Aspirin Recapitulates Features of Caloric Restriction

Pietrocola, Federico; Castoldi, Francesca; Markaki, Maria; Lachkar, Sylvie; Chen, Guo; Enot, David; Durand, Sylvère; Bossut, Noëlie; Tong, Mingming; Malik, Shoaib Ahmad; Loos, Friedemann; Dupont, Nicolas; Mariño, Guillermo; Abdelkader, Nejma; Madeo, Frank; Maiuri, Maria Chiara; Kroemer, Romano T.; Codogno, Patrice; Sadoshima, Junichi; Tavernarakis, Nektarios; Kroemer, Guido

doi:10.1016/j.celrep.2018.02.024

Cited by 103 publications

(72 citation statements)

References 63 publications

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“…In view of the disease-modulatory potential of autophagy, scientists working in academia, biotechnology, or pharmaceutical industry are developing pharmacological autophagy inhibitors and inducers [18,19]. This effort is encouraged by the increasingly accepted notion that the disease-preventive or therapeutic effects of some widely used drugs and food components can be explained by autophagy stimulation, as exemplified for aspirin [20], resveratrol [21], and spermidine [22,23]. In theory, there are multiple molecularly defined targets to suppress autophagy (each of the essential autophage gene [ATG]-encoded proteins) and to enhance autophagy (by targeting each of the numerous endogenous inhibitors of autophagy).…”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 99%

Therapeutic modulation of autophagy: which disease comes first?

Maiuri

Kroemer

2019

Cell Death Differ

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“…However, it may also suggest that aspirin targets the Wnt signaling pathway at multiple levels, which could be a therapeutic benefit. Indeed this has been demonstrated with aspirin reported to inhibit EP300, a transcriptional co-activator of β-catenin (Pietrocola et al, 2018). Using mouse and human CRC models our data identify novel phenotypic biomarkers of response to aspirin with an increased epithelial and reduced stem-like state potentially mediated by an increase in the Wnt antagonist DKK-1.…”

Section: Discussionmentioning

confidence: 60%

Aspirin-mediated DKK-1 increase rescues Wnt-driven stem-like phenotype in human intestinal organoids

Dunbar

Valančiūtė

Rajasekaran

et al. 2019

Preprint

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Aspirin reduces the incidence and mortality of colorectal cancer (CRC). Wnt signalling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations (CSC). Here, we investigated whether aspirin can rescue these pro-invasive phenotypes associated with CRC progression in Wnt-driven human and mouse intestinal organoids. Aspirin rescues the Wnt-driven cystic organoid phenotype by promoting budding in mouse and human Apc deficient organoids, which is paralleled by decreased stem cell marker expression. Aspirin-mediated Wnt inhibition in Apc Min/+ mice is associated with EMT inhibition and decreased cell migration, invasion and motility in CRC cell lines. Chemical Wnt activation induces EMT and stem-like alterations in CRC cells, which are rescued by aspirin. Aspirin increases expression of the Wnt antagonist Dickkopf-1 (DKK-1) in CRC cells and organoids derived from FAP patients. We provide evidence of phenotypic biomarkers of aspirin response with an increased epithelial and reduced stem-like state mediated by an increase in DKK-1. Thus we highlight a novel mechanism of aspirin-mediated Wnt inhibition and potential phenotypic and molecular biomarkers for trials.

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“…Furthermore, epidemiological evidence indicates that spermidine consumption is associated with reduced all-cause mortality in humans. 25 The anti-inflammatory drug acetylsalicylic acid (aspirin) and its metabolite salicylic acid were also shown to induce autophagy by inhibiting EP300 in worms and mice 109 (Table 1). Both compounds increased lifespan in worms, 108 and acetylsalicylic acid increased mean lifespan in genetically heterogeneous male mice but no effect was observed in female mice.…”

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confidence: 99%

Antiaging effects of bioactive molecules isolated from plants and fungi

Martel

Ojcius

et al. 2019

Medicinal Research Reviews

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Aging is influenced by many lifestyle choices that are under human control, including nutrition and exercise. The most effective known antiaging intervention consists of calorie restriction (CR), which increases lifespan in yeasts, worms, fruit flies, mice, and nonhuman primates. CR also improves healthspan by preventing the development of various aging‐related diseases such as cancer, cardiovascular disease, diabetes, and neurodegeneration. Many compounds isolated from plants and fungi prolong lifespan and prevent age‐related diseases in model organisms. These plant and fungal compounds modulate the same cellular and physiological pathways as CR, including those involving insulin and insulin‐like growth factor‐1, mammalian target of rapamycin, and sirtuins. Modulation of these aging‐related pathways results in the activation of various cellular processes such as autophagy, DNA repair, and neutralization of reactive oxygen species. Together, these cellular processes are believed to delay aging and prevent chronic diseases by improving bodily functions and stress resistance. We review here the mechanisms of action of plant and fungal molecules possessing antiaging properties and discuss the possibilities and challenges associated with the development of antiaging compounds isolated from natural products.

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Aspirin Recapitulates Features of Caloric Restriction

Cited by 103 publications

References 63 publications

Therapeutic modulation of autophagy: which disease comes first?

Therapeutic modulation of autophagy: which disease comes first?

Aspirin-mediated DKK-1 increase rescues Wnt-driven stem-like phenotype in human intestinal organoids

Antiaging effects of bioactive molecules isolated from plants and fungi

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