3,4-dimethoxychalcone induces autophagy and reduces neointimal hyperplasia and aortic lesions

Autophagy inducers can prevent cardiovascular aging and age-associated diseases including atherosclerosis. Therefore, we hypothesized that autophagy-inducing compounds that act on atherosclerosis-relevant cells might have a protective role in the development of atherosclerosis. Here we identified 3,4-dimethoxychalcone (3,4-DC) as an inducer of autophagy in several cell lines from endothelial, myocardial and myeloid/macrophagic origin, as demonstrated by the aggregation of the autophagosome marker GFP-LC3 in the cytoplasm of cells, as well as the downregulation of its nuclear pool indicative of autophagic flux. In this respect, 3,4-DC showed a broader autophagy-inducing activity than another chalcone (4,4- dimethoxychalcone), spermidine and triethylene tetramine. Thus, we characterized the potential antiatherogenic activity of 3,4-DC in two different mouse models, namely, (i) neointima formation with smooth muscle expansion of vein segments grafted to the carotid artery and (ii) genetically predisposed ApoE −/− mice fed an atherogenic diet. In the vein graft model, local application of 3,4-DC was able to maintain the lumen of vessels and to reduce neointima lesions. In the diet-induced model, intraperitoneal injections of 3,4-DC significantly reduced the number of atherosclerotic lesions in the aorta. In conclusion, 3,4-DC stands out as an autophagy inducer with potent antiatherogenic activity.

Open access paper:



This quote from the link is intriguing. “Of note, topically applied 3,4-DC also turned out to mediate beneficial effects against ultraviolet-A-induced skin damage [33]. Although this effect was attributed to the antioxidant activity of 3,4-DC, autophagy has previously been implicated in the natural and drug-induced protection of the skin against ultraviolet insult and photoaging [34,35,36]. Hence, it is possible, yet remains to be demonstrated that the skin-protective effects of 3,4-DC are secondary to local autophagy induction.”

Some related reading on 3,4 DC, and 4,4 DMC:

A Japanese relative of the carrot might hold the key to longevity, scientists have discovered.

The flowering ashitaba (Angelica keiskei) plant, traditionally used in Asian medicine, contains a flavonoid called 4,4’-dimethoxychalcone, or DMC. European researchers discovered the substance’s superior health benefits when testing 180 subclasses of flavonoids for their anti-ageing properties.

DMC was their “top hit”, as reported in the journal Nature Communications – even outperforming other known protective compounds, including resveratrol, a chemical found in red wine .

The large research team was led by Frank Madeo and Guido Kroemer from the University of Graz in Austria and the Centre de Recherche des Cordeliers in Paris, France.{%recommended 8427%}

February 19th, 2019 Nature Communications published a peer-reviewed paper, “The flavonoid 4,4′-dimethoxychalcone promotes autophagy-dependent longevity across species” authored by Samsara’s scientific team. The paper demonstrates the capability of the Samsara platform to identify novel MoA geroprotective small molecules that extend healthy lifespan across species and which are protective in mammalian models of disease.

The particular molecule (4,4’-dimethoxychalcone) is a natural product derived from the Japanese longevity herb known as Ashitaba, consumed on the island of Okinawa, which hosts the greatest number of ultra-long-lived supercentenarians. Samsara Therapeutics is conducting medicinal chemistry optimization of this compound and other Samsara platform-identified compounds in collaboration with Evotec.


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

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.


In a recent study, Zhang and his team from Guangzhou Medical University have investigated a potential therapeutic for Parkinson’s disease called 4,4-dimethoxychalcone, or DMC, which protects and promotes regeneration in cells. “In this study, we mainly focus on how to delay or attenuate dopaminergic neuron degeneration by using DMC,” stated Zhang.

Addressing concerns of DMC toxicity, the group showed that DMC conjugated to RVG is less toxic to cells than DMC alone. Furthermore, organs apart from the brain were not obviously adversely affected by DMC-RVG treatment.

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A related flavonoid has similar effects (4,4, not 3,4 dimethylchalcone)…

Notably, we identify DMC in the plant Angelica keiskei koidzumi , to which longevity- and health-promoting effects are ascribed in Asian traditional medicine.

Angelica koidzumi is available as “Japanese Ashitaba”.