The department of Translational Research and New Technologies in Medicine and Surgery at the university of University of Pisa put the ability of various polyphenolic compounds to activate sirtuins to the test. More specifically they tested the ability of compounds to activate SIRT1 and also tested whether combinations of compounds led to synergistic SIRT1 boosting effects. In addition they looked at related downstream increases of AMPK and the decrease of mTOR signaling.
Why the interest in boosting sirtuins? There are number of nuclear processes such as DNA replication, transcription, and repair which are regulated in the chromatin environment. So called histone proteins play a fundamental role in this gene regulation and histone modifying proteins and their post-translational actions influence the epigenetic profile and therefore influence human disease. Histone deacetylation is an important process to maintain the epigenetic profile. There are three classes human histone deacetylase enzymes defined (HDACs). So called Class III contains seven evolutionary conserved sirtuins SIRT1-7. Due to their diverse cellular localization’s, sirtuins impact numerous cellular functions and in the past decade have become a focus area for research in healthy living and anti-againg.
SIRT1, the focus of this research is the most studied sirtuin. That is because Sirt1 deacetylates numerous transcription factors and research has shown that it has significant roles in DNA repair, cell senescence, cardiovascular disorders, metabolic diseases, cancer, environmental stress, age related disease, viral infection and transactivation, female fertility, neurodegeneration and inflammation.
The experiment was carried out in vitro and at various concentrations. This tells us the absolute capability of a compound to raise SIRT1. However when the compounds are consumed orally their bio availability is a major factor to take into account. Bio availability is the portion of a drug or other substance that enters the circulation and is able to have an active effect. So this is something to keep in mind in the conclusions. After starting off with 36 substances the experiment continued with the ones that showed noticeable increases: resveratrol, quercetin, berberine, tyrosol, ferulic acid, niclosamide, catechin, curcumin and malvidin.
All compounds showed statistically significant increases in SIRT1 expression:
– Niclosamide showed a max increase of 24% after 24h at the lower concentration of 5uM dose and couple % lower at 10uM
– Curcumin showed a max increase of 30% after 24h with a couple % difference between 5 and 10uM dose
– Malvidin showed a max increase of 46% after 24h with a couple % difference between 5 and 10uM dose
– Quercetin showed a max increase of 55% after 24h at 25uM dose, this was significantly higher than the 30% increase at 10uM
– Resveratrol showed a max increase of 69% after 24h with minor differences between 5 and 10uM dose
– Berbine showed a max increase of 75% after 24h with minor differences between 5 and 10uM dose
– Ferulic Acid showed a max increase of 75% after 24h at 50uM dose, this was slightly higher than the 66% increase at 25uM
– Tyrosol showed a max increase of 101% after 24h at 20uM dose, this was significantly higher than the 69% increase at 10uM
Berberine, quercetin, ferulic acid and tyrosol were the substances to have increased more than the others the expression of SIRT1 and therefore selected to assess the activation of AMPK and the inhibition of mTOR. Resveratrol, the most known SIRT1 activator was not tested further due its known limitations e.g. high lipophilicity, its short biological half-life, and chemical instability. It was used in the study to asses the relative effectiveness of the other compounds.
All compounds showed statistically significant increases in AMPK activation:
– Berbine showed a maximum increase of 70% after 24h at 10uM dose, this was significantly higher than the 56% increase at 5uM
– Tyrosol showed a maximum increase of 85% after 24h at 20uM dose, this was significantly higher than the 70% increase at 10uM
– Ferulic Acid showed a maximum increase of 79% after 24h at 50uM dose, this was slightly higher than the 70% increase at 25uM
– Quercetin showed a maximum increase of 46% after 24h at 25uM dose, this was significantly higher than the 34% increase at 10uM
All compounds showed statistically significant decreases in mTOR activation:
– Berbine showed a maximum decrease of 38% after 24h at 10uM dose, this was similar to 35% decrease at 5uM
– Tyrosol showed a maximum decrease of 40% after 24h at 20uM dose, this was significantly better than the 23% decrease at 10uM
– Ferulic Acid showed a maximum decrease of 33% after 24h at 50uM dose, this was somewhat better than the decrease of 28% at 25uM
– Quercetin showed a maximum decrease of 29% after 24h at 25uM dose, this was significantly more than the 16% decrease at 10uM
The second part of the test was to analyse what combinations of compounds have a positive synergistic effect on SIRT1. Synergistic effect occurs when the simultaneous administration of two substances has a greater effect compared to the sum of the effects of the two substances individually administered.
The combinations of berberine + tyrosol, tyrosol + ferulic acid and ferulic acid + quercetin demonstrated synergetic effects that were 100% more than the combined individual effects resulting in overall increases of 300-400% of SIRT1 expression. These synergestic effect were however not seen in the AMPK activation and mTOR inhibition which were more or less similar to the sum of parts.
Of the above compounds the bioavaibility of Tyrosol, Quercetin, Ferulic Acid are often measured to be highest and therefore based on these results they are the most promising to boost SIRT1 expression (in combination or alone), AMPK activation and mTOR inhibition. It should be noted that in vivo studies would be needed to make final conclusions on the efficacy, in particular considering the discussion around bioavailability of polyphenols in general.
As a final note sirtuins are also highly dependent on NAD+ which can be boosted by the use of nicotinamide riboside. No research material exists to date to measure whether nicotinamide riboside in combination with other sirtuin boosters like above have a combinatory postive effect or are possibly overlapping. Polyphenols like quercetin have however also several other health properties and the finding of significant SIRT1 boosting simply adds to their appeal.
You can find the study here.