SRT501, for adjunctive therapy in multiple myeloma, due to an unexpected high incidence of renal failure. Though this may have been a statistical aberration and related to the underlying disease or primary therapy rather than SRT501, the company elected to discontinue all development of the drug.
As the study of sirtuin physiology has advanced, it has become clear that resveratrol is not a direct activator. Amgen and Pfizer were independently evaluating resveratrol-based sirtuin activators, and both published peer-reviewed papers announcing that resveratrol and derivatives were inactive.23 This confirmed earlier questions about the assay and variability of results, but left open the question of how the lifespan increase was produced.
An answer comes from the fact that resveratrol is an activator or inhibitor of at least 15 different enzymes. Another clue is that lifespan extension has been achieved in mice with the diabetes drug metformin and the immune suppressant rapamycin. Metformin, like resveratrol is a potentiator of AMP kinase, which is in turn a sirtuin activator.24 It is therefore possible that this indirect effect is responsible but that metformin is more active or less subject to variations of substrate medium. There is also evidence that metformin has similar degenerative disease-fighting capacity as resveratrol appears to, but may have better bioavailability. Clinical use of metformin remains restricted to treatment of type 2 diabetes, however, with off-label use for health maintenance unproven.
A more direct caloric restriction mimetic may be via mammalian target of rapamycin (mTOR), a protein kinase involved in cell growth regulation, proliferation, and survival. Upstream signals including nutrient status, oxidative stress, redox status, insulin, AMP kinase, and growth factors all influence mTOR activity, which functions at an epigenetic level. Rapamycin is a bacterial protein with immune suppressant and antiproliferative properties, and is clinically used in organ transplantation. Rapamycin has been shown to extend lifespan in mice by up to 38%, and anti-cancer and anti-Alzheimer’s properties are being explored. (Both rapamycin and AMP kinase are mTOR inhibitors.)
The use of rapamycin as a caloric restriction mimetic is highly impractical, given its immune suppressive properties, but does pave a more direct path. Interestingly, resveratrol, by activating AMP kinase which then competitively binds mTOR, functions at an even further upstream level through the same channels. Analogs of rapamycin (called rapalogs) are being developed with targeted specificity for mTOR binding, though none appear to be at the clinical testing stage.25 Epigallocatechin gallate (EGCG), from green tea, as well as caffeine and curcumin are also mTOR inhibitors. These common properties may explain the similar anticancer effects, as mTOR function may be dysregulated in cancer.
Figure 5. Lifespan extension pathways
BIOAVAILABILITY AND METABOLISM OF RESVERATROL
A primary reason for clinical failure of compounds with promising in vitro activities is limited bioavailability. Resveratrol appears to be well-absorbed from oral mucosa, but undergoes significant first-pass hepatic metabolism after absorption from the gastrointestinal tract. In human subjects, blood levels indicate no more than 20% overall bioavailability. A randomized crossover study demonstrated that when taken with food, peak levels are delayed to 1.5 hours as compared to 30 minutes when taken during fasting after a 400 milligram oral dose, though total absorption is unchanged.26 Other studies indicate a half-life of 1-3 hours, with high inter-individual variability. Adverse effects appear to be mild, and there is a suggestion that bioavailability is greater when taken in the morning. Some supplement manufacturers are developing micronized formulations to enhance bioavailability but little has been published.
Most of the research on clinical bioavailability of oral resveratrol comes from the cancer literature, where resveratrol is being explored as adjunctive therapy because of indications of its effectiveness in both enhancing the anticancer effects of chemotherapeutic agents while simultaneously ameliorating side-effects. However, one of the constraints on chemotherapeutic effectiveness is the emergence of what are known as multi-drug resistance proteins (e.g., MRP2, ABCC2) and breast cancer resistance protein (BCRP, ABCG2). These proteins appear to significantly impair the absorption of resveratrol from intestinal mucosa, placing further limits on its potential effectiveness in cancer therapy.
Resveratrol is metabolized within the intestinal lining to 3 dominant forms, resveratrol-4'-O-glucuronide (M1), resveratrol 3-O-gucuronide (M2), and resveratrol-3-O-sulfate. These may be preferentially absorbed and then reconverted to free resveratrol with the cell, and so serum levels may not accurately reflect intracellular levels. Accumulation of resveratrol in epithelial cells of the aerodigestive tract has been demonstrated despite nearly undetectable serum levels. Analogs of resveratrol may have greater bioavailability, though the therapeutic effects are less well-characterized. For example, the dimethylether analog pterostilbene has a 4-fold greater bioavailability after oral administration.
Cellular uptake is necessary for many of the actions of resveratrol, as they are involved in signal transduction. Lipid nanoparticles may facilitate the uptake of resveratrol in keratinocytes and improve bioavailability of topical preparations. Liposome-mediated transport has been reported to produce improved cell stress response from UV radiation. In a mouse model of prostate cancer, liposomal encapsulation of resveratrol plus curcumin significantly reduced the incidence of tumors and levels of cancer markers. Even without facilitated transmembrane transport, resveratrol appears to have good skin penetration, possibly related to its small molecular weight. This may explain the range of benefits to in skin health observed with resveratrol in experimental models.
CONCLUDING REMARKS
Despite the multitude of reported studies on resveratrol, the number of clinical trials completed and reported numbers in the single digits, and its potential as an anti-aging compound remains to be fully determined. Level 1 evidence is lacking, and so clinical use of resveratrol is somewhat speculative at this time. In terms of the criteria established for a “true” anti-aging compound, the first – support of youthful appearance – appears to be the closest to fulfillment.
The second criterion, slowing of age-related cellular processes leading to delayed onset and prevention of degenerative diseases, is well supported by in vitro and animal studies but clinical evidence is lacking. Given the long time frame involved in conducting prospective trials for diseases in this category, it could be many years before answers are in. Funding such studies is an ongoing challenge, so the private sector is focusing on proprietary derivatives, which may have more targeted and potent actions.
Resveratrol is not a direct sirtuin activator and appears unlikely to produce lifespan extension as a caloric restriction mimetic. On an experimental basis resveratrol has been useful in developing sirtuin science, and uncovering metabolic pathways that could possibly be exploited to achieve that goal. It is possible and even likely that resveratrol could produce a secondary effect of lifespan extension via reduction in the incidence of diseases of aging, but again that remains to be proven. The marketing of resveratrol supplements based on lifespan extension documented only in sub-mammalian organisms is therefore a questionable practice. Resveratrol alone does not provide an explanation for the known health benefits of moderate regular wine consumption, in that resveratrol content in wine is too low to produce the in vitro effects that correspond to epidemiologic patterns.
Bioavailability remains problematic as well. Newer formulations may help to overcome current limitations on the uptake and metabolism of resveratrol, along with better understanding of membrane transport, intracellular/extracellular partitioning, and the actions of resveratrol metabolites. But given the many open questions that remain, and potential risks (particularly related to its phytoestrogen activity), a cautionary approach is prudent and the widespread use of resveratrol supplements is not justified at the present time.
