Resveratrol, the longevity molecule

Resveratrol is a naturally occurring polyphenolic antioxidant found in over 70 plant species. Common sources include grapes, peanuts and ripe berries.  In nature, resveratrol serves to protect plants from ultraviolet light, infections and other environmental stressors.  Resveratrol is best known as the longevity molecule since scientific studies have demonstrated that resveratrol extends lifespan in a variety of animal species.¹ The life-extending benefits of resveratrol are attributed to the fact that, like caloric restriction, resveratrol modulates sirtuin gene expression.²  Sirtuins are a group of enzymes that influence important adaptive functions such as cell survival, DNA repair, gluconeogenesis, cell-cycle regulation, insulin sensitivity, lipid metabolism and fat mobilization.³ In addition to extending lifespan, resveratrol has been touted to improve healthspan.  Accordingly, resveratrol has been studied in almost all fields of medicine, and has significant potential value for treating a variety of disease states. Beneficial effects include neuroprotection, cardioprotection, anti-diabetic and anti-tumor activity.⁴   Resveratrol also has broad anti-inflammatory effects and inhibits a variety of inflammatory markers including cox-2, IL-2, IL-6, IL-8 and vascular endothelial growth factor^.5   Ongoing studies are being conducted to confirm the health benefits of resveratrol.

NEXT: Pharmacokinetics of resveratrol

 Pharmacokinetics of Resveratrol

The clinical use of resveratrol has been limited by the challenges of oral administration.⁶   Although 70% of orally administered resveratrol is absorbed, it is rapidly metabolized to glucuronide and sulfated forms. Even after large oral doses, only trace amounts of resveratrol can be detected in the bloodstream.  The health effects of the glucuronide and sulfated derivatives of resveratrol are yet to be determined.

READ: Resveratrol inhibits growth of acne-causing bacteria

Topical formulation with resveratrol is equally challenging. Resveratrol readily isomerizes to the less desirable “cis” form when exposed to ultraviolet light.⁷ Another challenge is that resveratrol is a hydrophobic molecule, with a water solubility estimated at 0.05 mg/mL, making it difficult to stabilize in meaningful concentrations in formulation.⁸ In view of these challenges, it is not surprising that few high concentration formulations of resveratrol have been commercialized.   

NEXT: Skin aging and resveratrol

Skin Aging and Resveratrol

Oxidative stress is known to contribute to skin aging.  Free radicals are produced as we age naturally and by extrinsic factors such as ultraviolet light, pollution and cigarette smoking.⁹   Reactive oxygen species (ROS) accumulate in cells where they damage lipid membranes, proteins and DNA.  Free radicals upregulate transcription factor activator protein 1 (AP-1) that turns on the synthesis of collagen digesting matrix metalloproteinases, reduces collagen content in skin and contributes to skin wrinkling. Oxidative stress also upregulates nuclear factor kappa beta (NF-kB), increasing the synthesis of a variety of inflammatory mediators that contribute to skin aging.  For these reasons, the use of topical and systemic antioxidants are of value for prevention of skin aging.

Resveratrol is unique among antioxidants in that it functions as an antioxidant in several ways.¹⁰   It serves as a free radical scavenger that effectively quenches reactive oxygen species such as hydroxyl, superoxide and metal-induced radicals.

READ: Examining molecular influences on aging

Resveratrol works synergistically with vitamin E to stabilized cell membranes and prevent lipid peroxidation.  Finally, resveratrol acts through the Nrf-2 pathway to promote synthesis of endogenous antioxidants including hemoxygenase 1, superoxide dismutase and catalase.  A recent study has provided some of the first evidence that a topical resveratrol formulation can activate endogenous antioxidant production via the Nrf2 pathway in human skin.¹¹   Thus, resveratrol is unique among antioxidants in its ability to boost intrinsic antioxidant capacity.

Because of its chemical structure, resveratrol is a member of the stilbenoid group of polyphenols.  Like the synthetic estrogen diethylstilbesterol, resveratrol has phytoestrogenic effects and is an estrogen beta receptor agonist.¹² It is known that estrogen replacement therapy in post-menopausal women can mitigate at least some of the collagen loss that is synonymous with advancing age. Thus, resveratrol is of interest as an estrogen alternative that can provide the skin benefits of estrogen without the side effects.  Stilbene polyphenols can also inhibit tyrosinase and lighten hyperpigmentation that is common in actinically damaged skin.

NEXT: Skin aging and mitrochondrial oxidative strees

Skin Aging and Mitrochondrial Oxidative Stress

The role of mitochondrial oxidative stress in skin aging has been reviewed by Krutmann and Schroeder.¹³  It is known that ROS are produced as a byproduct of ATP synthesis and that ultraviolet light and infrared radiation increase mitochondrial oxidative stress.  Mitochondrial DNA (mtDNA) is particularly vulnerable to attack by ROS as it lies in close proximity near the innermost membrane.  Mitochondrial DNA lacks histones that protect nuclear DNA from ROS and lacks an effective DNA repair mechanism compared to nuclear DNA.  These mtDNA mutations result in mitochondrial dysfunction that contributes to an increase in oxidative stress and subsequent skin aging.  Resveratrol can enhance mitochondrial function by promoting mitochondrial biogenesis and reducing mitochondrial oxidative stress. ^14,15  

Clinical Studies on Resveratrol

There are few published studies on topical resveratrol. In a comparative study, a 1% resveratrol cream was compared to 1% idebenone cream using the standard ORAC test for antioxidant activity.¹⁵  The resveratrol cream was found to have a 17-times-greater antioxidant capacity than the idebenone product.  More recently, a clinical trial on a 1% resveratrol, 1% vitamin E and 0.5% baiclin serum demonstrated improvement in a variety of parameters of skin aging, including firmness and elasticity.¹¹ Ultrasound showed increased skin density and biomarkers revealed an increase in collagen III and hemoxygensase 1 production.  These results demonstrate that high concentration of stabilized topical resveratrol can be used as an effective anti-aging ingredient.

NEXT: References

References

1.      Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425(6954):191-6.

2.      Wood JG, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004;430(7000):686-9.

3.      Dali-youcef N, Lagouge M, Froelich S, Koehl C, Schoonjans K, Auwerx J. Sirtuins: the 'magnificent seven', function, metabolism and longevity. Ann Med. 2007;39(5):335-45.

4.      Baur JA. Resveratrol, sirtuins and the promise of a DR mimetic. Mec Ageing Dev 2010;131:261-269.Sadruddin S, Arora R. Resveratrol: biologic and therapeutic implications. J Cardiometab Syndr 2009;33:1513:1523.

5.      De la lastra CA, Villegas I. Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications. Mol Nutr Food Res. 2005;49(5):405-30.

6.      Cottart CH, Nivet-antoine V, Laguillier-morizot C, Beaudeux JL. Resveratrol bioavailability and toxicity in humans. Mol Nutr Food Res. 2010;54(1):7-16.

7.      Waterhouse AL Trela BC. Resveratrol: isomeric molar absorptivities and stability. J Agr Food Chem. 1996;44(5):1253-1257.

8.      Belguendouz L, Fremont L, Linard A. Resveratrol inhibits metal ion-dependent and independent peroxidation of porcine low-density lipoproteins. Biochem Pharmacol. 1997;53(9):1347-55.

9.      Fisher GJ, Kang S, Varani J, et al. Mechanisms of photoaging and chronological skin aging. Arch Dermatol. 2002;138(11):1462-70.

10.   Farris P, Krutmann J, Li YH, Mcdaniel D, Krol Y. Resveratrol: a unique antioxidant offering a multi-mechanistic approach for treating aging skin. J Drugs Dermatol. 2013;12(12):1389-94.

11.   Farris P, Yatskayer M, Chen N, Krol Y, Oresajo C. Evaluation of efficacy and tolerance of a nighttime topical antioxidant containing resveratrol, baicalin, and vitamin e for treatment of mild to moderately photodamaged skin. J Drugs Dermatol. 2014;13(12):1467-72.

12.   Gehm BD, Mcandrews JM, Chien PY, Jameson JL. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci USA. 1997;94(25):14138-43.

13.   Krutmann J, Schroeder P. Role of mitochondria in photoaging of human skin: the defective powerhouse model. J Investig Dermatol Symp Proc. 2009;14(1):44-9.

14.   Csiszar A, Labinskyy N, Pinto JT, et al. Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol. 2009;297(1):H13-20.

15.   Ungvari Z, Labinskyy N, Mukhopadhyay P, et al. Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells. Am J Physiol Heart Circ Physiol. 2009;297(5):H1876-81.

16.   Baxter RA. Anti-aging properties of resveratrol: review and report of a potent new antioxidant skin care formulation. J Cosmet Dermatol. 2008;7(1):2-7.