tier II EDs and 5% at Tier III EDs were assayed by point-of-care (POC) instruments. Conclusion: Our TAT level is approaching the recommended international standard. However, the TAT evaluation from ED laboratories demonstrates that their existence does not decrease the waiting time for laboratory reports compared to central laboratory. Thus, they have not yet approached a level to share the burden of the ED overcrowding. Further arrangement should be assigned to separate the function of emergency laboratory and central laboratory. It is worth deploying the POC assay in the ED, which will save twice the TAT level. The idea of evaluating routine laboratory efficiency by TAT at ED is fast, convenient, although it does not represent the general level of laboratory efficiency.
Targeting of PP2A suggests a close link to tau-related cognitive and functional declines. However, little is known about how the expression of PP2A subunits and PP2A activity are dysregulated in the course of AD, precluding any specific targeting strategy for restoring PP2A in AD patients. Although the PP2A heterotrimer containing the regulatory subunit PR55/Bα (encoded by the PPP2R2A gene) is the major tau phosphatase, the involvement of other brain-specific PP2A regulatory subunits in tau dephosphorylation remains unknown. PR55/Bγ (encoded by the PPP2R2C gene) is a pivotal phosphatase in the brain, and singlenucleotide polymorphisms (SNPs) of PPP2R2C are involved in several mental disorders. By measuring the differential spatiotemporal expression patterns of PPP2R2C in Wt and transgenic AD mice, we revealed that PPP2R2C expression is downregulated in the aged AD mouse brain as compared to the Wt mouse brain. In cultured cells, PPP2R2C expression regulates PP2A activity and tau dephosphorylation. These results suggest that dysregulation of PPP2R2C expression may be involved in the onset of AD and that specifically targeting PPP2R2C expression or activity is a promising strategy against brain dementia disorders, including AD and other tauopathies.
AGING INTRODUCTIONTelomeres are specialized chromatin structures, which cap chromosome ends and provide chromosome stability. The maintenance of telomeres requires accurate protections against DNA damage response (DDR) that would otherwise permanently stop cell division by checkpoint activation [ataxia telangiectasia mutated (ATM), and ATM-and Rad3-related (ATR) signaling] and lead to end-to-end chromosomal fusions by non-homologous end joining (NHEJ). Another threat to genome integrity stems from the inability of the conventional replication machinery to fully replicate the extremities of parental DNA, erosion compensated for by telomerase or recombination mechanisms [1,2]. To achieve chromosome end protection, telomeres are composed of repetitive DNA sequences that can fold into a terminal loop (t-loop), nucleosomes, the noncoding telomeric repeat-containing RNA (TERRA), the protein complex shelterin, and an ill-defined network of nuclear factors . Shelterin is essential for telomere protection and is composed of six subunits: three bind specifically to telomeric DNA (TRF1, TRF2, and POT1) and three establish protein-protein contacts: RAP1 with TRF2, TIN2 with TRF1 and TRF2, and ABSTRACTShelterin forms the core complex of telomere proteins and plays critical roles in protecting telomeres against unwanted activation of the DNA damage response and in maintaining telomere length homeostasis. Although shelterin expression is believed to be ubiquitous for stabilization of chromosomal ends. Evidences suggest that some shelterin subunits have tissue-specific functions. However, very little is known regarding how shelterin subunit gene expression is regulated during development and aging. Using two different animal models, the mouse and zebrafish, we reveal herein that shelterin subunits exhibit distinct spatial and temporal expression patterns that do not correlate with the proliferative status of the organ systems examined. Together, this work shows that the shelterin subunits exhibit distinct spatiotemporal expression patterns, suggesting important tissue-specific functions during development and aging.
To the best of our knowledge, there are no previous reports of a gastro-colic fistula (GCF) secondary to primary high-grade B-cell gastric lymphoma associated with acquired immunodeficiency syndrome (AIDS). Here, we report a 37-year-old man who presented with paroxysmal abdominal pain for 4 months, diarrhea for 15 days and weight loss of 4 kg. He had a history of human immunodeficiency virus (HIV) infection and was diagnosed with AIDS in 2013. The patient was diagnosed with a GCF secondary to primary high-grade B-cell gastric lymphoma by gastroscopy and histopathological examination. Two weeks after diagnosis, he died in another hospital. This is an uncommon case in which the GCF occurred secondary to malignant gastric lymphoma in a patient with AIDS. Supported by the literature, patients with HIV infection who complain of abdominal pain or a mass, severe diarrhea, and weight loss should be assessed for a GCF secondary to lymphoma because of its worse prognosis.
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