A Regulated Response to Impaired Respiration Slows Behavioral Rates and Increases Lifespan in Caenorhabditis elegans

Cristina, David; Cary, Michael; Lunceford, Adam; Clarke, Catherine F.; Kenyon, Cynthia

doi:10.1371/journal.pgen.1000450

Cited by 150 publications

(159 citation statements)

References 41 publications

Supporting

Mentioning

142

Contrasting

Unclassified

Order By: Relevance

“…S3 and SI Appendix, Table S2. (17,43) in which gene-expression patterns of isp-1 mutants were compared with those of wild-type animals ( Table 1 and Dataset S1). Among the differentially regulated genes in our dataset (q < 0.05, Dataset S1), smf-3 and ftn-1 were intriguing, because these genes are implicated in the regulation of cellular levels of iron ions and ROS.…”

Section: Hif-1 May Mediate Ros-induced Longevity By Regulating Ironmentioning

confidence: 99%

Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans

Hwang

Ryu

Artan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

161

142

View full text Add to dashboard Cite

Mild inhibition of mitochondrial respiration extends the lifespan of many species. In Caenorhabditis elegans, reactive oxygen species (ROS) promote longevity by activating hypoxia-inducible factor 1 (HIF-1) in response to reduced mitochondrial respiration. However, the physiological role and mechanism of ROS-induced longevity are poorly understood. Here, we show that a modest increase in ROS increases the immunity and lifespan of C. elegans through feedback regulation by HIF-1 and AMP-activated protein kinase (AMPK). We found that activation of AMPK as well as HIF-1 mediates the longevity response to ROS. We further showed that AMPK reduces internal levels of ROS, whereas HIF-1 amplifies the levels of internal ROS under conditions that increase ROS. Moreover, mitochondrial ROS increase resistance to various pathogenic bacteria, suggesting a possible association between immunity and long lifespan. Thus, AMPK and HIF-1 may control immunity and longevity tightly by acting as feedback regulators of ROS.aging | mitochondria | immunity | reactive oxygen species | C. elegans M itochondria are essential for various physiological processes, including energy production, apoptosis, metabolism, and signaling (1). Thus, it is not surprising that defects in mitochondrial function are linked to many diseases. Interestingly, however, mild inhibition of mitochondrial respiration increases the lifespans of many organisms (2, 3). In particular, genetic inhibition of components of the mitochondrial electron transport chain (ETC) increases longevity of the roundworm Caenorhabditis elegans. For example, mutations in clk-1 (a ubiquinone hydroxylase) and isp-1 (iron-sulfur protein 1 in the mitochondrial complex III) extend the lifespans of worms (4, 5). Longevity resulting from mitochondrial ETC inhibition also has been observed in Drosophila (6, 7) and mice (8, 9). Thus, the mechanisms responsible for longevity may be evolutionarily conserved.Key genetic factors that mediate longevity caused by reduced mitochondrial respiration in C. elegans have been identified recently (10-17). However, the mechanisms are not completely understood. Hypoxia-inducible factor 1 (HIF-1), the master transcriptional regulator of cellular responses to hypoxia, is one of the mediators of longevity caused by inhibition of mitochondrial respiration in C. elegans (12). The physiological importance of HIF-1α in humans is underscored by the fact that mutations in VHL, the von HippelLindau tumor suppressor gene, which encodes an E3-ubiquitin ligase component required for the degradation of HIF-1, lead to an inherited form of cancer (18,19). HIF-1 regulates adaptation to low oxygen and various other biological processes, including axon guidance, immunity, iron homeostasis, and aging (20-29). Increased levels of HIF-1 by vhl-1 mutations or by overexpression of HIF-1 lengthen the lifespan of C. elegans (27, 28). In addition, we previously showed that inhibition of mitochondrial respiration promotes longevity by elevating reactive oxygen species (ROS) levels and incr...

show abstract

Section: Hif-1 May Mediate Ros-induced Longevity By Regulating Ironmentioning

confidence: 99%

Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans

Hwang

Ryu

Artan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

161

142

View full text Add to dashboard Cite

show abstract

“…Studies on the model organism C. elegans have revealed that perturbation in mitochondrial respiration and ROS induction can in fact have protective effects and lifespan extending properties. 30,31 Similarly, antioxidant treatments were found to abolish the positive metabolic effects (increase in insulin sensitivity) of exercise in humans. 32 Further studies are required to determine the potential of ROS and ROS signalling components for the treatment and prevention of age associated diseases and pathologies.…”

Section: Ros Induced Dna Damage and Checkpoint Responsesmentioning

confidence: 99%

ROS induced DNA damage and checkpoint responses: Influences on aging?

Guachalla

Rudolph²

2010

Cell Cycle

View full text Add to dashboard Cite

“…Dietary restriction shifts metabolism toward respiration (Lin et al., 2002) but, at the same time, impaired respiration can promote longevity in yeast and nematodes through enhanced retrograde response and activation of anaplerotic pathways (Cristina, Cary, Lunceford, Clarke & Kenyon, 2009). Although we did not follow up on this intriguing observation, we speculate that a higher demand for respiration during dietary restriction could lead to the activation of compensatory pathways.…”

Section: Resultsmentioning

confidence: 99%

Genomewide mechanisms of chronological longevity by dietary restriction in budding yeast

et al. 2018

View full text Add to dashboard Cite

SummaryDietary restriction is arguably the most promising nonpharmacological intervention to extend human life and health span. Yet, only few genetic regulators mediating the cellular response to dietary restriction are known, and the question remains which other regulatory factors are involved. Here, we measured at the genomewide level the chronological lifespan of Saccharomyces cerevisiae gene deletion strains under two nitrogen source regimens, glutamine (nonrestricted) and γ‐aminobutyric acid (restricted). We identified 473 mutants with diminished or enhanced extension of lifespan. Functional analysis of such dietary restriction genes revealed novel processes underlying longevity by the nitrogen source quality, which also allowed us to generate a prioritized catalogue of transcription factors orchestrating the dietary restriction response. Importantly, deletions of transcription factors Msn2, Msn4, Snf6, Tec1, and Ste12 resulted in diminished lifespan extension and defects in cell cycle arrest upon nutrient starvation, suggesting that regulation of the cell cycle is a major mechanism of chronological longevity. We further show that STE12 overexpression is enough to extend lifespan, linking the pheromone/invasive growth pathway with cell survivorship. Our global picture of the genetic players of longevity by dietary restriction highlights intricate regulatory cross‐talks in aging cells.

show abstract

A Regulated Response to Impaired Respiration Slows Behavioral Rates and Increases Lifespan in Caenorhabditis elegans

Cited by 150 publications

References 41 publications

Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans

Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans

ROS induced DNA damage and checkpoint responses: Influences on aging?

Genomewide mechanisms of chronological longevity by dietary restriction in budding yeast

Contact Info

Product

Resources

About