I’m surprised that no one has posted this:
Starting at 0:55, she says that she and other groups are working to find or develop SIRT6 activators. SIRT6 has two separate enzymatic activities: deacetylation and ribosylation, and to date, all the SIRT6 activators that have been reported have been deacetylation activators. While both activities are important for cellular functions, she thinks ribosylation may be particularly important for longevity because her research found human centenarians carry rare SIRT6 variants with enhanced ribosylation activity:
Characterization of this SIRT6 allele (centSIRT6) demonstrated it to be a stronger suppressor of LINE1 retrotransposons, confer enhanced stimulation of DNA double-strand break repair, and more robustly kill cancer cells compared with wild-type SIRT6. Surprisingly, centSIRT6 displayed weaker deacetylase activity, but stronger [mono-ADP ribosyl transferase (mADPr) ] activity, over a range of NAD+ concentrations and substrates. Additionally, centSIRT6 displayed a stronger interaction with Lamin A/C (LMNA), which was correlated with enhanced ribosylation of LMNA.
Her group went back and tested the reported activators to see if they also activated its robosylation activities, and found that fucoidan does. However, there are a diversity of different fucoidan molecular structures, with different backbones and degrees of sulfation, and not all fucoidan molecules work the same way: some even inhibit SIRT6. This was mentioned in the opening post by Alex:
Another naturally occurring molecule showing SIRT6 activation is fucoidan (4), a heterogeneous sulfated polysaccharide present in brown algae. Its backbone consists of repeating (1 → 3) or (1 → 3) and (1 → 4) linked α-l-fucopyranose residues, in which some hydroxyl groups form sulfated esters (Figure Figure55, lower panel).123 The oversulfated fucoidan subtype extracted from Fucus vesiculosus displayed a 355-fold increase of SIRT6 activity at a 100 μg/mL concentration. In addition, when tested against other SIRTs (SIRT1/2/3), it did not display significant changes in activity, suggesting a specific action toward SIRT6. 4 was also able to activate SIRT6 acetylation toward H3K9 in vitro. According to the authors of the study, sulfate esters may play a central role in SIRT6–4 interaction and hence SIRT6 activation.123 However, the heterogeneity of the mixture, the polymeric nature of the compound, and the absence of kinetic data makes it difficult to compare this macromolecule to small molecules and to devise structure–activity relationships.
Crude fucoidan content in two North Atlantic kelp species, Saccharina latissima and Laminaria digitata—seasonal variation and impact of environmental factors - PMC
Gorbunova is working with sugar chemists to identify the key chemical structures responsible for the SIRT6 activating activity. This would allow them to make a better (and presumably patentable) drug.
Starting at 5:38, Gorbunova has done experiments with their specific “crude extract” of fucoidan extract (“not just ground up seaweed”) as a SIRT6 activator. From what she says later on, it appears this is the extract used by DoNotAge. (No, I have no affiliation or conflict of interest). The mice were given the fucoidan extract in their chow, and “there was clear benefit:” it lowered frailty scores and inflammatory cytokines, improved physical activity, and increased lifespan. She estimates the human-equivalent dose would be 4 g of extract (which would be TEN of DoNotAge’s capsules).
She has tested DNA’s extract and confirmed that it activates SIRT6.