Reactive Oxygen Species and Aging in<i>Caenorhabditis elegans</i>: Causal or Casual Relationship?

Raamsdonk, Jeremy M. Van; Hekimi, Siegfried

doi:10.1089/ars.2010.3215

Cited by 166 publications

(128 citation statements)

References 286 publications

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“…1E–H). These results are consistent with many reports showing that mild inhibition of mitochondrial components confers longevity (reviewed in Van Raamsdonk & Hekimi, 2010; Hwang et al ., 2012). We then examined whether the longevity caused by these six RNAi clones was dependent on HIF‐1.…”

Section: Resultssupporting

confidence: 93%

Inhibition of elongin C promotes longevity and protein homeostasis via HIF‐1 in C. elegans

et al. 2015

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SummaryThe transcription factor hypoxia‐inducible factor 1 (HIF‐1) is crucial for responses to low oxygen and promotes longevity in Caenorhabditis elegans. We previously performed a genomewide RNA interference screen and identified many genes that act as potential negative regulators of HIF‐1. Here, we functionally characterized these genes and found several novel genes that affected lifespan. The worm ortholog of elongin C, elc‐1, encodes a subunit of E3 ligase and transcription elongation factor. We found that knockdown of elc‐1 prolonged lifespan and delayed paralysis caused by impaired protein homeostasis. We further showed that elc‐1 RNA interference increased lifespan and protein homeostasis by upregulating HIF‐1. The roles of elongin C and HIF‐1 are well conserved in eukaryotes. Thus, our study may provide insights into the aging regulatory pathway consisting of elongin C and HIF‐1 in complex metazoans.

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Section: Resultssupporting

confidence: 93%

Inhibition of elongin C promotes longevity and protein homeostasis via HIF‐1 in C. elegans

et al. 2015

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“…The description of these results and their impact on the validity and the future of the theory is the main subject of recent reviews in the field [22][23][24][25].…”

Section: Recent Results That Are Incompatible With the Mfrtamentioning

confidence: 99%

Taking a “good” look at free radicals in the aging process

Hekimi

Lapointe

Yang

2011

Trends in Cell Biology

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496

348

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The mitochondrial free radical theory of aging (MFRTA) proposes that aging is caused by damage to macromolecules from mitochondrial reactive oxygen species (ROS). This is based on the observed association of the rate of aging and the aged phenotype with the generation of ROS and with oxidative damage. The theory has led to the strong conviction in the general public that the consumption of antioxidants is crucial to health and beneficial to lifespan. However, a variety of recent findings convincingly demonstrate that ROS generation and oxidative damage cannot be the cause of aging. Here we propose that ROS play a role in mediating a stress response to agedependent damage, which could generate the observed correlation between aging and ROS without implying that ROS cause aging. Redefining our understanding of the relationship between ROS and agingMitochondria are a major source of reactive oxygen species (ROS), a type of molecule that includes free radicals such as superoxide. ROS spontaneously oxidize and damage macromolecules such as proteins, lipids and nucleic acids. Cells and organisms are said to be sustaining oxidative stress when an imbalance between ROS generation and detoxification or repair leads to an increase in the level of ROS-dependent damage. The mitochondrial free radical theory of aging (MFRTA) has provided an attractive framework that integrates numerous observations about the generation, the toxicity and the detoxification of ROS, as well as about how these parameters change with the physiological state of cells and organisms and with chronological age. The theory proposes that aging is actually caused by the toxicity of ROS through a vicious cycle in which ROS damage to the constituents of mitochondria leads to the generation of more ROS. The theory is based on numerous observations, including (1) that there is a strong correlation between chronological age and the level of ROS generation and oxidative damage, (2) that mitochondrial function is gradually lost during aging, (3) that inhibition of mitochondrial function can enhance ROS production, and (4) that several age-dependent diseases are associated with severe increases in oxidative stress.The strength of the MFRTA is that it provides a framework for many observations while also stating a plausible causal theory of aging. Furthermore, it provided a clear research program by proposing a theory to be tested as well as by suggesting that decreasing the generation of ROS will result in health benefits. In fact the MFRTA is often taught in textbooks and in *

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“…Both types of properties have been firmly implicated in the aging process, in particular in the nematode Caenorhabditis elegans (Van Raamsdonk & Hekimi, 2010; Yang & Hekimi, 2010a). One of the obstacles for understanding the role of ROS in any process is the difficulty of visualizing them directly in vivo , as they occur at low concentration, interact readily with other molecules, and are removed by powerful enzymatic systems.…”

Section: Introductionmentioning

confidence: 99%

“…NUO‐6 and GAS‐1 are subunits of mitochondrial complex I (Kayser et al ., 2001; Yang & Hekimi, 2010b). Mutations in all these genes result in defective mitochondrial function and increased mtROS generation (Van Raamsdonk & Hekimi, 2010; Yang & Hekimi, 2010a). In fact, the longevity of isp‐1 and nuo‐6 mutants depends on an elevated generation of mitochondrial superoxide, which triggers the apoptotic signaling pathway without inducing apoptosis (Yee et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

Antioxidants reveal an inverted U‐shaped dose‐response relationship between reactive oxygen species levels and the rate of aging in Caenorhabditis elegans

et al. 2016

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SummaryReactive oxygen species (ROS) are potentially toxic, but they are also signaling molecules that modulate aging. Recent observations that ROS can promote longevity have to be reconciled with the numerous claims about the benefits of antioxidants on lifespan. Here, three antioxidants [N‐acetylcysteine (NAC), vitamin C, and resveratrol (RSV)] were tested on Caenorhabditis elegans mutants that alter drug uptake, mitochondrial function, and ROS metabolism. We observed that like pro‐oxidants, antioxidants can both lengthen and shorten lifespan, dependent on concentration, genotypes, and conditions. The effects of antioxidants thus reveal an inverted U‐shaped dose–response relationship between ROS levels and lifespan. In addition, we observed that RSV can act additively to both NAC and paraquat, to dramatically increase lifespan. This suggests that the effect of compounds that modulate ROS levels can be additive when their loci of action or mechanisms of action are sufficiently distinct.

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Reactive Oxygen Species and Aging inCaenorhabditis elegans: Causal or Casual Relationship?

Cited by 166 publications

References 286 publications

Inhibition of elongin C promotes longevity and protein homeostasis via HIF‐1 in C. elegans

Inhibition of elongin C promotes longevity and protein homeostasis via HIF‐1 in C. elegans

Taking a “good” look at free radicals in the aging process

Antioxidants reveal an inverted U‐shaped dose‐response relationship between reactive oxygen species levels and the rate of aging in Caenorhabditis elegans

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