共查询到20条相似文献，搜索用时 15 毫秒
1.
Amber C. Howard Jarod Rollins Santina Snow Sarah Castor Aric N. Rogers 《Aging cell》2016,15(6):1027-1038
2.
3.
George L. Sutphin Grant Backer Susan Sheehan Shannon Bean Caroline Corban Teresa Liu Marjolein J. Peters Joyce B. J. van Meurs Joanne M. Murabito Andrew D. Johnson Ron Korstanje the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium Gene Expression Working Group 《Aging cell》2017,16(4):672-682
We report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on orthology to human genes differentially expressed with age. We find substantial enrichment in genes for which knockdown increased lifespan. This enrichment is markedly higher than published genomewide longevity screens in C. elegans and similar to screens that preselected candidates based on longevity‐correlated metrics (e.g., stress resistance). Of the 50 genes that affected lifespan, 46 were previously unreported. The five genes with the greatest impact on lifespan (>20% extension) encode the enzyme kynureninase (kynu‐1), a neuronal leucine‐rich repeat protein (iglr‐1), a tetraspanin (tsp‐3), a regulator of calcineurin (rcan‐1), and a voltage‐gated calcium channel subunit (unc‐36). Knockdown of each gene extended healthspan without impairing reproduction. kynu‐1(RNAi) alone delayed pathology in C. elegans models of Alzheimer's disease and Huntington's disease. Each gene displayed a distinct pattern of interaction with known aging pathways. In the context of published work, kynu‐1, tsp‐3, and rcan‐1 are of particular interest for immediate follow‐up. kynu‐1 is an understudied member of the kynurenine metabolic pathway with a mechanistically distinct impact on lifespan. Our data suggest that tsp‐3 is a novel modulator of hypoxic signaling and rcan‐1 is a context‐specific calcineurin regulator. Our results validate C. elegans as a comparative tool for prioritizing human candidate aging genes, confirm age‐associated gene expression data as valuable source of novel longevity determinants, and prioritize select genes for mechanistic follow‐up. 相似文献
4.
Anupama Singh Neeraj Kumar Latika Matai Vaibhav Jain Amit Garg Arnab Mukhopadhyay 《Aging cell》2016,15(4):694-705
5.
6.
7.
Laura K. Herzog va Kevei Ricardo Marchante Claudia Bttcher Christian Bindesbll Alf Hkon Lystad Annika Pfeiffer Maria E. Gierisch Florian A. Salomons Anne Simonsen Thorsten Hoppe Nico P. Dantuma 《Aging cell》2020,19(1)
The pathology of spinocerebellar ataxia type 3, also known as Machado‐Joseph disease, is triggered by aggregation of toxic ataxin‐3 (ATXN3) variants containing expanded polyglutamine repeats. The physiological role of this deubiquitylase, however, remains largely unclear. Our recent work showed that ATX‐3, the nematode orthologue of ATXN3, together with the ubiquitin‐directed segregase CDC‐48, regulates longevity in Caenorhabditis elegans. Here, we demonstrate that the long‐lived cdc‐48.1; atx‐3 double mutant displays reduced viability under prolonged starvation conditions that can be attributed to the loss of catalytically active ATX‐3. Reducing the levels of the autophagy protein BEC‐1 sensitized worms to the effect of ATX‐3 deficiency, suggesting a role of ATX‐3 in autophagy. In support of this conclusion, the depletion of ATXN3 in human cells caused a reduction in autophagosomal degradation of proteins. Surprisingly, reduced degradation in ATXN3‐depleted cells coincided with an increase in the number of autophagosomes while levels of lipidated LC3 remained unaffected. We identified two conserved LIR domains in the catalytic Josephin domain of ATXN3 that directly interacted with the autophagy adaptors LC3C and GABARAP in vitro. While ATXN3 localized to early autophagosomes, it was not subject to lysosomal degradation, suggesting a transient regulatory interaction early in the autophagic pathway. We propose that the deubiquitylase ATX‐3/ATXN3 stimulates autophagic degradation by preventing superfluous initiation of autophagosomes, thereby promoting an efficient autophagic flux important to survive starvation. 相似文献
8.
Fiona R. Savory Timothy G. Benton Varun Varma Ian A. Hope Steven M. Sait 《Ecology and evolution》2014,4(7):1176-1185
Longevity is modulated by a range of conserved genes in eukaryotes, but it is unclear how variation in these genes contributes to the evolution of longevity in nature. Mutations that increase life span in model organisms typically induce trade‐offs which lead to a net reduction in fitness, suggesting that such mutations are unlikely to become established in natural populations. However, the fitness consequences of manipulating longevity have rarely been assessed in heterogeneous environments, in which stressful conditions are encountered. Using laboratory selection experiments, we demonstrate that long‐lived, stress‐resistant Caenorhabditis elegans age‐1(hx546) mutants have higher fitness than the wild‐type genotype if mixed genotype populations are periodically exposed to high temperatures when food is not limited. We further establish, using stochastic population projection models, that the age‐1(hx546) mutant allele can confer a selective advantage if temperature stress is encountered when food availability also varies over time. Our results indicate that heterogeneity in environmental stress may lead to altered allele frequencies over ecological timescales and indirectly drive the evolution of longevity. This has important implications for understanding the evolution of life‐history strategies. 相似文献
9.
10.
Alicia N. Minniti Hctor Arriagada Soledad Zúiga Marcela Bravo‐Zehnder Ivn E. Alfaro Rebeca Aldunate 《Aging cell》2019,18(1)
The insulin‐IGF‐1/DAF‐2 pathway has a central role in the determination of aging and longevity in Caenorhabditis elegans and other organisms. In this paper, we measured neuronal insulin secretion (using INS‐22::Venus) during C. elegans lifespan and monitored how this secretion is modified by redox homeostasis. We showed that INS‐22::Venus secretion fluctuates during the organism lifetime reaching maximum levels in the active reproductive stage. We also demonstrate that long‐lived daf‐2 insulin receptor mutants show remarkable low levels of INS‐22::Venus secretion. In contrast, we found that short‐lived mutant worms that lack the oxidation repair enzyme MSRA‐1 show increased levels of INS‐22::Venus secretion, specifically during the reproductive stage. MSRA‐1 is a target of the insulin‐IGF‐1/DAF‐2 pathway, and the expression of this antioxidant enzyme exclusively in the nervous system rescues the mutant insulin release phenotype and longevity. The msra‐1 mutant phenotype can also be reverted by antioxidant treatment during the active reproductive stage. We showed for the first time that there is a pattern of neuronal insulin release with a noticeable increment during the peak of reproduction. Our results suggest that redox homeostasis can modulate longevity through the regulation of insulin secretion, and that the insulin‐IGF‐1/DAF‐2 pathway could be regulated, at least in part, by a feedback loop. These findings highlight the importance of timing for therapeutic interventions aimed at improving health span. 相似文献
11.
Many species use dormant stages for habitat selection by tying recovery to informative external cues. Other species have an undiscerning strategy in which they recover randomly despite having advanced sensory systems. We investigated whether elements of a species' habitat structure and life history can bar it from developing a discerning recovery strategy. The nematode Caenorhabditis elegans has a dormant stage called the dauer larva that disperses between habitat patches. On one hand, C. elegans colonization success is profoundly influenced by the bacteria found in its habitat patches, so we might expect this to select for a discerning strategy. On the other hand, C. elegans' habitat structure and life history suggest that there is no fitness benefit to varying recovery, which might select for an undiscerning strategy. We exposed dauers of three genotypes to a range of bacteria acquired from the worms' natural habitat. We found that C. elegans dauers recover in all conditions but increase recovery on certain bacteria depending on the worm's genotype, suggesting a combination of undiscerning and discerning strategies. Additionally, the worms' responses did not match the bacteria's objective quality, suggesting that their decision is based on other characteristics. 相似文献
12.
Sung Min Han Matthew J Eckwahl Benjamin Isaiah Meyer Sally Peach Jay R Hesselberth Sandra L Wolin Marc Hammarlund 《EMBO reports》2014,15(12):1278-1285
RNA ligation can regulate RNA function by altering RNA sequence, structure and coding potential. For example, the function of XBP1 in mediating the unfolded protein response requires RNA ligation, as does the maturation of some tRNAs. Here, we describe a novel in vivo model in Caenorhabditis elegans for the conserved RNA ligase RtcB and show that RtcB ligates the xbp‐1 mRNA during the IRE‐1 branch of the unfolded protein response. Without RtcB, protein stress results in the accumulation of unligated xbp‐1 mRNA fragments, defects in the unfolded protein response, and decreased lifespan. RtcB also ligates endogenous pre‐tRNA halves, and RtcB mutants have defects in growth and lifespan that can be bypassed by expression of pre‐spliced tRNAs. In addition, animals that lack RtcB have defects that are independent of tRNA maturation and the unfolded protein response. Thus, RNA ligation by RtcB is required for the function of multiple endogenous target RNAs including both xbp‐1 and tRNAs. RtcB is uniquely capable of performing these ligation functions, and RNA ligation by RtcB mediates multiple essential processes in vivo. 相似文献
13.
Yanwei Wu Shiya Cheng Hongyu Zhao Wei Zou Sawako Yoshina Shohei Mitani Hong Zhang Xiaochen Wang 《EMBO reports》2014,15(9):973-981
Autophagosome formation is promoted by the PI3 kinase complex and negatively regulated by myotubularin phosphatases, indicating that regulation of local phosphatidylinositol 3‐phosphate (PtdIns3P) levels is important for this early phase of autophagy. Here, we show that the Caenorhabditis elegans myotubularin phosphatase MTM‐3 catalyzes PtdIns3P turnover late in autophagy. MTM‐3 acts downstream of the ATG‐2/EPG‐6 complex and upstream of EPG‐5 to promote autophagosome maturation into autolysosomes. MTM‐3 is recruited to autophagosomes by PtdIns3P, and loss of MTM‐3 causes increased autophagic association of ATG‐18 in a PtdIns3P‐dependent manner. Our data reveal critical roles of PtdIns3P turnover in autophagosome maturation and/or autolysosome formation. 相似文献
14.
15.
16.
M. Zhou J. Zhu H. Yu X. Yin P.M. Sabour L. Zhao W. Chen J. Gong 《Journal of applied microbiology》2014,117(1):217-226
17.
Detection of β‐exotoxin synthesis in Bacillus thuringiensis using an easy bioassay with the nematode Caenorhabditis elegans 
下载免费PDF全文
下载免费PDF全文 A.I. Sánchez‐Soto G.I. Saavedra‐González J.E. Ibarra R. Salcedo‐Hernández J.E. Barboza‐Corona M.C. Del Rincón‐Castro 《Letters in applied microbiology》2015,61(6):562-567
18.
Dietary restriction (DR) robustly delays the aging process in all animals tested so far. DR slows aging by negatively regulating the target of rapamycin (TOR) and S6 kinase (S6K) signaling pathway and thus inhibiting translation. Translation inhibition in C. elegans is known to activate the innate immune signal ZIP‐2. Here, we show that ZIP‐2 is activated in response to DR and in feeding‐defective eat‐2 mutants. Importantly, ZIP‐2 contributes to the improvements in longevity and healthy aging, including mitochondrial integrity and physical ability, mediated by DR in C. elegans. We further show that ZIP‐2 is activated upon inhibition of TOR/S6K signaling. However, DR‐mediated activation of ZIP‐2 does not require the TOR/S6K effector PHA‐4/FOXA. Furthermore, zip‐2 was not activated or required for longevity in daf‐2 mutants, which mimic a low nutrition status. Thus, DR appears to activate ZIP‐2 independently of PHA‐4/FOXA and DAF‐2. The link between DR, aging, and immune activation provides practical insight into the DR‐induced benefits on health span and longevity. 相似文献
19.