Why Can’t I

Think ClearlyWalk Straight

Be Happy?

Luigi Ferrucci, MD, PhDLongitudinal Studies Section

Clinical Research Branch

National Institute of Aging

Walking

Physical Function

Cognition

Mood

?

Walking

PhysicalFunction

Mood Cognition

HomeostaticEquilibrium

(Biological Housekeeping Mechanisms)

Specific Interactive MechanismsIncluding 1. Underlying Physiological Mechanisms2. “Use or Lose” Mechanisms”3. Changes in Behavioral and Social Constraints

Walking

A Bioenergetic

HYPOTHESIS1. The dysregulation of one or more elements of the network of mechanisms that maintain a stable homeostasis have negative effects on physical function, cognition and mood;

2. Such dysregulation may trigger a contro-regulatory response aimed at slowing down the human machine (principle of Maximum Efficiency). As a side effect, these events trigger a vicious cycle that leads to accelerated functional decline.

Walking

The Homeostatic Network in the BLSA

CNS

PNS

Muscles

Bone, Joints

Energy

Feedback

Insul., Ghrelin, Leptin, Adiponectin, Resistin, IGF-1, Testosterone, Estradiol, DHEAs, Cortisol, Thyroid, PTH

PCR, IL-6, sIL-6R, gp130, TNF-α, TNFr1, TNFr2, IL-18, IL-15, Homocysteine

Heart Rate Variability

Carbonylated Proteins

Food Intake, VitD,VitB12, Folate, VitE,Albumine.

Self-ReportAccelerometer

Hormones

Inflammation

Autonomic

Nutrition

Phys Activity

Ox Stress

Mobility DomainsHomeostatic Network

Mobility

Outcome

Inflammation

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-1

-0.5

0

0.5

1

1.5

IL-6

IL-6r

IL-1ra

IL-18

-1.5

-1

-0.5

0

0.5

1

CRP

Fibrinogen

-1.5

-1

-0.5

0

0.5

1

CRP

Fibrinogen

-1

-0.5

0

0.5

1

1.5

IL-6

IL-6r

IL-1ra

IL-18

20-39 40-49 50-64 65-74 75-84 85+20-39 40-49 50-64 65-74 75-84 85+

n o

f S

D f

rom

th

e se

x-sp

ecif

ic m

ean

Age Groups Age Groups

Men Women

Men Women

n o

f S

D f

rom

th

e se

x-sp

ecif

ic m

ean

The Mild Pro-Inflammatory State of Aging

Ferrucci L et al. Blood. 2005;105:2294-9.

Walking Ferrucci et al. JAGS 1999;47: 639-44

0

0.2

0.4

0.6

0.8

1.0

-0.5 0 0.5 1 1.5 2 2.5 3

Ln (IL-6)

Pro

babi

lity

ofM

obili

ty D

isab

ility

2.5 pg/ml

Adjustedprobability

95% CI

95% CI

Interleukin-6 Serum Levels Predict Incident DisabilityA Case Cohort Study Nested in the EPESE

Walking

Walking Speed

0 1 2 3

Follow-up (yrs)

0.4

0.5

0.6

0.7

Wa

lkin

g S

pe

ed

on

a 4

-m C

ou

rse

(m

/se

c)

Ferrucci L et al. J Am Geriatr Soc 2002; 50: 1947-54

Walking Speed Adjustingfor Hip Flexor Strength

0 1 2 3

Follow-up (yrs)

0.4

0.5

0.6

0.7

Wa

lkin

g S

pe

ed

on

a 4

-m C

ou

rse

(m

/se

c)

Inflammation, Muscle Strength, and Physical Performance

The Women’s Health and Aging Study

Walking

Walking

IKKγIKKβ

RelA (p65)NF-κB1(p50)

IKKα

IkB

Nucleus

Virus Growth FactorsMitogens

InflammatoryCytokines

BacterialProducts

StressSignals

LPS

P P u

Ubiquiti

nation

u

IkBProteasome-Degradation

RelA (p65)NF-κB1(p50)

Inflammation(Chemokines, Cytokines, Immune Receptors, Adhesion Molecules)

SynthesisIkB

ImmortalityTelomerase expression Cell Survival and Cell Death

Antiapoptotic (i.e. Bcl-xl, hs-20) and pro-apoptotic gene expression (i.e. Fas)

AngiogenesisRegulation of VEGF, TNF, IL-1

Cell ProliferationCyclin D1, c-myc

Walking

GA

PD

H r

elat

ive

un

its

in

ten

sit

y

C 2h 4h

0

2

4

6

8

10

12P65/Rel A (Western Blot)

Nuclear p65/RelA

Inte

nsi

ty

**

* p<0.01 compared non-stimulated

C 2h 4h0

1

2

3

4

5

6

P65/Rel A (Western Blot)

P=0.06

-0.092 ± 0.021 Age*Time 4h

-0.035 ± 0.019 Age*Time 2h

8.726 ± 1.325 Time 4h

4.072 ± 1.250 Time 2h

0.032 ± 0.008Age

Age < 60 years

Age ≥ 60 years

<.0001

0.0697

<.0001

0.0011

<.0001Variable b ± S.E. P-value

Age and NF-κB Activation

Thinking C.J.Pike

Senile PlaqueFocus of Inflammatory Reaction

Thinking

Thinking

Thinking

Thinking

Thinking

Buntix, 1996

Devanand, 1996

Henderson, 1997

Chen, 1999

Palsson, 1999

Geerlings, 2000

Summary estimate

.05Risk (Odds) Ratio and 95% Confidence Interval

.01 1.0.5 5.0

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Well,How is This Going to Help?

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Physical Function

Cognition

Mood

NF-κB?

"It would be so nice if something made sense for a change."(Alice’s Adventures in Wonderland; July 4, 1865 - Charles L. Dodgson)

Thank You for Your Attention

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