scholarly journals A novel approach to assess the dynamics of extra-chromosomal circular ribosomal DNA in human cells

2014 ◽  
Author(s):  
Joerg R Leheste ◽  
Emily Forbes ◽  
Kristin DiGregorio ◽  
Victoria Katz ◽  
Alyssa Miceli ◽  
...  
Keyword(s):  
Life Span ◽  
Signaling Pathways ◽  
Ribosomal Dna ◽  
Experimental Manipulation ◽  
Human Cells ◽  
Model Organisms ◽  
Age Related ◽  
Novel Approach ◽  
Extend Life Span ◽  
Nutrient Signaling

Several nutrient-signaling pathways that extend life span have been described in model organisms. Thus, parallel and redundant signaling pathways that are similar across species might be subject to experimental manipulation. Here, we develop a PCR-based technique for testing the hypothesis that mitotic accumulation of extra-chromosomal ribosomal DNA circles might also determine life span in human cells. Using resveratrol, a phytochemical that counters age-related signs, we find treatment-dependent subcellular accumulations of extra-chromosomal 5S ribosomal DNA in human cell lines. These data suggest an association between DNA circles and intrinsic aging and demonstrate the utility of a PCR-based technique for studying the accumulation of dysfunctional molecules that promote senescence.

scholarly journals A novel approach to assess the dynamics of extra-chromosomal circular ribosomal DNA in human cells

2014 ◽  
Author(s):  
Joerg R Leheste ◽  
Emily Forbes ◽  
Kristin DiGregorio ◽  
Victoria Katz ◽  
Alyssa Miceli ◽  
...  
Keyword(s):  
Life Span ◽  
Signaling Pathways ◽  
Ribosomal Dna ◽  
Experimental Manipulation ◽  
Human Cells ◽  
Model Organisms ◽  
Age Related ◽  
Novel Approach ◽  
Extend Life Span ◽  
Nutrient Signaling

Several nutrient-signaling pathways that extend life span have been described in model organisms. Thus, parallel and redundant signaling pathways that are similar across species might be subject to experimental manipulation. Here, we develop a PCR-based technique for testing the hypothesis that mitotic accumulation of extra-chromosomal ribosomal DNA circles might also determine life span in human cells. Using resveratrol, a phytochemical that counters age-related signs, we find treatment-dependent subcellular accumulations of extra-chromosomal 5S ribosomal DNA in human cell lines. These data suggest an association between DNA circles and intrinsic aging and demonstrate the utility of a PCR-based technique for studying the accumulation of dysfunctional molecules that promote senescence.

scholarly journals Linking Peroxiredoxin and Vacuolar-ATPase Functions in Calorie Restriction-Mediated Life Span Extension

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Mikael Molin ◽  
Ayse Banu Demir
Keyword(s):  
Life Span ◽  
Signaling Pathways ◽  
Calorie Restriction ◽  
Iron Homeostasis ◽  
Vacuolar Atpase ◽  
Beneficial Effects ◽  
Age Related ◽  
Nutrient Signaling ◽  
Physiological Benefits ◽  
Vacuolar Atpases

Calorie restriction (CR) is an intervention extending the life spans of many organisms. The mechanisms underlying CR-dependent retardation of aging are still poorly understood. Despite mechanisms involving conserved nutrient signaling pathways proposed, few target processes that can account for CR-mediated longevity have so far been identified. Recently, both peroxiredoxins and vacuolar-ATPases were reported to control CR-mediated retardation of aging downstream of conserved nutrient signaling pathways. In this review, we focus on peroxiredoxin-mediated stress-defence and vacuolar-ATPase regulated acidification and pinpoint common denominators between the two mechanisms proposed for how CR extends life span. Both the activities of peroxiredoxins and vacuolar-ATPases are stimulated upon CR through reduced activities in conserved nutrient signaling pathways and both seem to stimulate cellular resistance to peroxide-stress. However, whereas vacuolar-ATPases have recently been suggested to control both Ras-cAMP-PKA- and TORC1-mediated nutrient signaling, neither the physiological benefits of a proposed role for peroxiredoxins in H2O2-signaling nor downstream targets regulated are known. Both peroxiredoxins and vacuolar-ATPases do, however, impinge on mitochondrial iron-metabolism and further characterization of their impact on iron homeostasis and peroxide-resistance might therefore increase our understanding of the beneficial effects of CR on aging and age-related diseases.

scholarly journals Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila

2016 ◽  
Vol 113 (40) ◽  
pp. 11277-11282 ◽  
Author(s):  
Jason G. Wood ◽  
Brian C. Jones ◽  
Nan Jiang ◽  
Chengyi Chang ◽  
Suzanne Hosier ◽  
...  
Keyword(s):  
Life Span ◽  
Dietary Restriction ◽  
Fat Body ◽  
Transcriptase Inhibitor ◽  
Dna Double Strand Breaks ◽  
Expression Of Genes ◽  
Age Related ◽  
Extend Life Span ◽  
Genetic Interventions ◽  
Heterochromatin Structure

Transposable elements (TEs) are mobile genetic elements, highly enriched in heterochromatin, that constitute a large percentage of the DNA content of eukaryotic genomes. Aging in Drosophila melanogaster is characterized by loss of repressive heterochromatin structure and loss of silencing of reporter genes in constitutive heterochromatin regions. Using next-generation sequencing, we found that transcripts of many genes native to heterochromatic regions and TEs increased with age in fly heads and fat bodies. A dietary restriction regimen, known to extend life span, repressed the age-related increased expression of genes located in heterochromatin, as well as TEs. We also observed a corresponding age-associated increase in TE transposition in fly fat body cells that was delayed by dietary restriction. Furthermore, we found that manipulating genes known to affect heterochromatin structure, including overexpression of Sir2, Su(var)3–9, and Dicer-2, as well as decreased expression of Adar, mitigated age-related increases in expression of TEs. Increasing expression of either Su(var)3–9 or Dicer-2 also led to an increase in life span. Mutation of Dicer-2 led to an increase in DNA double-strand breaks. Treatment with the reverse transcriptase inhibitor 3TC resulted in decreased TE transposition as well as increased life span in TE-sensitized Dicer-2 mutants. Together, these data support the retrotransposon theory of aging, which hypothesizes that epigenetically silenced TEs become deleteriously activated as cellular defense and surveillance mechanisms break down with age. Furthermore, interventions that maintain repressive heterochromatin and preserve TE silencing may prove key to preventing damage caused by TE activation and extending healthy life span.

scholarly journals Klotho: An Elephant in Aging Research

2019 ◽  
Vol 74 (7) ◽  
pp. 1031-1042 ◽  
Author(s):  
Amin Cheikhi ◽  
Aaron Barchowsky ◽  
Amrita Sahu ◽  
Sunita N Shinde ◽  
Abish Pius ◽  
...  
Keyword(s):  
Life Span ◽  
Accelerated Aging ◽  
Model Organisms ◽  
Aging Research ◽  
Promising Tool ◽  
Age Related ◽  
Organ Systems ◽  
Single Protein ◽  
20Th Anniversary ◽  
Biology Of Aging

Abstract The year 2017 marked the 20th anniversary of the first publication describing Klotho. This single protein was and is remarkable in that its absence in mice conferred an accelerated aging, or progeroid, phenotype with a dramatically shortened life span. On the other hand, genetic overexpression extended both health span and life span by an impressive 30%. Not only has Klotho deficiency been linked to a number of debilitating age-related illnesses but many subsequent reports have lent credence to the idea that Klotho can compress the period of morbidity and extend the life span of both model organisms and humans. This suggests that Klotho functions as an integrator of organ systems, making it both a promising tool for advancing our understanding of the biology of aging and an intriguing target for interventional studies. In this review, we highlight advances in our understanding of Klotho as well as key challenges that have somewhat limited our view, and thus translational potential, of this potent protein.

scholarly journals Identification of conserved transcriptome features between humans and Drosophila in the aging brain utilizing machine learning on combined data from the NIH Sequence Read Archive

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255085
Author(s):  
Joe L. Webb ◽  
Simon M. Moe ◽  
Andrew K. Bolstad ◽  
Elizabeth M. McNeill
Keyword(s):  
Morphological Changes ◽  
Age Groups ◽  
Model Organisms ◽  
Aging Brain ◽  
Sequencing Data ◽  
Genetic Changes ◽  
Age Related ◽  
Novel Approach ◽  
Increased Risk ◽  
The Brain

Aging is universal, yet characterizing the molecular changes that occur in aging which lead to an increased risk for neurological disease remains a challenging problem. Aging affects the prefrontal cortex (PFC), which governs executive function, learning, and memory. Previous sequencing studies have demonstrated that aging alters gene expression in the PFC, however the extent to which these changes are conserved across species and are meaningful in neurodegeneration is unknown. Identifying conserved, age-related genetic and morphological changes in the brain allows application of the wealth of tools available to study underlying mechanisms in model organisms such as Drosophila melanogaster. RNA sequencing data from human PFC and fly heads were analyzed to determine conserved transcriptome signatures of age. Our analysis revealed that expression of 50 conserved genes can accurately determine age in Drosophila (R2 = 0.85) and humans (R2 = 0.46). These transcriptome signatures were also able to classify Drosophila into three age groups with a mean accuracy of 88% and classify human samples with a mean accuracy of 69%. Overall, this work identifies 50 highly conserved aging-associated genetic changes in the brain that can be further studied in model organisms and demonstrates a novel approach to uncovering genetic changes conserved across species from multi-study public databases.

scholarly journals A novel approach of human geroprotector discovery by targeting the converging subnetworks of aging and age-related diseases

2018 ◽  
Author(s):  
Jialiang Yang ◽  
Bin Zhang ◽  
Sander Houten ◽  
Eric Schadt ◽  
Jun Zhu ◽  
...  
Keyword(s):  
Model Organisms ◽  
Human Longevity ◽  
Effective Interventions ◽  
Age Related ◽  
Novel Approach ◽  
Transcriptional Changes ◽  
Speed Up ◽  
Genetic Interventions ◽  
Novel Strategy

AbstractA key goal of geroscience research is to discover effective interventions to extend human healthspan, the years of healthy life. Currently, majority of the geroprotectors are found by testing compounds in model organisms; whether these compounds will be effective in humans is largely unknown. Here we present a novel strategy called ANDRU (aging network based drug discovery) to help the discovery of human geroprotectors. Instead of relying on model organisms, this approach is driven by human genomic and pharmacogenomic data. It first identifies human aging subnetworks that putatively function at the interface between aging and age-related diseases; it then screens for pharmacological or genetic interventions that may “reverse” the age-associated transcriptional changes seen in these subnetworks. We applied ANDRU to human adipose and artery tissues. In adipose tissue, PTPN1, a target for diabetes treatment and APOE, a known genetic factor for human longevity and diseases like Alzheimer’s disease, were ranked at the top. For small molecules, conjugated linoleic acid and metformin, a drug commonly used to treat type 2 diabetes, were ranked among the top compounds. In artery tissue, N-methyl-D-aspartate antagonists and curcumin were ranked at the top. In summary, ANDRU represents a promising human data-driven strategy that may speed up the discovery of interventions to extend human healthspan.

Additive regulation of hepatic gene expression by dwarfism and caloric restriction

2004 ◽  
Vol 17 (3) ◽  
pp. 307-315 ◽  
Author(s):  
Tomoshi Tsuchiya ◽  
Joseph M. Dhahbi ◽  
Xinping Cui ◽  
Patricia L. Mote ◽  
Andrzej Bartke ◽  
...  
Keyword(s):  
Gene Expression ◽  
Life Span ◽  
Caloric Restriction ◽  
Additive Effects ◽  
Age Related ◽  
Genome Wide ◽  
Extend Life Span ◽  
Ames Dwarf ◽  
Independent Effects ◽  
Microarray Expression

Disrupted growth hormone/insulin-like growth factor-1 signaling (DF) and caloric restriction (CR) extend life span and delay the onset of age-related diseases in rodents. In combination, these interventions additively extend life span. To investigate the molecular basis for these effects, we performed genome-wide, microarray expression analysis of liver from homozygous and heterozygous Ames dwarf mice fed ad libitum or CR. CR and DF additively affected a group of 95 genes. Individually and together, DF and CR independently affected the expression of 212 and 77 genes, respectively. These results indicate that DF and CR affect overlapping sets of genes and additively affect a subset of genes. Together, the interventions produced changes in gene expression consistent with increased insulin, glucagon and catecholamine sensitivity, gluconeogenesis, protein turnover, lipid β-oxidation, apoptosis, and xenobiotic and oxidant metabolism; and decreased cell proliferation, lipid and cholesterol synthesis, and chaperone expression. These data suggest that the additive effects of DF and CR on life span develop from their additive effects on the level of expression of some genes and from their independent effects on other genes. These results provide a novel and focused group of genes closely associated with the regulation of life span in mammals.

scholarly journals A Novel Approach to Assess the Dynamics of Extra-Chromosomal Circular Ribosomal DNA in Human Cells

2015 ◽  
Vol 1 (1) ◽  
Author(s):  
Joerg R Leheste ◽  
Forbes E Katz V ◽  
Miceli A ◽  
Husko C ◽  
Ramos RL ◽  
...  
Keyword(s):  
Ribosomal Dna ◽  
Human Cells ◽  
Novel Approach

Age-Related Increase in Lactate Dehydrogenase Activity in Skeletal Muscle Reduces Life Span in Drosophila

2021 ◽  
Author(s):  
Liam C Hunt ◽  
Fabio Demontis
Keyword(s):  
Skeletal Muscle ◽  
Lactate Dehydrogenase ◽  
Life Span ◽  
Glycolytic Enzymes ◽  
Lactate Dehydrogenase Activity ◽  
Muscle Aging ◽  
Age Related ◽  
Extend Life Span ◽  
Shorten Life Span ◽  
Skeletal Muscle Aging

Abstract Metabolic adaptations occur with aging but the significance and causal roles of such changes are only partially known. In Drosophila, we find that skeletal muscle aging is paradoxically characterized by increased readouts of glycolysis (lactate, NADH/NAD+) but reduced expression of most glycolytic enzymes. This conundrum is explained by lactate dehydrogenase (LDH), an enzyme necessary for anaerobic glycolysis and whose expression increases with aging. Experimental Ldh overexpression in skeletal muscle of young flies increases glycolysis and shortens life span, suggesting that age-related increases in muscle LDH contribute to mortality. Similar results are also found with overexpression of other glycolytic enzymes (Pfrx/PFKFB, Pgi/GPI). Conversely, hypomorphic mutations in Ldh extend life span, whereas reduction in PFK, Pglym78/PGAM, Pgi/GPI, and Ald/ALDO levels shorten life span to various degrees, indicating that glycolysis needs to be tightly controlled for optimal aging. Altogether, these findings indicate a role for muscle LDH and glycolysis in aging.

scholarly journals Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Anastasiya Börsch ◽  
Daniel J. Ham ◽  
Nitish Mittal ◽  
Lionel A. Tintignac ◽  
Eugenia Migliavacca ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Inflammatory Responses ◽  
Molecular Data ◽  
Model Organisms ◽  
Sequencing Data ◽  
Phenotypic Analysis ◽  
Age Related ◽  
Analogous Data ◽  
Species Specific ◽  
And Function

AbstractSarcopenia, the age-related loss of skeletal muscle mass and function, affects 5–13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in human sarcopenia, while inflammatory responses are conserved at pathway but not gene level. Perturbations in the extracellular matrix are shared by rats, while mice recapitulate changes in RNA processing and autophagy. We inferred transcription regulators of early and late transcriptome changes, which could be targeted therapeutically. Our study demonstrates that phenotypic measurements, such as muscle mass, are better indicators of muscle health than chronological age and should be considered when analyzing aging-related molecular data.

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