Deadly Fate: Klotho variant might shorten life-span in humans as well as rodents (Premature aging)

2002 ◽  
Vol 2002 (3) ◽  
pp. 9nw-9
Author(s):  
R. J. Davenport
Keyword(s):  
Life Span ◽  
Premature Aging ◽  
Shorten Life Span

scholarly journals The Short Life Span of Saccharomyces cerevisiae sgs1 and srs2 Mutants Is a Composite of Normal Aging Processes and Mitotic Arrest Due to Defective Recombination

Genetics ◽  
2001 ◽  
Vol 157 (4) ◽  
pp. 1531-1542 ◽  
Author(s):  
Mitch McVey ◽  
Matt Kaeberlein ◽  
Heidi A Tissenbaum ◽  
Leonard Guarente
Keyword(s):  
Cell Cycle ◽  
Life Span ◽  
Mitotic Cell ◽  
Dna Helicase ◽  
Premature Aging ◽  
Growth Defect ◽  
Short Life Span ◽  
Single Strand Annealing ◽  
Late Generation ◽  
Strand Annealing

Abstract Evidence from many organisms indicates that the conserved RecQ helicases function in the maintenance of genomic stability. Mutation of SGS1 and WRN, which encode RecQ homologues in budding yeast and humans, respectively, results in phenotypes characteristic of premature aging. Mutation of SRS2, another DNA helicase, causes synthetic slow growth in an sgs1 background. In this work, we demonstrate that srs2 mutants have a shortened life span similar to sgs1 mutants. Further dissection of the sgs1 and srs2 survival curves reveals two distinct phenomena. A majority of sgs1 and srs2 cells stops dividing stochastically as large-budded cells. This mitotic cell cycle arrest is age independent and requires the RAD9-dependent DNA damage checkpoint. Late-generation sgs1 and srs2 cells senesce due to apparent premature aging, most likely involving the accumulation of extrachromosomal rDNA circles. Double sgs1 srs2 mutants are viable but have a high stochastic rate of terminal G2/M arrest. This arrest can be suppressed by mutations in RAD51, RAD52, and RAD57, suggesting that the cell cycle defect in sgs1 srs2 mutants results from inappropriate homologous recombination. Finally, mutation of RAD1 or RAD50 exacerbates the growth defect of sgs1 srs2 cells, indicating that sgs1 srs2 mutants may utilize single-strand annealing as an alternative repair pathway.

scholarly journals Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
So-mi Kang ◽  
Min-Ho Yoon ◽  
Su-Jin Lee ◽  
Jinsook Ahn ◽  
Sang Ah Yi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Life Span ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Werner Syndrome ◽  
Genetic Disorder ◽  
Dna Helicase ◽  
Premature Aging ◽  
Lamin A ◽  
Short Life Span

AbstractWerner syndrome (WRN) is a rare progressive genetic disorder, caused by functional defects in WRN protein and RecQ4L DNA helicase. Acceleration of the aging process is initiated at puberty and the expected life span is approximately the late 50 s. However, a Wrn-deficient mouse model does not show premature aging phenotypes or a short life span, implying that aging processes differ greatly between humans and mice. Gene expression analysis of WRN cells reveals very similar results to gene expression analysis of Hutchinson Gilford progeria syndrome (HGPS) cells, suggesting that these human progeroid syndromes share a common pathological mechanism. Here we show that WRN cells also express progerin, an abnormal variant of the lamin A protein. In addition, we reveal that duplicated sequences of human WRN (hWRN) from exon 9 to exon 10, which differ from the sequence of mouse WRN (mWRN), are a natural inhibitor of progerin. Overexpression of hWRN reduced progerin expression and aging features in HGPS cells. Furthermore, the elimination of progerin by siRNA or a progerin-inhibitor (SLC-D011 also called progerinin) can ameliorate senescence phenotypes in WRN fibroblasts and cardiomyocytes, derived from WRN-iPSCs. These results suggest that progerin, which easily accumulates under WRN-deficient conditions, can lead to premature aging in WRN and that this effect can be prevented by SLC-D011.

scholarly journals Mutations in the WRN Gene in Mice Accelerate Mortality in a p53-Null Background

2000 ◽  
Vol 20 (9) ◽  
pp. 3286-3291 ◽  
Author(s):  
David B. Lombard ◽  
Caroline Beard ◽  
Brad Johnson ◽  
Robert A. Marciniak ◽  
Jessie Dausman ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Life Span ◽  
Human Disease ◽  
Dna Helicase ◽  
Premature Aging ◽  
Mutant Mice ◽  
Helicase Domain ◽  
C Terminus ◽  
Accelerated Senescence

ABSTRACT Werner's syndrome (WS) is a human disease with manifestations resembling premature aging. The gene defective in WS, WRN, encodes a DNA helicase. Here, we describe the generation of mice bearing a mutation that eliminates expression of the C terminus of the helicase domain of the WRN protein. Mutant mice are born at the expected Mendelian frequency and do not show any overt histological signs of accelerated senescence. These mice are capable of living beyond 2 years of age. Cells from these animals do not show elevated susceptibility to the genotoxins camptothecin or 4-NQO. However, mutant fibroblasts senesce approximately one passage earlier than controls. Importantly,WRN−/− ;p53−/− mice show an increased mortality rate relative toWRN+/− ;p53−/− animals. We consider possible models for the synergy betweenp53 and WRN mutations for the determination of life span.

scholarly journals Lack of Peroxisomal Catalase Causes a Progeric Phenotype inCaenorhabditis elegans

2004 ◽  
Vol 279 (19) ◽  
pp. 19996-20001 ◽  
Author(s):  
Oleh I. Petriv ◽  
Richard A. Rachubinski
Keyword(s):  
Life Span ◽  
Aging Process ◽  
Target Genes ◽  
Egg Laying ◽  
C Elegans ◽  
Extend Life Span ◽  
Genes Encoding ◽  
Shorten Life Span ◽  
Development And Aging ◽  
Genetic Mutants

Studies using the nematodeCaenorhabditis elegansas a model system to investigate the aging process have implicated the insulin/insulin-like growth factor-I signaling pathway in the regulation of organismal longevity through its action on a subset of target genes. These targets can be classified into genes that shorten or extend life-span upon their induction. Genes that shorten life-span include a variety of stress response genes, among them genes encoding catalases; however, no evidence directly implicates catalases in the aging process of nematodes or other organisms. Using genetic mutants, we show that lack of peroxisomal catalase CTL-2 causes a progeric phenotype inC. elegans. Lack of peroxisomal catalase also affects the developmental program ofC. elegans, since Δctl-2mutants exhibit decreased egg laying capacity. In contrast, lack of cytosolic catalase CTL-1 has no effect on either nematode aging or egg laying capacity. The Δctl-2mutation also shortens the maximum life-span of the long lived Δclk-1mutant and accelerates the onset of its egg laying period. The more rapid aging of Δctl-2worms is apparently not due to increased carbonylation of the majorC. elegansproteins, although altered peroxisome morphology in the Δctl-2mutant suggests that changes in peroxisomal function, including increased production of reactive oxygen species, underlie the progeric phenotype of the Δctl-2mutant. Our findings support an important role for peroxisomal catalase in both the development and aging ofC. elegansand suggest the utility of the Δctl-2mutant as a convenient model for the study of aging and the human diseases acatalasemia and hypocatalasemia.

scholarly journals Loss of Aklotho Causes Reduced Motor Ability and Short Lifespan in Zebrafish

2020 ◽  
Author(s):  
Yurie Ogura ◽  
Kota Ujibe ◽  
Yuma Wakamatsu ◽  
Hiromi Hirata
Keyword(s):  
Life Span ◽  
Swimming Performance ◽  
Transmembrane Protein ◽  
Growth Factor Receptor ◽  
Accelerated Aging ◽  
Premature Death ◽  
Premature Aging ◽  
Motor Ability ◽  
Physiological Basis ◽  
Spontaneous Movements

Abstract The klotho gene encodes a transmembrane protein aKlotho that interacts with a fibroblast growth factor receptor in renal tubular epithelial cells and functions as a co-receptor for FGF23, which is an osteocytes-derived hormone. It is known that this bone-to-kidney signal promotes urinary phosphate excretion. Interestingly, aKlotho-deficient mice show accelerated aging and shortened life span in addition to dysregulation of serum phosphorus. However, physiological basis of aging-related function of aklotho and its generality in animals remain unclear. The aklotho-deficient vertebrate animals other than mice have been awaited as an alternative premature aging model. We here employed zebrafish in our aklotho study and revealed that aklotho mutant zebrafish appear to be normal at 3 months postfertilization (mpf) in young adults but eventually undergo premature death by 9 mpf, while normal zebrafish is known to survive for 42 months. We also assessed motor ability of zebrafish in a forced swimming assay and found that aklotho mutant zebrafish displayed reduced swimming performance before their survival declined. A recent study also reported a similar finding that aklotho-deficient zebrafish exhibited short life span and reduced spontaneous movements. Taken together, these results suggest that aKlotho mutant zebrafish show premature aging and are useful to investigate aging in vertebrates.

scholarly journals Loss of αklotho causes reduced motor ability and short lifespan in zebrafish

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yurie Ogura ◽  
Ryoji Kaneko ◽  
Kota Ujibe ◽  
Yuma Wakamatsu ◽  
Hiromi Hirata
Keyword(s):  
Life Span ◽  
Swimming Performance ◽  
Transmembrane Protein ◽  
Premature Death ◽  
Premature Aging ◽  
Motor Ability ◽  
Short Life ◽  
Physiological Basis ◽  
Short Life Span ◽  
Spontaneous Movements

AbstractThe klotho gene encodes a transmembrane protein αKlotho that interacts with a fibroblast growth factor (FGF) receptor in renal tubular epithelial cells and functions as a co-receptor for FGF23, which is an osteocytes-derived hormone. This bone-to-kidney signal promotes urinary phosphate excretion. Interestingly, αKlotho knockout mice show an accelerated aging and a shortened life span. Similarly, C. elegans lacking the αklotho homologue showed a short life span. However, the physiological basis of aging-related function of αklotho remain unclear. The αklotho-deficient vertebrate animals other than mice have been awaited as an alternative model of premature aging. We here employed zebrafish in our study and revealed that αklotho mutant zebrafish appeared to be normal at 3 months postfertilization (mpf) but eventually underwent premature death by 9 mpf, while normal zebrafish is known to survive for 42 months. We also assessed the motor ability of zebrafish in a forced swimming assay and found that αklotho mutant zebrafish displayed reduced swimming performance before their survival declined. A recent study also reported a similar finding that αklotho-deficient zebrafish exhibited a short life span and reduced spontaneous movements. Taken together, these results suggest that αKlotho mutant zebrafish show premature aging and are useful to investigate aging in vertebrates.

scholarly journals Mutations in DNA Replication Genes Reduce Yeast Life Span

2002 ◽  
Vol 22 (12) ◽  
pp. 4136-4146 ◽  
Author(s):  
Laura L. Mays Hoopes ◽  
Martin Budd ◽  
Wonchae Choe ◽  
Tao Weitao ◽  
Judith L. Campbell
Keyword(s):  
Dna Replication ◽  
Life Span ◽  
Genomic Instability ◽  
Replicative Senescence ◽  
Premature Aging ◽  
Wild Type ◽  
Cell Cycle Time ◽  
Replicative Stress ◽  
Age Related ◽  
In The Wild

ABSTRACT Surprisingly, the contribution of defects in DNA replication to the determination of yeast life span has never been directly investigated. We show that a replicative yeast helicase/nuclease, encoded by DNA2 and a member of the same helicase subfamily as the RecQ helicases, is required for normal life span. All of the phenotypes of old wild-type cells, for example, extended cell cycle time, age-related transcriptional silencing defects, and nucleolar reorganization, occur after fewer generations in dna2 mutants than in the wild type. In addition, the life span of dna2 mutants is extended by expression of an additional copy of SIR2 or by deletion of FOB1, which also increase wild-type life span. The ribosomal DNA locus and the nucleolus seem to be particularly sensitive to defects in dna2 mutants, although in dna2 mutants extrachromosomal ribosomal circles do not accumulate during the aging of a mother cell. Several other replication mutations, such as rad27Δ, encoding the FEN-1 nuclease involved in several aspects of genomic stability, also show premature aging. We propose that replication fork failure due to spontaneous, endogenous DNA damage and attendant genomic instability may contribute to replicative senescence. This may imply that the genomic instability, segmental premature aging symptoms, and cancer predisposition associated with the human RecQ helicase diseases, such as Werner, Bloom, and Rothmund-Thomson syndromes, are also related to replicative stress.

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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