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Spermidine, a naturally occurring polyamine, extends the lifespan of mice and is cardioprotective in both aged mice and hypertensive rats. In humans, high dietary spermidine intake is associated with reduced blood pressure and a lower incidence of cardiovascular disease. Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo , coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.

In the search for interventions against aging and age-related diseases, biological screening platforms are indispensable tools to identify anti-aging compounds among large substance libraries. The budding yeast, Saccharomyces cerevisiae, has emerged as a powerful chemical and genetic screening platform, as it combines a rapid workflow with experimental amenability and the availability of a wide range of genetic mutant libraries. Given the amount of conserved genes and aging mechanisms between yeast and human, testing candidate anti-aging substances in yeast gene-deletion or overexpression collections, or de novo derived mutants, has proven highly successful in finding potential molecular targets. Yeast-based studies, for example, have led to the discovery of the polyphenol resveratrol and the natural polyamine spermidine as potential anti-aging agents. Here, we present strategies for pharmacological anti-aging screens in yeast, discuss common pitfalls and summarize studies that have used yeast for drug discovery and target identification.

Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4′-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi , to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug. Although ageing is the most important risk factor for chronic ailments, effective interventions remain rare. Here, the authors identify the flavonoid 4,4’-dimethoxychalcone and demonstrate that it extends lifespan and promotes health in multiple organisms by inducing autophagy.

The target of rapamycin complex 1 (TORC1) is an evolutionarily conserved sensor of nutrient availability. Genetic and pharmacological studies in the yeast Saccharomyces cerevisiae have provided mechanistic insights on the regulation of TORC1 signaling in response to nutrients. Using a highly specific antibody that recognizes phosphorylation of the bona fide TORC1 target ribosomal protein S6 (Rps6) in yeast, we found that nutrients rapidly induce Rps6 phosphorylation in a TORC1-dependent manner. Moreover, we demonstrate that Ypk3, an AGC kinase which exhibits high homology to human S6 kinase (S6K), is required for the phosphorylation of Rps6 in vivo. Rps6 phosphorylation is completely abolished in cells lacking Ypk3 (ypk3Δ), whereas Sch9, previously reported to be the yeast ortholog of S6K, is dispensable for Rps6 phosphorylation. Phosphorylation-deficient mutations in regulatory motifs of Ypk3 abrogate Rps6 phosphorylation, and complementation of ypk3Δ cells with human S6 kinase restores Rps6 phosphorylation in a rapamycin-sensitive manner. Our findings demonstrate that Ypk3 is a critical component of the TORC1 pathway and that the use of a phospho-S6 specific antibody offers a valuable tool to identify new nutrient-dependent and rapamycin-sensitive targets in vivo.

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. Synopsis From a library of polyphenols and polyamines, the 3,4‐dimethoxychalcone (3,4‐DC) was screened and identified as a caloric restriction mimetic (CRM) that induces autophagy through TFEB and TFE3 and results in cardioprotection and improved efficacy of anticancer chemotherapy in mice. 3,4‐DC induces all hallmarks of caloric restriction mimicry, i.e. the combination of autophagy, reduced protein acetylation and absence of toxicity. 3,4‐DC induces autophagy in a TFEB‐ and TFE3‐regulated, transcription and translation‐dependent manner. 3,4‐DC causes cardioprotection and enhances anticancer effects of chemotherapy in an autophagy‐dependent fashion in vivo in mice. Graphical Abstract From a library of polyphenols and polyamines, the 3,4‐dimethoxychalcone (3,4‐DC) was screened and identified as a caloric restriction mimetic (CRM) that induces autophagy through TFEB and TFE3 and results in cardioprotection and improved efficacy of anticancer chemotherapy in mice.

The pharmacological targeting of polyamine metabolism is currently under the spotlight for its potential in the prevention and treatment of several age-associated disorders. Here, we report the finding that triethylenetetramine dihydrochloride (TETA), a copper-chelator agent that can be safely administered to patients for the long-term treatment of Wilson disease, exerts therapeutic benefits in animals challenged with hypercaloric dietary regimens. TETA reduced obesity induced by high-fat diet, excessive sucrose intake, or leptin deficiency, as it reduced glucose intolerance and hepatosteatosis, but induced autophagy. Mechanistically, these effects did not involve the depletion of copper from plasma or internal organs. Rather, the TETA effects relied on the activation of an energy-consuming polyamine catabolism, secondary to the stabilization of spermidine/spermine N1-acetyltransferase-1 (SAT1) by TETA, resulting in enhanced enzymatic activity of SAT. All the positive effects of TETA on high-fat diet-induced metabolic syndrome were lost in SAT1-deficient mice. Altogether, these results suggest novel health-promoting effects of TETA that might be taken advantage of for the prevention or treatment of obesity.

Huntington's disease (HD) is a neurodegenerative disorder that leads to progressive neuronal loss, provoking impaired motor control, cognitive decline, and dementia. So far, HD remains incurable, and available drugs are effective only for symptomatic management. HD is caused by a mutant form of the huntingtin protein, which harbors an elongated polyglutamine domain and is highly prone to aggregation. However, many aspects underlying the cytotoxicity of mutant huntingtin (mHTT) remain elusive, hindering the efficient development of applicable interventions to counteract HD. An important strategy to obtain molecular insights into human disorders in general is the use of eukaryotic model organisms, which are easy to genetically manipulate and display a high degree of conservation regarding disease-relevant cellular processes. The budding yeast has a long-standing and successful history in modeling a plethora of human maladies and has recently emerged as an effective tool to study neurodegenerative disorders, including HD. Here, we summarize some of the most important contributions of yeast to HD research, specifically concerning the elucidation of mechanistic features of mHTT cytotoxicity and the potential of yeast as a platform to screen for pharmacological agents against HD.

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.