Lifespan Extension Induced by Caffeine in Caenorhabditis elegans is Partially Dependent on Adenosine Signaling

Bridi, Jéssika Cristina; Barros, Alexandre Guimarães de Almeida; Sampaio, Letícia Reis; Ferreira, Júlia Castro Damásio; Soares, Félix Alexandre Antunes; Romano-Silva, Marco Aurélio

doi:10.3389/fnagi.2015.00220

Cited by 36 publications

(39 citation statements)

References 56 publications

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“…This higher concentration could suggest that ciliobrevin has a lower affinity for C. elegans IFT dynein, but it more likely reflects limited penetration of the drug or absorption-related drug loss in the nematode. Moreover, it is consistent with dosing regimens of other small-molecule drugs in C. elegans that have been reported to be in the millimolar-range [23, 24].…”

Section: Resultssupporting

confidence: 83%

Inhibiting IFT dynein with ciliobrevin in C. elegans chemosensory cilia

Mijalkovic

2019

Preprint

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Cytoplasmic dyneins play a role in a myriad of cellular processes, such as retrograde intracellular transport and cell division. Small-molecule cytoplasmic dynein antagonists, ciliobrevins, have recently been developed as tools to acutely probe cytoplasmic dynein function. Although widely used to investigate cytoplasmic dynein 1, far fewer studies explore the effect of ciliobrevin on cytoplasmic dynein 2 or IFT dynein. Here, we use ciliobrevin A to partially disrupt IFT dynein in the chemosensory cilia of living C. elegans. Acute, low-concentration ciliobrevin treatment results in shortening of cilia and reduction of transport velocity in both directions. After longer exposure to ciliobrevin, we find concentration-dependent motor accumulations and axonemal deformations. We propose that maintenance of ciliary length requires a high fraction of active IFT-dynein motors, while structural integrity can be preserved by only a few active motors.

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Section: Resultssupporting

confidence: 83%

Inhibiting IFT dynein with ciliobrevin in C. elegans chemosensory cilia

Mijalkovic

2019

Preprint

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“…It is of particular interest that, among the nutraceutical compounds tested, only caffeine demonstrated growth kinetics consistent with mTORC1 inhibition in our yeast assay. This supports prior studies of caffeine on mTOR activity in budding yeast (Reinke et al 2006;Wanke et al 2008) and fission yeast (Rallis et al 2013), and is of interest in light of numerous reports that caffeine can extend life span in invertebrate models (Sutphin et al 2012;Bridi et al 2015) and that coffee consumption is associated with reduced mortality in people (Loftfield et al 2015;Je and Giovannucci 2014). It is intriguing to speculate that these effects could be related to the caffeine's mTOR inhibitory activities.…”

Section: Discussionsupporting

confidence: 86%

A system to identify inhibitors of mTOR signaling using high-resolution growth analysis in Saccharomyces cerevisiae

et al. 2017

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The mechanistic target of rapamycin (mTOR) is a central regulator of growth and proliferation and mTOR inhibition is a promising therapy for a variety of diseases and disorders. Inhibition of mTOR complex I (mTORC1) with rapamycin delays aging and increases healthy longevity in laboratory animals and is used clinically at high doses to prevent organ transplant rejection and to treat some forms of cancer. Clinical use of rapamycin is associated with several unwanted side effects, however, and several strategies are being taken to identify mTORC1 inhibitors with fewer side effects. We describe here a yeast-based growth assay that can be used to screen for novel inhibitors of mTORC1. By testing compounds using a wild-type strain and isogenic cells lacking either TOR1 or FPR1, we can resolve not only whether a compound is an inhibitor of mTORC1 but also whether the inhibitor acts through a mechanism similar to rapamycin by binding Fpr1. Using this assay, we show that rapamycin derivatives behave similarly to rapamycin, while caffeine and the ATP competitive inhibitors Torin 1 and GSK2126458 are mTORC1 inhibitors in yeast that act independently of Fpr1. Some mTOR inhibitors in mammalian cells do not inhibit mTORC1 in yeast, and several nutraceutical compounds were not found to specifically inhibit mTOR but resulted in a general inhibition of yeast growth. Our screening method holds promise as a means of effectively assaying drug libraries for mTOR-inhibitory molecules in vivo that may be adapted as novel treatments to fight diseases and extend healthy longevity.

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“…For pharyngeal pumping assay, nematodes were transferred to fresh plate and their pharynx contractions were counted under an upright microscope during 1 min . For the growth alteration assay, photographs of nematodes were taken and the body length of each animal was analysed by the Nikon software (NIS‐Elements; Nikon, Tokyo, Japan) . To check the body movement, nematodes were transferred to normal NGM plate and observed their travel distance using microscope during 1 min .…”

Section: Methodssupporting

confidence: 72%

“…[22] For the growth alteration assay, photographs of nematodes were taken and the body length of each animal was analysed by the Nikon software (NIS-Elements; Nikon, Tokyo, Japan). [23] To check the body movement, nematodes were transferred to normal NGM plate and observed their travel distance using microscope during 1 min. [22] To determine the intestinal lipofuscin level, 15 nematodes were mounted onto 2% agarose pads on the 15th day of adulthood and fluorescence intensity was quantified as described.…”

Section: Measurements Of Ageing-related Factorsmentioning

confidence: 99%