scholarly journals Life span extension by glucose restriction is abrogated by methionine supplementation: Cross-talk between glucose and methionine and implication of methionine as a key regulator of life span

2020 ◽  
Vol 6 (32) ◽  
pp. eaba1306 ◽  
Author(s):  
Ke Zou ◽  
Silvia Rouskin ◽  
Kevin Dervishi ◽  
Mark A. McCormick ◽  
Arjun Sasikumar ◽  
...  
Keyword(s):  
Life Span ◽  
Cross Talk ◽  
Molecular Mechanisms ◽  
Glucose Sensing ◽  
Ribosome Profiling ◽  
General Mechanism ◽  
Life Span Extension ◽  
Extend Life Span ◽  
Genetic Perturbations ◽  
Glucose Restriction

Caloric restriction (CR) is known to extend life span across species; however, the molecular mechanisms are not well understood. We investigate the mechanism by which glucose restriction (GR) extends yeast replicative life span, by combining ribosome profiling and RNA-seq with microfluidic-based single-cell analysis. We discovered a cross-talk between glucose sensing and the regulation of intracellular methionine: GR down-regulated the transcription and translation of methionine biosynthetic enzymes and transporters, leading to a decreased intracellular methionine concentration; external supplementation of methionine cancels the life span extension by GR. Furthermore, genetic perturbations that decrease methionine synthesis/uptake extend life span. These observations suggest that intracellular methionine mediates the life span effects of various nutrient and genetic perturbations, and that the glucose-methionine cross-talk is a general mechanism for coordinating the nutrient status and the translation/growth of a cell. Our work also implicates proteasome as a downstream effector of the life span extension by GR.

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 UPRER promotes lipophagy independent of chaperones to extend life span

2020 ◽  
Vol 6 (1) ◽  
pp. eaaz1441 ◽  
Author(s):  
Joseph R. Daniele ◽  
Ryo Higuchi-Sanabria ◽  
Jenni Durieux ◽  
Samira Monshietehadi ◽  
Vidhya Ramachandran ◽  
...  
Keyword(s):  
Life Span ◽  
Genetic Factors ◽  
Protein Homeostasis ◽  
Life Span Extension ◽  
Unfolded Protein ◽  
Extend Life Span ◽  
Protein Chaperones ◽  
Ectopic Activation ◽  
The Unfolded Protein Response ◽  
Protein Response

Longevity is dictated by a combination of environmental and genetic factors. One of the key mechanisms to regulate life-span extension is the induction of protein chaperones for protein homeostasis. Ectopic activation of the unfolded protein response of the endoplasmic reticulum (UPRER) specifically in neurons is sufficient to enhance organismal stress resistance and extend life span. Here, we find that this activation not only promotes chaperones but also facilitates ER restructuring and ER function. This restructuring is concomitant with lipid depletion through lipophagy. Activation of lipophagy is distinct from chaperone induction and is required for the life-span extension found in this paradigm. Last, we find that overexpression of the lipophagy component, ehbp-1, is sufficient to deplete lipids, remodel ER, and promote life span. Therefore, UPR induction in neurons triggers two distinct programs in the periphery: the proteostasis arm through protein chaperones and metabolic changes through lipid depletion mediated by EH domain binding protein 1 (EHBP-1).

Rtg2 Protein Links Metabolism and Genome Stability in Yeast Longevity

Genetics ◽  
2004 ◽  
Vol 166 (2) ◽  
pp. 765-777
Author(s):  
Corina Borghouts ◽  
Alberto Benguria ◽  
Jaroslaw Wawryn ◽  
S Michal Jazwinski
Keyword(s):  
Life Span ◽  
Ribosomal Dna ◽  
Genome Stability ◽  
Molecular Mechanisms ◽  
Retrograde Signaling ◽  
Response Signal ◽  
Life Span Extension ◽  
Retrograde Signal ◽  
In Cells ◽  
Retrograde Response

Abstract Mitochondrial dysfunction induces a signaling pathway, which culminates in changes in the expression of many nuclear genes. This retrograde response, as it is called, extends yeast replicative life span. It also results in a marked increase in the cellular content of extrachromsomal ribosomal DNA circles (ERCs), which can cause the demise of the cell. We have resolved the conundrum of how these two molecular mechanisms of yeast longevity operate in tandem. About 50% of the life-span extension elicited by the retrograde response involves processes other than those that counteract the deleterious effects of ERCs. Deletion of RTG2, a gene that plays a central role in relaying the retrograde response signal to the nucleus, enhances the generation of ERCs in cells with (grande) or in cells without (petite) fully functional mitochondria, and it curtails the life span of each. In contrast, overexpression of RTG2 diminishes ERC formation in both grandes and petites. The excess Rtg2p did not augment the retrograde response, indicating that it was not engaged in retrograde signaling. FOB1, which is known to be required for ERC formation, and RTG2 were found to be in converging pathways for ERC production. RTG2 did not affect silencing of ribosomal DNA in either grandes or petites, which were similar to each other in the extent of silencing at this locus. Silencing of ribosomal DNA increased with replicative age in either the presence or the absence of Rtg2p, distinguishing silencing and ERC accumulation. Our results indicate that the suppression of ERC production by Rtg2p requires that it not be in the process of transducing the retrograde signal from the mitochondrion. Thus, RTG2 lies at the nexus of cellular metabolism and genome stability, coordinating two pathways that have opposite effects on yeast longevity.

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.

SOD2 Functions Downstream of Sch9 to Extend Longevity in Yeast

Genetics ◽  
2003 ◽  
Vol 163 (1) ◽  
pp. 35-46 ◽  
Author(s):  
Paola Fabrizio ◽  
Lee-Loung Liou ◽  
Vanessa N Moy ◽  
Alberto Diaspro ◽  
Joan Selverstone Valentine ◽  
...  
Keyword(s):  
Life Span ◽  
Stress Resistance ◽  
Reversible Inactivation ◽  
Life Span Extension ◽  
Resistance Proteins ◽  
Mitochondrial Superoxide ◽  
Mitochondrial Aconitase ◽  
Chronological Life Span ◽  
Survival Extension ◽  
Mitochondrial Superoxide Dismutase

Abstract Signal transduction pathways inactivated during periods of starvation are implicated in the regulation of longevity in organisms ranging from yeast to mammals, but the mechanisms responsible for life-span extension are poorly understood. Chronological life-span extension in S. cerevisiae cyr1 and sch9 mutants is mediated by the stress-resistance proteins Msn2/Msn4 and Rim15. Here we show that mitochondrial superoxide dismutase (Sod2) is required for survival extension in yeast. Deletion of SOD2 abolishes life-span extension in sch9Δ mutants and decreases survival in cyr1:mTn mutants. The overexpression of Sods—mitochondrial Sod2 and cytosolic CuZnSod (Sod1)—delays the age-dependent reversible inactivation of mitochondrial aconitase, a superoxide-sensitive enzyme, and extends survival by 30%. Deletion of the RAS2 gene, which functions upstream of CYR1, also doubles the mean life span by a mechanism that requires Msn2/4 and Sod2. These findings link mutations that extend chronological life span in S. cerevisiae to superoxide dismutases and suggest that the induction of other stress-resistance genes regulated by Msn2/4 and Rim15 is required for maximum longevity extension.

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