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The Secrets of Healthy LongevityGamma Sigma Delta Fall Lecture Series

December 7, 2007; Baton Rouge, LA

Eric RavussinDon WilliamsonSteven R SmithFrank GreenwayLeonie Heilbronn

Corby MartindLeanne Redman

Anthony Civitarese

and the Pennington CALERIE, LHAS

Teams

Supported by NIARavusse@pbrc.edu

• By 2020, there will be 10 million Americans above the age of 85 yearsthe age of 85 years.

• Assistance is required by 45% of those over 85 years of age.

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Presidential Public Policy Meeting

Total Federal Spending for Medicare and Medicaid under Assumptions about the Health Cost Growth Differential

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On the surface, aging is obvious.

The Aging of Albert

Aging is a hypothetical construct.Aging is a hypothetical construct.

Unsuccessful Aging Successful Aging

Individuals of the Same Chronological Age Can AppearIndividuals of the Same Chronological Age Can AppearTo be of Very Different Biological AgeTo be of Very Different Biological Age

AGE 62 AGE 91

But is this appearance a real biological phenomenon But is this appearance a real biological phenomenon or merely superficial?or merely superficial?

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No!No!B t bB t bBut, maybeBut, maybewe can slow it we can slow it down a bit. down a bit.

HEALTHY AGING

DEPENDS ON A

MULTITUDE OF

FACTORS

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Significant factors in the ability toSignificant factors in the ability to maintain health and independence in old age include:

• Genetic predisposition

• Diet• Physical activityy y

• Healthy weight

• A decrease in total energy intake is commonly observed with aging.

A COMMENT ON NUTRITION

• However, some nutrients are required in higher amounts to compensate for the reduced metabolic efficiency associated with aging.g g

• Hence, the paradox: lower caloric requirements but higher nutrient needs.

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Type 2 diabetes, heart disease, osteoarthritis,

stroke, and others

Cognitive functions

POOR NUTRITION

Bone weakening

Loss of muscle mass

RECENT RESEARCH RELEVANT TO AGING PERFORMED AT THE PENNINGTON BIOMEDICAL RESEARCH CENTER

The mission of the

Pennington Biomedical Research Centeris “to promote healthier lives through research

and education in nutrition and preventive medicine.“

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PENNINGTON BIOMEDICAL RESEARCH CENTER

• Established in 1988, the Center has grown steadily and i 600 000 f f h b id 2003comprises 600,000 square feet of research space by mid 2003

• At present, PBRC employs 85 faculty scientists, with 650 staff and support personnel

• The center has a yearly operational budget of $65 M

• The Center has performed more than 280 clinical research projects

Di t A h t St H t i

RECENT RESEARCH RELEVANT TO AGING PERFORMED AT THE PENNINGTON BIOMEDICAL RESEARCH CENTER

• Dietary Approaches to Stop Hypertension (DASH)

• Diabetes Prevention Program• HERITAGE Family Study (Physical

Activity)Activity)• Metabolic Adaptations to Two-Year Caloric

Restriction (CALERIE)

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128

130

132

134

OL

IC

Weekly Blood Pressure During DASH Intervention Feeding

86

88

90

120

122

124

126

128

Control

Fruits/Veg

Fruits/Veg & low fat

SY

ST

O

WEEKS

78

80

82

84

B 1 2 3 4 5 6 7,8

Effect of the DASH Diet in Hypertensive

Fruits/Veg Fruits/Veg/ L FLow Fat

Normotensive n=326

-0.8/-0.3 -3.5/-2.1

Hypertensive n=133

-7.2/-2.8 -11.4/-5.5 n=133

Changes in Systolic/diastolic pressure, adjusted for controls

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DASH Summary

A diet high in fruits and vegetables and low in fat was found to:

Find pic

• Significantly lower both systolic and diastolic blood pressure

• Benefit a wide variety of people: • women and men, • ethnic groups, • normotensives and hypertensives, • younger and older.

Diabetes Prevention

Over 3,200 volunteers aged 21 to over 85 were tested in 27 centers, including the Pennington CenterPennington Center.

There were 3 arms: lifestyle, placebo, and pharmaceutical (metformin).

The Intensive Lifestyle was so effective that the first phase of the trial terminated early.

• 58% reduction in development of diabetes

• Higher weight loss in older subjects

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Incidence of Diabetes

40%)

Placebo (n=1082)Metformin (n=1073)Lifestyle (n=1079)

10

20

30

ulat

ive

inci

denc

e (%

Risk reduction31% by metformin58% by lifestyle

0

10

0 1 2 3 4Years from randomization

Cum

u

Physical Activity and Health

Hea

lth B

enef

its

Physical Activity Level

H

Very Light Moderate High high

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Decrease in Physical Working Capacity with Age

1211

13hy

sica

l wor

king

pa

city

in M

ETs

6

4

10987

5 ? Social dancing, gardening? Walking (3.5 mph), painting a wall

25 35 45 55 65 75Age in years

Ph cap

0

4321

? Walking (3.5 mph), painting a wall? Walking (3 mph), housework, bowling? Walking (2 mph), changing clothes? Sleep

• 800 subjects from 200 families exercised at 4 clinical centers for 5 months with no dietary changes.

L i t i di id l

HERITAGE Family Study

• Large inter-individual differences in the response to regular exercise were observed.

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The HERITAGE Family StudyDistribution of the VO2max training

responses

•

1000

1200x

train

ing

resp

onse

, m

l/min

400

600

800

1000 N = 720

Individuals

VO

2max

.

0 200 400 600-200

0

200

• Strong aggregation with high responders or low responders

HERITAGE Family Study

g gg g g p pclustering in some families.

• An understanding of the effects of nutrition will be achieved only if the role of physical activity and the interactions with biological individuality are taken into account.

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CALERIE = Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy

•Pennington was 1 of 3 centers selected by the National e gto was o 3 ce te s se ected by t e Nat o aInstitute on Aging to study caloric restriction ($15M/7yrs). – Caloric restriction in rodents prolongs life, as well as causing weight

loss.– One hypothesis is that metabolic rate is decreased, and the production of

free radicals is reduced.•PBRC scientists are investigating in controlled human trials the role of caloric restriction in:– Metabolic rates– Gene expression – Risk factors for chronic diseases– Oxidative stress in tissues

CALERIE = Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy• NIA sponsored studies of caloric restriction

in non obese humansin non obese humans• Study the feasibility and safety of caloric restriction

in non obese humans

• Biomarkers of longevity• DM risk factors: insulin sensitivity

C di l i k f• Cardiovascular risk factors• GH secretion• Metabolic adaptation and oxidative stress• Physical activity during CR• Muscle mitochondrial biogenenesis

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• Aging is thought to bring deterioration of specific cell components resulting in increased release of free radicals, which attack DNA, li id d t i i f th dlipids and proteins causing further damage.

• One method of coping with free radicals is use of nutritional antioxidants.

• PBRC has one of the most progressive laboratories in the US to measure specific DNA alterations associated with aging, as well as study of reparative enzymes.

Subjects and Interventions48 healthy men and women

Age 25 - 50y (45y for women)BMI 25-30 kg/m2

Exercise < 3 times per week.

R d i d t 4 t t tRandomized to 4 treatment groups25% CRLCD to -15% Body weight12.5% CR + 12.5% ↑ EE (exercise)Control healthy diet (AHA – STEP1)

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Study Design

Baseline zatio

n

25% CR (CR)

12 5% CR 12 5% EX (CR EX)

Healthy Diet Control (Control)

BL

• Energy Expenditure– RMR (ventilated hood)– 24-h Energy Expenditure (chamber)

• Weight• DEXA

– % fat, FFM, FMBMC BMD

BaselineTDEE by DLW

Ran

dom

i 12.5% CR + 12.5% EX (CR+EX)

Food Provided M3 M6Food at Home

15% Wt. loss + Maintenance (LCD)

24 h Energy Expenditure (chamber)– TDEE (Doubly labeled water)

• Oxidative Stress (DNA, Prot, Lipids)• Biomarkers of Longevity

(body temperature, Insulin, DHEAS)• Muscle and adipose biopsies• QOL, Psychological Assessment

– BMC, BMD• CT

– VAT, SQAT, DSQAT– BMC, BMD

• Insulin Sensitivity (FSIGTT)• CVD risk factors• 24-h blood sampling

Body Weight and Composition

Body Mass ChangesChanges at week 24

eigh

t cha

nge

(kg)

-8

-6

-4

-2

0

2 Body Mass Changes

eigh

t cha

nge

(kg)

-8

-6

-4

-2

0

Weeks2 4 6 8 10 12 14 16 18 20 22 24

We

-14

-12

-10Control LCD CR+EX CR

Control CR CREX LCD

We

-12

-10

8

FM FFM

∗

∗

∗

~10%

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Biomarkers of Aging & Longevity

ers • Fasting Insulin

• Wrinkles?

• DHEAS• GH ?

Long

evity

Mar

ke • ?

20 40 60 80 20 40 60 80

Chronological Age (y)

Possible Molecular Biomarkers of Aging

Telomere shorteningDNA damage and repairGlycation of proteinOxidation of proteins

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Hypothesis: Biomarkers of “Longevity” are improved

• CR decreased core temperaturep• CR decreased fasting insulin ( IS )

• CR did not influence DHEAS

T t f 3 bi k f l it Two out of 3 biomarkers of longevity were

improved from baseline following 6-mo of CR

intervention in non-obese humans

A. SI B. Acute insulin response to glucose

Caloric Restriction Improved Insulin Sensitivity and Decreased Insulin Secretion

ta S

I (10

-4 m

U/L

/min

)

0.5

1.0

1.5

2.0

2.5

3.0

lta A

IRg

(mU

/L/m

in)

-300

-200

-100

0∗

Control CR CREX LCD

Del

t

-1.0

-0.5

0.0

Control CR CREX LCD

De

-500

-400

∗

Larson-Meyer et al, Diabetes Care, 2006

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IHL but not IMCL is Reduced in Response to Caloric Restriction

B. IHL

% o

f oil

phan

tom

)

0 5

0.0

0.5

1.0

1.5

A. IMCL

% o

f oil

phan

tom

)

-0.2

0.0

0.2

0.4

0.6

0.8

Control CR CREX LCD

Del

ta IH

L (%

-2.0

-1.5

-1.0

-0.5

Control CR CREX LCD

Del

ta IM

CL

(%

-1.2

-1.0

-0.8

-0.6

-0.4

∗

Larson-Meyer et al, Diabetes Care, 2006

CR and CREX decreased LDL-C, increased HDL-C and decreased TG

Lefevre et al, in press, 2007

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Conclusions

• CR with or without exercise improved insulin• CR with or without exercise improved insulin sensitivity and decreased IHL

• CR with or without exercise improved the cardio vascular risk profile (lowers LDL* and TG and increases HDL)(lowers LDL and TG and increases HDL)

• Together, these factors improved the estimated CVD risks by 30-40%

* CR alone did not significantly lower LDL or raise HDL

No change in pulse frequency*18L) Y

CR+EX, LCD

CR may reverse the impaired GH axis in aging

**

* ******

*

*

* **

No change in half-life

3

6

9

12

15

GH

Con

cent

ratio

n (u

g/L Young

Reduced GH concentrations

Elderly

Increased amplitude & mass

Increased GH concentrations

G

0800 1400 2000 0200 0800Clock time (h)

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Program Project on Aging

• In 2002, there were 35.6 million people over the age of 65y in the US, a 10.2% increase since 1992US, a 10.2% increase since 1992

• In 1997, more than half of this older population (55%) reported having at least one disability of some type with over a third (38%) reported having at least one severe disability

• Population based study• Genetics, Physiology, Physical function, Cognitive function• “Successful agers”• Assess biological age

Louisiana Healthy Aging Study

One comprehensive research project is being conducted by scientists from the Louisiana State University Health Sciences Center in New Orleans, LSU in BTR and the Pennington Center with the aim of defining metabolic factors in the aging process in subjects aged 90

Louisiana Healthy Aging Study

defining metabolic factors in the aging process, in subjects aged 90 yrs and older.

Aging, Metabolism, Oxidative Stress, Physical and Cognitive Functionality

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Metabolic measurements, risk factor assessments dietaryfactor assessments, dietary evaluation, and the oxidative stress

Determinants of Human Longevity and Healthy Aging (P01)

Program project PI: M. JazwinskiCore A: Administrative. M. Jazwinski; D. WelshCore B: Sampling and Data Management. J. SuCore C: Recruitment and Clinical Testing. E. Ravussin (C Traylor)

Project 1 (877): Genetics & Genomics. M. Jazwinski; M. BatzerProject 2 (207): Glucose Metabolism and T Cell Function in Aging

D Scott J MountzD. Scott, J. MountzProject 3 (207): Energy Metabolism and Oxidative Stress in Aging

E. RavussinProject 4 (303): Vascular Status and Physical Function in Aging. M. WelshProject 5 (331): Cognitive Function in Aging. K. Cherry

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Resting Metabolic Rate Decreased with Aging but is not Correlated to Oxidative Stress

(kca

l/d)

2000

2200

2400

100

150

Fat Free Mass (kg)20 30 40 50 60 70 80 90

Res

ting

Met

abol

ic R

ate

600

800

1000

1200

1400

1600

1800

2000

20-34 y60-74 yNonagenarians

20-34y 60-74y >90y-100

-50

0

50

AlthoughProte in Carbonyls

20-34y 60-74y >90y

Car

bony

l Con

cent

ratio

n (n

mol

/mg)

0 .0

0.2

0.4

0.6

0.8

1.0

Isoprostanes

20-34y 60-74y >90y

ISoP

s C

once

ntra

tion

(ng/

mg

Cr)

10

20

30

40

50

60

70NS NS

FLARE Assay

20-34y 60-74y >90y

DN

A F

ragm

enta

tion

(au)

16.0

16.5

17.0

17.5

18.0p=0.003 p=0.02

Although nonagenarians appear to be protected from the age-related increase in oxidative damage to DNA, reduced RMR could not be implicated in the mechanism

Physical Activity Level is Correlated to Physical Functionality

cal/d

)

4000

4500 60-74y>90y

TEERMR

or R

MR

)

100

200

20 30 40 50 60 70 80 90

Ener

gy E

xpen

ditu

re (k

c

500

1000

1500

2000

2500

3000

3500AEEPAL

50100Whole Population Nonagenarians

60-74 y > 90y

TEE

kca

l (A

djus

ted

fo

-300

-200

-100

0

Fat Free Mass (kg)20 30 40 50 60 70 80 90

PAL (TEE/RMR)

1.0 1.2 1.4 1.6 1.8 2.0

CS

-PFP

10 to

tal (

au)

-10

0

10

20

30

40

PAL (TEE / RMR)

1.0 1.2 1.4 1.6 1.8 2.0 2.2

CS

-PFP

10

Tota

l (au

)

0

20

40

60

80

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A HaPE Laboratory (Human Physiology)

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Multi-site StudySponsor

Clinical Sites

PI: Susan Roberts PI: John Holloszy

Coordinating Center

PI: Jim Rochon

PI: Eric Ravussin

Hypotheses & AimsPrimary specific aim• As in rodents, CR in humans causes sustained (over two years) metabolicAs in rodents, CR in humans causes sustained (over two years) metabolic

adaptation as defined by: – a reduction in core body temperature and– reduced resting metabolic rate (RMR) corrected for changes in body

composition.– PBRC Ancillary R01s - 24h EE in metabolic chamber and

MRS/mitochondria

Secondary aimsy• CR in humans:

– Reduces serum T3. – Reduces inflammation as reflected in plasma concentrations of Tumor

Necrosis Factor-α (TNF-α). – To determine whether CR has adverse effects in humans and to

evaluate their seriousness.

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Design

• Multi center parallel group RCT• Multi-center, parallel group RCT

• Enroll 250 participants (80 per site)

– CR (sustained 25% CR)

– Control

• 24 month study

• No dietary restrictions. Controlled feeding for first 4 weeks. No ramping of CR

Subjects• Healthy men & women• Age 25-45 years (inclusive)• BMI 22.0 - <28.0 kg/m2

• Exclusion criteria– Medical– Laboratory– Psychiatric/behavioral– Medication– Other

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Healthy Aging?

What is healthy aging?

Retention of: - Quality of life

C iti f ti- Cognitive function

- Physical function

The ChallengeThe Challenge

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Lucas Cranach the Elder, 1546The Fountain of Youth

But what are the mechanisms?

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Calorie Restriction in Humans:Lessons from Mice and Rats

1) How much calorie restriction?The more the better

2) When should calorie restriction start?The earlier the better

3) Does long-term restriction cause adaptation with decreased hunger?Not sure!!!

Eric and Jacqueline Ravussin

on July 4, 1975

CR of 15% for next 52 years

Benefit: 4.7 years

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32 years later

30% CR f 2030% CR for 20 years

Benefit?

Two Months!

I prefer that…

… or take resveratrol possibly in a wine bottle

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Bare-minimum diet: Is long life the payoff?By Kathleen FackelmannKhurram Hashmi has drastically cut the calories he consumes — eating mostly salads and raw vegetables— in the hopes of living a longer, better life.10/24/05

At 5-11, Khurram Hashmi has adopted a bare-minimum diet that has reduced his weight from about 180 pounds to 129.

But he's hungry almost all the time. "That's something for me that has never gone away, but it is easier to accept now," says Hashmi, 37. He says he used to cheat, but not anymore. The hunger tells him that the diet's working, he says.The diet is not for everyone: Hunger and low libido are facts of life for Hashmi and other followers. But they put up with what amounts to a near-starvation diet because a slew of studies has shown that mice and other lab animals that eat a very low-calorie diet live about 30% longer than they otherwise would. These studies also suggest that the diet protects the body from age-related diseases such as diabetes."It is the only nutritional regimen thought to retard aging," says Richard Weindruch at the University of Wisconsin-Madison. His studies have suggested that middle-aged mice can start the diet and still get the longevity benefit.

3000 l i 2000 l i

A 30% Calorie RestrictionA 30% Calorie Restrictiona tough diet!a tough diet!

3000 calories 2000 calories

2400 calories 1600 calories

2100 calories 1400 calories

So this diet should be stressful.So this diet should be stressful.

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XX

X

X

X

Caloric Restriction MimeticsCaloric Restriction Mimetics

What are they and will they work?What are they and will they work?

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Scientific American, 287: 24-29, 2002

Resveratrol is a polyphenolic phytoalexin.

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Resveratrol as a Candidate CR Mimetic

Resveratrol improves health and increases survival of mice on a high-calorie diet

Nature. 444: 337-342, 2006

Joseph A. Baur, Kevin J. Pearson, Nathan L. Price, Hamish A. Jamieson, Carles Lerin, Avash Kalra, Vinayakumar V. Prabhu, Joanne S. Allard, Guillermo Lopez-Lluch, Kaitlyn Lewis, Paul J.

Pistell, Suresh Poosala, Kevin G. Becker, Olivier Boss, Dana Gwinn, Mingyi Wang, Sharan Ramaswamy, Kenneth W. Fishbein, Richard G. Spencer, Edward G. Lakatta, David Le Couteur, Reuben J.

Shaw, Placido Navas, Pere Puigserver, Donald K. Ingram, Rafael de Cabo, and David A. Sinclair

Cooperating Units

National Institute on AgingDepartment of Pathology, Paul F. Glenn Laboratories for the Biological Mechanisms of

Aging Harvard Medical SchoolAging, Harvard Medical School Centre for Education and Research on Ageing, and the ANZAC Research Institute

University of SydneyDepartment of Cell Biology, Johns Hopkins University School of MedicineCentro Andaluz de Biologia del Desarrollo, Universidad Pablo de OlavideSirtris Pharmaceuticals, Inc.Molecular and Cell Biology Laboratory, The Salk Institute

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Baur et al. Nature 444:342, 2006

40

60

80

100

120

140

ma

Glu

cose

(m

g/dl

)

*

0

20

Standard Hi Cal Hi Cal+Res

Pla

sm

1 5

2

2.5

3

ulin

(ng

/ml)

*

0

0.5

1

1.5

Standard Hi Cal Hi Cal+Res

Diet Group

Pla

sma

Insu

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10

12

Standarddiet

400

Glucose Tolerance TestIn

sulin

(ng/

mL)

0

2

4

6

8

10 Standard dietHigh calHigh cal + resv

100

200

300

AU

C *

Time (min)0 10 20 30 40 50 60

0 0

SD HC HCR

Live

r pat

holo

gy (A

U)

1

2

3

4

*

Liver Morphology *

0

art p

atho

logy

(AU

)

1

2

3

4

*

#

*

Heart Morphology*

Hea

0

1

SD HC HCR

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Exercise Performance

* *

to fa

ll fr

om ro

taro

d (s

)40

60

80

100

120

140

16015 months 18 months 21 months 24 months

**

Standard diet High cal High cal + resv

Late

ncy

t

0

20

40

SD HC HCRDiet Group

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Proanthocyanidin fraction was most effectivefor lifespan and thermotolerance.

90100

FEMALES: Survival curve of Canton S. flies on cranberry diet

1020304050607080

Perc

ent S

urvi

val

1:1 Control

1:1 2% AM

010

0 10 20 30 40 50 60

Age (days)

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CR MIMETICS WANNABES

Hypothesized Mechanisms of the Anti-Aging Effects ofHypothesized Mechanisms of the Anti Aging Effects of Calorie Restriction

Reduced oxidative stressReduced glycation of proteinsReduced DNA damage and increased repairReduced inflammation and autoimmunityeduced a at o a d auto u tyIncreased metabolic efficiencyMaintain control over gene expression (chromatin?)Improved stress responses--hormesis

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Young Adult Middle-Aged Old Very Old

18 45 65 85 122

6 14 18 25 40

Will CR mimetics allow us to have our cake and eat it, too?

So I wish you many happy birthdays!!!

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Cocktails, anyone?

The Ultimate CR Mimetic “Cocktail”

• Anti-glycolytic• Anti glycolytic• Insulin sensitizer• PPAR agonist• Antioxidant• Mitochondrial efficiency enhancery• Sirtuin activator• Autophagy enhancer• Lipid regulator

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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 57:B211-B224 (2002)

Calorie Restriction in Biosphere 2: Alterations in Physiologic, Hematologic, Hormonal, and Biochemical Parameters in Humans Restricted for a 2-Year Period

Roy L. Walforda, Dennis Mockb, Roy Verderyc and Taber MacCallumda Department of Pathology, Center for Health Sciences, University of California, Los Angelesb San Diego Supercomputer Center, University of California, San Diegoc D.W. Reynolds Department of Geriatrics, The University of Arkansas for Medical Sciences, Little Rockd Paragon Development Co., Tucson, Arizona