Resveratrol latest tips from sinclair

[mccoy]

I've listened to the latest podcast of Rhonda Patrick with Dave Sinclair (has it been posted anywhere else? I'm not aware of it ).

I found this one maybe a little different from the others. Among the others, one very useful tip is the fact that resveratrol powder is very susceptible to light and heat and degrades in warm temperatures and in the presence of humidity. This made me ruminate... The supplement goes from the production facility to the warehouse/distributor's shelf. How long does it remain on the shelves? In which temperatures? With which likelihood it starts to degrade? Then it hits our homes. How long do we keep it and in which conditions?

Considering that resveratrol should be kept in the freezer or fridge just after manufacturing, it's easy to understand that in many cases it constitutes just a placebo when it is ingested by the final consumer.

Beyond that, it's interesting to hear yet again about NAD, NMN, NR.... If I'm not wrong Sinclair ceased to be involved into supplements development and is into drugs development (NMN is an example, but I didn't know that it is a prescription drug).

 

[Clinton]

Is anyone here taking resveratrol??

 I know Ron indicated before Christmas in his supplement thread that he was.

 I am curious to know your rationale for taking and what you are taking (dose, type/brand ).

 I am considering taking a small amount (100mg per day) trans resveratrol Doctors Best brand which includes some other polyphenols.

 I understand it blunts some of the positive effects of HIIT and other forms of exercise; however I (sadly/honestly) do zero HIIT these days or exercise other than resistance training and also don’t even follow what one would consider CR.  
I don’t over eat, stay lean , practice TRF and think that there may be some cardiovascular, insulin sensitivity, autophagy benefits to be had given my diet and lifestyle.

150mg per day had impressive results in obese men.

Thanks for comments,

Clinton

[UserReqDel20200217]

If you are on a calorie restriction site why don't you practice CR? How many calories do you consume, what are your lipid parameters, what is your blood pressure and other blood tests?
BMI 22 is not the best we have this impression because centenarians are generally low (4 feet and 11 inches on average) and consumes a lower number of calories which gives this impression, but high centenarians have a lower BMI generally as is the case Walter Breuning who was 5 feet 8 inches and had a BMI 19

If you are on a calorie restriction site why don't you practice CR? How many calories do you consume, what are your lipid parameters, what is your blood pressure and other blood tests?
BMI 22 is not the best we have this impression because centenarians are generally low (4 feet and 11 inches on average) and consumes a lower number of calories which gives this impression, but high centenarians have a lower BMI generally as is the case Walter Breuning who was 5 feet 8 inches and had a BMI 19
If you want to leave the weight training aside and after you stop losing muscle, lower the fat percentage to 5-10% and then keep it for a while and then do the blood test.

Edited February 14, 2020 by Fernando Gabriel

[Clinton]

Gents,

I was hoping for feedback other than the above 'post' & interested in any comments,

Thank you,

Clinton

Edited February 14, 2020 by Clinton

[Clinton]

1 hour ago, Fernando Gabriel said:

If you are on a calorie restriction site why don't you practice CR?

Fernando,

I ask that you please do not respond to any of my posts,

Clinton

[Todd Allen]

Clinton, I considered taking resveratrol but haven't seen compelling evidence of benefits to justify the cost.   I think it is slightly more compelling for those with metabolic syndrome but I haven't seen much to suggest benefits for those already well engaged in exercise and diet optimization with CR and/or fasting.  I'd reconsider if someone here made a good case for it with links to large RCTs showing substantial benefits additive to other healthy lifestyle factors.

[mccoy]

Clionton, I've listened to many podcasts featuring Dr. Sinclair but at the end I decided I won't take resveratrol for now. 

My suggestion would be that you try it out and report here in a few months.

[Ron Put]

About six months ago started taking about 1400 resveratrol daily. I may have been suckered by the latest wave of Sinclair product pitches, but since I don't see a significant downside, I added it to my daily pills: This is the one I take.

[Ron Put]

As my current supply of Resveratrol is dwindling and I am deciding if I should restock, I came across this:

Resveratrol, an activator of SIRT1, improves ER stress by increasing clusterin expression in HepG2 cells

Endoplasmic reticulum stress (ER stress) is involved in lipid metabolism and lipotoxicity and can lead to apoptosis. Resveratrol, a sirtuin 1 (SIRT1) agonist, prevents ER stress and improves ER stress-induced hepatic steatosis and cell death. Clusterin is a secreted chaperone and has roles in various physiological processes. However, changes in the expression of clusterin upon ER stress and the connection between SIRT1 and clusterin in protection against ER stress are not well known. In cells treated with tunicamycin, resveratrol increased the expression of clusterin mRNA and protein and the secreted clusterin protein level in conditioned medium. Resveratrol decreased protein expression of the ER stress markers, p-PERK, p-IRE1α, and CHOP, and increased the expression of the ER-associated degradation (ERAD) factors, SEL1L and HRD1, in tunicamycin-treated cells. However, no changes in the expression of these genes were observed in clusterin siRNA-transfected cells. Moreover, increased LAMP2 and LC3 expression and decreased Rubicon expression were observed in cells treated with resveratrol or secreted clusterin. These data suggest that SIRT1 activation by resveratrol attenuates ER stress by promoting protective processes such as ERAD and autophagy pathways and that these protective effects are mediated by clusterin.

[Clinton]

Ron, fwiw I began taking 200mg of trans-resveratrol (Japanese Knotwood); the NOW brand, along w 300mg of Nicotinamide Riboside with breakfast.

Resveratrol went from the initial excitement and hype and then went through a major cooling-off period and plenty of 'debunking'.  Sinclair spend much time and resources to validate the benefits of it and still today takes plenty of it.  Combined with NMN or N(R) might be an effective way to positively affect sirtuins and DNA repair - of course I don't understand this - only repeating remarks from Sinclair.

I like taking the sirtuin/DNA repair combo w breakfast of 300mg N(R) and 200mg trans-resveratrol.

With lunch I take AOR's green tea extract capsul loaded w all catechins and plenty of EGCg along w 1500mg glucosamine sulfate.  (Plenty of in-vivo evidence for health benefits in humans and also seem to act as mild rapamycin & metformin (respectively) mimetics).

Ref: https://www.researchgate.net/publication/321139544_Towards_natural_mimetics_of_metformin_and_rapamycin

 

Edited May 19, 2020 by Clinton

[Sibiriak]

Like a number of other polyphenols,  resveratrol exhibits a hormetic biphasic dose–response relationship   in various circumstances.  

It may be that low doses of resveratrol (like those obtained from moderate red wine intake) support endothelial function and are cardioprotective while at the same time being tumor-promoting.   T

 

Argument for low-dose resveratrol:

Hormetic shifting of redox environment by pro-oxidative resveratrol protects cells against stress

http://www.sciencedirect.com/science/article/pii/S0891584916303793?via%3Dihub

 

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Abstract

 

Resveratrol has gained tremendous interest owing to multiple reported health-beneficial effects. However, the underlying key mechanism of action of this natural product remained largely controversial. Here, we demonstrate that under physiologically relevant conditions major biological effects of resveratrol can be attributed to its generation of oxidation products such as reactive oxygen species (ROS). At low nontoxic concentrations (in general <50 µM), treatment with resveratrol increased viability in a set of representative cell models, whereas application of quenchers of ROS completely truncated these beneficial effects. Notably, resveratrol treatment led to mild, Nrf2-specific gene expression reprogramming. For example, in primary epidermal keratinocytes derived from human skin this coordinated process resulted in a 1.3-fold increase of endogenously generated glutathione (GSH) and subsequently in a quantitative reduction of the cellular redox environment by 2.61 mV mmol GSH per g protein. After induction of oxidative stress by using 0.78% (v/v) ethanol, endogenous generation of ROS was consequently reduced by 24% in resveratrol pre-treated cells.

 

In contrast to the common perception that resveratrol acts mainly as a chemical antioxidant or as a target protein-specific ligand, we propose that the cellular response to resveratrol treatment is essentially based on oxidative triggering. In physiological microenvironments this molecular training can lead to hormetic shifting of cellular defense towards a more reductive state to improve physiological resilience to oxidative stress.

 

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Polyphenols represent a large collection of natural products featuring health-beneficial effects [1]. Resveratrol (3,5,4′-trihydroxy-trans-stilbene, RSV), an antimicrobial phytoalexin originally found in white hellebore (Veratrum grandiflorum O Loes) and later in red grapes and other plants, is one of the most prominent polyphenols. Early studies indicated cancer chemo-preventive properties of RSV [2]. Over the last 15 years, numerous studies claimed additional benefits including cardio-protective and anti-aging effects [3]. Consequently, a number of products based on RSV have been developed for dietary and dermatological application [4,5]. Nevertheless, the efficiencies of RSV treatments and underlying mechanisms of action remained largely controversial. For example, RSV had been suggested to modulate estrogen receptor activity [6], or to act as a caloric mimetic by directly increasing the enzymatic activity of the histone deacetylase sirtuin 1 (SIRT1) [7]. Recently, it was shown that inhibition of phosphodiesterase 4 (PDE4) by RSV increased intracellular amounts of the hunger signalling molecule cAMP [8]. Notably, the reported interaction of RSV with these and further target proteins was in many cases low and unspecific. In general, most of these studies assumed a proportional dose-response relationship of compounds, i.e. a conventional pharmacological (linear) threshold model [9].

 

However, in contrast to the standard pharmacological model, hundreds of studies reported (in many cases probably unconsciously) beneficial effects of RSV at “low” but detrimental outcomes at “high” doses. In general, this potentially counterintuitive bi-phasic property of RSV was widely ignored [10]. The large body of data would nevertheless hint to hormesis, a dose-response relationship that is characterized by low-dose stimulation and high-dose inhibition, consistent with the Arndt-Schulz law, Hueppe’s rule and other terms describing a beneficial stimulation (of poisons) at low doses [11,12]. General acceptance of the hormesis concept for therapeutic application seems to remain minor, due to generally faint stimulatory effects and the lack of mechanistic explanation of hormetic phenomena.

 

Interestingly, polyphenols including RSV are considered as antioxidants mainly owing to chemical properties such as scavenging of free radicals or due to indirect effects in a given biological system. Depending on the chemical context RSV and other polyphenols can also become pro-oxidative [1], a fact that seems to be often ignored. Depending on the reaction conditions RSV can be (auto-) oxidized to generate semiquinones and the relatively stable 4′-phenoxyl radical; finally this oxidation process can lead to production of reactive oxygen species (ROS) [13,14]. Oxidative reactions of polyphenols are influenced by changing pH, particularly the presence of hydroxyl anions or organic bases [15,16]. Additionally, metal ions (e.g. iron II ions) facilitate oxidative reactions and generation of radicals via the Fenton reaction [17].

 

The here presented study aimed to explore new aspects and connect fragmented pieces of the chemical and resulting biological properties of RSV to contribute to a comprehensive understanding of the purported health-beneficial effects of RSV.

 

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In general, hormetic induction of cellular fitness by pro-oxidative polyphenols such as RSV might represent a powerful approach to protect cells against physiological stress and to inhibit age-related diseases.

 

However:

Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity (2012)

https://www.sciencedirect.com/science/article/pii/S0925443911002523

 

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8.4. A focus on the hormetic role of resveratrol

Due to its remarkably broad range of effects, including mostly antioxidant and anti-inflammatory activities, immunomodulation, chemoprevention, cardiovascular protection and longevity, resveratrol has attracted numerous researchers investigating the hormetic mechanisms underlining its biological responses in cells and organisms [168]. The emerging body of evidence indicates that the wide range of resveratrol induced end-points displayed a biphasic dose response with quantitative features consistent with the hormetic relationship.

Interestingly, many in vitro studies demonstrated the resveratrol ability to hormetically induce and inhibit cell proliferation in numerous human cancer cell lines, at low and high concentrations, respectively. Several cell lines were affected, such as breast [328], [329], [330], [331], [332], [333], [334], [335], prostate [336], [337], [338], [339], leukemia [340], [341], colon [342], [343], uterus [344], and lung [345] tumor cell lines. These results suggest that resveratrol may prevent or enhance tumor development, according to the extent of the dose applied. It is a crucial point of discussion in consideration of both the relevance given to resveratrol potential chemo-preventive effects, to the implications that resveratrol dietary amount may have for human health and the potential therapeutic dose management [168], [334].

Similarly a consistent hormetic biphasic dose–response relationship was detected by Gu et al. [346] for endothelial human cell proliferation, and also for cell migration, as well as cell adherence and eNOS expression/concentration in injured arteries. These in vitro findings were supported also in subsequent in vivo studies with a rat model. Such studies demonstrated that a low dose of resveratrol enhanced the mobilization of endothelial cells, facilitated re-endothelialization, reduced the occurrence of neointimal formation and up-regulated the expression of eNOS following an induced balloon injury. These findings were not only supported in subsequent research of Xia et al. [347] which corroborated the hormetic-like response of resveratrol on endothelial progenitor cell proliferation and cell migration, but further extended other observations by linking these responses to telomerase activity via AKT-dependent mechanisms. As in the case of the endothelial cell parameters measured, the resveratrol-induced alterations in telomerase activity were also indicative of hormetic responses.

Szende et al. [342] demonstrated that resveratrol biphasically affected proliferation with a low-concentration stimulation and a high-concentration inhibition in human endothelial cells. Using bovine aortic endothelial cells (BAECs), In et al. [348] showed that the resveratrol biphasically affected endothelial cell migration. While the authors acknowledged the capacity of resveratrol to induce a biphasic concentration response, they emphasized that their data revealed that high concentrations of resveratrol might have utility as a potent anti-angiogenesis drug. However, at lower concentrations, the response could switch to angiogenic effects.

Resveratrol has anti-inflammatory properties such as shown with the inhibition of COX-1 [300] and COX-2 [349], down-regulation of prostaglandin biosynthesis and suppression of carrageenan-induced paw edema [300], [350]. Since these collective findings suggested a possible effect on immune response, Falchetti et al. [351] explored, in detail, the effects of resveratrol on multiple immune functions of human T-cells in vitro. These included the development of cytokine-producing CD4 + and CD8 + T cells by stimulating peripheral blood mononuclear cells (PBMC) with anti-CD3/antiCD28, specific antigen-induced generation of cytotoxic T lymphocytes and natural killer (NK) activity of peripheral blood mononuclear cells. These authors reported that there was a hormetic-like biphasic dose response for each endpoint assessed. According to Falchetti et al. [351] these findings suggested a regulatory effect of resveratrol on the immune response. Gao et al. [352], [353] revealed that resveratrol inhibited the Con A induced proliferation of the spleen cells but only at high concentrations. At lower concentrations, the proliferative response was significantly increased. These findings generally supported the conclusion that resveratrol has the capacity to suppress or upregulate immune response depending on the concentration.

Interestingly, a 2005 study by Juan et al. [354] provided such a mechanistic insight into how resveratrol affects a hormetic response in human aortic smooth muscle cells (HASMCs). Resveratrol induced HO-1 expression in a manner that conformed to the hormetic dose response, markedly enhancing HO-1 expression at low concentrations whereas at higher concentrations, this response was diminished. Resveratrol induction of the HO-1 gene was mediated via the NF-kB pathway. In fact, two separate NF-kB inhibitors abolished the capacity of resveratrol to induce HO-1 expression and the activity of the HO-1 promoter. Low concentrations of resveratrol enhanced NF-kB-binding activity based upon experiments assessing electrophoretic mobility shifts. At these low concentrations, the resveratrol trans-activated the NF-kB and this activation process enhanced the transmigration of NF-kB into the nucleus, which then led to the modulation of HO-1 gene expression.

It was demonstrated also that resveratrol had chemopreventive effects with respect to several conditions such as cardiovascular disease [355], Alzheimer's disease [304], osteoporosis [356] and gastric ulcers [357]. From a hormetic perspective, in these conditions, low doses of resveratrol were shown to confer protection whereas higher doses showed adverse health effects. However, in relation to digestive disorders, there are contradictory results that identified resveratrol as a beneficial agent at different doses, without detecting any biphasic dose responses [358].

Various parasitic diseases were also hormetically influenced by resveratrol. Animal models showed that elevated doses protected against Leishmaniasis and Trichinella, while low concentrations consistently enhanced their proliferation [359], [360].

Globally viewing, low concentrations of resveratrol can be potentially beneficial or harmful, depending on the endpoint investigated. In this regard, low doses of resveratrol would have the capacity to increase the risk of tumor development of a number of organs and in contrast to be significantly cardio-protective. This type of conflict between beneficial or harmful effects is not uncommon and it is maybe related to the different biological system, tissue and chemical agent investigated.

Resveratrol is probably the most studied molecule of a series of phytochemicals, including sulforaphane, curcumin, fumaric acid and other chemicals (as previously detailed), that, as hormetic paradigmatic cases, may induce adaptive stress response at subtoxic doses while may be toxic to mammalian cells at high concentrations [18]. However, even if the evidence regarding the hormetic dose–response induced by resveratrol is quite strong, the molecular mechanisms underlining this phenomenon, at present, are not fully understood and deserve greater attention in future research. Moreover, future studies should be focused in putting the findings described into a realistic biological framework to determine whether or not these effects are relevant for human health [361].

 

Resveratrol: A Double-Edged Sword in Health Benefits (2018)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164842/
 

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[...]A study carried out by Martins et al. revealed that resveratrol can modulate different pathways at a time, which can result in distinct and even opposite biological effects, depending on its concentration or treatment time defined. The authors documented that, although a dose-dependent resveratrol pro-oxidative effect leads to cells oxidative stress over lesser time exposure, at same dose but with an increase in exposure time, less expressive cytotoxicity was found. This suggest that surviving cells seemed to be more resistant to resveratrol-induced damages, being its effects attenuated over treatment time [114].

Additionally, low resveratrol doses (0.1–1.0 μg/mL) has been documented to enhance cell proliferation, whereas higher doses (10.0–100.0 μg/mL) induces apoptosis (Figure 2) and decreases mitotic activity on human tumors and endothelial cells [122]. Recently, dual resveratrol pattern effects on HT-29 colon cancer cells death and proliferation were observed, where at low concentrations (1 and 10 μmol/L), resveratrol increased cells number, while at higher doses (50 or 100 μmol/L) resveratrol reduced cells number and increased apoptotic or necrotic cells percentage [123].

 

Also interesting:

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[...] All the above highlighted studies show the pivotal role of dose-dependency and aging in resveratrol-induced responses towards health benefits. Also, in another study, aiming to compare resveratrol effects on aging-induced and re-nutrition-induced insulin resistance and its consequences on arterial system, the authors found that resveratrol improved insulin sensitivity in old mice fed standard diet, while did not improve insulin resistance status in old mice receiving high-protein diets. In contrast, resveratrol exhibited deleterious effects by increasing inflammation state and superoxide production and decreasing aortic distensibility.

This data demonstrates that resveratrol seemed to be beneficial to malnourished state of physiological aging, whereas when associated with high protein diets in old mice, may increase atherogenesis-associated risk factors by triggering vascular alterations that could represent an additional risk factor for cardiovascular system [138].

 

Finally,  this recent report:

Red wine component [ resveratrol ] mimics oestrogen to support healthy ageing 6 April 2020
 

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Some dietary compounds such as resveratrol, which is commonly found in red wine, can mimic oestrogen to activate anti-ageing proteins called sirtuins, finds a new UCL study.  The findings, published in Scientific Reports, may explain the impact of both sirtuins and resveratrol on health and ageing.

Resveratrol only mimicked oestrogen at low doses, but had the opposite effect at high doses, which may lend credence to suggestions that a small glass of red wine a day, but no more, can support healthy ageing.

[...] while resveratrol behaves like oestrogen at low doses, Dr Bayele found that in high concentrations, it acts like an antioestrogen and has the opposite effect, suppressing sirtuin signalling. Some STACs were even better than oestrogen at activating sirtuin signalling, including isoliquiritigenin, which is found in liquorice.

 

The study itself is worth reading in its entirety  as it demonstrates how sirtuin biology is so "fiendishly complex,"  to use the author's expression.

Sirtuins transduce STACs signals through steroid hormone receptors March 24, 2020

 

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[...] Resveratrol was particularly remarkable on two levels.

First, its dosage-sensitivity or non-monotonicity hints at a potential for hormetic signalling, an indication that it may evoke adaptive stress responses in vivo consistent with the xenohormesis hypothesis that dSTACs may be plant stress signalling molecules⁵⁶. This may also be useful cautionary information because it suggests that contrary to popular lore, high doses of resveratrol may not be necessary to activate sirtuin signalling and may in fact be harmful, i.e. less is more. Instead, low dietary doses⁵⁷ may suffice to elicit the hormetic responses required to prime defence mechanisms against incipient disease⁵⁸.

Secondly and more importantly, resveratrol elicited oestrogenicity in low doses but in large amounts it behaved like an antioestrogen, reducing sirtuin signalling through the ERs both in the absence and presence of E2. This janus-faced feature has been previously described as mixed agonism^22,59,60, and may enable it to protect against a spectrum of diseases.

For example, in low doses resveratrol induces gene expression signatures that mimic calorie restriction, delays ageing-related neurodegeneration, protects against obesity and non-alcoholic fatty liver disease, improves motor and cognitive functions and increases insulin-sensitivity in patients with type 2 diabetes^{61,62,63,64,65}; all these effects remarkably overlap those of oestradiol^{42,43,44,45,46,47,48,49}.

In small amounts (5 µM) resveratrol also increased worm lifespan⁶⁶. It is therefore interesting to speculate that in low doses it may mimic oestradiol, enabling it to up-regulate SIRT1 signalling through the ERs to confer all of the above health benefits as well as protect against other diseases associated with SIRT1 including the metabolic syndrome. Interestingly, SIRT1 has been shown to form transcriptional complexes with PGC-1α on regions of mitochondrial DNA that bind both ERα and ERβ^67,68.

This may partly explain why mice fed a resveratrol diet showed extended lifespan, increased mitochondrial biogenesis and metabolic capacity, and were protected from the damaging effects of high-calorie diets^61,69,70. Of note, Sirt1 or Sir-2.1 ablation in cell culture and in animals severely attenuated responses to resveratrol and related dSTACs^36,71 while the converse was true with sirtuin overexpression (see ref. ¹² and references therein). Importantly, Sirt1 deletion reduced the ability of resveratrol to protect against skin cancer in mice⁷².

Together these studies strongly suggest that these sirtuins may be critically important for transducing and translating the health benefits of dSTACs signals perhaps through steroid hormone receptors.

In very low doses, resveratrol also rapidly and ER-dependently induces nitric oxide in endothelial cells⁷³, indicating a possible mechanism by which it might protect against cardiovascular disease.

Conversely, its antagonism of the ER in high doses hints at how resveratrol may reduce the risk of oestrogen-dependent cancers^74,75,76; however, these effects may not be solely due to antioestrogenicity but also to its ability to induce cytostasis at those doses⁶⁰. Hence these results are intriguing because they may partly explain the French paradox, i.e. the reduced incidence of cardiovascular diseases and certain types of cancer in some populations despite their consumption of high-fat diets^57,77.

It may be important to note that the biphasic responses evoked by resveratrol and its non-monotonicity are typical of steroid hormones in general but of oestradiol in particular (see ref. ³² and references therein); this may prove consequential in vivo.

At the molecular level, it could be speculated that in low doses, resveratrol may recruit ER coactivators such as SIRT1 and PGC-1α²³. This may be supported by co-crystal structures showing that it induces a conformational change in ERα LBD that facilitates coactivator recruitment³⁹.

Alternatively, low-dose resveratrol may induce an open chromatin landscape permissive to SIRT1-ER coactivator complexes while in high doses it may either induce chromatin compaction that occludes these complexes or actively promote corepressor recruitment. It could also be that high-dose resveratrol induces a conformational change that inhibits ER binding/coactivation by SIRT1 (see Figs. 3 and 4).

These assumptions may be consistent with reports that agonists and antagonists induce distinct ER conformations that respectively recruit coactivators and corepressors to the LBD^78,79. Were similar conformers to be induced by low and high doses of resveratrol, they would explain its bifunctionality and the biphasic ER responses to it.

 

Edited May 20, 2020 by Sibiriak

[TomBAvoider]

I'm probably biased due to my intense distaste for the resveratrol hype back in the day. But, be that as it may, from what I've read, resveratrol doesn't seem like something I'd like to f*** with - YMMV, just speaking for myself. And thank you Sibirak, for those finds. 

[Sibiriak]

At 1:03:32 in the video above,  Sinclair tells us:

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I never recommend anything because,  first of all, I'm not a physician, I'm just a scientist,  and I mostly study mice.  So I don't really know, yet, how all this is going to play out in people.

 

The evidence regarding reservatrol from actual clinical trials is inconsistent and uncertain,   and, of course, the studies are generally very short term.

Here's a summary from  a recent review (March 2020):

 

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4. Clinical Trials

In light of the positive epidemiological evidence and the promising results from experimental studies, resveratrol has been investigated in the human population as a potential nutraceutical (Table 3). There are certain encouraging outcomes reported. Specifically, resveratrol intake (500 mg/day for 30 days) was demonstrated to reduce CVD risk factors by increasing SIRT1, enhancing total antioxidant capacity in healthy individuals, decreasing low-density lipoprotein cholesterol (LDL-C), ApoB, and oxidized LDL [113,114,115]. Moreover, resveratrol prevented bone density loss (500 mg/day for 6 months) in type-2 diabetic patients [116]. In addition, resveratrol showed benefits in obesity, NAFLD, and neurodegenerative diseases [15,16,117,118].

However, some null outcomes have also been reported. For instance, resveratrol intake (250 mg/day for 8 weeks) did not increase SIRT1 nor improve many cardiovascular risk factors in healthy aged men [58].

In some other studies, no significant improvements were found in metabolic biomarkers in patients with Alzheimer’s disease, obesity or type-2 diabetes, respectively, though their resveratrol intake ranged from 150 to 1000 mg/day with different duration of 4–52 weeks [119,120,121,122].

Therefore, the outcomes of clinical studies are not always consistent. Of note, the health effects of resveratrol as a therapeutic intervention may be affected by many factors, such as baseline health status of the subjects, their demographic profile, lifestyle, eating pattern, resveratrol dose, and intervention period. Nevertheless, a well-designed study, proper sample size, and a scientific evaluation system are also needed.

Furthermore, although resveratrol is well-tolerated and safe as reported by most of the clinical trials, very few adverse effects (e.g., nausea and diarrhea) were observed, as well as some unfavorable results like an increase in total cholesterol, ApoB, the homeostatic model assessment-insulin resistance (HOMA-IR) score, fasting blood glucose, body fat, and the inflammatory markers [15,114,118].

Interestingly, resveratrol was reported to mask the exercise training-induced benefits, blunting the improved cardiovascular health parameters [58]. It might be attributable to the potent antioxidant capability of resveratrol, which could scavenge the free radicals induced by exercise training, because the appropriate number of free radicals is necessary for health maintenance. Therefore, it could be suggested that foods containing resveratrol should not be consumed during exercise.

 

 

Regarding dosage,   keep in mind that 1,000mg/day of  resveratrol is a massive amount,  far higher than the highest amount you could  possibly get from  normal dietary sources. A full liter of red wine, for example,  would contain at most around  2 mg of resveratrol,   so you would need to drink some 500 liters of red wine to get to the suggested 1,000mg.

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Typical resveratrol concentrations reported for conventional food products are: peanuts without seed coats, 0.03–0.14 μg/g (126); red wines, 0.361–1.972 mg/L (127); white wines, 0–1.089 mg/L (128); rosé wines, 0.29 mg/L (129); beers, 1.34–77.0 μg/L (130); skin of tomatoes, ∼19 μg/g dry weight (131); dark chocolate, 350 μg/kg; milk chocolate, 100 μg/kg (132); Itadori tea, 68 μg/100 mL (37); red grapes, 92–1604 μg/kg fresh weight (133); white grapes, 59–1759 μg/kg fresh weight (133); and apples, 400 μg/kg fresh weight (4).

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...adopting that red/rosé wines contain ∼2 mg/L resveratrol and white wines contain ∼0.5 mg resveratrol/L, the annual consumption [in France] of 31.7 L of red wine and 11.7 L of white wine is equal to an uptake of ∼70 mg resveratrol/y (or 0.2 mg/d) or 5000 times less than the proposed therapeutic dose of 1 g/d.

 

For those taking, or contemplating taking,  high/ mega-doses of resveratrol (I personally consider anything over 20mg/day a high dose),  see also:

Potential Adverse Effects of Resveratrol: A Literature Review

Int J Mol Sci. 2020 Mar; 21(6): 2084.

Published online 2020 Mar 18. doi: 10.3390/ijms21062084

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9. Current Concerns and Recommendations

The biological effects of RE, as well as its in vitro and in vivo outcomes, appear to be strongly associated with a hormetic effect where RE low doses usually are associated with beneficial effects while high doses usually have a toxic effect [44]. In this regard, evidence suggests that RE’s hormetic property may be due to its dose-associated biphasic effect on the cellular redox state, which was reported to be antioxidant at low doses and a pro-oxidant at high doses [38,43,44,63].

As such, there are concerns that studies on the compound mostly focused on the short-term outcomes of RE intake. Given that we suggest that many of the controversial results present in the literature may be due to this hermetic aspect, it is suggested that RE dosage and RE interaction with the redox state of the environment appear to be of primary importance; especially when precise redox modulation is needed to allow a physiological function or to promote a deleterious effect. Other aspects related to RE controversial data appear to be differences in the characteristics of the enrolled patients, RE doses used, and the duration of RE supplementation; therefore, more extensive studies in more complex models are warranted in order to validate the current findings.

Notwithstanding the substantial number of human and animal studies that support the beneficial and protective properties of RE [60,181,219,220,221,222], there are not enough clinical studies that report on RE’s harmful effects, which are indeed full of controversy. Moreover, the molecular mechanism of RE action needs to be better identified. All of these contradictions call for an urgent need to appraise and investigate the adverse outcomes of this compound despite its documented benefits.

Above all, the high level of variability among all the different studies calls for a more uniform design of clinical trials to properly investigate the effects of RE and define its mechanisms of disease therapy and prevention.

 

Edited May 20, 2020 by Sibiriak

[Clinton]

Thanks much, Sibiriak.  I understand that the potential positive effects of any? polyphenol are due to hormesis; I'm curious as to what the 'sweet spot' would be to conservatively gain a little benefit and be sure that the quantity was not too much. 

Sinclair is taking https://fastlifehacks.com/david-sinclair-supplements/  1g per day; 200mg doesn't seem like a whole lot.

[Clinton]

My reasoning for taking 200mg (instead of 1g like Sinclair) was influence by THIS study where they used 150mg: "Calorie Restriction-like Effects of 30 Days of Resveratrol Supplementation on Energy Metabolism and Metabolic Profile in Obese Humans"

https://pubmed.ncbi.nlm.nih.gov/22055504/

Here is the summary:

"Resveratrol is a natural compound that affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity. Here we treated 11 healthy, obese men with placebo and 150 mg/day resveratrol in a randomized double-blind cross-over study for 30 days. Resveratrol significantly reduced sleeping- and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels, and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction."

 

Any thoughts or comments??

Edited May 22, 2020 by Clinton

[Clinton]

This study used 80mg resv for 1 whole year then increased in to 480mg for an entire second year on rhesus monkeys.

https://pubmed.ncbi.nlm.nih.gov/24093677/

Here is part of the summary:

"Resveratrol supplementation (80 and 480 mg/day for the first and second year, respectively) decreased adipocyte size, increased sirtuin 1 expression, decreased NF-κB activation, and improved insulin sensitivity in visceral, but not subcutaneous, WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS ± resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys. "

 

Regarding the dose, taking 200mg is about 40% of the 480mg dose, which was found to be safe in a smaller primate that a human; according to this study was "well tolerated at the tested concentrations"

On average male rhesus monkeys weigh abuot 17lbs. 

Based on my body weight being more than 8x that of the average rhesus monkey, and taking only 40% of the 480mg dose which according to this study was "well tolerated at the tested concentrations" - I believe that 200mg is not risky.

Edited May 23, 2020 by Clinton
monkeys

[Clinton]

Does resveratrol make your canines grow??  vampires live a long time too.   17lbs of this shiz coming at you, you don't want.

 

[Annik]

On 11/11/2019 at 3:46 PM, mccoy said:

I've listened to the latest podcast of Rhonda Patrick with Dave Sinclair (has it been posted anywhere else? I'm not aware of it ).

I found this one maybe a little different from the others. Among the others, one very useful tip is the fact that resveratrol powder is very susceptible to light and heat and degrades in warm temperatures and in the presence of humidity. This made me ruminate... The supplement goes from the production facility to the warehouse/distributor's shelf. How long does it remain on the shelves? In which temperatures? With which likelihood it starts to degrade? Then it hits our homes. How long do we keep it and in which conditions?

Considering that resveratrol should be kept in the freezer or fridge just after manufacturing, it's easy to understand that in many cases it constitutes just a placebo when it is ingested by the final consumer.

Beyond that, it's interesting to hear yet again about NAD, NMN, NR.... If I'm not wrong Sinclair ceased to be involved into supplements development and is into drugs development (NMN is an example, but I didn't know that it is a prescription drug).

 

NMN is not a prescription drug.

[Annik]

On 5/22/2020 at 5:36 PM, Clinton said:

My reasoning for taking 200mg (instead of 1g like Sinclair) was influence by THIS study where they used 150mg: "Calorie Restriction-like Effects of 30 Days of Resveratrol Supplementation on Energy Metabolism and Metabolic Profile in Obese Humans"

https://pubmed.ncbi.nlm.nih.gov/22055504/

Here is the summary:

"Resveratrol is a natural compound that affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity. Here we treated 11 healthy, obese men with placebo and 150 mg/day resveratrol in a randomized double-blind cross-over study for 30 days. Resveratrol significantly reduced sleeping- and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels, and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction."

 

Any thoughts or comments??

What kind of resveratrol are you taking? You need the micronized form.  I am presently taking 1g daily.

[Annik]

On 5/19/2020 at 4:57 PM, Clinton said:

Ron, fwiw I began taking 200mg of trans-resveratrol (Japanese Knotwood); the NOW brand, along w 300mg of Nicotinamide Riboside with breakfast.

Resveratrol went from the initial excitement and hype and then went through a major cooling-off period and plenty of 'debunking'.  Sinclair spend much time and resources to validate the benefits of it and still today takes plenty of it.  Combined with NMN or N(R) might be an effective way to positively affect sirtuins and DNA repair - of course I don't understand this - only repeating remarks from Sinclair.

I like taking the sirtuin/DNA repair combo w breakfast of 300mg N(R) and 200mg trans-resveratrol.

With lunch I take AOR's green tea extract capsul loaded w all catechins and plenty of EGCg along w 1500mg glucosamine sulfate.  (Plenty of in-vivo evidence for health benefits in humans and also seem to act as mild rapamycin & metformin (respectively) mimetics).

Ref: https://www.researchgate.net/publication/321139544_Towards_natural_mimetics_of_metformin_and_rapamycin

 

I have been trying to decide between NR and NMN. I think I'll go with NMN. I'm looking into DoubleWood NMN which I will encapsulate myself. I think you need a gram/day for good results.

Have you noticed any differences in energy levels?

[Clinton]

I have never noticed any difference in energy levels at all with N(R) - or any supplement I’ve ever taken.

[Annik]

On 5/19/2020 at 3:38 PM, Ron Put said:

As my current supply of Resveratrol is dwindling and I am deciding if I should restock, I came across this:

Resveratrol, an activator of SIRT1, improves ER stress by increasing clusterin expression in HepG2 cells

Endoplasmic reticulum stress (ER stress) is involved in lipid metabolism and lipotoxicity and can lead to apoptosis. Resveratrol, a sirtuin 1 (SIRT1) agonist, prevents ER stress and improves ER stress-induced hepatic steatosis and cell death. Clusterin is a secreted chaperone and has roles in various physiological processes. However, changes in the expression of clusterin upon ER stress and the connection between SIRT1 and clusterin in protection against ER stress are not well known. In cells treated with tunicamycin, resveratrol increased the expression of clusterin mRNA and protein and the secreted clusterin protein level in conditioned medium. Resveratrol decreased protein expression of the ER stress markers, p-PERK, p-IRE1α, and CHOP, and increased the expression of the ER-associated degradation (ERAD) factors, SEL1L and HRD1, in tunicamycin-treated cells. However, no changes in the expression of these genes were observed in clusterin siRNA-transfected cells. Moreover, increased LAMP2 and LC3 expression and decreased Rubicon expression were observed in cells treated with resveratrol or secreted clusterin. These data suggest that SIRT1 activation by resveratrol attenuates ER stress by promoting protective processes such as ERAD and autophagy pathways and that these protective effects are mediated by clusterin.

You should switch to a micronized resveratrol , as it absorbs much better. Take it with some fat (I take it with a spoon of flax oil.) This is the one I use: https://store.revgenetics.com/products/m98-bulk-micronized-resveratrol?variant=37911648392

[Annik]

59 minutes ago, Clinton said:

I have never noticed any difference in energy levels at all with N(R) - or any supplement I’ve ever taken.

Have you considered switching to NMN?

[Sibiriak]

20 minutes ago, Annik said:

You should switch to a micronized resveratrol , as it absorbs much better. Take it with some fat

If you really are bent on achieving potentially unhealthy long term levels of resveratrol (and metabolites) in your system,  here's another tip:

Quote

Resveratrol pharmacokinetics have shown circadian variation, with higher bioavailability after morning administration

[Sibiriak]

On 5/22/2020 at 9:07 PM, Clinton said:

I'm curious as to what the 'sweet spot' would be to conservatively gain a little benefit and be sure that the quantity was not too much. 

Clinton,  I’ve  reached the following conclusions after a long review of the literature:  

If you have a particular disease such as cancer, diabetes,  obesity, then higher dose resveratrol might have potential as a relatively short term therapeutic agent (evidence is preliminary and mixed).  

But if you are basically healthy and are simply trying to  protect that health, avoid disease   and possibly increase  lifespan,  then chronic low dose resveratrol  would be preferable to high doses.

Having said that,  I wouldn't elevate resveratrol  above all the other possible health-enhancing phytochemicals such those as found in/extracted from turmeric,  ginger,  garlic, green tea, olives, pomegranates, cacao, cruciferous vegetables, grapes, berries, , citrus fruits, various herbs and  spices,  etc.

In any case,  what's a low dose of reseveratrol?    I'd say something like  4-20mg/day,  ideally from chemical-free (organic) sources together with modest amounts of other grape/wine phytochemicals. (6mg resv. = about the amount in six  5.0 oz glasses of red wine).   I'll try to post  more at some point on the reasoning and  evidence supporting this determination.

I know,  you want the BIG gun,  I know you do.  But the SMALL one might be what you really  need!

 

 

Edited June 5, 2020 by Sibiriak