Cholesterol regulates DAF-16 nuclear localization and fasting-induced longevity in C. elegans

Ihara, Akiko; Uno, Masaharu; Miyatake, Koichi; Honjoh, Sakiko; Nishida, Eisuke

doi:10.1016/j.exger.2016.10.011

Cited by 14 publications

(17 citation statements)

References 36 publications

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“…DAF-16 is transferred to nucleus in response to environmental stressors such as oxidative stress, heat shock, and UV irradiation ( 40 ). DR also induces nuclear localization of DAF-16 ( 40 , 41 ). Based on the result that DAF-16 was required for increased resistance to Aβ-induced toxicity by selenocysteine, we hypothesized that selenocysteine might induce nuclear localization of DAF-16.…”

Section: Resultsmentioning

confidence: 97%

Selenocysteine mimics the effect of dietary restriction on lifespan via SKN‑1 and retards age‑associated pathophysiological changes in Caenorhabditis�elegans

Kim

Park

2018

Mol Med Report

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Selenocysteine, a sulfur-containing amino acid, can modulate cellular oxidative stress defense systems by incorporating into anti-oxidant enzymes such as glutathione peroxidase and thioredoxin reductase. Selenocysteine can also prevent cancer, neurodegenerative diseases and cardiovascular diseases. A recent study revealed that dietary supplementation with selenocysteine can increase the resistance of Caenorhabditis elegans to environmental stressors and its lifespan. The objective of the present study was to identify the underlying mechanism involved in the lifespan-extending effect of selenocysteine and the effect of selenocysteine on age-associated pathophysiological changes. Lifespan assays with known long-lived mutants of age-1 (the ortholog of the phosphoinositide 3-kinase), clk-1 (the ortholog of demethoxyubiquinone hydroxylase) and eat-2 (a ligand-gated ion channel subunit) revealed that the effect of selenocysteine on lifespan specifically overlapped with that of the eat-2 mutation, a genetic model of dietary restriction (DR). Selenocysteine mimicked the effect of DR on the bacterial dilution method. It required SKN-1 (the ortholog of mammalian nuclear factor-erythroid-related factor) for lifespan extension. In addition, selenocysteine significantly delayed the paralysis induced by human amyloid-β gene, positively correlated with the incidence of Alzheimer's disease. The effect of selenocysteine on amyloid-β-induced toxicity was dependent on the nuclear localization of DAF-16. Reduced survival caused by high-glucose-diet was recovered by selenocysteine. Selenocysteine also reduced the cellular level of reactive oxygen species known to be increased by high-glucose-diet. The results of the present study suggested that selenocysteine can mimic the effect of DR on lifespan and age-associated pathophysiological alterations, providing scientific evidence for the development of DR mimetics using selenocysteine.

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Section: Resultsmentioning

confidence: 97%

Selenocysteine mimics the effect of dietary restriction on lifespan via SKN‑1 and retards age‑associated pathophysiological changes in Caenorhabditis�elegans

Kim

Park

2018

Mol Med Report

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“…Among them, nap‐1 and acdh‐1 have been previously linked to lipid metabolism and aging regulation. NAP‐1 is a conserved nucleosome assembly protein (NAP) family member that can function as a sensor of cholesterol and interact with DAF‐16 to regulate transcription of longevity genes (Cheong et al, ; Ihara, Uno, Miyatake, Honjoh, & Nishida, ). NAP‐1 overexpression is sufficient to extend lifespan and enhance fat storage in wild‐type animals (Cheong et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…Many of these genes (e.g., fatty acid desaturase genes and acyl‐CoA dehydrogenase genes) are targets of DAF‐16 (Murphy et al, ). Among the genes whose expression is regulated in opposite directions between the two long‐lived and short‐lived MT regulator mutants, nap‐1 encodes a conserved nucleosome assembly protein (NAP) family member that can function as a cofactor of DAF‐16 to regulate transcription of longevity genes (Cheong et al, ; Ihara et al, ). acdh‐1 was previously reported as a target of DAF‐16 (Murphy et al, ).…”

Section: Discussionmentioning

confidence: 99%

Microtubule regulators act in the nervous system to modulate fat metabolism and longevity through DAF‐16 in C. elegans

Zhang

et al. 2019

Aging Cell

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Microtubule (MT) regulation is involved in both neuronal function and the maintenance of neuronal structure, and MT dysregulation appears to be a general downstream indicator and effector of age‐related neurodegeneration. But the role of MTs in natural aging is largely unknown. Here, we demonstrate a role of MT regulators in regulating longevity. We find that loss of EFA‐6, a modulator of MT dynamics, can delay both neuronal aging and extend the lifespan of C. elegans. Through the use of genetic mutants affecting other MT‐regulating genes in C. elegans, we find that loss of MT stabilizing genes (including ptrn‐1 and ptl‐1) shortens lifespan, while loss of MT destabilizing gene hdac‐6 extends lifespan. Via the use of tissue‐specific transgenes, we further show that these MT regulators can act in the nervous system to modulate lifespan. Through RNA‐seq analyses, we found that genes involved in lipid metabolism were differentially expressed in MT regulator mutants, and via the use of Nile Red and Oil Red O staining, we show that the MT regulator mutants have altered fat storage. We further find that the increased fat storage and extended lifespan of the long‐lived MT regulator mutants are dependent on the DAF‐16/FOXO transcription factor. Our results suggest that neuronal MT status might affect organismal aging through DAF‐16‐regulated changes in fat metabolism, and therefore, MT‐based therapies might represent a novel intervention to promote healthy aging.

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“…Many transcription factors that modulate stress response and aging have been identified in the nematode, like DAF-16, HSF-1, and SKN-1 [ 33 ]. Worms under adverse conditions, such as food depletion, overcrowding, high temperature, or oxidative stress, DAF-16 would be translocated to the nucleus and activate the expression of its targeted genes [ 34 , 35 , 36 ]. Therefore, we measured whether compound 3 could activate the nuclear localization of DAF-16.…”

Section: Resultsmentioning

confidence: 99%

Aspirin Derivative 5-(Bis(3-methylbut-2-enyl)amino)-2-hydroxybenzoic Acid Improves Thermotolerance via Stress Response Proteins in Caenorhabditis elegans

Huang

et al. 2018

Molecules

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Aging is a major risk factor for many prevalent diseases. Pharmacological intervention to improve the health span and extend the lifespan could be a preventive elixir for aging and age-related diseases. The non-steroid anti-inflammation medicine aspirin was reported to delay aging in Caenorhabditis elegans (C. elegans) and mice. We are wondering if the analogues of aspirin could also present antiaging activity. Here, we synthesized several aspirin derivatives and investigated their thermotolerance and antiaging effect in C. elegans. One of the compounds, 5-(bis(3-methylbut-2-en-1-yl)amino)-2-hydroxybenzoic acid, moderately increased the survival of C. elegans under heat stress, but could not extend the lifespan under optimum conditions. This compound could increase the mRNA level of stress response gene gst-4, and the mRNA and protein expression level of heat shock protein hsp-16.2 under heat stress. The failure of activating the transcription factor DAF-16 might explain why this compound could not act as aspirin to extend the lifespan of C. elegans. Our results would help further the investigation of the pharmacological activity of aspirin analogues and the relationship between structures and activity.

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Cholesterol regulates DAF-16 nuclear localization and fasting-induced longevity in C. elegans

Cited by 14 publications

References 36 publications

Selenocysteine mimics the effect of dietary restriction on lifespan via SKN‑1 and retards age‑associated pathophysiological changes in Caenorhabditis�elegans

Selenocysteine mimics the effect of dietary restriction on lifespan via SKN‑1 and retards age‑associated pathophysiological changes in Caenorhabditis�elegans

Microtubule regulators act in the nervous system to modulate fat metabolism and longevity through DAF‐16 in C. elegans

Aspirin Derivative 5-(Bis(3-methylbut-2-enyl)amino)-2-hydroxybenzoic Acid Improves Thermotolerance via Stress Response Proteins in Caenorhabditis elegans

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