The flavonoid 4,4′-dimethoxychalcone promotes autophagy-dependent longevity across species

Carmona-Gutiérrez, Didac; Zimmermann, Andreas; Kainz, Katharina; Pietrocola, Federico; Chen, Guo; Maglioni, Silvia; Schiavi, Alfonso; Nah, Jihoon; Mertel, Sara; Beuschel, Christine B.; Castoldi, Francesca; Sica, Valentina; Trausinger, Gert; Raml, Reingard; Sommer, Christina; Schroeder, Sabrina; Hofer, Sebastian J.; Bauer, Maria A.; Pendl, Tobias; Tadić, Jelena; Dammbrueck, Christopher; Hu, Zehan; Ruckenstuhl, Christoph; Eisenberg, Tobias; Durand, Sylvère; Bossut, Noëlie; Aprahamian, Fanny; Abdellatif, Mahmoud; Sedej, Simon; Enot, David; Wolinski, Heimo; Dengjel, Jörn; Kepp, Oliver; Magnes, Christoph; Sinner, Frank; Pieber, Thomas R.; Sadoshima, Junichi; Ventura, Natascia; Sigrist, Stephan J.; Kroemer, Guido; Madeo, Frank

doi:10.1038/s41467-019-08555-w

Cited by 112 publications

(102 citation statements)

References 75 publications

(89 reference statements)

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“…We also compared the effects of 3,4‐DC to another, structurally related compound, 4,4′‐DC, that we recently described for its autophagy‐inducing effects (Carmona‐Gutierrez et al , ). While 3,4‐DC causes classical autophagy (with autophagosomes in the cytoplasm), 4,4′‐DC causes accumulation of GFP‐LC3 dots in or around nuclei ().…”

Section: Resultsmentioning

confidence: 99%

3,4‐Dimethoxychalcone induces autophagy through activation of the transcription factors TFE 3 and TFEB

et al. 2019

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Caloric restriction mimetics (CRMs) are natural or synthetic compounds that mimic the health‐promoting and longevity‐extending effects of caloric restriction. CRMs provoke the deacetylation of cellular proteins coupled to an increase in autophagic flux in the absence of toxicity. Here, we report the identification of a novel candidate CRM, namely 3,4‐dimethoxychalcone (3,4‐DC), among a library of polyphenols. When added to several different human cell lines, 3,4‐DC induced the deacetylation of cytoplasmic proteins and stimulated autophagic flux. At difference with other well‐characterized CRMs, 3,4‐DC, however, required transcription factor EB (TFEB)‐ and E3 (TFE3)‐dependent gene transcription and mRNA translation to trigger autophagy. 3,4‐DC stimulated the translocation of TFEB and TFE3 into nuclei both in vitro and in vivo, in hepatocytes and cardiomyocytes. 3,4‐DC induced autophagy in vitro and in mouse organs, mediated autophagy‐dependent cardioprotective effects, and improved the efficacy of anticancer chemotherapy in vivo. Altogether, our results suggest that 3,4‐DC is a novel CRM with a previously unrecognized mode of action.

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Section: Resultsmentioning

confidence: 99%

3,4‐Dimethoxychalcone induces autophagy through activation of the transcription factors TFE 3 and TFEB

et al. 2019

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“…Moreover, there are naturally occurring food items containing elevated levels of CRMs, such as the polyamine spermidine or polyphenols, which may enhance autophagy, hence posponing the manifestation of age-associated pathologies. It appears fascinating that, for therapeutic purposes, folk medicine often prescribes fasting, exercise and CRM-containing plants (such as ashitaba containing dimethoxychalcone) [103]. In this sense, autophagy induction is already used in traditional medicine (Fig.…”

Section: Natural Versus Drug Treatmentsmentioning

confidence: 99%

Therapeutic modulation of autophagy: which disease comes first?

Maiuri

Kroemer

2019

Cell Death Differ

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The relentless efforts of thousands of researchers have allowed deciphering the molecular machinery that regulates and executes autophagy, thus identifying multiple molecular targets to enhance or block the process, rendering autophagy "druggable". Autophagy inhibition may be useful for preserving the life of cells that otherwise would succumb to excessive self-digestion. Moreover, autophagy blockade may reduce the fitness of cancer cells or interrupt metabolic circuitries required for their growth. Autophagy stimulation is probably useful for the prevention or treatment of aging, cancer (when stimulation of immunosurveillance is the therapeutic goal), cardiovascular disease, cystic fibrosis, infection by intracellular pathogens, obesity, and intoxication by heavy metals, just to mention a few examples. Epidemiological evidence suggests broad health-improving effects for lifestyles, micronutrients, and drugs that favor autophagy. In this review, we discuss the role of autophagy in disease pathogenesis while focusing on the question, which disease will become the first clinically approved indication for therapeutic autophagy modulation. Facts • Autophagy is one of the best-studied phenomena in cell biology. Drugs for enhancing or inhibiting general or specific autophagy are being developed. • Acquired or genetically determined alterations in autophagic flux are involved in multiple pathologies across the entire spectrum of human diseases. • Autophagy inhibition might be useful for the avoidance of unwarranted autophagy-dependent cell death. • Chronic autophagy stimulation has a positive impact on preclinical models of aging and multiple distinct agedependent diseases, including arteriosclerosis, cancer, and neurodegeneration. Acute autophagy stimulation also has organ-protective effects in models of ischemia or intoxication.

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“…Macroautophagy, which is generally referred to as autophagy, is a conserved intracellular degradation mechanism that removes dangerous, unnecessary or dysfunctional cytoplasmic constituents and invading microbes (Mizushima, 2007;Schuck et al, 2014;Dou et al, 2015;Mochida et al, 2015;Chai et al, 2019). Autophagic activity declines during aging, and autophagy is required for lifespan extension by caloric restriction or caloric restriction mimetics (CRM) such as resveratrol, spermidine, and several chalcones Rubinsztein et al, 2011;Lopez-Otin et al, 2016;Madeo et al, 2018;Carmona-Gutierrez et al, 2019). Although the relation between autophagy and aging has been firmly established as an important mitochondrial quality control mechanism, the role of mitophagy in aging and age-related disorders has remained elusive for a long time.…”

Section: Introductionmentioning

confidence: 99%

Mitophagy: An Emerging Role in Aging and Age-Associated Diseases

Guo

Kroemer

2020

Front. Cell Dev. Biol.

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Mitochondrial dysfunction constitutes one of the hallmarks of aging and is characterized by irregular mitochondrial morphology, insufficient ATP production, accumulation of mitochondrial DNA (mtDNA) mutations, increased production of mitochondrial reactive oxygen species (ROS) and the consequent oxidative damage to nucleic acids, proteins and lipids. Mitophagy, a mitochondrial quality control mechanism enabling the degradation of damaged and superfluous mitochondria, prevents such detrimental effects and reinstates cellular homeostasis in response to stress. To date, there is increasing evidence that mitophagy is significantly impaired in several human pathologies including aging and age-related diseases such as neurodegenerative disorders, cardiovascular pathologies and cancer. Therapeutic interventions aiming at the induction of mitophagy may have the potency to ameliorate these dysfunctions. In this review, we summarize recent findings on mechanisms controlling mitophagy and its role in aging and the development of human pathologies.

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The flavonoid 4,4′-dimethoxychalcone promotes autophagy-dependent longevity across species

Cited by 112 publications

References 75 publications

3,4‐Dimethoxychalcone induces autophagy through activation of the transcription factors TFE 3 and TFEB

3,4‐Dimethoxychalcone induces autophagy through activation of the transcription factors TFE 3 and TFEB

Therapeutic modulation of autophagy: which disease comes first?

Mitophagy: An Emerging Role in Aging and Age-Associated Diseases

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