scholarly journals Age-Related Phenotypes Linked to Aberrant Expression and Localization of a Telomeric Protein

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 665-665
Author(s):  
Amanda Stock ◽  
Kun Wang ◽  
Chengyu Liu ◽  
Ross McDevitt ◽  
Chongkui Sun ◽  
...  
Keyword(s):  
Causal Mechanism ◽  
Cell Fractionation ◽  
Aberrant Expression ◽  
Behavioral Deficits ◽  
Telomere Attrition ◽  
Age Related ◽  
Cytokine Levels ◽  
Primary Fibroblasts ◽  
Telomere Capping ◽  
Telomere Biology

Abstract Telomere attrition is associated with telomere biology disorders and age-related diseases. In telomere biology disorders, telomere uncapping induces a DNA damage response that evokes cell death or senescence. However, a causal mechanism for telomere attrition in age-related diseases remains elusive. Telomere capping and integrity are maintained by shelterin, a six-protein complex. Rap1 is the only shelterin member that is not required for telomere capping and is expressed at non-telomeric genomic and cytosolic regions. The objective of this study was to determine aberrant phenotypes attributed to non-telomeric Rap1. To test this, we generated a Rap1 mutant knock-in (KI) mouse model using CRISPR/Cas9 editing, in which Rap1 at telomeres is prevented, leaving only non-telomeric Rap1. Cell fractionation/western blotting of primary fibroblasts from Rap1 KI mice demonstrated decreased Rap1 expression and Rap1 re-localization off telomeres, with an altered cellular distribution. This same difference in Rap1 is also observed in human cells with telomere erosion, indicating that aberrant Rap1 in our model may recapitulate Rap1 in aging and human telomere biology disorders. Compared to wild-type control mice, Rap1 KI mice exhibited increased body weight, altered cytokine levels, behavioral deficits, and decreased lifespan. In conclusion, our results reveal a novel mechanism by which telomere shortening may contribute to age-related pathologies by disrupting Rap1 expression and cell localization.

scholarly journals Telomere Biology and Human Phenotype

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 73 ◽  
Author(s):  
Kara Turner ◽  
Vimal Vasu ◽  
Darren Griffin
Keyword(s):  
Genome Stability ◽  
Telomere Shortening ◽  
Human Phenotype ◽  
Telomere Attrition ◽  
Age Related ◽  
Telomere Homeostasis ◽  
Telomere Biology ◽  
And Function

Telomeres are nucleoprotein structures that cap the end of each chromosome arm and function to maintain genome stability. The length of telomeres is known to shorten with each cell division and it is well-established that telomere attrition is related to replicative capacity in vitro. Moreover, telomere loss is also correlated with the process of aging in vivo. In this review, we discuss the mechanisms that lead to telomere shortening and summarise telomere homeostasis in humans throughout a lifetime. In addition, we discuss the available evidence that shows that telomere shortening is related to human aging and the onset of age-related disease.

scholarly journals A DNA Damage Response-Independent Mechanism for Telomere Shortening-Elicited Age-Related Pathologies

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 885-885
Author(s):  
Amanda Stock ◽  
Kun Wang ◽  
Chongkui Sun ◽  
Chengyu Liu ◽  
Yi Gong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Gene Transcription ◽  
Dna Damage Response ◽  
Cell Fractionation ◽  
Telomeric Dna ◽  
Independent Manner ◽  
Telomere Shortening ◽  
Telomere Attrition ◽  
Age Related ◽  
Damage Response

Abstract Telomere attrition is associated with telomeropathies and age-related pathologies. In telomeropathies, telomere uncapping induces a DNA damage response (DDR) that drives apoptosis or senescence. However, a defined mechanism by which telomere attrition contributes to other age-related pathologies has not been determined. Telomere integrity is maintained by shelterin, a six-protein complex. Rap1 is the only shelterin member that is not essential for telomere capping but engages non-telomeric DNA and regulates gene transcription. We hypothesized that non-telomeric Rap1 accumulation could contribute to age-related pathologies in a DDR-independent manner. To test this, we used CRISPR/Cas9 editing to generate a Rap1 mutant mouse model in which Rap1 at telomeres is prevented, leaving only non-telomeric Rap1. Indirect immunostaining showed no differences in telomere dysfunction-induced DDR foci in Rap1 mutant compared to wild-type primary fibroblasts. Cell fractionation/western blotting of fibroblasts from Rap1 mutants demonstrated decreased Rap1 expression and Rap1 re-localization off telomeres, which mimics the same alteration of Rap1 in human cells with telomere attrition. Rap1 mutant mice exhibited increased body weight and altered metabolic and immune-response transcripts in various tissues, indicating that altered transcription could account for some of the observed phenotypes related to telomere attrition. In conclusion, telomere shortening may facilitate non-telomeric Rap1, which alters gene transcription and drives metabolic and immune dysfunction in a DDR-independent manner.

scholarly journals Telomere Attrition and Clonal Hematopoiesis of Indeterminate Potential in Cardiovascular Disease

2021 ◽  
Vol 22 (18) ◽  
pp. 9867
Author(s):  
Yi-Chun Huang ◽  
Chao-Yung Wang
Keyword(s):  
Cardiovascular Disease ◽  
Dna Methyltransferase ◽  
Gene Mutations ◽  
Cvd Risk ◽  
Telomere Attrition ◽  
Clonal Hematopoiesis ◽  
Age Related ◽  
Cell Clones ◽  
Important Relationship ◽  
Increased Risk

Clinical evidence suggests that conventional cardiovascular disease (CVD) risk factors cannot explain all CVD incidences. Recent studies have shown that telomere attrition, clonal hematopoiesis of indeterminate potential (CHIP), and atherosclerosis (telomere–CHIP–atherosclerosis, TCA) evolve to play a crucial role in CVD. Telomere dynamics and telomerase have an important relationship with age-related CVD. Telomere attrition is associated with CHIP. CHIP is commonly observed in elderly patients. It is characterized by an increase in blood cell clones with somatic mutations, resulting in an increased risk of hematological cancer and atherosclerotic CVD. The most common gene mutations are DNA methyltransferase 3 alpha (DNMT3A), Tet methylcytosine dioxygenase 2 (TET2), and additional sex combs-like 1 (ASXL1). Telomeres, CHIP, and atherosclerosis increase chronic inflammation and proinflammatory cytokine expression. Currently, their epidemiology and detailed mechanisms related to the TCA axis remain incompletely understood. In this article, we reviewed recent research results regarding the development of telomeres and CHIP and their relationship with atherosclerotic CVD.

scholarly journals Age-related cytokine profile in uncomplicated Plasmodium malaria infection

2011 ◽  
pp. 323-327 ◽  
Author(s):  
Youtchou Mirabeau Tatfeng ◽  
Dennis Edo Agbonlahor
Keyword(s):  
Malaria Infection ◽  
Malaria Diagnosis ◽  
Blood Parameters ◽  
Enzyme Linked Immunosorbent Assay ◽  
Monocyte Count ◽  
Healthy Controls ◽  
Age Related ◽  
Cytokine Levels ◽  
Adolescents And Adults ◽  
The Mean

Objective: Malaria infection is severe in children who are believed to be more at risk because of their relative poor immunity against the disease. Some cytokine levels (IFN-g, IL-2, IL-4, and IL-10) of children, adolescents, and adults were assessed in this study. Methods: Cytokine levels were assayed by using Enzyme Linked Immunosorbent Assay (ELISA). Malaria diagnosis and blood parameters were carried out by using standard parasitological and haematological techniques. Results: The mean cytokine levels were significantly elevated in children, adolescent, and adult subjects when compared to their respective healthy controls (p<0.05). Also, mean IFN-g and IL-2 levels were significantly higher in children than in adults (IFN-g: 57.31±77.79 pg/ml vs. 20.37± 2.95 pg/ml, and IL-2: 108.75±63.53 pg/ml vs. 66.09±45.34 pg/ml) (p<0.05) and adolescents (IFN-g: 20.37± 2.95 pg/ml and IL-2: 66.09±45.34 pg/ml) respectively. Furthermore, mean IL-10 level was significantly lower in children (7.39±15.08 pg/ml) than mean level in adults (22.73±13.89 pg/ml). The mean haematological parameters revealed significant increase in total white blood cell, CD4, and CD8 count and significant decrease in the hematocrit of children in relation to adolescent and adult subjects (p<0.05). However, mean monocyte count was significantly higher in subjects than in their respective healthy controls (p<0.05). Conclusion: Findings in this study revealed better Th1 driven immune response in children than in adolescents and adults.

Telomerase-Positive Somatic Tissues of Honeybee Queens (Apis mellifera) Display No DNA Replication

2021 ◽  
pp. 1-6
Author(s):  
Justina Koubová ◽  
Radmila Čapková Frydrychová
Keyword(s):  
Apis Mellifera ◽  
Dna Replication ◽  
Cell Types ◽  
Telomerase Activity ◽  
Protective Mechanism ◽  
Aging Research ◽  
Telomere Attrition ◽  
Eusocial Insects ◽  
Somatic Tissues ◽  
Telomere Biology

Telomere biology is closely linked to the process of aging. The restoration of telomere length by maintaining telome­rase activity in certain cell types of human adults allows for the proliferative capacity of the cells and preserves the regeneration potential of the tissue. The absence of telome­rase, that leads to telomere attrition and irreversible cell cycle arrest in most somatic cells, acts as a protective mechanism against uncontrolled cancer growth. Nevertheless, there have been numerous studies indicating noncanonical functions of telomerase besides those involved in telomere lengthening. Eusocial insects serve as a great system for aging research. This is because eusocial reproductives, such as queens and kings, have a significantly extended lifespan compared to nonreproductive individuals of the same species. We report that the somatic tissues of honeybee queens (<i>Apis mellifera</i>) are associated with upregulated telomerase activity; however, this upregulation does not fully correlate with the rate of DNA replication in the tissues. This indicates a noncanonical role of telomerase in the somatic tissues of honeybee queens.

Correlation Between Telomere Attrition of Zona Fasciculata and Adrenal Weight Reduction in Older Men

2019 ◽  
Vol 105 (3) ◽  
pp. e200-e210
Author(s):  
K Nonaka ◽  
Junko Aida ◽  
Kaiyo Takubo ◽  
Yuto Yamazaki ◽  
Xin Gao ◽  
...  
Keyword(s):  
Sex Differences ◽  
Weight Reduction ◽  
Adrenal Glands ◽  
Older Men ◽  
Adrenal Weight ◽  
Zona Fasciculata ◽  
Biological Mechanisms ◽  
Telomere Attrition ◽  
Age Related ◽  
Age Related Changes

Abstract Context Although numerous theories are reported on sex differences in longevity, the underlying biological mechanisms remain unknown. We previously reported that telomere length in the zona reticularis cells of the human adrenal cortex was significantly longer in older than that in younger subjects. However, we could not evaluate sex differences in the telomere lengths. Objective To compare the telomere lengths of adrenocortical and adrenal medullar cells between men and women from infancy through older adulthood. Methods Adrenal glands of 30 male (aged 0 to 100 years) and 25 female (aged 0 to 104 years) autopsied subjects were retrieved from autopsy files. Using quantitative fluorescence in situ hybridization, relative telomere lengths were determined in the parenchymal cells of the 3 adrenocortical zones and medulla. Age-related changes in the weight of adrenal glands were also investigated. Main results Older male subjects (aged 65 years or older) had significantly shorter telomere lengths in zona fasciculata (ZF) cells compared to the corresponding female subjects. In men, older subjects exhibited a significant age-related reduction in adrenal weight; however, no age-related changes in adrenal weight were detected in women. Conclusion Telomere attrition of ZF cells was correlated with adrenal weight reduction in older men but not in older women, suggesting a decreased number of ZF cells in older men. This may help us understand the possible biological mechanisms of sex difference in longevity of humans.

scholarly journals Telomere length and age-dependent telomere attrition: the blood-and-muscle model

2019 ◽  
Vol 97 (4) ◽  
pp. 328-334 ◽  
Author(s):  
Mirna N. Chahine ◽  
Simon Toupance ◽  
Sandy El-Hakim ◽  
Carlos Labat ◽  
Sylvie Gautier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Telomere Length ◽  
Cross Sectional Study ◽  
Muscle Model ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cross Sectional ◽  
Telomere Attrition ◽  
Age Related ◽  
Age Dependent ◽  
Muscle Biopsies

Short telomere length (TL) is associated with atherosclerotic cardiovascular disease (ACVD) and other age-related diseases. It is unclear whether these associations originate from having inherently short TL or a faster TL attrition before or during disease development. We proposed the blood-and-muscle model to assess TL dynamics throughout life course. Our objective was to measure TL in leukocytes (LTL) and in skeletal muscle (MTL), which served as a proxy of TL at birth. The delta (MTL–LTL) represented life-long telomere attrition. Blood draws and skeletal muscle biopsies were performed on 35 Lebanese individuals undergoing surgery. Following DNA extraction, LTL and MTL were measured by Southern blot. In every individual aged between 30 and 85 years, MTL was longer than LTL. With age, MTL and LTL decreased, but the delta (MTL–LTL) increased by 14 bp/year. We validated the blood-and-muscle model that allowed us to identify TL, TL at birth, and lifelong TL attrition in a cross-sectional study. This model can be used in larger cross-sectional studies to evaluate the association of telomere dynamics with age-related diseases onset and progression.

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