Error Catastrophe? None Detected. · heritable even in a population of isogenic animals. Models: 1)...
Transcript of Error Catastrophe? None Detected. · heritable even in a population of isogenic animals. Models: 1)...
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Questions about Aging• Can We Slow It? WE SURE CAN!
• Can We Produce Drugs To Do This? YES!• Is Aging an Extension of Development? NO!• How Much Expression Variation?
Protein: No New Proteins (~1800 seen)RNA: 163 Vary Significantly (Differentially)
with AgeWhole Transcriptome Decreases 3XWhole Translational System Decreases 12X
• Error Catastrophe?None Detected.
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Questions about Aging• Can We Slow It? WE SURE CAN!
• Can We Produce Drugs To Do This?• Is Aging an Extension of Development? NO• How Much Expression Variation? Not much• Error Catastrophe? None Detected• Is Aging Regulated?
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AGE-1
PD
K-1
P PP P
DAF-18PP
P P
AKT-1/2
DAF-16
DAF-2
Target gene
nucleus
Good Times
AGE-1
PD
K-1
P P
DAF-18PP
P
AKT-1/2
DAF-2
Stress
CBP-1
Target gene
DAF-16CBP-1
nucleus
P14-3-3 14-3-3
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R13H8
daf-16a1
daf-16a2
daf-16b
daf-16::gfp
A B C
D
E
10/29/02 Henderson & J, 2001
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Starvation causes nuclear localization of DAF-16::GFP
0hr 1hr
1hr 15min 1hrrecovery
Henderson & J, 2001
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DAF-16::GFP responds to stress in adult animals
Well fed
Starvation
Heat
Juglone
+E. coli
-E. coli 6hr
35°C 2hr
200 µM juglone
Henderson & J, 2001
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20%
Higher DAF-16::GFP Increases Life Span
0 2 4 6 8 10 12 14 16 18 20 22 240.0
0.2
0.4
0.6
0.8
1.0
pRF4 (control)zIs daf-16::GFP
Days
Surv
ivin
g fr
actio
n
Henderson & J, 20013/25/06
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Reduction of daf-16 by RNAi reduces life span
0 2 4 6 8 10 12 14 16 18 20 22 240.0
0.2
0.4
0.6
0.8
1.0
pRF4 daf pRF4 vec
Days
Frac
tion
surv
ivin
g
20%
Henderson & J, 20013/25/06
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RepairReproduction
Allocation of resources may alter lifespan
After Kirkwood
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RepairReproduction
Allocation of resources may alter lifespan
Changes in subcellular localization of DAF-16 may allow for rapid reallocation of resources in response to a changing environment.
Changes in subcellular localization of DAF-16 may allow for rapid reallocation of resources in response to a changing environment.
After Kirkwood
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Questions about Aging• Can We Slow It? WE SURE CAN!
• Can We Produce Drugs To Do This?• Is Aging an Extension of Development? NO• How Much Expression Variation? Not much• Error Catastrophe? None Detected• Is Aging Regulated? No; Living Is Regulated.
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Upregulated by DAF-16 (select 40)•Xenobiotic Detoxification (10)•Alpha crystallin like: hsp-16.1, .2, .11, .49, hsp-12.1, sip-1 (6)•Oxidative Stress: ctl-1, -2, sod-3, mtl-1•Bacterial Response: lys-7, saposins (3)•Insulin: ins-18
Downregulated by DAF-16 (19)•Vitellogenin: vit-2, -5•Insulin, ins-7↓•old-1
DAF-16 Regulates Response to Toxins
Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer
J, Li H, Kenyon C. 2003 Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature, 424:277-83.
3/25/06
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Favorable conditions•IGF-1↑•DAF-16 retained in cytoplasm•Reproduction and growth favored•Fewer resources are put into maintenance and repair.•Life span is shorter.
Unfavorable conditions:•IGF-1↓•DAF-16 transported to nucleus.•Cellular repair and maintenance genes induced•Reproduction and growth genes repressed•Life span is longer.
DAF-16 Is a “GERONTOSTAT”
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Questions about Aging
• Can We Slow It? WE SURE CAN!
• Can We Produce Drugs To Do This?• Is Aging an Extension of Development?• What Causes Stochastic Variation in
Life Span?
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Ages at Death of Wild-type and age-1 Worms
0
5
10
15
20
25
30
35
0 10 20 30 40 50
Days
No
dyin
g
Wild type age-1
Kirkwood & Finch Nature 2002 (data from T. Johnson)
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Green Fluorescent Protein Is a Surrogate (“Reporter”) of HSP-16
hsp-16::GFPtransform
induce
GP73
5/20/02
Isogenic population
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• hsp-16.2 encodes a 16-kD heat shock protein (HSP)• Member of the hsp16/hsp20/alphaB-crystallin (HSP16)
family of heat shock proteins; 6 near identical homologs• hsp-16.2 expression, strongest in intestine and pharynx• Under Daf-16 & HSF-1 • Induced in response to heat shock, hypoxia, or other
environmental stresses • Mount 36; other HSPs• Up regulated in Age mutants• Over expression has modest life extension• Interacts with intracellular human beta amyloid peptide, a
primary component of plaques in Alzheimer's disease• HSP-16.2 is likely to function as a passive ligand temporarily
preventing unfolded proteins from aggregating
HSP-16.2
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Induction Methods
Young Adulthours
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Not All Worms Are Created Equal
Nature Genetics, 2005
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GFP Is Normally Distributed
GFP Level (Arbitrary Units)
2 hour induction, 19 hour sort, 60,000 worms
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Optical Analysis During Flow Sorting
5/20/02
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COPAS Worm SorterRed laser: to measure both size and density of worms.
Green laser: to measure green Fluorescence level of worms.
Parameters are real time analyzed. Those worms meeting the criteria are collected in microwells.
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Questions about Aging
• What Causes Stochastic Variation?
Does HSP-16 Expression Correlate with Differential Thermotolerance?With Differential Lifespan?
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Variance Increases with Time after Sort
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Sorting for Differential Brightness
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Brighter Worms Are Longer Lived
(P < 0.0001)
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0 5 10 15 20 25 30 35-5
0
5
10
15
TJ375, p<0.05TJ375, p>0.05TJ550, p<0.05
Sort Time (hours)
Hig
h - L
ow (d
ays)
Differential Longevity Bright - Dim: All Individual Experiments
(two-hour heat shock)
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(P = 8.0 x 10-29)
Combined Longevity
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Conclusions:• Isogenic worms are not the same
- Variable response to stress- Variable life span
• Response to stress is a predictor of life span• Not due to genetic changes• Probably not due to HSP-16 alone? • “Physiologic State” on first day of adulthood
predicts life expectancy
5/20/02
NATURE GENETICS August, 2005
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Questions about Aging
• What Causes Stochastic Variation?Can We Explain It?Is Any of It Heritable?Are There Other Genes Differentially
Expressed?What Causes Differential Survival?
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0
20
40
60
80
100
120
140
160
180
hsp-16.1
hsp-16.2
hsp-16.41
hsp-16.48
Gen
e Ex
pres
sion
, % o
f Dim
DimBright
Induction of hsp-16 class in Bright worms
*** **
* 0.05 < p-value < 0.1** p-value < 0.05
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The effect on the expression of other hsp
0
20
40
60
80
100
120
140
160
180
hsp-1 hsp-3 hsp-4 hsp-6 hsp-6 hsp-12.1
hsp-12.2
hsp-43 hsp-60 hsp-70
Gen
e Ex
pres
sion
, % o
f Dim
DimBright
** p-value < 0.05
**
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0
2040
60
80100
120
140160
180
ctl-2 ctl-1,3 sod-1 sod-2 sod-4
Gen
e Ex
pres
sion
, % o
f Dim
DimBright
The effect on the expression of antioxidant genes
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0
20
4060
80
100
120140
160
180
gst-1 gst-3 gst-4 gst-5 gst-7 gst-10 gst-13 gst-20 gst-22 gst-24 gst-27 gst-36 gst-38 gst-39 gst-40 gst-41 gst-42 gst-43
Gen
e Ex
pres
sion
, % o
f Dim
DimBright
The effect on the expression of gst
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Dim All Bright24 hr egg lay
Progeny of Dim
1 hourheat
SorterMeasure GFP
Inheritance of Brightness
Maturation
24 hr egg lay
Progeny of Bright
SorterMeasure GFP
Maturation
24 hr egg lay
Progeny of All
SorterMeasure GFP
Maturation
Expectation: All groups of progeny should have similar GFP expression
1 hourheat
1 hourheat
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0
5
10
15
20
25
030
060
090
012
0015
0018
0021
00
GFP Expression
Freq
uenc
y (%
)
F1-AllF1-DimF1-MediumF1-Bright
GFP Expression of Progeny
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GFP Expression of F1 (Progeny)Experiment 1
0.00
0.05
0.10
0.15
0.20
0 500 1000 1500 2000 2500
GFP Score
% o
f Ani
mal
s
F1 of AllF1 of DimF1 of Bright
Mean ± SD ~nF1 of All 847 ± 273 6300F1 of Dim 835 ± 271 3300F1 of Bright 1167 ± 371 3100
Dim vs. Bright: p << 10-17 2א) test)
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Inheritance Summary
Degree of expression of GFP driven by hsp-16.2 isheritable even in a population of isogenic animals.
Models:1) Duplications/deletions of the hsp-16.2::GFP transgene
occur rapidly creating subpopulations withdifferent copy numbers
2) Difference in promoter sequence variation3) Differences in epigenetic state
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Anti Histone 3
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Classical (simple) definition of the transcription
5’ 3’
Promoter Gene
Binding Motif
TFTranscription (mRNA)
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Question
• DNA sequence is completely same in all cells. But the proteins contained are different in each cell. How the transcription is regulated?
5’ 3’
Promoter Gene
Binding Motif
TFTranscription
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Answers• Transcription factor modification (especially,
phosphorylation)• DNA modification (especially, methylation)• Chromatin remodeling• Others (Micro RNA, mRNA modificatiions, etc.)• Abnormal (DNA mutation <- Cancer etc.)
5’ 3’
Promoter Gene
Binding Motif
TFTranscriptionp
MeMe Me Me
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Chromatin Remodeling
Transcription Active Transcription Inactive
Chromatin Unwinding,
HistoneEviction
NucleosomeAssembly
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Histone “Code”
Genes Dev. 2004; 18: 2315-2335
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Demography Group
Demography Group
Shane Rea Jim Cypser Deqing Wu
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Questions about Aging• Is Aging an Extension of Development?
NO• How Much Expression Variation?
VERY LITTLE (>1% RNA)• Error Catastrophe?
NO EVIDENCE• Is Aging Regulated?
NO. LIFE IS SELECTED FOR!• Can We Block Aging?
NO. WE CAN MODIFY IT.