Telomere Shortening in Kidneys with Age

Abstract. The histology and function of the kidney deteriorates with age and age-related diseases, but the mechanisms involved in renal aging are not known. In vitro studies suggest that telomere shortening is important in replicative senescence, and is accelerated by stresses that increase replication. This study explored the relationship between age and telomere length in surgical samples from 24 human kidneys, which were either histologically normal (17) or displayed histologic abnormalities (7). Telomere loss was assessed by two independent methods: Southern blotting of terminal restriction fragments (TRF) and slot blotting using telomere-specific probes. The results of these methods correlated with each other. The mean TRF length determined by Southern blotting in cortex was about 12 kb pairs (kbp) in infancy and was shorter in older kidneys. The slope of the regression line was about 0.029 kbp (0.24%, P = 0.023) per year. Telomere DNA loss in cortex by the slot blot method was 0.25% per year (P = 0.011). By both methods, the telomere loss in medulla was not significant and was less than in cortex. Comparisons of TRF length from 20 paired samples from cortex and medulla showed that TRF was greater in cortex than medulla, with the differences being greater in young kidneys and lessening with age due to telomere loss in cortex. These findings indicate that telomeres shorten in an age-dependent manner in the kidney, either due to developmental factors or aging, particularly in renal cortex.

Download Full-text

Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish

Cell Death and Disease ◽

10.1038/s41419-021-03438-9 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Ting Zhao ◽

Shengfan Ye ◽

Zimu Tang ◽

Liwei Guo ◽

Zhipeng Ma ◽

...

Keyword(s):

Replicative Senescence ◽

Brain Aging ◽

Ventricular Zone ◽

Human Fibroblasts ◽

Cell Lineage ◽

Lineage Tracing ◽

Dependent Manner ◽

Loss Of Function ◽

Antioxidant Genes ◽

Age Related

AbstractReactive oxygen species (ROS) stress has been demonstrated as potentially critical for induction and maintenance of cellular senescence, and been considered as a contributing factor in aging and in various neurological disorders including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). In response to low-level ROS stress, the expression of Δ133p53, a human p53 isoform, is upregulated to promote cell survival and protect cells from senescence by enhancing the expression of antioxidant genes. In normal conditions, the basal expression of Δ133p53 prevents human fibroblasts, T lymphocytes, and astrocytes from replicative senescence. It has been also found that brain tissues from AD and ALS patients showed decreased Δ133p53 expression. However, it is uncharacterized if Δ133p53 plays a role in brain aging. Here, we report that zebrafish Δ113p53, an ortholog of human Δ133p53, mainly expressed in some of the radial glial cells along the telencephalon ventricular zone in a full-length p53-dependent manner. EDU-labeling and cell lineage tracing showed that Δ113p53-positive cells underwent cell proliferation to contribute to the neuron renewal process. Importantly, Δ113p53M/M mutant telencephalon possessed less proliferation cells and more senescent cells compared to wild-type (WT) zebrafish telencephalon since 9-months old, which was associated with decreased antioxidant genes expression and increased level of ROS in the mutant telencephalon. More interestingly, unlike the mutant fish at 5-months old with cognition ability, Δ113p53M/M zebrafish, but not WT zebrafish, lost their learning and memory ability at 19-months old. The results demonstrate that Δ113p53 protects the brain from aging by its antioxidant function. Our finding provides evidence at the organism level to show that depletion of Δ113p53/Δ133p53 may result in long-term ROS stress, and finally lead to age-related diseases, such as AD and ALS in humans.

Download Full-text

Photobiomodulation with 590 nm Wavelength Delays the Telomere Shortening and Replicative Senescence of Human Dermal Fibroblasts In Vitro

Photobiomodulation Photomedicine and Laser Surgery ◽

10.1089/photob.2020.4822 ◽

2020 ◽

Vol 38 (11) ◽

pp. 656-660

Author(s):

Borislav Arabadjiev ◽

Roumen Pankov ◽

Ivelina Vassileva ◽

Lyuben Sashov Petrov ◽

Ivan Buchvarov

Keyword(s):

Replicative Senescence ◽

Dermal Fibroblasts ◽

Human Dermal Fibroblasts ◽

Telomere Shortening

Download Full-text

Telomere length and human hippocampal neurogenesis

Neuropsychopharmacology ◽

10.1038/s41386-020-00863-w ◽

2020 ◽

Vol 45 (13) ◽

pp. 2239-2247 ◽

Cited By ~ 1

Author(s):

Alish B. Palmos ◽

Rodrigo R. R. Duarte ◽

Demelza M. Smeeth ◽

Erin C. Hedges ◽

Douglas F. Nixon ◽

...

Keyword(s):

Cognitive Function ◽

Psychiatric Disorder ◽

Telomere Length ◽

Gene Networks ◽

Hippocampal Neurogenesis ◽

Telomere Maintenance ◽

Adult Hippocampal Neurogenesis ◽

Telomere Shortening ◽

Age Related

Abstract Short telomere length is a risk factor for age-related disease, but it is also associated with reduced hippocampal volumes, age-related cognitive decline and psychiatric disorder risk. The current study explored whether telomere shortening might have an influence on cognitive function and psychiatric disorder pathophysiology, via its hypothesised effects on adult hippocampal neurogenesis. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Serially passaged progenitors demonstrated shorter telomeres (P ≤ 0.05), and reduced rates of cell proliferation (P ≤ 0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene-set enrichment analyses revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts in our model showed a significant overlap with genes regulating cognitive function (P ≤ 1 × 10−5), and risk for schizophrenia (P ≤ 1 × 10−10) and bipolar disorder (P ≤ 0.005). Collectively, our results suggest that telomere shortening could represent a mechanism that moderates the proliferative capacity of human hippocampal progenitors, which may subsequently impact on human cognitive function and psychiatric disorder pathophysiology.

Download Full-text

Progressive Telomere Shortening in Aplastic Anemia

Blood ◽

10.1182/blood.v91.10.3582 ◽

1998 ◽

Vol 91 (10) ◽

pp. 3582-3592 ◽

Cited By ~ 187

Author(s):

Sarah E. Ball ◽

Frances M. Gibson ◽

Siân Rizzo ◽

Jennifer A. Tooze ◽

Judith C.W. Marsh ◽

...

Keyword(s):

Aplastic Anemia ◽

Late Complication ◽

Blood Leukocytes ◽

Telomere Shortening ◽

Hematopoietic Stem ◽

Age Related ◽

High Incidence ◽

Telomere Loss ◽

Cell Fractions ◽

Telomere Erosion

Abstract Improved survival in aplastic anemia (AA) has shown a high incidence of late clonal marrow disorders. To investigate whether accelerated senescence of hematopoietic stem cells might underlie the pathophysiology of myelodysplasia (MDS) or paroxysmal nocturnal hemoglobinuria (PNH) occurring as a late complication of AA, we studied mean telomere length (TRF) in peripheral blood leukocytes from 79 patients with AA, Fanconi anemia, or PNH in comparison with normal controls. TRF lengths in the patient group were significantly shorter for age than normals (P < .0001). Telomere shortening was apparent in both granulocyte and mononuclear cell fractions, suggesting loss at the level of the hematopoietic stem cell. In patients with acquired AA with persistent cytopenias (n = 40), there was significant correlation between telomere loss and disease duration (r = −.685; P < .0001), equivalent to progressive telomere erosion at 216 bp/yr, in addition to the normal age-related loss. In patients who had achieved normal full blood counts (n = 20), the rate of telomere loss had apparently stabilised. There was no apparent association between telomere loss and secondary PNH (n = 13). However, of the 5 patients in the study with TRF less than 5.0 kb, 3 had acquired cytogenetic abnormalities, suggesting that telomere erosion may be relevant to the pathogenesis of MDS in aplastic anemia.

Download Full-text

Telomere loss, senescence, and genetic instability in CD4+ T lymphocytes overexpressing hTERT

Blood ◽

10.1182/blood-2004-10-4144 ◽

2005 ◽

Vol 106 (1) ◽

pp. 43-50 ◽

Cited By ~ 44

Author(s):

Alexander Röth ◽

Gabriela M. Baerlocher ◽

Mike Schertzer ◽

Elizabeth Chavez ◽

Ulrich Dührsen ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Cd4 T Cells ◽

Genetic Instability ◽

Replicative Senescence ◽

Green Fluorescence Protein ◽

Retroviral Vectors ◽

Human Telomerase Reverse Transcriptase ◽

Telomere Loss

Little is known about the long-term consequences of overexpression of the human telomerase reverse transcriptase (hTERT) gene in T lymphocytes. To address this issue, we transduced polyclonal as well as clonally derived populations of naive and memory CD4+ T cells from 2 healthy donors (aged 24 and 34 years) with retroviral vectors encoding green fluorescence protein (GFP) and hTERT (GFP-hTERT) or GFP alone. After transduction, cells were sorted on the basis of GFP expression and cultured in vitro until senescence. T cells transduced with hTERT exhibited high stable telomerase activity throughout the culture period. Relative to GFP controls, minor changes in overall gene expression were observed yet the proliferative lifespan of the hTERT-transduced populations was significantly increased and the rate of telomere loss was lower. Nevertheless, hTERT-transduced cells showed progressive telomere loss and had shorter telomeres at senescence than controls (2.3 ± 0.3 kilobase [kb] versus 3.4 ± 0.1 kb). Furthermore, a population of cells with 4N DNA consisting of binucleated cells with connected nuclei emerged in the hTERT-transduced cells prior to senescence. We conclude that overexpression of hTERT in CD4+ T cells provides a proliferative advantage independent of the average telomere length but does not prevent eventual genetic instability and replicative senescence.

Download Full-text

Metformin improves cognition of aged mice by promoting cerebral angiogenesis and neurogenesis

10.1101/2020.03.25.006767 ◽

2020 ◽

Author(s):

Xiaoqi Zhu ◽

Junyan Shen ◽

Shengyu Feng ◽

Ce Huang ◽

Zhongmin Liu ◽

...

Keyword(s):

Blood Flow ◽

Mrna Expression ◽

Mononuclear Cells ◽

Vascular Density ◽

Aged Mouse ◽

Dependent Manner ◽

Peripheral Blood Mononuclear ◽

Age Related ◽

Glycolysis Pathway

AbstractThe cerebral microvasculature is essential for preservation of normal cerebral function. Age-related decreases of neurogenesis and cognitive function are accompanied by reduced blood flow and a decline in neural stem cell (NSC) number. Here, we report that metformin administered by tail vein injection enhanced cognition in aged but not young mice in a dose-dependent manner. Further, metformin restored cerebral blood flow and brain vascular density and promoted neurogenic potential of the subependymal zone/subventricular zone both in vivo and in vitro. RNA-Seq result indicated that metformin could enhance glycolysis in blood, with an increase in relative mRNA expression of the enzyme in the glycolysis pathway from hippocampal tissue of metformin-treated mice. Mechanistically, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a key enzyme in the glycolysis pathway, may contribute to angiogenic and neurogenic potentials of NSCs. Interestingly, examination of peripheral blood mononuclear cells from people of various ages showed that mRNA expression of GAPDH gradually decreased with age, while its expression level positively correlated with cognitive levels. Our results indicate that metformin represents a candidate pharmacological approach for recruitment of NSCs in aged mouse brain by enhancing glycolysis and promoting neurovascular generation, a strategy that might be of therapeutic value for anti-aging in humans.Graphical Abstract

Download Full-text

Human Aging DNA Methylation Signatures are Conserved but Accelerated in Cultured Fibroblasts

10.1101/605295 ◽

2019 ◽

Author(s):

Gabriel Sturm ◽

Andres Cardenas ◽

Marie-Abèle Bind ◽

Steve Horvath ◽

Shuang Wang ◽

...

Keyword(s):

Dna Methylation ◽

Replicative Senescence ◽

Human Fibroblasts ◽

High Temporal Resolution ◽

Global Changes ◽

Mrna Levels ◽

Cultured Fibroblasts ◽

Age Related ◽

Epigenetic Aging

SummaryAging is associated with progressive and site-specific changes in DNA methylation (DNAm). These global changes are captured by DNAm clocks that accurately predict chronological age in humans but relatively little is known about how clocks perform in vitro. Here we culture primary human fibroblasts across the cellular lifespan (∼6 months) and use four different DNAm clocks to show that age-related DNAm signatures are conserved and accelerated in vitro. The Skin & Blood clock shows the best linear correlation with chronological time (r=0.90), including during replicative senescence. Although similar in nature, the rate of epigenetic aging is approximately 62x times faster in cultured cells than in the human body. Consistent with in vivo data, cells aged under hyperglycemic conditions exhibit an approximately three years elevation in baseline DNAm age. Moreover, candidate gene-based analyses further corroborate the conserved but accelerated biological aging process in cultured fibroblasts. Fibroblasts mirror the established DNAm topology of the age-related ELOVL2 gene in human blood and the rapid hypermethylation of its promoter cg16867657, which correlates with a linear decrease in ELOVL2 mRNA levels across the lifespan. Using generalized additive modeling on twelve timepoints across the lifespan, we also show how single CpGs exhibit loci-specific, linear and nonlinear trajectories that reach rates up to −47% (hypomethylation) to +23% (hypermethylation) per month. Together, these high temporal resolution global, gene-specific, and single CpG data highlight the conserved and accelerated nature of epigenetic aging in cultured fibroblasts, which may constitute a system to evaluate age-modifying interventions across the lifespan.Graphical Abstract

Download Full-text

Telomere dysfunction represses HNF4α leading to impaired hepatocyte development and function

10.1101/619601 ◽

2019 ◽

Author(s):

Evandro L. Niero ◽

Wilson C. Fok ◽

Alexandre T. Vessoni ◽

Kirsten A. Brenner ◽

Luis F.Z. Batista

Keyword(s):

Liver Disease ◽

Molecular Mechanisms ◽

Embryonic Stem ◽

Dependent Manner ◽

Telomere Dysfunction ◽

Down Regulation ◽

Telomere Shortening ◽

Conditional Expression ◽

And Function

ABSTRACTTelomere attrition is a risk factor for end-stage liver disease. Due to a lack of adequate models and intrinsic difficulties in studying telomerase in physiologically relevant cells, the molecular mechanisms responsible for liver disease in patients with telomere syndromes remain elusive. To circumvent that, we used genome editing to generate isogenic human embryonic stem cell lines (hESCs) harboring a clinically relevant mutation in telomerase (DKC1_A353V) and subjected them to an in vitro, stage-specific hepatocyte differentiation protocol, that resembles hepatocyte development in vivo. Our results show that while telomerase is highly expressed in hESCs, it is quickly silenced, due to TERT down-regulation, after endoderm differentiation, and completely absent in in vitro derived hepatocytes, similarly to what is observed in primary hepatocytes. While endoderm derivation is not impacted by telomere shortening, progressive telomere dysfunction impaired hepatic endoderm formation. Consequently, hepatocyte-derivation, as measured by expression of specific markers, as well by albumin expression and secretion, is severely compromised in telomerase mutant cells with short telomeres. Interestingly, this phenotype was not caused by cell death induction or senescence. Rather, telomere shortening induces down regulation of the human hepatocyte nuclear factor 4α (HNF4α), in a p53 dependent manner. Telomerase reactivation, as well as p53 silencing, rescued hepatocyte formation in telomerase mutants. Likewise, conditional expression of HNF4α, even in cells that retained short telomeres, accrued DNA damage, and p53 stabilization, successfully restored hepatocyte formation from hESCS.ConclusionsCombined, our data shows that telomere dysfunction acts a major regulator of HNF4α during hepatocyte development and function, pointing to a potential novel target for the clinical management of liver disease in telomere-syndrome patients.

Download Full-text

Protein Oxidative Damage at the Crossroads of Cellular Senescence, Aging, and Age-Related Diseases

Oxidative Medicine and Cellular Longevity ◽

10.1155/2012/919832 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 56

Author(s):

Martin A. Baraibar ◽

Liang Liu ◽

Emad K. Ahmed ◽

Bertrand Friguet

Keyword(s):

Lipid Peroxidation ◽

Protein Modification ◽

Replicative Senescence ◽

Human Fibroblasts ◽

Potential Effect ◽

Senescent Phenotype ◽

Intermediate Metabolism ◽

Age Related ◽

Cellular Pathways

Protein damage mediated by oxidation, protein adducts formation with advanced glycated end products and with products of lipid peroxidation, has been implicated during aging and age-related diseases, such as neurodegenerative diseases. Increased protein modification has also been described upon replicative senescence of human fibroblasts, a valid model for studying agingin vitro. However, the mechanisms by which these modified proteins could impact on the development of the senescent phenotype and the pathogenesis of age-related diseases remain elusive. In this study, we performedin silicoapproaches to evidence molecular actors and cellular pathways affected by these damaged proteins. A database of proteins modified by carbonylation, glycation, and lipid peroxidation products during aging and age-related diseases was built and compared to those proteins identified during cellular replicative senescencein vitro. Common cellular pathways evidenced by enzymes involved in intermediate metabolism were found to be targeted by these modifications, although different tissues have been examined. These results underscore the potential effect of protein modification in the impairment of cellular metabolism during aging and age-related diseases.

Download Full-text