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

Desjardins, David; Cacho-Valadez, Briseida; Liu, Ju-Ling; Wang, Ying; Yee, Callista; Bernard, Kristine; Khaki, Arman; Breton, Lionel; Hekimi, Siegfried

doi:10.1111/acel.12528

Cited by 71 publications

(59 citation statements)

References 46 publications

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“…mTOR inhibition extends life span and improves age‐related pathologies in a variety of species . Interestingly, a recent report established that mTOR is activated through a PI3K/Akt/mTOR pathway during replicative senescence in vascular smooth muscle cells . Linking geroconversion to oxidants, we have shown that activation of Akt by a O 2 •− ‐driven prooxidant state mimics growth‐factor signaling and promotes proliferation in the absence of growth factors .…”

Section: Oxidants and Cellular Senescence Beyond Cell Cycle Arrestmentioning

confidence: 70%

“…In an effort to understand the molecular pathways involved in geroconversion, it was shown that PI3K/Akt/mTOR pathway is upregulated in aging cells compared to young cells. Inhibitors of PI3K or mTOR blocks the cellular changes in old cells toward senescence . Moreover, Akt deficiency makes cells more resistant to replicative senescence, while activation of Akt shortens the lifespan of human endothelial cells .…”

Section: Oxidants and Cellular Senescence Beyond Cell Cycle Arrestmentioning

confidence: 99%

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Organismal Aging and Oxidants beyond Macromolecules Damage

Clément

Luo

2020

Proteomics

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The relationship between oxidants and organismal aging was first articulated through the free radical theory of aging. One of the major predictions of the free radical theory of aging is that oxidative stress shortens organisms’ lifespan because of an increased level of oxidants, which are damaging to macromolecules. However, challenging the role of oxidants in age‐related diseases, there is now sufficient evidence that antioxidant supplements do not provide significant health benefits. Interestingly, in addition to an increase in oxidant‐mediated macromolecules damage, there is convincing experimental data to support the role of senescent cells in the process of aging. Here, the current knowledge regarding the role of oxidants and cellular senescence in organismal aging is reviewed and it is proposed that, in addition to the role of oxidants as inducers of macromolecular damage, oxidants may also function as regulators of signaling pathways involved in the establishment of cellular senescence. If this role for oxidants is established, it may be necessary to modify the free radical theory of aging from “Organisms age because cells accumulate reactive oxygen species‐dependent damage over time” to: “Organisms age because cells accumulate oxidants’‐dependent damage and oxidants’‐dependent senescent characteristics over time.”

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Section: Oxidants and Cellular Senescence Beyond Cell Cycle Arrestmentioning

confidence: 70%

Section: Oxidants and Cellular Senescence Beyond Cell Cycle Arrestmentioning

confidence: 99%

Organismal Aging and Oxidants beyond Macromolecules Damage

Clément

Luo

2020

Proteomics

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“…Indeed, PQQ-induced lifespan extension was abolished upon treatment with the antioxidant NAC (Benrahmoune et al, 2000;Desjardins et al, 2017) (Fig. 4A; Fig.…”

Section: Bli-3-dependent Ros Production Is Necessary and Sufficient Fmentioning

confidence: 96%

“…Given that low levels of ROS, namely mtROS and DUOX-mediated ROS, extend lifespan, the intake of vitamins could eliminate such low levels of ROS and cancel their longevity-promoting effects (Desjardins et al, 2017). We propose that PQQ is an effective chemical in lifespan extension acting through generating longevity-promoting ROS at the plasma membrane by the peroxidase and dual oxidase system, which is a fundamentally different action from those of existing antioxidants.…”

Section: Pqq Is a Lifespan Extension Chemical With A Novel Action Mecmentioning

confidence: 97%

Lifespan extension by peroxidase and dual oxidase-mediated ROS signaling through pyrroloquinoline quinone in C. elegans

Sasakura

Moribe

Nakano

et al. 2017

Journal of Cell Science

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Reactive oxygen species (ROS), originally characterized based on their harmful effects on cells or organisms, are now recognized as important signal molecules regulating various biological processes. In particular, low levels of ROS released from mitochondria extend lifespan. Here, we identified a novel mechanism of generating appropriate levels of ROS at the plasma membrane through a peroxidase and dual oxidase (DUOX) system, which could extend lifespan in Caenorhabditis elegans. A redox co-factor, pyrroloquinoline quinone (PQQ), activates the C. elegans DUOX protein BLI-3 to produce the ROS H 2 O 2 at the plasma membrane, which is subsequently degraded by peroxidase (MLT-7), eventually ensuring adequate levels of ROS. These ROS signals are transduced mainly by the oxidative stress transcriptional factors SKN-1 (Nrf2 or NFE2L2 in mammals) and JUN-1, and partially by DAF-16 (a FOXO protein homolog). Cell biology experiments demonstrated a similarity between the mechanisms of PQQ-induced activation of human DUOX1 and DUOX2 and that of C. elegans BLI-3, suggesting that DUOXs are potential targets of intervention for lifespan extension. We propose that low levels of ROS, fine-tuned by the peroxidase and dual oxidase system at the plasma membrane, act as second messengers to extend lifespan by the effect of hormesis.

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“…Although ectopic overexpression of the peroxiredoxin Prx5 increases lifespan in Drosophila (Radyuk et al ., 2009), indicating that decreasing ROS production can attenuate the mitochondrial death spiral as expected, the effects of feeding antioxidants on lifespan have been inconsistent. Difficulties in enabling antioxidant access to the cytoplasm might represent one issue, as the effectiveness of specific antioxidants can vary depending on the precise method of antioxidant presentation (Shibamura et al ., 2009; in data interpretation include the difficulty in determining the Desjardins et al ., 2017). Additional difficulties extent to which the antioxidant feeding actually reduces the cytoplasm.…”

Section: Role Of Antioxidants In Lifespanmentioning

confidence: 99%

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

Stern

2017

Aging Cell

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SummaryThe antagonistic pleiotropy (AP) theory posits that aging occurs because alleles that are detrimental in older organisms are beneficial to growth early in life and thus are maintained in populations. Although genes of the insulin signaling pathway likely participate in AP, the insulin‐regulated cellular correlates of AP have not been identified. The mitochondrial quality control process called mitochondrial autophagy (mitophagy), which is inhibited by insulin signaling, might represent a cellular correlate of AP. In this view, rapidly growing cells are limited by ATP production; these cells thus actively inhibit mitophagy to maximize mitochondrial ATP production and compete successfully for scarce nutrients. This process maximizes early growth and reproduction, but by permitting the persistence of damaged mitochondria with mitochondrial DNA mutations, becomes detrimental in the longer term. I suggest that as mitochondrial ATP output drops, cells respond by further inhibiting mitophagy, leading to a further decrease in ATP output in a classic death spiral. I suggest that this increasing ATP deficit is communicated by progressive increases in mitochondrial ROS generation, which signals inhibition of mitophagy via ROS‐dependent activation of insulin signaling. This hypothesis clarifies a role for ROS in aging, explains why insulin signaling inhibits autophagy, and why cells become progressively more oxidized during aging with increased levels of insulin signaling and decreased levels of autophagy. I suggest that the mitochondrial death spiral is not an error in cell physiology but rather a rational approach to the problem of enabling successful growth and reproduction in a competitive world of scarce nutrients.

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

Cited by 71 publications

References 46 publications

Organismal Aging and Oxidants beyond Macromolecules Damage

Organismal Aging and Oxidants beyond Macromolecules Damage

Lifespan extension by peroxidase and dual oxidase-mediated ROS signaling through pyrroloquinoline quinone in C. elegans

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

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