Natural polyphenols as sirtuin 6 modulators

[David PS]

Natural polyphenols as sirtuin 6 modulators (2018)

Flavonoids are polyphenolic secondary metabolites synthesized by plants and fungus with various pharmacological effects. Due to their plethora of biological activities, they have been studied extensively in drug development. They have been shown to modulate the activity of a NAD+-dependent histone deacetylase, SIRT6. Because SIRT6 has been implicated in longevity, metabolism, DNA-repair, and inflammatory response reduction, it is an interesting target in inflammatory and metabolic diseases as well as in cancer. Here we show, that favonoids can alter SIRT6 activity in a structure dependent manner. Catechin derivatives with galloyl moiety displayed significant inhibition potency against SIRT6 at 10µM concentration. The most potent SIRT6 activator, cyanidin, belonged to anthocyanidins, and produced a 55-fold increase in SIRT6 activity compared to the 3–10 fold increase for the others. Cyanidin also significantly increased SIRT6 expression in Caco-2 cells. Results from the docking studies indicated possible binding sites for the inhibitors and activators. Inhibitors likely bind in a manner that could disturb NAD+ binding. The putative activator binding site was found next to a loop near the acetylated peptide substrate binding site. In some cases, the activators changed the conformation of this loop suggesting that it may play a role in SIRT6 activation.

Sirtuin 6 - Wikipedia

For my purposes, I think of SIRT6 as the Infrastructure Sirtuin. Here in the US, our infrastructure (roads and bridges) is crumbling and our aging infrastructure is in need of repair. SIRT6 is involved in infrastructure repair in mammals and as a general rule the more SIRT6 the better. More is better especially as we age. The decline in SIRT6 may be part of the reason for things not working as well in old age. Basically, everything is crumbling.

SIRT6 in Vascular Diseases, from Bench to Bedside​

Anthocyanins in Chronic Diseases: The Power of Purple​

The common dietary sources of anthocyanins are berries, cherries, peaches, grapes, pomegranates, plums, blackcurrants, red onions, red radishes, black beans, eggplants, purple corn, purple carrots, red cabbages and purple sweet potatoes [36]. The average daily intake of flavonoids in 1183 middle-aged Australian men and women was 625.51 ± 578.87 mg/day including 32.88 ± 24.22 mg/day anthocyanins with roughly half or 14.54 ± 12.07 mg/day as cyanidins [37]. The main sources of cyanidins were apples/pears (38%), canned fruits/fruits in juices/syrups (28%), berries (12%), plums (10%) and raisins/sultanas (9%). The bioavailability of flavonoids is quite low with only 1–2% of intact anthocyanins found after oral ingestion [38]. However, this value may be an under-estimate as bioactive metabolites from the gut microbiota may not be measured and anthocyanidin metabolites may be extensively degraded during storage of plasma before analysis [38]. Recent studies have compared the bioactivity of anthocyanins with their catabolites and gut microbiota metabolites. These studies have postulated that the bioactivity of anthocyanins results from exposure to a range of catabolites of anthocyanins, which can modulate inflammatory and cellular adhesion pathways [39,40].​

Anthocyanin contents of these fruits and vegetables vary across plant species and cultivars along with differences introduced by environmental factors including light and temperature [36]. Berry fruits, the most popular and the richest source of anthocyanins, include blackberries (70.3 to 201 mg/100 g) [41], strawberries (20 to 60 mg/100 g) [42], blueberries (57 to 503 mg/100 g) [43], cherries (680 mg/100 g) [44], currants (0.205 to 2.253 mg/100 g) [45], chokeberries (141 to 2468 mg/100 g) [46], gooseberries (30 to 223 mg/100 g) [47], elderberries (670 mg/100 g) [44] and lingonberries (27.4 to 52.6 mg/100 g) [48]. The Saskatoon berry (Amelanchier alnifolia) native to Canada contains increased amounts of anthocyanins compared to many other berries (294 mg/100 g) [49]. The anthocyanins of these cold-climate berries are cyanidin 3-galactoside, cyanidin 3-glucoside and other cyanidin glycosides, delphinidin 3-glucoside, malvidin 3-glucoside and malvidin 3-galactoside [50,51]. Queen Garnet plums (Prunus salicina Lindl., a variety of Japanese plum) contain ~180 mg/100 g anthocyanins mostly as cyanidin 3-glucoside [52].​

Apart from fruits and vegetables, anthocyanins are also present in black-, purple-, blue-, pink-, red- and brown-coloured varieties of cereals such as corn, rice, wheat, rye, barley and sorghum [53,54,55]. These coloured cereals can form a valuable supplement to standard human diets by providing both fibre and anthocyanins for additional health benefits.​

Two issues with berries are the calories and the cost.

There Ain't No Such Thing as a Free Lunch (TANSTAAFL)​

Also,

Dirty Dozen™ Fruits and Vegetables with the Most Pesticides

Check out EWG's Dirty Dozen list to help decide when you should splurge for organic produce – part of our annual Shopper’s Guide to Pesticides in Produce™

www.ewg.org

 

[Grapelander]

As noted by others on the forum - polyphenols can chelate iron.

Green tea catechins as brain-permeable, non toxic iron chelators to "iron out iron" from the brain​

Multifunctional activities of green tea catechins in neuroprotection. Modulation of cell survival genes, iron-dependent oxidative stress and PKC signaling pathway​

Synthetic and natural iron chelators: therapeutic potential and clinical use​

 

[Kram]

Fucoidan is supposed to be a good sirt6 activator.

SIRT6 Activator®

SIRT6 Activator® is a specially curated, all-natural product, derived from seaweed. It is the first and only of its kind in the world. Activating Sirtuin 6 promotes DNA repair, protects telomeres, supports genomic stability and reduces inflammation.

donotage.org

 

[David PS]

As noted by others on the forum - polyphenols can chelate iron.

Green tea catechins as brain-permeable, non toxic iron chelators to "iron out iron" from the brain​

Multifunctional activities of green tea catechins in neuroprotection. Modulation of cell survival genes, iron-dependent oxidative stress and PKC signaling pathway​

Synthetic and natural iron chelators: therapeutic potential and clinical use​

Thanks for the links. I tested my iron levels about 5 years ago and they were at the low end of normal. So I haven't paid much attention to iron chelators. Maybe it is time for me to reconsider.

 

[David PS]

Fucoidan is supposed to be a good sirt6 activator.

SIRT6 Activator®

SIRT6 Activator® is a specially curated, all-natural product, derived from seaweed. It is the first and only of its kind in the world. Activating Sirtuin 6 promotes DNA repair, protects telomeres, supports genomic stability and reduces inflammation.

donotage.org

Thanks for the link. I was aware of fucoidan and I am also aware of its price. It is out of my range. (click on the link and prepare to be sticker-shocked)

I consider the cyanidin containing berries to be the low-lying fruit (pun intended).

This table quantifies how potent fucoidan is compared to cyanidin. (6X stronger)
https://www.researchgate.net/figure/Identified-SIRT6-activators_tbl3_356890313

Is this cherry-picking?

 

[GTW]

Chokeberries aka aronia look like a powerhouse.

 

[David PS]

Chokeberries aka aronia look like a powerhouse.

I agree, they are hard to find. In addition, they many be nicknamed Chokeberries for a reason. The name does not seem to be too appealing.

 

[GTW]

Not at all. Less bitter/tannic than chokecherries. They are edible off the bush or dried. Dried readily available for reasonable price.

 

[David PS]

Not at all. Less bitter/tannic than chokecherries. They are edible off the bush or dried. Dried readily available for reasonable price.

Thanks I will look for them.

I get most of my cyanidins from blueberries which are in every supermarket these days. The wide range of cyanidins from the original post is blueberries (57 to 503 mg/100 g) I get frozen organic at Walmart. They claim to have 2X the antioxidants and may account for the high end of the range.

 

[Motorneuron]

Thanks for the links. I tested my iron levels about 5 years ago and they were at the low end of normal. So I haven't paid much attention to iron chelators. Maybe it is time for me to reconsider.

I don't think the simple serum test can reflect exactly where it is deposited (organ / tissue).

Anyway, you answered me on my thread regarding quercetin ... I wanted to ask you so it activates and does not inhibit SIRT6, right?

 

[GTW]

Aronia are native to Northeast USA but adopted and now grow wild in Russia. Commercial and garden varieties improved in Russia came back to the USA.
I have a couple aronia bushes. And prolific black currants.

 

[David PS]

I don't think the simple serum test can reflect exactly where it is deposited (organ / tissue).

Anyway, you answered me on my thread regarding quercetin ... I wanted to ask you so it activates and does not inhibit SIRT6, right?

I was wondering about that as well. I decided that the word 'modulates' covers both possibilities and that quercetin is generally recognized being very healthy. I have not gone back to look at the papers, but something might have gotten confused if it was translated.

 

[David PS]

Aronia are native to Northeast USA but adopted and now grow wild in Russia. Commercial and garden varieties improved in Russia came back to the USA.
I have a couple aronia bushes. And prolific black currants.

Variety is the spice of life,

25 Different Types of Berries (and Why You Should Be Eating Each and Every One of Them)

You’re no stranger to blueberries , strawberries ,...

www.yahoo.com

 

[David PS]

When I was young my other told me to eat carrots because they were good for my eyes. No one told me about the brain benefits of blueberries.
I began eating blueberries a few years ago for brain health based on these three studies. (I do not have access to the full studies.)

Dietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trial

Methods: In this study, 13 men and 24 women, between the ages of 60 and 75 years, were recruited into a randomized, double-blind, placebo-controlled trial in which they consumed either freeze-dried blueberry (24 g/day, equivalent to 1 cup of fresh blueberries) or a blueberry placebo for 90 days. Participants completed a battery of balance, gait, and cognitive tests at baseline and again at 45 and 90 days of intervention.

Results: Significant supplement group by study visit interactions were observed on tests of executive function. Participants in the blueberry group showed significantly fewer repetition errors in the California Verbal Learning test (p = 0.031, ηp2 = 0.126) and reduced switch cost on a task-switching test (p = 0.033, ηp2 = 0.09) across study visits, relative to controls. However, no improvement in gait or balance was observed.

Conclusions: These findings show that the addition of easily achievable quantities of blueberry to the diets of older adults can improve some aspects of cognition.

Enhanced task-related brain activation and resting perfusion in healthy older adults after chronic blueberry supplementation​

Blueberries are rich in flavonoids, which possess antioxidant and anti-inflammatory properties. High flavonoid intakes attenuate age-related cognitive decline, but data from human intervention studies are sparse. We investigated whether 12 weeks of blueberry concentrate supplementation improved brain perfusion, task-related activation, and cognitive function in healthy older adults. Participants were randomised to consume either 30 mL blueberry concentrate providing 387 mg anthocyanidins (5 female, 7 male; age 67.5 ± 3.0 y; body mass index, 25.9 ± 3.3 kg·m-2) or isoenergetic placebo (8 female, 6 male; age 69.0 ± 3.3 y; body mass index, 27.1 ± 4.0 kg·m-2). Pre- and postsupplementation, participants undertook a battery of cognitive function tests and a numerical Stroop test within a 1.5T magnetic resonance imaging scanner while functional magnetic resonance images were continuously acquired. Quantitative resting brain perfusion was determined using an arterial spin labelling technique, and blood biomarkers of inflammation and oxidative stress were measured. Significant increases in brain activity were observed in response to blueberry supplementation relative to the placebo group within Brodmann areas 4/6/10/21/40/44/45, precuneus, anterior cingulate, and insula/thalamus (p < 0.001) as well as significant improvements in grey matter perfusion in the parietal (5.0 ± 1.8 vs -2.9 ± 2.4%, p = 0.013) and occipital (8.0 ± 2.6 vs -0.7 ± 3.2%, p = 0.031) lobes. There was also evidence suggesting improvement in working memory (2-back test) after blueberry versus placebo supplementation (p = 0.05). Supplementation with an anthocyanin-rich blueberry concentrate improved brain perfusion and activation in brain areas associated with cognitive function in healthy older adults.

Cognitive effects following acute wild blueberry supplementation in 7- to 10-year-old children​

Methods: Using a double-blind cross-over design, on three occasions children (n = 21; 7-10 years) consumed placebo (vehicle) or blueberry drinks containing 15 or 30 g freeze-dried wild blueberry (WBB) powder. A cognitive battery including tests of verbal memory, word recognition, response interference, response inhibition and levels of processing was performed at baseline, and 1.15, 3 and 6 h following treatment.

Results: Significant WBB-related improvements included final immediate recall at 1.15 h, delayed word recognition sustained over each period, and accuracy on cognitively demanding incongruent trials in the interference task at 3 h. Importantly, across all measures, cognitive performance improved, consistent with a dose-response model, with the best performance following 30 g WBB and the worst following vehicle.

Conclusion: Findings demonstrate WBB-related cognitive improvements in 7- to 10-year-old children. These effects would seem to be particularly sensitive to the cognitive demand of task.

 

[David PS]

A clip of Ray Peat about berries (and bear fat).

View: https://youtu.be/5j-SodZE6C8?t=6041

 

[Dave Clark]

Thanks for the links. I tested my iron levels about 5 years ago and they were at the low end of normal. So I haven't paid much attention to iron chelators. Maybe it is time for me to reconsider.

You may want to look into IP-6, which is a natural phytate taken away from food that binds with free iron, the form that creates the hydroxyl radical.
Some links : Cancer Inhibition by Inositol Hexaphosphate (IP6) and Inositol: From Laboratory to Clinic
IP6 Research
Inositol hexa phosphoric acid (phytic acid), a nutraceuticals, attenuates iron-induced oxidative stress and alleviates liver injury in iron overloaded mice - PubMed

 

[David PS]

You may want to look into IP-6, which is a natural phytate taken away from food that binds with free iron, the form that creates the hydroxyl radical.
Some links : Cancer Inhibition by Inositol Hexaphosphate (IP6) and Inositol: From Laboratory to Clinic
IP6 Research
Inositol hexa phosphoric acid (phytic acid), a nutraceuticals, attenuates iron-induced oxidative stress and alleviates liver injury in iron overloaded mice - PubMed

Thanks for the suggestion.

 

[David PS]

Berry anthocyanin intake and cardiovascular health - another area of infrastructure repair.

 

[David PS]

Effects of Berries Consumption on Cardiovascular Risk Factors: A Meta-analysis with Trial Sequential Analysis of Randomized Controlled Trials​

Here, we aimed to conduct a meta-analysis with trial sequential analysis to estimate the effect of berries consumption on CVD risk factors. PubMed, Embase and CENTRAL were searched for randomized controlled trials (RCTs) that regarding the effects of berries consumption in either healthy participants or patients with CVD. Twenty-two eligible RCTs representing 1,251 subjects were enrolled. The pooled result showed that berries consumption significantly lowered the low density lipoprotein (LDL)-cholesterol[weighted mean difference (WMD), −0.21 mmol/L; 95% confidence interval (CI), −0.34 to −0.07; P = 0.003], systolic blood pressure (SBP) (WMD, −2.72 mmHg; 95% CI, −5.32 to −0.12; P = 0.04), fasting glucose (WMD, −0.10 mmol/L; 95% CI, −0.17 to −0.03; P = 0.004), body mass index (BMI) (WMD, −0.36 kg/m2; 95% CI, −0.54 to −0.18, P < 0.00001),Hemoglobin A1c (HbA1c) (WMD, −0.20%; 95% CI, −0.39 to −0.01; P = 0.04) and tumor necrosis factor-α (TNF-α) (WMD, −0.99 ρg/mL; 95% CI, −1.96 to −0.02; P = 0.04). However, no significant changes were seen in other markers. The current evidence suggests that berries consumption might be utilized as a possible new effective and safe supplementary option to better prevent and control CVD in humans.

 

[David PS]

No mention of SIRT6 but still berries.

Favorable effects of berry consumption on platelet function, blood pressure, and HDL cholesterol

ABSTRACT. Background: Berries are a particularly rich source of polyphenols. They also contain other bioactive substances, such as vitamin C. Previous studies i

academic.oup.com

Conclusion: The consumption of moderate amounts of berries resulted in favorable changes in platelet function, HDL cholesterol, and BP. The results indicate that regular consumption of berries may play a role in the prevention of cardiovascular disease.