Circulatory benefits of resveratrol a key to healthy brain ageing

Professor Peter HoweClinical Nutrition Research Centre

University of Newcastle and University of Southern Queensland

Healthy Aging SummitSingapore, 11th July 2019

addressing the increasing gap between life expectancy and health-adjusted life expectancy

Institute for Health Metrics and Evaluation. Global burden of disease study 2016 (GBD 2016). Disability-adjusted life years and healthy life expectancy 1990-2016. http://ghdx.healthdata.org/record/global-burden-disease-study-2016-gbd-2016-disability-adjusted-life-years-and-healthy-life

Preventive Health for an Aging Population

Disability threshold

range of functionin individuals

• genes

• diet

• lifestyle

Age

Early Life Adult Life Older Age

Functional capacity (physical & mental fitness)

Preventive Health for an Aging PopulationDietary Guidelines for Americans 2005

Center for Nutrition Policy and Promotion, USDA

WHO/HPS Geneva, 2000

The shape of things to come?The Economist, 2003

Are the public health recommendations failing us?Metabolic Syndrome

obesity

highblood

pressure

high blood fats

highblood glucose,insulin

predisposes to heart disease, diabeteschronic inflammatory conditionscognitive decline and dementia

Singapore Longitudinal Ageing Study Cohort(Tze Pin Ng et al JAMA Neurol 2016)

Increased risk of incident MCIMetS 1.5; obesity 1.4; T2DM 2.8;dyslipidemia 1.5; ≥3 CVR risk factors 1.6

Increased risk of MCI → dementiaMetS 4.3; T2DM 2.5; ≥3 CVR risk factors 4.9

Inflammation

Cerebral blood flow is reduced in mild cognitive impairment Sun Z et al Eur J Neurol 2007

No damage Neuronal dysfunction Cell death

Cerebral blood flow

Mild hypoperfusionImpaired learning & memory

Moderate-severe hypoperfusion• ↓ neuron action potential• pH, H20 & electrolyte shifts• White matter damage• ↑ accumulation of toxins

(Aβ, tau, heavy metals)

100

80

90

(%)

Seals & Alexander J Appl Physiol 2018

arterial disease cognitive declinedepression

neurodegenerative diseases

hypertensioncoronary

diseaseheart failurestroke

renal disease

impaired blood flow

systemic inflammationimpaired fat, glucose metabolisminsulin resistance

bone, muscle lossphysical incapacity

Impact of diet/lifestyle on the circulation

endothelial dysfunction• impaired vasodilatation

(early change detected by FMD)• pro-thrombotic and

inflammatory mediators • Increased arterial stiffness due

to vascular remodelling and hypertrophy (long term change)

Metabolic Syndrome• Abdominal obesity• High blood pressure• High blood sugar• High blood fatHigh salt intakePhysical inactivitySmoking

healthy endothelium

• regulates vasomotor tone • inhibits cell adhesion,

platelet aggregation• controls capillary exchange

(selective permeability)• controls vascular integrity

(counteracts hypertrophy)

(assess endothelial function non-invasively)Flow mediated dilatation (FMD)

↑ NO

Impaired vascular function and its pathological consequences

can be prevented or attenuated by regular aerobic exercise and supplementation with selected

bioactive (vasoactive) nutrients,e.g. omega-3, plant polyphenols

Bioactive nutrients from plants

>10,000

>6,000

Generic antioxidants? or

mediators of specific physiological functions, e.g. anti-inflammatory, endothelial dilatation?

Erdman J et al J Nutr 2007

Phytochemicals

FlavonoidsResveratrol

(berries, nuts)

(tea, cocoa)

(soy)

O

OH

HOOH

OHOH

lutein

Cocoa flavanol supplementation for 12 weeks improves FMD (Davison K et al. Int J Obesity 2008)• independent of antioxidant activity• mediated by epicatechin → NO↑

“Cocoa flavanols help maintain endothelium-dependent vasodilation, which contributes to normal blood flow”

They can also lower BP improve insulin sensitivityincrease cerebral blood flowenhance cognitive function

Multi-faceted benefits of resveratrol

Cardiovascular protection

Counteracts neuro-

degeneration

Cancer protection

Reduces chronic

inflammation

Improves fat regulation & metabolism

Combats oxidative stress

(anti-aging)

Protects against

bone loss

Improves insulin

sensitivity

Xia N et al Molecules 2014

adapted fromLi & Forstermann, Cardiovasc Drugs Ther 2009

Resveratrol

eNOSproduction

NO inactivation

Endothelial vasodilator function

Cerebral perfusion

Cognitive performance

NO bioavailability

adapted from Chachay et al Br J Clin Pharm 2011

Clinical evaluation of circulatory and health benefits of resveratrol

+1.9%+2.4%

+3.4%

+1.5%

1 Lekakis et al Eur J Card Prev Rehab 2005;12:5962 Davison et al Int J Obes: 2008;32:12893 Widlansky et al Free Rad Bio Med: 2005;38:499 4 Widlansky et al J Am Coll Nutr: 2007;26:95

+2.5%+2.4%

Red wine polyphenol

extract (600mg)1

Cocoa flavanols(902mg)2

Tea (450ml)3

EGCG (300mg)4

+3.7%

0

1

2

3

4

5

6

7

8

9

10

0 30 90 270

FMD

resp

onse

(%)

Resveratrol dose (mg)

Acute dose-response study

Chronic supplementation trialResveratrol 75mg/d for 6 weeks

= 20% ↓ in CVD risk

Resveratrol improved word reading (speed and accuracy) in Stroop CWTCan resveratrol improve cognition by enhancing cerebral blood flow?

Global vasodilatation breathing CO2 (CVR to hypercapnia)

40

60

80

100

120

140

155

111

0116

5122

0127

5133

0138

5144

0149

5155

0160

5166

0171

5177

0182

5188

0193

5199

0110

451

1100

111

551

1210

112

651

1320

113

751

1430

114

851

1540

115

951

1650

117

051

1760

118

151

1870

119

251

1980

120

351

2090

121

451

2200

122

551

2310

123

651

MCA L Mean

MCA R MEAN

Time (s x 10-2)

Basal3 min hypercapnia

Room air

Mean blood flow velocity (cm/s)

We use bilateral TCD probes to assess• steady state mean blood flow velocity

and pulsatility index (arterial stiffness) in the middle cerebral artery

• cerebrovascular responsiveness (CVR) to hypercapnic or cognitive stimuli (dynamic measures similar to FMD)

Transcranial Doppler Ultrasound (TCD) assessment of cerebrovascular function

30

35

40

45

50

138

376

511

4715

2919

1122

9326

7530

5734

3938

2142

0345

8549

6753

4957

3161

1364

9568

7772

5976

4180

2384

0587

8791

6995

5199

3310

315

1069

711

079

1146

111

843

1222

512

607

1298

913

371

1375

314

135

1451

714

899

1528

115

663

Left Right

Mean blood flow velocity (cm/s)

During 90s of Stroop testpre-test

blood flow velocity increases within 5s of commencing test

Regional vasodilatation during performance of a cognitive task

A: Pericallosal ArteryB: Anterior Cerebral ArteryC: Middle Cerebral ArteryD: Anterior Choroidal ArteryE: Ophthalmic ArteryF: Internal Carotid ArteryG: Posterior Cerebral Artery

Effects of resveratrol on cerebrovascular responsiveness (CVR) in T2DM

Why diabetes?• Cognitive decline is accelerated in T2DM

• CVR is reduced in T2DM

• Cognitive deficits are associated with ↓CVR (Nealon R et al, J Diabetes Complications 2017)

Are these effects sustained with chronic supplementation?

-5

0

5

10

15

20

0mg 75mg 150mg 300mg

*0·001

*0·016

*<0·001

% change in CVR to a hypercapnic stimulus

Double-blind crossover trial36 older adults with stable T2DM

took single doses at weekly intervals 0

5

10

15

20

25

0mg 75mg 150mg 300mg

*P=0.019

↑35%

CVR (%) to performing a demanding cognitive test

Cerebrovascular and cognitive benefits of resveratrol in postmenopausal women

Why postmenopausal women?• Both systemic and cerebral vasodilator

function declines more rapidly after menopause than in age-matched men

• Risks of dementia and osteoporosis are far greater in elderly women than men

• These changes are partly attributable to loss of protective effects of estrogen

• Resveratrol activates both ERα and ERβ

Prevalence of dementia in AustraliaAIHW 2012

(2 x 75mg/day)

-5

-3

-1

1

3

5

Placebo Resveratrol

P< 0.016 P<0.020P<0.006

P<0.047 P<0.014

Semantic fluency Semantic memory Verbal memory

Visuospatialworkingmemory

Executive function

Change in CVR (%) to cognitive stimuli (35)(37)

RESFEM studyResveratrol improves cerebrovascular responsiveness and cognition

0

2

4

6

8

10

placebo

Resveratrol

P<0.011

Change in CVR (%) to hypercapnia

Improvements in overall cognitive scores correlate

with improvements in overall CVR to cognitive tasks (r= 0.363, P = 0.01)

(28)

(33)

-0.4-0.2

00.20.40.60.8

1

P<0.01

Change in z-score for performance of cognitive task

RESFEM studyResveratrol improves mood and reduces pain perception

-12

-10

-8

-6

-4

-2

0

2Tension Depression Anger Fatigue Confusion

Total mooddisturbances Vigour

Placebo ResveratrolP<0.033

Reduction in overall pain correlated with improvements in CVR to both hypercapnic(r=-0.404) and cognitive (r=-0.459) stimuli

Change in mood score

-3.0-2.5-2.0-1.5-1.0-0.50.00.51.01.52.0

Pain scores VAS (cm) Pain intensity

P=0.004

P=0.010

P=0.032

Short form McGill Pain Questionnaireincludes scores for overall pain (15 descriptors), present pain intensity and Visual Analogue rating

Change in pain score

Clinical evaluation of circulatory and health benefits of resveratrol

Resveratrol (2x75mg/day) for 14 weeks improved: •cerebrovascular function •cognitive performance•pain symptoms•overall well-beingin postmenopausal women

AimConduct a larger, longer term trial to evaluate effects of resveratrol in in post-menopausal women on

• Cognition (Primary outcome)• Cardiovascular function• Body composition• Cardiometabolic biomarkers• Mood and well being

+Rey’s Auditory Verbal Learning Test

Forward Spatial Span TestTrail Making Task

Addenbrooke’s Cognitive Exam-III

Cognitive domains• Attention• Processing speed• Semantic memory• Episodic memory• Working memory

Overall cognitive performance = sum of Z-scores for each test

• Verbal memory• Visual-spatial memory• Executive function• Global cognition

Systemic circulation• Blood pressure, heart rate• Large artery elasticity• Small artery elasticity• Systemic vascular resistance

Cerebral circulation • Blood flow velocity• Cerebral artery stiffness • CVR to hypercapnia• CVR to cognitive stimuli

Measures Questionnaires

Mood states Profile of Mood States (POMS)

Depressive symptoms Center for Epidemiological Studies Depression Scale (CES-D)

Pain Short-form McGill Pain questionnaire

Menopausal symptoms Menopausal Rating Scale (MRS)

Sleep quality Pittsburgh Sleep Quality Index

Quality of Life Short Form-36 (SF-36)

Subjective memory complaints

20 questions on everyday memory difficulties

Plasma lipidsGlucose, insulin

CRPFSH

Alk-P Osteocalcin

RESHAW

RESHAW trial(Resveratrol Supporting Healthy Ageing in Women)

RESHAW

2 × 12 month Crossover RCT(powered on 86, enrolled 146:65 yrs, 15 yrs postmenopausal)

Study design

Randomisation (146)

Baseline visit

12 month visit (129)

2 × 75 mg resveratrol

Placebo

24 month visit (125)

2 × 75 mg resveratrol

Placebo

Supplementing postmenopausal women for 12 months with low-dose resveratrol:-• improved cerebrovascular function• improved overall cognitive performance• reduced symptoms of pain• improved overall well-beingconfirming observations from our preliminary 14 week (RESFEM) study.

Additionally, resveratrol supplementation in the RESHAW trial:-

• slowed bone loss in the lumbar spine and proximal femur, reducing risk of fractures• lowered blood insulin and increased insulin sensitivityWe anticipate further positive outcomes from the 24-month crossover analysis.

RESHAW

RESHAW trial: summary of interim findingsOverall ConclusionsRESHAW

We attribute these benefits of resveratrol (at least partially) to circulatory improvements.By helping to maintain a healthy circulation, supplementation with vasoactive nutrients such as resveratrol can help to counteract heightened risks of cardiovascular disease, diabetes, osteoporosis and dementia in our ageing population. Long term trials of resveratrol and other vasoactives, alone or in combination, should be undertaken in other target populations (e.g. older men, men and women with T2DM or hypertension) to determine efficacy and optimal dose requirements for each indication.

AcknowledgementsNHMRC/ARC, Evolva SA, DSM-NP and study participants