Many questions still remain about the research aiming to link resveratrol with calorie restriction (CR), SIRT1 and anti-ageing. These were highlighted in a 2011 review by Agarwal and Baur, who are prominent researchers in the field.1 They began by pointing out that even the research on CR is not entirely consistent when it comes to increasing lifespan, with some strains of lab mice failing to respond or even exhibiting decreased longevity in response to the standard CR protocol.
They do, however, also point out that regardless of its ultimate effects on longevity, numerous studies (including human) show that CR has a profound potential to improve health. They point out that: “since it is unlikely that a large proportion of the population would be willing or able to adopt a CR lifestyle, and because of lingering concerns about potential tradeoffs such as decreased immune or reproductive function, there has been great interest in developing drugs to recapitulate the beneficial effects of CR.”
As noted in part 1 of this article (see August 2014, Nutrition & Healing), based on the idea that sirtuins such as SIRT1 might mediate the beneficial effects of CR, Sinclair’s team in 2003 performed a screen of small molecule activators of SIRT1 and identified resveratrol as possessing high activity. However, as Agarwal and Baur point out, the assay used in this screen has become a major source of controversy, and other researchers using different techniques have been unable to show that resveratrol directly activates SIRT1. This led to a 2012 study, hailed as a significant breakthrough, which demonstrated resveratrol indirectly activated SIRT1 via AMP-activated protein kinase (AMPK), an energy sensor in the cell involved in some of the same pathways as SIRT1.2 AMPK phosphorylates (activates) one of SIRT1’s targets directly, namely proliferator activator gamma coactivator 1 alpha (PGC-1alpha).
However, the Harvard team rejected this claim in a 2013 publication, when they provided conclusive evidence that resveratrol does indeed activate SIRT1 directly.3 “In the history of pharmaceuticals, there has never been a drug that binds to a protein to make it run faster in the way that resveratrol activates SIRT1,” said David Sinclair, “almost all drugs either slow or block them.”
Although this scientific paper was highly technical, it still received media coverage around the world. Sinclair was quoted as saying the SIRT1 pathway was “… like a policeman that directs traffic in the cell and prompts it to repair itself. There are a lot of repair processes in our body, for example repairing broken DNA or mopping up free radicals. SIRT1 is at the centre of this and co-ordinates all of the activities in the cell, so if you activate it you’re turning on tens, if not hundreds, of defence mechanisms in the body.”
Targeting SIRT1 with resveratrol may lead to a more efficient metabolism
While a discussion of the finer points of research on basic cellular mechanisms of resveratrol might seem an academic curiosity, the potential implications of SIRT1 activation by resveratrol are in fact far reaching. For example, Gad Asher, clinician and medical researcher from the Weizmann Institute of Science in Israel, is studying disruptions to our biological clock potentially linked to metabolic disorders such as obesity and type 2 diabetes, and the key role of SIRT1.4 He suggests it is likely that SIRT1 connects cellular metabolism to the circadian core clockwork circuitry.5
Shift workers tend to put on weight because there’s a disconnect between their eating patterns and cellular energy metabolism. In other words, they are taking in fuel when SIRT1 is less active at ensuring the appropriate utilization of this energy in the cell. Hence targeting (activating) SIRT1 might not only help shift workers not put on extra weight from eating at odd hours, it may also improve the efficiency of anyone’s metabolism, helping them to burn more body fat.
The ‘hidden’ rolePGC-1alpha – and resveratrol – could play in our fitness
As mentioned above, resveratrol activates PGC-1alpha, either via AMPK or SIRT1. Professor John Hawley, Head of the Exercise Metabolism Research Group at an Australian university, is studying genetic factors involved in peak athletic capacity. Quoting from an article by Dean published in the July/August 2012 issue of Australian Life Scientist:
“He and his colleagues took a handful of healthy young males – all fit but none athletic – and had them perform a standardised bout of endurance exercise before taking blood and muscle samples. They then scanned for the levels of signature genes that are triggered by exercise. One gene was of particular interest: PGC-1alpha. This is the gene that operates as a ‘master switch’ for mitochondrial biogenesis and is known to play a role in energy metabolism. Interestingly, there was little or no increase in PGC-1alpha after exercise in some subjects, while others saw up to a 12-fold increase. This would prove a telling difference. Hawley then had the subjects undertake a 10-day intensive training regime to see how far they would improve in metrics such as VO2max and a battery of lab-based ‘performance’ tests. Unsurprisingly, they all improved their fitness levels in response to the training, but there was a mix of ‘high responders’ and ‘low responders.’ And lo, when looking at the original gene samples they took, they saw a correlation between variation in performance improvements and variations in levels of PGC-1alpha after their initial exercise session. This suggests that variations in the exercise-induced activation of PGC-1alpha might influence the degree to which someone will respond to exercise. High activation and you’re likely to benefit from the exercise a lot more, and maybe even reach champion level. Low activation and you might train and train and train and never be competitive.”
This research suggests a potential role for resveratrol to improve our fitness response during intensive training.
Busting the resveratrol bioavailability myth
The bioavailability of resveratrol has been hugely underestimated. For example, one review stated that: “resveratrol has a short initial half-life and is metabolized extensively in the body”.6 Despite this, one well-informed reviewer recently pointed out: “There is mistaken information that resveratrol is not bioavailable; however, to explain, free, unbound resveratrol has a half-life of ~14 minutes, whereas liver-metabolized resveratrol that is conjugated with sulfate or glucuronate has a half-life of ~9 hours. Liver metabolism prolongs half-life. While not biologically available as a conjugated molecule, resveratrol is released as a free, unbound molecule by an enzyme (glucuronidase) that has 13-20 times greater activity at sites of inflammation, infection, or malignancy. This is nature’s drug delivery system.”7 This position is backed up by the growing body of clinical trials on resveratrol showing significant biological activity at doses as low as 16mg. Such marked activity would not be seen for a molecule with poor bioavailability.
In support of this, a recent study found that phase II sulfate metabolites of resveratrol were active in colorectal cancer cells.8 The effect was quashed with the addition of a sulfatase inhibitor, which significantly reduced intracellular resveratrol levels. This suggests that resveratrol itself was giving rise to this activity following its production from resveratrol sulfate by the cells.
Another key issue with resveratrol is setting a safe and appropriate dose. Most of the clinical trials quoted above and elsewhere assessed the activity of 200mg/day or less. Consumption of resveratrol through diet is probably 2 to 3mg/day at best. Yet there are trials that have used 1 to 3g/day and more. There are still many unknowns, and given that 200mg/day and less is quite active (even 16mg/day produced profound results), any higher doses taken long term are best avoided until we understand more about this amazing molecule. Animal studies have in fact shown that resveratrol can be beneficial at lower doses and detrimental at higher doses.9 There is also the discovery in a clinical trial that 1g/day of resveratrol inhibited a range of phase I enzymes, including CYP3A4, and induced CYP1A2, suggesting the potential for interaction with many pharmaceutical drugs at that dose.10
To your better health,
Nutrition & Healing
Vol. 8, Issue 9 – September 2014
Full references and citations for this article are available in the downloadable PDF version of the monthly Nutrition and Healing issue in which this article appears.