Dietary restriction in C. elegans: From rate-of-living effects to nutrient sensing pathways

As the most energetically expensive cellular process, translation must be finely tuned to environmental conditions. Dietary restriction attenuates signaling through the nutrient sensing mTOR pathway, which reduces translation and redirects resources to preserve the soma. These responses are associated with increased lifespan but also anabolic impairment, phenotypes also observed when translation is genetically suppressed. Here, we restricted translation downstream of mTOR separately in major tissues in C. elegans to better understand their roles in systemic adaptation and whether consequences to anabolic impairment were separable from positive effects on lifespan. Lowering translation in neurons, hypodermis, or germline tissue led to increased lifespan under well-fed conditions and improved survival upon withdrawal of food, indicating that these are key tissues coordinating enhanced survival when protein synthesis is reduced. Surprisingly, lowering translation in body muscle during development shortened lifespan while accelerating and increasing reproduction, a reversal of phenotypic trade-offs associated with systemic translation suppression. Suppressing mTORC1 selectively in body muscle also increased reproduction while slowing motility during development. In nature, this may be indicative of reduced energy expenditure related to foraging, acting as a “GO!” signal for reproduction. Together, results indicate that low translation in different tissues helps direct distinct systemic adaptations and suggest that unknown endocrine signals mediate these responses. Furthermore, mTOR or translation inhibitory therapeutics that target specific tissues may achieve desired interventions to aging without loss of whole-body anabolism.

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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

10.1101/2020.07.09.195503 ◽

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.

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Transgenerational fitness effects of lifespan extension by dietary restriction in Caenorhabditis elegans

10.1101/2020.06.24.168922 ◽

2020 ◽

Author(s):

Edward R. Ivimey-Cook ◽

Kris Sales ◽

Hanne Carlsson ◽

Simone Immler ◽

Tracey Chapman ◽

...

Keyword(s):

Dietary Restriction ◽

Mortality Risk ◽

Future Generations ◽

Lifespan Extension ◽

Dietary Interventions ◽

C Elegans ◽

Trade Offs ◽

Wide Range ◽

Broad Variety

AbstractDietary restriction increases lifespan in a broad variety of organisms and improves health in humans. However, long-term transgenerational consequences of dietary interventions are poorly understood. Here we investigated the effect of dietary restriction by temporary fasting (TF) on mortality risk, age-specific reproduction and fitness across three generations of descendants in C. elegans. We show that while TF robustly reduces mortality risk and improves late-life reproduction in the parental generation (P0), it has a wide range of both positive and deleterious effects on future generations (F1-F3). Remarkably, great-grandparental exposure to TF in early-life reduces fitness and increases mortality risk of F3 descendants to such an extent that TF no longer promotes a lifespan extension. These findings reveal that transgenerational trade-offs accompany the instant benefits of dietary restriction underscoring the need to consider fitness of future generations in pursuit of healthy ageing.

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Serotonin and dopamine modulate aging in response to food perception and availability

10.1101/2021.03.23.436516 ◽

2021 ◽

Author(s):

Hillary A. Miller ◽

Shijiao Huang ◽

Megan L. Schaller ◽

Elizabeth S. Dean ◽

Angela M. Tuckowski ◽

...

Keyword(s):

Dopamine Receptors ◽

Signaling Pathway ◽

Dopamine Receptor ◽

Dietary Restriction ◽

Mammalian Cells ◽

Serotonin Receptor ◽

Enteric Neuron ◽

C Elegans ◽

Food Perception ◽

A Cell

AbstractAn organism’s ability to perceive and respond to changes in its environment is crucial for its health and survival. Here we reveal how the most well-studied longevity intervention, dietary restriction (DR), acts in-part through a cell non-autonomous signaling pathway that is inhibited by the perception of attractive smells. Using an intestinal reporter for a key gene induced by DR but suppressed by attractive smells, we identify three compounds that block food perception in C. elegans, thereby increasing longevity as DR mimetics. These compounds clearly implicate serotonin and dopamine in limiting lifespan in response to food perception. We further identify an enteric neuron in this pathway that signals through the serotonin receptor 5-HT1A/ser-4 and dopamine receptor DRD2/dop-3. Aspects of this pathway are conserved in D. melanogaster and mammalian cells. Thus, blocking food perception through antagonism of serotonin or dopamine receptors is a plausible approach to mimic the benefits of dietary restriction.

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An AMPK-FOXO Pathway Mediates Longevity Induced by a Novel Method of Dietary Restriction in C. elegans

Current Biology ◽

10.1016/j.cub.2007.08.047 ◽

2007 ◽

Vol 17 (19) ◽

pp. 1646-1656 ◽

Cited By ~ 476

Author(s):

Eric L. Greer ◽

Dara Dowlatshahi ◽

Max R. Banko ◽

Judit Villen ◽

Kimmi Hoang ◽

...

Keyword(s):

Dietary Restriction ◽

C Elegans ◽

Novel Method

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Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans

Nature ◽

10.1038/nature20789 ◽

2016 ◽

Vol 541 (7635) ◽

pp. 102-106 ◽

Cited By ~ 85

Author(s):

Caroline Heintz ◽

Thomas K. Doktor ◽

Anne Lanjuin ◽

Caroline C. Escoubas ◽

Yue Zhang ◽

...

Keyword(s):

Dietary Restriction ◽

Splicing Factor ◽

C Elegans ◽

Splicing Factor 1

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A Dihydroflavonoid Naringin Extends the Lifespan of C. elegans and Delays the Progression of Aging-Related Diseases in PD/AD Models via DAF-16

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/6069354 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Qing Zhu ◽

Yuan Qu ◽

Xiao-Gang Zhou ◽

Jian-Ning Chen ◽

Huai-Rong Luo ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Biological Activities ◽

Nutrient Sensing ◽

Null Mutant ◽

Oxidative Stress Tolerance ◽

C Elegans ◽

Expression Of Genes ◽

Wide Range ◽

And Oxidative Stress

Naringin is a dihydroflavonoid, which is rich in several plant species used for herbal medicine. It has a wide range of biological activities, including antineoplastic, anti-inflammatory, antiphotoaging, and antioxidative activities. So it would be interesting to know if naringin has an effect on aging and aging-related diseases. We examined the effect of naringin on the aging of Caenorhabditis elegans (C. elegans). Our results showed that naringin could extend the lifespan of C. elegans. Moreover, naringin could also increase the thermal and oxidative stress tolerance, reduce the accumulation of lipofuscin, and delay the progress of aging-related diseases in C. elegans models of AD and PD. Naringin could not significantly extend the lifespan of long-lived mutants from genes in insulin/IGF-1 signaling (IIS) and nutrient-sensing pathways, such as daf-2, akt-2, akt-1, eat-2, sir-2.1, and rsks-1. Naringin treatment prolonged the lifespan of long-lived glp-1 mutants, which have decreased reproductive stem cells. Naringin could not extend the lifespan of a null mutant of the fox-head transcription factor DAF-16. Moreover, naringin could increase the mRNA expression of genes regulated by daf-16 and itself. In conclusion, we show that a natural product naringin could extend the lifespan of C. elegans and delay the progression of aging-related diseases in C. elegans models via DAF-16.

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10-Hydroxy-2-decenoic Acid, the Major Lipid Component of Royal Jelly, Extends the Lifespan ofCaenorhabditis elegansthrough Dietary Restriction and Target of Rapamycin Signaling

Journal of Aging Research ◽

10.1155/2015/425261 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 21

Author(s):

Yoko Honda ◽

Yoko Araki ◽

Taketoshi Hata ◽

Kenji Ichihara ◽

Masafumi Ito ◽

...

Keyword(s):

Dietary Restriction ◽

Royal Jelly ◽

Target Of Rapamycin ◽

Control Mechanisms ◽

Tor Signaling ◽

Decenoic Acid ◽

C Elegans ◽

Lipid Component ◽

Extended Lifespan ◽

And Oxidative Stress

Royal jelly (RJ) produced by honeybees has been reported to possess diverse health-beneficial properties and has been implicated to have a function in longevity across diverse species as well as honeybees. 10-Hydroxy-2-decenoic acid (10-HDA), the major lipid component of RJ produced by honeybees, was previously shown to increase the lifespan ofCaenorhabditis elegans.The objective of this study is to elucidate signaling pathways that are involved in the lifespan extension by 10-HDA. 10-HDA further extended the lifespan of thedaf-2mutants, which exhibit long lifespan through reducing insulin-like signaling (ILS), indicating that 10-HDA extended lifespan independently of ILS. On the other hand, 10-HDA did not extend the lifespan of theeat-2mutants, which show long lifespan through dietary restriction caused by a food-intake defect. This finding indicates that 10-HDA extends lifespan through dietary restriction signaling. We further found that 10-HDA did not extend the lifespan of the long-lived mutants indaf-15, which encodes Raptor, a target of rapamycin (TOR) components, indicating that 10-HDA shared some longevity control mechanisms with TOR signaling. Additionally, 10-HDA was found to confer tolerance against thermal and oxidative stress. 10-HDA increases longevity not through ILS but through dietary restriction and TOR signaling inC. elegans.

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