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 The genetic paradigms of dietary restriction fail to extend life span in cep-1(gk138) mutant of C. elegans p53 due to possible background mutations

2020 ◽  
Author(s):  
Anita Goyala ◽  
Aiswarya Baruah ◽  
Arnab Mukhopadhyay
Keyword(s):  
Life Span ◽  
Dietary Restriction ◽  
Model Systems ◽  
Regulation Of Expression ◽  
Life Span Extension ◽  
Phenotypic Differences ◽  
C Elegans ◽  
Xenobiotic Detoxification ◽  
Organismal Biology ◽  
Extend Life Span

AbstractDietary restriction (DR) increases life span and improves health in most model systems tested, including non-human primates. In C. elegans, as in other models, DR leads to reprogramming of metabolism, improvements in mitochondrial health, large changes in gene expression, including increase in expression of cytoprotective genes, better proteostasis etc. Understandably, multiple global transcriptional regulators like transcription factors FOXO/DAF-16, FOXA/PHA-4, HSF1/HSF-1 and NRF2/SKN-1 are important for DR longevity. Considering the wide-ranging effects of p53 on organismal biology, we asked whether the C. elegans ortholog, CEP-1 is required for DR-mediated longevity assurance. We employed the widely-used TJ1 strain of cep-1(gk138). We show that cep-1(gk138) suppresses the life span extension of two genetic paradigms of DR, but two non-genetic modes of DR remain unaffected in this strain. We find that in cep-1(gk138), two aspects of DR, increased autophagy and the up-regulation of expression of cytoprotective xenobiotic detoxification program (cXDP) genes are dampened. Importantly, we find that background mutation(s) in the strain may be the actual cause for the phenotypic differences that we observed and cep-1 may not be directly involved in genetic DR-mediated longevity assurance in worms. Identifying these mutation(s) may reveal a novel regulator of longevity required specifically by genetic modes of DR.

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 The genetic paradigms of dietary restriction fail to extend life span in cep-1(gk138) mutant of C. elegans p53 due to possible background mutations

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0241478
Author(s):  
Anita Goyala ◽  
Aiswarya Baruah ◽  
Arnab Mukhopadhyay
Keyword(s):  
Life Span ◽  
Dietary Restriction ◽  
Transcriptional Regulators ◽  
Model Systems ◽  
Life Span Extension ◽  
Phenotypic Differences ◽  
C Elegans ◽  
Xenobiotic Detoxification ◽  
Organismal Biology ◽  
Extend Life Span

Dietary restriction (DR) increases life span and improves health in most model systems tested, including non-human primates. In C. elegans, as in other models, DR leads to reprogramming of metabolism, improvements in mitochondrial health, large changes in expression of cytoprotective genes and better proteostasis. Understandably, multiple global transcriptional regulators like transcription factors FOXO/DAF-16, FOXA/PHA-4, HSF1/HSF-1 and NRF2/SKN-1 are important for DR longevity. Considering the wide-ranging effects of p53 on organismal biology, we asked whether the C. elegans ortholog, CEP-1 is required for DR-mediated longevity assurance. We employed the widely-used TJ1 strain of cep-1(gk138). We show that cep-1(gk138) suppresses the life span extension of two genetic paradigms of DR, but two non-genetic modes of DR remain unaffected in this strain. We find that two aspects of DR, increased autophagy and up-regulation of the expression of cytoprotective xenobiotic detoxification program (cXDP) genes, are dampened in cep-1(gk138). Importantly, we find that background mutation(s) in the strain may be the actual cause for the phenotypic differences that we observed and cep-1 may not be directly involved in genetic DR-mediated longevity assurance in worms. Identifying these mutation(s) may reveal a novel regulator of longevity required specifically by genetic modes of DR.

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 Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis

2019 ◽  
Vol 116 (35) ◽  
pp. 17383-17392 ◽  
Author(s):  
Latika Matai ◽  
Gautam Chandra Sarkar ◽  
Manish Chamoli ◽  
Yasir Malik ◽  
Shashi Shekhar Kumar ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Life Span ◽  
Dietary Restriction ◽  
Adult Life ◽  
Dependent Manner ◽  
Adult Life Span ◽  
Unfolded Protein ◽  
Age Related ◽  
Protein Response ◽  
Polyglutamine Aggregation

Unfolded protein response (UPR) of the endoplasmic reticulum (UPRER) helps maintain proteostasis in the cell. The ability to mount an effective UPRER to external stress (iUPRER) decreases with age and is linked to the pathophysiology of multiple age-related disorders. Here, we show that a transient pharmacological ER stress, imposed early in development on Caenorhabditis elegans, enhances proteostasis, prevents iUPRER decline with age, and increases adult life span. Importantly, dietary restriction (DR), that has a conserved positive effect on life span, employs this mechanism of ER hormesis for longevity assurance. We found that only the IRE-1–XBP-1 branch of UPRER is required for the longevity effects, resulting in increased ER-associated degradation (ERAD) gene expression and degradation of ER resident proteins during DR. Further, both ER hormesis and DR protect against polyglutamine aggregation in an IRE-1–dependent manner. We show that the DR-specific FOXA transcription factor PHA-4 transcriptionally regulates the genes required for ER homeostasis and is required for ER preconditioning-induced life span extension. Finally, we show that ER hormesis improves proteostasis and viability in a mammalian cellular model of neurodegenerative disease. Together, our study identifies a mechanism by which DR offers its benefits and opens the possibility of using ER-targeted pharmacological interventions to mimic the prolongevity effects of DR.

scholarly journals Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span

2008 ◽  
Vol 8 (2) ◽  
pp. 157-168 ◽  
Author(s):  
Kevin J. Pearson ◽  
Joseph A. Baur ◽  
Kaitlyn N. Lewis ◽  
Leonid Peshkin ◽  
Nathan L. Price ◽  
...  
Keyword(s):  
Life Span ◽  
Dietary Restriction ◽  
Age Related

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 Comparative proteomic analysis of Bombyx mori hemolymph and fat body after calorie restriction.

2010 ◽  
Vol 57 (4) ◽  
Author(s):  
Huiqing Chen ◽  
Yijia Li ◽  
Keping Chen ◽  
Qin Yao ◽  
Guohui Li ◽  
...  
Keyword(s):  
Life Span ◽  
Bombyx Mori ◽  
Calorie Restriction ◽  
Growth And Development ◽  
Fat Body ◽  
Silkworm Larvae ◽  
Proteomic Approach ◽  
Extend Life Span ◽  
Regulation Of Growth ◽  
Insight Into

Calorie restriction (CR) is known to extend life span from yeast to mammals. To gain an insight into the effects of CR on growth and development of the silkworm Bombyx mori at protein level, we employed comparative proteomic approach to investigate proteomic differences of hemolymph and fat body of the silkworm larvae subjected to CR. Thirty-nine differentially expressed proteins were identified by MALDI TOF/TOF MS. Among them, 19 were from the hemolymph and 20 from the fat body. The hemolymph of the CR group contained two down-regulated and 17 up-regulated proteins, whereas the fat body contained 15 down-regulated and five up-regulated ones. These proteins belonged to those functioning in immune system, in signal transduction and apoptosis, in regulation of growth and development, and in energy metabolism. Our results suggest that CR can alter the expression of proteins related to the above four aspects, implying that these proteins may regulate life span of the silkworm through CR.

scholarly journals Dietary Restriction for Kidney Protection: Decline in Nephroprotective Mechanisms During Aging

2021 ◽  
Vol 12 ◽  
Author(s):  
Nadezda V. Andrianova ◽  
Marina I. Buyan ◽  
Anastasia K. Bolikhova ◽  
Dmitry B. Zorov ◽  
Egor Y. Plotnikov
Keyword(s):  
Dietary Restriction ◽  
Hormonal Regulation ◽  
Ketone Bodies ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Production Improvement ◽  
Age Related ◽  
Physiological Alterations ◽  
Extend Life Span ◽  
Stress Sensing

Dietary restriction (DR) is believed to be one of the most promising approaches to extend life span of different animal species and to delay deleterious age-related physiological alterations and diseases. Among others, DR was shown to ameliorate acute kidney injury (AKI) and chronic kidney disease (CKD). However, to date, a comprehensive analysis of the mechanisms of the protective effect of DR specifically in kidney pathologies has not been carried out. The protective properties of DR are mediated by a range of signaling pathways associated with adaptation to reduced nutrient intake. The adaptation is accompanied by a number of metabolic changes, such as autophagy activation, metabolic shifts toward lipid utilization and ketone bodies production, improvement of mitochondria functioning, and decreased oxidative stress. However, some studies indicated that with age, the gain of DR-mediated positive remodeling gradually decreases. This may be an obstacle if we seek to translate the DR approach into a clinic for the treatment of kidney diseases as most patients with AKI and CKD are elderly. It is well known that aging is accompanied by impairments in a huge variety of organs and systems, such as hormonal regulation, stress sensing, autophagy and proteasomal activity, gene expression, and epigenome profile, increased damage to macromolecules and organelles including mitochondria. All these age-associated changes might be the reasons for the reduced protective potential of the DR during aging. We summarized the available mechanisms of DR-mediated nephroprotection and described ways to improve the effectiveness of this approach for an aged kidney.

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.

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