Vascular dementia and cerebrovascular diseases are emerging as the leading causes of death for older women in Australia.¹ Vascular dementia is associated with increased reactive oxygen species (ROS), leading to a reduction in nitric oxide (NO) bioavailability and endothelial dysfunction.² Further, ageing and menopause contribute to endothelial dysfunction, causing impaired cerebral perfusion, which is in turn associated with accelerated cognitive decline.² While there is a current lack of preventative strategies to counteract the pathogenesis of cognitive ageing, there is considerable interest in finding solutions to offset cognitive decline and preserve endothelial health.

A potential approach to counteract age and oestrogen deficiency related endothelial dysfunction is to supplement the diet with resveratrol.² Of particular interest in cerebrovascular disease prevention is its neuroprotective effects, which are due to its antioxidant properties and ability to activate nuclear factor-erythroid factor 2-related factor 2 (Nrf2), maintain cellular redox status and modulate NO synthesis.³

Key functions of Resveratrol

• Interacts with several important molecular targets involved in disease and ageing:
  • Stimulates SIRT1 via the AMPK-SIRT1-PGC-1α^[1] axis, regulating mitochondrial biogenesis.⁴
  • Stimulates Nrf2 through blockage of Keap1, reducing oxidative stress, apoptosis and inflammation.⁵
  • Inhibits mTOR activity, slowing cellular aging.⁶

^[1] SIRT1: Silent mating type information regulation 2 homolog 1; AMPK: AMP-activated protein kinase; PGC-1α: Peroxisome proliferator-activated receptor-gamma coactivator-1alpha 

Dosing recommendations

• Clinically effective dose: 75 mg twice daily²
• Duration: 12 months²
• Form: trans-resveratrol²
• Drug interactions:
  • Resveratrol may slow metabolism of drugs via inhibition of CYP3A4, increasing the risk of adverse events. Very unlikely to be clinically relevant. Monitor.⁷
  • May have additional antiplatelet effects, increasing risk of adverse effects. Monitor for increased bruising or bleeding.⁸
  • Appears to stimulate Nrf2/ARE, thereby improving antioxidant protection. Therefore, use with chemotherapeutic drugs should be undertaken under the approval of the patient’s oncologist. Ensure separation of doses by 48 hours.⁵
  • Preliminary evidence suggests Giant Knotweed (a common source of resveratrol) has oestrogenic activity and is not recommended in hormone sensitive cancers/conditions.⁹
• Safe dosing: 200 mg/day for 26 weeks¹⁰; 1500 mg/day for 4 weeks.¹¹

150 mg/day of Resveratrol improves cognitive performance in post-menopausal women

In a randomised, double-blind, placebo-controlled trial, the effects of resveratrol on cognitive performance, mood and cerebrovascular function were investigated in post-menopausal women. In this trial, 80 women aged 45 to 85 years received 75 mg of resveratrol twice daily or placebo for 14 weeks. Resveratrol was shown to improve cerebrovascular responsiveness by 17%, improve cognitive tasks (verbal memory) and improve overall cognitive performance. Mood also improved; however, this was not significant.¹²

To further examine the effects of resveratrol on cognitive performance in aging and menopause, researchers undertook a follow-up 24-month randomised, placebo-controlled crossover trial. One hundred and twenty-five postmenopausal women aged 45 to 85 years were given either 75 mg of trans-resveratrol or placebo twice daily for 12 months, crossover to the alternative treatment was then done for another 12 months.²

Researchers evaluated individual differences between each treatment period in measures of cognition, cerebrovascular function in the middle cerebral artery (cerebral blood flow velocity (CBFV), cerebrovascular responsiveness (CVR) and cardiometabolic markers.

Studies found that compared to placebo, resveratrol resulted in a significant 33% improvement in overall cognitive performance. Regarding individual cognitive tasks, resveratrol improved dimensional change card sort test (DCCS) by 113% and forward spatial span test by 208% (Table 1). Further, subgroup analyses showed that in women older than 65 years, there was a relative improvement in verbal memory with resveratrol, when compared with midlife women.

In addition to the improvements in overall cognition and individual cognitive tasks following resveratrol supplementation, researchers also found sustained increases in resting CBFV, CVR to hypercapnia (Figure 1) and overall neurovascular coupling; reflecting improvements in cerebral blood flow and perfusion of brain regions at rest and in response to increased cognitive demands.

Additional testing also found improvements in cardiometabolic blood biomarkers following resveratrol supplementation. This included reduced fasting insulin by 9% and homeostatic model assessment of insulin resistance (HOMA-IR) by 8%.

Conclusion

Ageing and menopause contribute to endothelial dysfunction, causing impaired cerebral perfusion and accelerated cognitive decline. There is a current lack of preventative strategies with demonstrated efficacy to counteract cognitive ageing, particularly in older women.

In this trial by Zaw et al. researchers found 150 mg/day of resveratrol taken in divided doses for 12 months improved cognitive performance, cerebrovascular function and insulin sensitivity in post-menopausal women.

This study provides validation for regular supplementation with low dose resveratrol as an effective, nonpharmacological intervention to counteract age and menopause related cognitive decline in elderly women.

The information contained within is intended to be used as an educational tool and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for your own health professional's advice.

References

1. Australian Bureau of Statistics. Causes of death, Australia. Available from: https://www.abs.gov.au/statistics/health/causes-death/causes-death-australia/latest-release
2. Zaw JJ, Howe PR, Wong RH. Long-term effects of resveratrol on cognition, cerebrovascular function and cardio-metabolic markers in postmenopausal women: a 24-month randomised, double-blind, placebo-controlled, crossover study. Clin Nutr. 2021 Mar 1;40(3):820-9.
3. Kennedy DO, Wightman EL, Reay JL et al. Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation. Am J Clin Nutr. 2010 Jun 1;91(6):1590-7.
4. Kulkarni SS, Cantó C. The molecular targets of resveratrol. Biochim Biophys Acta Mol Basis Dis. 2015 Jun 1;1852(6):1114-23.
5. Farkhondeh T, Folgado SL, Pourbagher-Shahri AM et al. The therapeutic effect of resveratrol: Focusing on the Nrf2 signaling pathway. Biomedicine & Pharmacotherapy. 2020 Jul 1;127:110234.
6. Chang YC, Liu HW, Chen YT et al. Resveratrol protects muscle cells against palmitate-induced cellular senescence and insulin resistance through ameliorating autophagic flux. journal of food and drug analysis. 2018 Jul 1;26(3):1066-74.
7. Deng R, Xu C, Chen X et al. Resveratrol suppresses the inducible expression of CYP3A4 through the pregnane X receptor. J Pharmacol Sci. 2014;126(2):146-54.
8. Wu CC, Wu CI, Wang WY et al. Low concentrations of resveratrol potentiate the antiplatelet effect of prostaglandins. Planta Med. 2007 May;73(5):439-43.
9. Böttger A, Vothknecht U, Bolle C, Wolf A. Phenylpropanoids. InLessons on Caffeine, Cannabis & Co 2018 (pp. 171-178). Springer, Cham.
10. Witte AV, Kerti L, Margulies DS, Floel A. Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci 2014;34(23):7862e70.
11. Poulsen MM, Vestergaard PF, Clasen BF et al. High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes 2013;62(4):1186e95.
12. Evans HM, Howe PR, Wong RH. Effects of resveratrol on cognitive performance, mood and cerebrovascular function in post-menopausal women; a 14-week randomised placebo-controlled intervention trial. Nutrients. 2017 Jan;9(1):27.