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.
- MeSH
- Angelica chemie MeSH
- autofagie účinky léků MeSH
- buněčná smrt účinky léků MeSH
- buněčné linie účinky léků MeSH
- Caenorhabditis elegans účinky léků MeSH
- dlouhověkost účinky léků fyziologie MeSH
- Drosophila melanogaster účinky léků MeSH
- flavonoidy aplikace a dávkování farmakologie MeSH
- ischemická choroba srdeční farmakoterapie MeSH
- lidé MeSH
- mechanistické cílové místo rapamycinového komplexu 1 metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- proteiny přenášející kationty genetika MeSH
- regulace genové exprese účinky léků MeSH
- rostlinné extrakty farmakologie MeSH
- Saccharomyces cerevisiae - proteiny genetika MeSH
- Saccharomyces cerevisiae účinky léků metabolismus MeSH
- signální transdukce MeSH
- sirolimus farmakologie MeSH
- stárnutí účinky léků fyziologie MeSH
- tradiční orientální medicína MeSH
- transkripční faktory GATA účinky léků MeSH
- transkripční faktory účinky léků genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300. While salicylate readily stimulates autophagic flux in control cells, it fails to further increase autophagy levels in EP300-deficient cells, as well as in cells in which endogenous EP300 has been replaced by salicylate-resistant EP300 mutants. Accordingly, the pro-autophagic activity of aspirin and salicylate on the nematode Caenorhabditis elegans is lost when the expression of the EP300 ortholog cpb-1 is reduced. Altogether, these findings identify aspirin as an evolutionary conserved CRM.
- MeSH
- acetylkoenzym A metabolismus MeSH
- Aspirin farmakologie MeSH
- autofagie účinky léků genetika MeSH
- kalorická restrikce * MeSH
- lidé MeSH
- metabolom účinky léků MeSH
- metabolomika MeSH
- myši inbrední C57BL MeSH
- nádorové buněčné linie MeSH
- protein p300 asociovaný s E1A metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH