AGINGAGING

Young wormYoung worm Old wormOld worm

Mutants in Mutants in daf-2 daf-2 are long are long livedlived

aaa

Age (Days).2.4.6.80

1

01020304050607080

N2daf-2(e1370)daf-2 encodes an insulin/IGF-1 receptor homologdaf-2 encodes an insulin/IGF-1 receptor homolog

daf-2

N2daf-16

aa

Age (Days)0.2.4.6.810102030405060708090F

ract

ion

aliv

e

daf-16;daf-2

In order for In order for daf-2 daf-2 mutants to live long, mutants to live long, they need they need daf-16 daf-16 activity. activity.

DAF-16 is a forkhead-family transcription factorDAF-16 is a forkhead-family transcription factor

aaa

.5

Days

0

1

0 20 40 60 80

wild typedaf-2daf-16:daf-2

Lifespan effect of mutations in daf-2Lifespan effect of mutations in daf-2

daf-16 daf-16 activityactivity is required for the long is required for the long lifespans of lifespans of daf-2 daf-2 mutantsmutants

Model: In the wild type, DAF-2 turns off DAF-16Model: In the wild type, DAF-2 turns off DAF-16,, preventing DAF-16 from extending lifespanpreventing DAF-16 from extending lifespan

daf-2daf-2 Encodes a Hormone Encodes a Hormone ReceptorReceptor

35% aa identity to:35% aa identity to:

Human Insulin ReceptorHuman Insulin ReceptorIGF-1 ReceptorIGF-1 ReceptorInsulin Related ReceptorInsulin Related Receptor

Kimura et al., 1997Kimura et al., 1997

aaa

C. elegans Life Cycle

Good EnvironmentHarsh EnvironmentADULT

Egg

L4

L1DAUERL3

L2 L2d

Eggs

aaa

C. elegans Life Cycle

Good EnvironmentHarsh EnvironmentADULT

Egg

L4

L1DAUERL3

L2 L2d

Eggs

daf-2daf-2 OFF OFF

PP

PP - 2DAF

-DAF- 16

PI(4,5)P2PI(3,4,5)P3

PDK-1AKT-1

AKT-2

DAF- 18

PTEN

AGE-1

PI 3K

The DAF-2 pathway controls a second signal or The DAF-2 pathway controls a second signal or hormonehormone

DownstreamDownstream hormonehormone

a

EnvironmentalSignal SensoryNeuronsInsulin-likeHormoneDAF-2ReceptorDownstreamSignalModelModel

YeastYeast WormsWorms FliesFlies MiceMice

Stationary Phase Stationary Phase GlucoseGlucose Sensory Signals?Sensory Signals? Normal ConditionsNormal ConditionsNormal ConditionsNormal Conditions

Pituitary GlandPituitary Gland

Growth HormoneGrowth Hormone

IGF-1?IGF-1?

IGF-1 Receptor?IGF-1 Receptor?Other Insulin/Other Insulin/IGF-1 Pathways?IGF-1 Pathways?

LongevityLongevityLongevityLongevityLongevityLongevityLongevityLongevity

Insulin/IGF-1Insulin/IGF-1ReceptorReceptor

Insulin/IGF-1?Insulin/IGF-1?

Chico (IRS)Chico (IRS)

JuvenileJuvenileHormoneHormone

Insulin/IGF-1Insulin/IGF-1

DAF-2 ReceptorDAF-2 Receptor

AKT-1AKT-1

DAF-16DAF-16

Downstream SignalDownstream Signal

SIR-2SIR-2

??

??

PKA PKA PathwayPathway

Sir2Sir2NADNAD

Sch9Sch9

From Kenyon,From Kenyon,Cell, April 20,Cell, April 20,2001.2001.

Decreasing signaling activityDecreasing signaling activity

Extends lifespanExtends lifespanIncreases stress resistanceIncreases stress resistanceIncreases production of food storage substancesIncreases production of food storage substancesCan inhibit reproductionCan inhibit reproduction

This system probably arose early in evolutionThis system probably arose early in evolutionto allow animals to outlive unfavorable conditions, to allow animals to outlive unfavorable conditions, postponing reproduction until conditions improve. postponing reproduction until conditions improve.

Lifespan extension can be uncoupled from infertility,Lifespan extension can be uncoupled from infertility,changes in food utilization pathways, and stress resistance.changes in food utilization pathways, and stress resistance.

ModelModel

daf-16daf-16daf-2daf-2

LONGEVITYLONGEVITYLONGEVITYLONGEVITY

Sensory Sensory neuronsneurons

a

EnvironmentalSignal The Big Picture