metabolism, energetic, and the pathway to disability in older persons luigi ferrucci, md chief –...

Metabolism, Energetic,and the Pathway to

Disability in Older Persons

Luigi Ferrucci, MD

Chief – Longitudinal Studies Section,Clinical Research Branch

National Institute on AgingBaltimore, MD

Preferred Walking Speed Declines with Age

Age (years)

20 40 60 80 100

PW

S (

m/s

ec

)

0

1

2

Preferred Walking SpeedPredicts Mortality

0.50

0.75

1.00

0 2 4 6

Follow-up (years)

PWS lowest quintile

PWS second

tofifth quintile

Long rank test p<0.0001

Ble & Ferrucci (unpublished)

Cancer

Ble & Ferrucci (unpublished)

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,Albumin

Self-ReportAccelerometer

Hormones

Inflammation

Autonomic

Nutrition

Phys Activity

Ox Stress

Mobility DomainsHomeostatic Network

Mobility

Outcome

No. NeurologicalSymptoms

MuscleStrength

Cortical BoneDensity Heart Rate

VisualAcuity

Nerve ConductionVelocity

0.21 0.11

0.110.02

0.06

0.180.07

0.050.09

0.12 0.23

0.14

0.00

Age-Adjusted r=0.13 (p<.001)

Correlations Between Rates of Change inPhysiological Parameters Important for Mobility

(InCHIANTI, n=1055)

0.51 0.41

0.310.32

0.26

0.380.27

0.250.29

0.42 0.53

0.45

0.00

Crude Average r=0.39 (p<.001)

Inflammation

Autonomic

Food Intake

Physical Activity

Ox Stress

Homeostatic Network

Oxygen Consumption

Cognitive Activity

Resting Metabolic Rate

Hormones

input

output

0 1 2 3 4 5 6 7Mass [log(grams)]

0

1

2

3

4

RM

R [

log(

mlO

2g

-1)]

Elephant

Domestic CattleHuman

CheetahCoyote

Rabbit Bandicut

Wood Duck

Dwarf Lemur

Rat

Ruddy Turdstone

NorthenBirch Mouse

(4.8-0.38) Savi'spygmy shrew

0 1 2 3 4 5 6 7Mass [log(grams)]

0

1

2

3

4

RM

R [

log(

mlO

2g

-1)]

Elephant

Domestic CattleHuman

CheetahCoyote

Rabbit Bandicut

Wood Duck

Dwarf Lemur

Rat

Ruddy Turdstone

NorthenBirch Mouse


0 1 2 3 4 5 6 70.5

2.0

3.5

Mass [log(grams)]

Ma

x L

ife S

pa

n [

log(

year

s)] (4.8-4.8) Human

Domestic Cattle

(4.18-6.5) ElephantCoyote

Cheetah

Wood Duck

Rabbit Bandicut

RatNorthenBirch Mouse

Savi'spygmy shrew

Ruddy Turdstone

Dwarf Lemur

0 1 2 3 4 5 6 70.5

2.0

3.5

Mass [log(grams)]

Ma

x L

ife S

pa

n [

log(

year

s)] (4.8-4.8) Human

Domestic Cattle

(4.18-6.5) ElephantCoyote

Cheetah

Wood Duck

Rabbit Bandicut

RatNorthenBirch Mouse

Savi'spygmy shrew

Ruddy Turdstone

Dwarf Lemur

1 2 3 4 50

1

2

3

4

RM

R [

log(

mlO

2g

-1)]

Max Life Span [log(years)]

Human

Elephant

Coyote

Domestic Cattle

CheetahDwarf Lemur

Wood Duck

Rabbit Bandicut

Rat

Ruddy Turdstone

NorthenBirch Mouse


1 2 3 4 50

1

2

3

4

RM

R [

log(

mlO

2g

-1)]

[log(years)]

Human

Elephant

Coyote

Domestic Cattle

CheetahDwarf Lemur

Wood Duck

Rabbit Bandicut

Rat

Ruddy Turdstone

NorthenBirch Mouse


Data on RMR, body mass and maximum life span are plotted from 241 (153 terrestrial and 88 avian) animals. from the AnAge Database (http://genomics.senescence.info/species/query.php).

Ruggiero C, Ferrucci L. The Endeavor of High Maintenance Homeostasis: Resting Metabolic Rate and theLegacy of LongevityJ Gerontol A Biol Sci Med Sci. 2006 May;61(5):466-73.

Figure 1. Maximum life-span estimates in various populations. Mutations or (caloric restriction) increase maximum survival in mice by ~50% at most. In contrast, porcupine longevity is greater by about 500%.

Richard A. Miller. The Anti-Ageing Sweepstakes: Catalase Runs for the ROSes

Science (2005) 308, 1875-6.

Rodents

Mammals

Mouse

Porcupine

Mutant Mouse

Human

Bowhead Whale

Maximum Life Span (years)0 50 100 150 200 250

Lifespan of DogsSize Isn’t Everything

Papillon (3 kg) Labrador (30 kg) Great Dane (63 kg)15 years 12 Years 8 years

From Speakman et al. Dog Metabolism and Life Expectancy. Ageing Cell (2003) 2, 265-275.

Per

cen

tag

e o

f E

ner

gy

Uti

liza

tio

n p

er D

ay

100

50

0

RMR

60% – 70%

Physical Activity

15% - 30%Reduced Phys. Activity (- 46%)

Reduced RMR (- 44%)

60

Age (years)

0

10

20

30

40

50

0 20 40 60 80 100

RM

R (

k c

a l

/ K

g /

d i

e ) MEB

Enzymatic Activity

Es. Na+K+ATPase

Lean Body Mass

Post-Prandial Thermogenesis

8% -12 %

Other Thermogenesis 2% – 3%

Unknown

Delayed Thermogenic Zenith and Reduced Thermogenesis (-10%)

Gastric Emptying

(Wilson AA, J Appl Physiol 2003)

RMR and Longevity

Higher RMR is associated with Excess Mortality (BLSA)

20 25 30 35 40 45

Basal Metabolic Rate (kcal/hr/m2)

-1

0

1

2

Exc

essi

ve M

ort

alit

y

Res

tin

g M

eta

bo

lic R

ate

, (k

cal/

m2 /

hr)

20 30 40 50 60 70 80 90 100

25

30

35

4035-49 years

C

Age,(years)

10

Age at Study Entry

20 30 40 50 60 70 80 90 100

Res

tin

g M

eta

bo

lic R

ate

, (k

cal/

m2 /

hr)

25

30

35

10

Predicted RMR by decade

40

<35 years

50+ years

Longitudinal Changes in RMR in the General Population and According to Mortality

MVO2maxPost-Prandial andOther Thermogenesis

Physical and CognitiveActivities(Walking, Talking,Watching, Thinking, etc.)

Theoretical MinimumEnergy Requirement For Homeostasis(Age, Sex, BodyComposition and Physical Activity)

Extra Energy forUnstable Homeostasis(Homeostatic Effort)

Behavior

Bed Rest

Behavioral Disability

SedentaryState

Low PhysicalActivity

Moderate PhysicalActivity

Intense PhysicalActivity

Competitive PhysicalActivity

FIT

TN

ES

S

An Extended Model of Energetic Frailty

Fatigue

PWS and fuel selection

00.5 1.1 1.6 2.0

10

20

30

40

50

60

*

*

*

*

Willis et al. 2005

PWS

Fu

el o

xid

atio

n (

cal*

min

-1*K

g-1)

Fatty acid utilization

Carbohydrate utilization

Walking speed (m/sec)

0.8

The Trouble with Markers

“You could call something a biomarker of aging if it were documented that those people who show rapid changes in the marker also show rapid changes in most other traits that change with age, and those who show slow changes in the marker also show slow changes in a wide range of other age-sensitive traits”

Richard Miller (University of Michigan)

20 40 60 80 100

100

120

140

160

180

200

Age (yr)

OG

TT

12

0 m

in G

luco

se (

mg

/dL

)

Cohorts (Age at BLSA Study Entry)

20-30

31-40

41-50

51-60

61-70

71-80

80+

Longitudinal Changes in OGTT 120 min GlucoseAccording to Age Group at Study Entry

(BLSA, n=184, Visits=2757)

60 70 80 90 100

-100

-50

0

50

Age (yr)

Per

cen

tag

e C

han

ge

fro

m 6

0 y

ears

Hearing (1/db; 8kHz)

Lower Extr Power (Kg)CrCl (mL/min)Muscle Mass (%)FEV1 (l/sec)(

Hb (g/dL)

WBC (k/mm3)

Creatinine (mg/dL)

Handgrip (kg)

Percent Longitudinal Change of MultiplePhysiological Parameters After Age 60


60 70 80 90 100

-100

-50

0

50

Age (yr)

Per

cen

tag

e C

han

ge

fro

m 6

0 y

ears

Handgrip (kg)

Distribution of Percent Longitudinal Changeof Handgrip After Age 60

(Schematic example)

1/3

0 1 2 3 4 5 6 7 8

No. Parameters in “Worst” Tertile of Change

Nu

mb

er o

f S

ub

ject

s

0

10

20

30

40

50

BLSA Participants According to No. of PhysiologicalParameters in the Worst Tertile of Speed Deterioration


Normal Aging Accelerated Aging

60 65 70 75 80 85 90

120

140

160

180

200

Age

OG

TT

12

0 M

inu

tes

Glu

cos

e (m

g/d

L)

Normal Aging

Accelerated Aging

Longitudinal Changes in OGTT in Normaland Accelerated Aging BLSA Participants


60 65 70 75

30

31

32

33

34

35

Age

Res

tin

g M

eta

bo

lic

Rat

e (k

cal/

(m²·

h)

80

Normal Aging

Accelerated Aging

Longitudinal Changes in RMR in Normaland Accelerated Aging BLSA Participants


metabolism, energetic, and the pathway to disability in older persons luigi ferrucci, md chief –...

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