LE MAGAZINE

Woman picking grapes that contain beneficial resveratrol

Resveratrol in the Prevention of Aging

Obtaining resveratrol’s full benefits has been challenging. Combining resveratrol with galactomannan increases bioavailability up to 10 times.

By William Faloon.

William Faloon

In 2003, a plant compound called resveratrol emerged as the hottest topic in anti-aging medicine.

The sizzling enthusiasm came from a Harvard study showing an astounding 70% increase in the lifespans of yeast given resveratrol.1

Several follow-up studies supported lifespan benefits in resveratrol-supplemented model organisms.2

What got scientists fired up are mechanisms behind resveratrol’s age-delaying effects.

It turned out that resveratrol induced some of the favorable gene expression changes seen with calorie restriction.1

This has led to resveratrol appearing in thousands of published papers about the multiple disorders that it might protect against.

For example, a PubMed® search for “resveratrol” yields 16,000 citations over the past four decades, including 260 clinical trials since year 2002.

A review article published in 2021 concluded:

“Resveratrol could be an effective and safe compound for the prevention and treatment of aging and age-related diseases.”3

We at Life Extension funded costly laboratory studies aimed at identifying what dose of resveratrol might enable humans to live longer and healthier lives.

The challenge, however, was finding a way to make resveratrol bioavailable to the human body.

Resveratrol is rapidly metabolized in the liver, kidneys, and other tissues despite relatively good intestinal absorption.4,5

This helps explain the longevity-enhancing effects of resveratrol found in flies, fish, worms, and yeast, but inconsistent benefits when tested in mammals.2

Intensive research has uncovered a way to protect resveratrol from rapid metabolic degradation.

It is now possible to better explore the potential of resveratrol to combat degenerative disorders and assist in the prevention and treatment of aging.

In 1997, a paper was published describing the biological effects of resveratrol as it relates to the prevention of cancer and other illnesses.6

This led to intensive investigations, thousands of published papers, resveratrol-focused conferences, and patents on resveratrol analogs.

The public reacted to the media blitz by ingesting resveratrol supplements and increasing their consumption of red wine, despite there being little resveratrol in redwine (and other foods).

Longevity Impact of Resveratrol

Published studies document the ability of resveratrol to extend lifespans in laboratory models.

A meta-analysis of 19 published papers indicated that resveratrol acts as a life-extending agent.7 The species studied were yeast, roundworms, mice, fruit flies, and turquoise killifish.

Resveratrol has been shown to induce autophagy in human cells in test tubes (in vitro) and in the bodies of roundworms (in vivo).3

Autophagy is a cleansing process that promotes the clearance of internal cellular debris.

The induction of autophagy by resveratrol is thought to be a longevity-enhancing mechanism.

Bees fed with resveratrol syrup live longer than controls.8 Depending on resveratrol concentration, mean and maximum lifespan of these bees increased by 33% to 38% respectively.

Short-lived flies fed with different resveratrol concentrations had mean lifespan extension of 10% to 29%, while other models found resveratrol also conveyed neuroprotective benefits. 2,9,10

Resveratrol-fed fish lived longer and demonstrated better cognitive ability and locomotor function than the control fish group.11 The fish fed resveratrol showed reduced markers of senescent cells and less buildup of a wear-and-tear residue called lipofuscin.

In a genetically altered strain of mice predisposed to neurodegenerative disease and accelerated aging, oral administration of resveratrol increased the median survival of these mice from 32 days to 42 days.12 Resveratrol additionally helped preserve motor function and protect against degenerative changes in the brain.

Not all studies demonstrate these kinds of elongated lifespans. One study found that resveratrol delayed vascular aging in rats but had no effect on overall survival.13

Another study found that in mice fed a standard diet, resveratrol did not enhance lifespan.14 In mice eating a high-calorie diet, however, resveratrol reduced the risk of death by 31% and improved insulin sensitivity, suggesting it helps protect against diet-related metabolic diseases.15

Effect on Neurodegenerative Disorders

The aging brain is afflicted with neuroinflammation, autophagy defects, mitochondrial dysfunction, cell loss, and elevated oxidative status. This all contributes to memory loss and motor impairments.16,17

A large body of data shows how resveratrol protects against neurodegenerative disorders in rodents.3

Resveratrol-supplemented animals demonstrate improved memory performance, enhanced secretion of neurotransmitters, and increased production of new brain cells with beneficial decreases in inflammation and oxidative stress.18-21

A human trial using 200 mg a day of resveratrol showed enhanced memory performance accompanied with improved glucose metabolism and hippocampal functional connectivity.22

Effect on Cardiovascular Disorders

Aging is associated with endothelial dysfunction that leads to arterial blockages and increased risks of cardiovascular diseases.23

In animal models, resveratrol was shown to exert a cardioprotective effect mainly through enhancing the production of endothelial nitric oxide, improving blood vessel dilation, reducing blood pressure, and ameliorating oxidative stress.24-26

Effect on other Disorders

Research findings show how resveratrol may help protect against cancer, osteoporosis, sarcopenia and possibly even infertility.27-30

What impresses scientists are the many pathological mechanisms of aging that resveratrol has been shown to thwart.

The challenge up to now has been how to deliver enough bioavailable resveratrol to the bloodstream to induce systemic (whole-body) effects.

After oral administration in humans, a resveratrol hydrogel formula boosted plasma concentration (ng/mL) about 10-fold higher than unformulated resveratrol.

530 mg of Resveratrol Hydrogel providing 80 mg of trans-resveratrol (red)

380 mg of unformulated resveratrol providing 80 mg of trans-resveratrol (green)

Adapted from: Joseph A, Balakrishnan A, Shanmughan P, et al. Micelle/Hydrogel Composite as a “Natural Self-Emulsifying Reversible Hybrid Hydrogel (N’SERH)”

Enhances the Oral Bioavailability of Free (Unconjugated) Resveratrol. ACS Omega. 2022 Apr 19;7(15):12835-45.

Up to 10 Times Greater Bioavailability

Orally ingested resveratrol is rapidly metabolized and transformed primarily in the digestive tract and the liver.4,5 This leaves very little free resveratrol in circulation.

Scientists found a solution to this by combining resveratrol with galactomannan fibers from fenugreek seed. This creates a hydrogel coating that allows greater resveratrol bioavailability.

Compared to unformulated resveratrol, this resveratrol-galactomannan hydrogel showed up to 10 times greater bioavailability.31

The graph on this page shows the magnitude of resveratrol increase and the longer period this proprietary hydrogel formulation of resveratrol remained in the blood compared to unformulated resveratrol.

It’s Time for More Clinical Research!

Resveratrol is a widely studied plant extract in the health and longevity fields.

Physician-scientists have been frustrated with resveratrol research because most of what is orally ingested is quickly degraded in the human body.

With the advent of a new bioavailable resveratrol, far better dosing schedules can be tested, and consistently higher blood levels achieved.

The good news for consumers is lower cost, as fewer milligrams of resveratrol need to be ingested to achieve higher circulatory levels.

I look forward to this new bioavailable resveratrol being used in upcoming clinical trials that seek to extend healthy human longevity.

Your ongoing support enables us to fund many of these human studies.

For longer life,

For Longer Life

William Faloon

References

  1. Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature.2003 Sep 11;425(6954):191-6.
  2. Bhullar KS, Hubbard BP. Lifespan and healthspan extension by resveratrol. Biochim Biophys Acta.2015 Jun;1852(6):1209-18.
  3. Zhou DD, Luo M, Huang SY, et al. Effects and Mechanisms of Resveratrol on Aging and Age-Related Diseases. Oxid Med Cell Longev.2021;2021:9932218.
  4. Springer M, Moco S. Resveratrol and Its Human Metabolites-Effects on Metabolic Health and Obesity. Nutrients.2019 Jan 11;11(1).
  5. Walle T, Hsieh F, DeLegge MH, et al. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos.2004 Dec;32(12):1377-82.
  6. Jang M, Cai L, Udeani GO, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science.1997 Jan 10;275(5297):218-20.
  7. Hector KL, Lagisz M, Nakagawa S. The effect of resveratrol on longevity across species: a meta-analysis. Biol Lett.2012 Oct 23;8(5):790-3.
  8. Rascon B, Hubbard BP, Sinclair DA, et al. The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction. Aging (Albany NY).2012 Jul;4(7):499-508.
  9. Khan M, Park S, Kim HJ, et al. The Resveratrol Rice DJ526 Callus Significantly Increases the Lifespan of Drosophila (Resveratrol Rice DJ526 Callus for Longevity). Nutrients.2019 Apr 29;11(5).
  10. Islam MS, Jin YY, Chung HJ, et al. Effect of the Resveratrol Rice DJ526 on Longevity. Nutrients.2019 Aug 5;11(8).
  11. Yu X, Li G. Effects of resveratrol on longevity, cognitive ability and aging-related histological markers in the annual fish Nothobranchius guentheri. Exp Gerontol.2012 Dec;47(12):940-9.
  12. Gerhardt E, Graber S, Szego EM, et al. Idebenone and resveratrol extend lifespan and improve motor function of HtrA2 knockout mice. PLoS One.2011;6(12):e28855.
  13. da Luz PL, Tanaka L, Brum PC, et al. Red wine and equivalent oral pharmacological doses of resveratrol delay vascular aging but do not extend life span in rats. Atherosclerosis.2012 Sep;224(1):136-42.
  14. Pearson KJ, Baur JA, Lewis KN, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab.2008 Aug;8(2):157-68.
  15. Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature.2006 Nov 16;444(7117):337-42.
  16. Azam S, Haque ME, Balakrishnan R, et al. The Ageing Brain: Molecular and Cellular Basis of Neurodegeneration. Front Cell Dev Biol.2021;9:683459.
  17. Hou Y, Dan X, Babbar M, et al. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol.2019 Oct;15(10):565-81.
  18. Torres-Perez M, Tellez-Ballesteros RI, Ortiz-Lopez L, et al. Resveratrol Enhances Neuroplastic Changes, Including Hippocampal Neurogenesis, and Memory in Balb/C Mice at Six Months of Age. PLoS One.2015;10(12):e0145687.
  19. Kodali M, Parihar VK, Hattiangady B, et al. Resveratrol prevents age-related memory and mood dysfunction with increased hippocampal neurogenesis and microvasculature, and reduced glial activation. Sci Rep.2015 Jan 28;5:8075.
  20. Sarubbo F, Ramis MR, Aparicio S, et al. Improving effect of chronic resveratrol treatment on central monoamine synthesis and cognition in aged rats. Age (Dordr).2015 Jun;37(3):9777.
  21. Gocmez SS, Gacar N, Utkan T, et al. Protective effects of resveratrol on aging-induced cognitive impairment in rats. Neurobiol Learn Mem.2016 May;131:131-6.
  22. Witte AV, Kerti L, Margulies DS, et al. Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci.2014 Jun 4;34(23):7862-70.
  23. Fajemiroye JO, da Cunha LC, Saavedra-Rodriguez R, et al. Aging-Induced Biological Changes and Cardiovascular Diseases. Biomed Res Int.2018;2018:7156435.
  24. Rajapakse AG, Yepuri G, Carvas JM, et al. Hyperactive S6K1 mediates oxidative stress and endothelial dysfunction in aging: inhibition by resveratrol. PLoS One.2011 Apr 22;6(4):e19237.
  25. Tasatargil A, Tanriover G, Barutcigil A, et al. Protective effect of resveratrol on methylglyoxal-induced endothelial dysfunction in aged rats. Aging Clin Exp Res.2019 Mar;31(3):331-8.
  26. Restini CBA, Garcia AFE, Natalin HM, et al. Resveratrol Supplants Captopril’s Protective Effect on Cardiac Remodeling in a Hypertension Model Elicited by Renal Artery Stenosis. Yale J Biol Med.2022 Mar;95(1):57-69.
  27. Rauf A, Imran M, Butt MS, et al. Resveratrol as an anti-cancer agent: A review. Crit Rev Food Sci Nutr.2018 Jun 13;58(9):1428-47.
  28. Tou JC. Resveratrol supplementation affects bone acquisition and osteoporosis: Pre-clinical evidence toward translational diet therapy. Biochim Biophys Acta.2015 Jun;1852(6):1186-94.
  29. Kan NW, Ho CS, Chiu YS, et al. Effects of Resveratrol Supplementation and Exercise Training on Exercise Performance in Middle-Aged Mice. Molecules.2016 May 18;21(5).
  30. Pasquariello R, Verdile N, Brevini TAL, et al. The Role of Resveratrol in Mammalian Reproduction. Molecules.2020 Oct 5;25(19).
  31. Joseph A, Balakrishnan A, Shanmughan P, et al. Micelle/Hydrogel Composite as a “Natural Self-Emulsifying Reversible Hybrid Hydrogel (N’SERH)” Enhances the Oral Bioavailability of Free (Unconjugated) Resveratrol. ACS Omega. 2022 Apr 19;7(15):12835-45.