Benefits of Resveratrol are dose-dependent: little is fine, too much is harmful!

[DR_P]

As we discussed in previous section, several studies have shown that resveratrol possess biphasic function depending on dose. The cardioprotective properties of resveratrol also appear to be dose-dependent. At lower dose of 5 μM, resveratrol functions as an antioxidant, while at higher dose it may function as a pro-oxidant (Dudley et al., 2008a). Our previous studies regarding cardioprotection of resveratrol showed that in low doses (5–10 μM), resveratrol functions as a cardioprotective agent (Penumathsa and Maulik 2009; Xi et al. 2009; Das et al. 2006b; Kaga et al. 2005). Red wines and white wines that contain resveratrol also possess cardioprotective properties at low to moderate doses (10–15 μM) (Sato et al. 2004, Dudley et al. 2008b).

At low concentration, resveratrol (<10 (M) can protect the heart from ischemia/reperfusion related injury by making the heart pharmacologically preconditioned in a NO-dependent manner (Hattori et al. 2002), which was further confirmed by a subsequent study, which showed that the same concentration of resveratrol could not protect the heart from ischemia/reperfusion induced injury in case of iNOS knockout mice (Imamura et al. 2002). It has been shown that 10 (M resveratrol could protect the heart by activating the survival signal through PI3-Kinase- Akt- Bcl2 signaling pathway (Das et al., 2005b) and through adenosine A(3) receptor signaling, which accelerates the CREB phosphorylation through both Akt-dependent and -independent pathways (Das et al. 2005b). In related studies, low doses of resveratrol (e.g., 10 (M or 2.5 mg/kg) protected the mammalian hearts from ischemia/reperfusion injury by activating the phase II enzymes, HO-1 and Trx-1 and by Map Kinase signaling (Das et al. 2006b; Das et al. 2006c). In a related study, it was shown that 2.5 mg/kg resveratrol alleviated cardiac dysfunction in streptozotocin-induced diabetes by upregulating NO, thioredoxin, and heme oxygenase and MnSOD activity (Thirunavukkarasu et al. 2007).

A specially designed study to determine the optimal concentration of resveratrol where the authors showed that there were no effects on ventricular function at 3.7 and 7.4 (M resveratrol, nor did any effect on myocardial infarct size. The maximum beneficial effect of resveratrol was noticed at 10 (M resveratrol. The higher dose (25 (M) of resveratrol still exerts cardioprotective effects, but the effects tend to be slightly reduced (Das et al, 2006c). In a more recent study, we randomly assigned the rats in five groups: control group (vehicle treated), low dose groups (treated with 2.5 mg/kg and 5.0 mg/kg resveratrol) and high dose groups (treated with 25 mg/kg and 50 mg/kg resveratrol). All rats were gavaged with either vehicle or different doses of resveratrol for 14 days. After 14 days of gavaging all rats were sacrificed and isolated hearts were perfused by working heart method in a working heart apparatus. All the hearts were subjected to 30 min ischemia followed by 2h reperfusion to examine the effects of different doses of resveratrol in ischemia/reperfusion induced cardiac injury. We have shown in this paper (Dudley et al. 2008a) that post ischemic cardiac functional parameters were improved by resveratrol treatment only at low doses (2.5 and 5 mg/kg). High dose resveratrol (25 and 50 mg/kg) significantly reduced the recovery of functional parameters like aortic flow, LVDP (left ventricular developed pressure), and LVdp/dt (First Derivative of Left Ventricular Developed Pressure). Cardiomyocyte apoptosis and myocardial infarction due to ischemia/reperfusion injury were reduced only in the low doses of resveratrol treatment, but not with high doses resveratrol treatment.

As resveratrol is a well known antioxidant, we determined the effects of different doses of resveratrol on regulation of mRNA transcripts of some redox proteins, which were directly related to cardioprotection, like Trx-1, Trx-2, Grx-1 and Grx-2. These redox proteins play crucial role to maintain the redox homeostasis in mammalian system. Our result showed that ischemia/reperfusion reduced the level of mRNA transcript of these redox proteins due to oxidative stress and low dose resveratrol could prevent this reduction, whereas high dose resveratrol was unable to protect the reduction of redox protein mRNA transcript. Redox effector factor-1 (Ref-1) is an important enzyme ubiquitously present in the mammalian system. Ref-1 plays a major role in DNA base excision repair pathway (Evans et al. 2000; Wilson and Barsky 2001)[2] D.M. Wilson III and D. Barsky, The major human abasic endonuclease: formation, consequences, and repair of abasic sites in DNA, Mutat. Res. 485 (2001), pp. 283–307. Article | PDF (720 K) | View Record in Scopus | Cited By in Scopus (113) It also serves as a transcriptional coactivator by stimulating the DNA binding activity of redox-sensitive transcription factors such as AP-1, nuclear factor _B (NF_B), p53, and cAMP response element binding protein (Xanthoudakis and Curran 1992; Huang and Adamson 1993). Consistently, Ref-1 enhanced Nrf2 binding to the ARE (Iwasaki et al. 2006), which in turn regulated the expression of a variety of enzyme proteins (Chan 2000).


A recent study showed that ischemia/reperfusion could potentiate a rapid translocation of thioredox-in-1 into the nucleus which then interacts with Ref-1, leading to the generation of a survival signal (Malik et al. 2006). The same author also showed that Ref-1 induced a survival signal in ischemic heart via protein- protein interaction between NF_B, Ref-1, Trx-1 and Nrf2. (Gurusamy et al. 2007) Based on these studies we determined whether different doses of resveratrol could have diverse effects on Ref-1 profile in ischemic/reperfused heart. We have shown that ischemia/reperfusion downregulated Ref-1 level, but resveratrol could induce Ref-1 expression, only at a low dose. High dose resveratrol could not prevent the down-regulation of Ref-1 during ischemia/reperfusion injury (Figure 3. Data taken from Dudley et al. 2008a). The above study suggested that low dose resveratrol activated Ref-1 in ischemic heart and triggered Nrf-2 binding to ARE region and upregulated the expression of redox proteins like Trx and Grx.
Upon ischemic stress, these redox proteins translocate into nucleus and bind with Ref-1, leading to activation of a survival signal to protect the heart. At low dose, resveratrol treatment can activate the survival signal by inducing Akt phosphorylation, which in turn activates Bcl2 and triggers cardiac cell survival whereas the reverse is true for the high dose of resveratrol (Figure 4. Data reproduced from Dudley et al. 2008a). Thus resveratrol appears to be dose-dependent in providing cardioprotection. Table 2 shows the effects of low and high doses of resveratrol on health benefits. The precise reason for generation of death signal at higher resveratrol dose is not clear. It is speculated that differential redox cycling of resveratrol between high and low dose might be responsible for survival and death signal. Resveratrol contains two phenol groups in it. A study by Boyer et al. (1988) showed that phenol reduces Fe3+ to Fe2+. Iron plays a crucial role in free radical reactions leading to iron–oxygen complexes that remove hydrogen atoms from the polyunsaturated fatty acid membrane (Minotti and Aust 1989; Sotomatsu et al., 1990; Rice-Evans and Burdon 1993). Miura et al. (2000) found that resveratrol possesses both antioxidant and pro-oxidant effects. Resveratrol promoted the reduction of Fe3+ by increasing the formation of hydroxyl radicals through the Fenton reaction producing hydroxyl radicals and iron species (Yamazaki and Piette 1990). At higher doses, resveratrol causes DNA strand breakage by the accumulation of reduced ADP-Fe3+ in the presence of hydrogen peroxide. Fukuhara and Miyata (1998) found that resveratrol could bind to DNA and promoted DNA plasmid cleavage in presence of Cu2+ under aerobic conditions and neutral pH. Resveratrol also reduces Cu2+ to Cu+ in the presence of the reactive oxygen species.

Dose Response. 2010; 8(4): 478–500.

PMCID: PMC2990065

Dose-Dependency of Resveratrol in Providing Health Benefits
Subhendu Mukherjee, Jocelyn I. Dudley, and Dipak K. Das
Cardiovascular Research Center, University of Connecticut Health Center, School of Medicine, 263 Farmington Avenue, Farmington, CT 06030-1110, USA
Address correspondence to Prof. Dipak K. Das PhD, Sc.D, FAHA; Cardiovascular Research Center, School of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1110, USA; Tel: (860)-679-3687; Fax: (860)-679-4606; E-mail: ddas@neu-ron.uchc.edu

[Skigazzi]

Interesting...back to having 4 ounces of Pinot Noir with dinner I suppose...oh the horror

[DR_P]

Interesting...back to having 4 ounces of Pinot Noir with dinner I suppose...oh the horror

Haha, indeed. I read somewhere that even the legendary Mr. Kurzweil, who is one of the major proponents of the life-extensionist movement (and by the way who created the legendary musical Kurzweil-synthesizers in the 1980ies) officially cut back his resveratrol supplementation to 50 mg/d. Before he used to take A LOT more of it (he also used to drink a dozen of cups of green tea per day etc.)

[Mickfootie]

This can be said for many other nutrients and ingredients in supplements. Many people see a write up at a dose that is beneficial and automatically assume that adding more will give more benefit, this is not always a correct assumption and should read more into any product before upping any dosages.
Nice find DR_P.

[PinchTheBear]

Excellent review- certainly strikes a chord with other recent discussions of lower and upper limits in dose dependency (e.g. other antioxidants, new unstandardized dry extracts).

[Peter LeDrew]

I appreciate this post!

[JornT]

Homeopathy was right all along!

[wakingmalice]

I've never been really "in" to this stuff. Need to do more reading. Any good sources?

Interesting study nonetheless.

Maybe we should just figure out how to stop the degradation of lisomes and we wouldn't have to worry about plant extracts.

[Koznasty]

certainly strikes a chord with other recent discussions of lower and upper limits in dose dependency

Very intriguing point. It seems that more and more research finds in many cases that the marginal benefit of SUPPXYZ above a certain limit doesn't just taper, it actually reverses. "More isn't always better" as they say.

[kfairhurst]

Fantastic writeup Dr.P!

[Dacookie]

FUUUUUUUUUUUUUU

Just bought some resveratrol supps before seeing this.So what do you recommend I do?Open capsule and take only a portion of it?Optimal dosing wise how does this correlate to humans?Cheers

[Guardian]

The more I research supplements especially for longevity and health, the more I realize that when you take almost anything in a higher dose then you would normally be able to consumer it, bad side effects begin to occur.

In terms of resveratrol, I have also read and heard feedback that higher doses cause a noticable decrease in collagen formation/repair which for bodybuilders would not be wise.

To much fish oil hampers immune function. To much BCAAs effect serotonin production. Etc.

Where the grey area comes into play is when someone is "active" like bodybuilders some compounds more is needed since its used up faster. One example I would say is magnesium. You also have people who genetically may benefit from more or less of some compounds. Individuals prone to depression may benefit from extra B vitamins or TMG where some people may get too manic on similar doses. So alot of it is knowing your body and being aware of effects.

[skaffer]

following up on guardian...it just seems like everything in moderation