somatotropic (gh) effects on methionine metabolism and...
TRANSCRIPT
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Somatotropic (GH) effects on methionine metabolism and aging
International Symposium on Geroscience2016
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Acknowledgements
UNDSharlene RakoczyVanessa ArmstrongDeb RaasakkaNicole RaasakkaJoy RojanathammaneeJoe Wonderlich
SIUAndrzej Bartke
USDA HNRCEric Uthus
University of GlasgowPeter AdamsJohn ColeNeil RobertsonMohammad Iqbal Rather
Support: Glenn Foundation for Medical ResearchNIH National Institute on AgingEllison Medical Foundation
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Take home message: Reduced somatotropicsignaling allows for metabolic reprogramming –
shifting resources away from growth & proliferationtowards stress resistance & cytoprotection.
Outcome of reprogramming: A more stableepigenome that in turn, results in extendedhealth and life spans.
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Endocrine Lifespan Plasma Stress Insulin Genotype effect extension GH resistancesensitivity Reference Amesdwarf GHdeficient 49-68% Brown-Borgetal.,1996Prop1df +PRL&TSH
deficientAmesdwarf ““ +12% ND Bartkeetal.,2001+calorierestrictionSnelldwarf GHdeficient 42-50% Flurkeyetal.,2001Pit1dw +PRL&TSH
deficientLittle GHdeficient 23-25% Flurkeyetal.,2001GHRHRlitGHRH-/- GHdeficient 43-51% Sunetal.,2013GHR/BP-/- GHresistant 38-55% Coschiganoetal.,2000(GHRKO) GHRKO ““ noincrease ND Bonkowskietal.,2006+calorierestriction FGF21Tg GHresistant 36% ND Zhangetal.,2012IGF1R+/- partialGH 33%*+ ND Holzenbergeretal.,2003
resistance
IGF1R+/- partialGH 5%* ND Bokovetal.,2011 resistance
*
*
**
**some studies have been repeated on different background strains with same* or different results**
Phenotypic Characteristics of GH/IGF Mutant Mice
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GHRH SS
liver
AnteriorPituitaryGH (+)
Target cells
IGF-1 (+)IGF-1 (+)
IGFBP (-)
IGFBPproteases (-)
Somatotropic axis mutants
IGF-1 (+)
LittleGHRHKO
Ames, Snell
GHRKO
IGF1R+/-
Klotho tgMidiPAPP-A Reduced IGF-1 levels/signaling
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Lifespan
49-68%
Ames Mice Prop-
1 gene mutation
GH, prolactin,
TSH deficient
Insulin sensitivity
Stress resistance
Growth Hormone Mutant Mice
0 5 10 15 20 25 30 35 40 45 500
10
20
30
40
50
60
70
80
90
100 Normal
Dwarf
Months
Perc
en
t su
rviv
al
wild typedwarf
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Kidney aging
Immune system aging
Cataract development
Collagenaging
Neuromuscular dysfunction
Joint cartilage & osteoarthrosis
Learning & memory loss
Fatal disease
Cancer incidence
Glucose homeostasis disruption
GH deficient mice have longer healthspans
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Guivere-Aguirre et al, 2011
GH receptor deficiency
****
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GH & IGF-1 in Humans*Congenital IGF-1 deficiency confers protection against cancer, diabetes (Steuerman et al., 2011; Guivere-Aguirre et al., 2011)
Intrachromasomal interactions among IGF1R, IRS2 & UCP2 associated with longevity (Barbieri et al., 2012)
*Insulin/IGF1 pathway mutations associated with longevity (van Heemst et al., 2005; Pawlikowska et al., 2009; Willcox et al., 2008; Flachsbart et al., 2009; Sorensen et al., 2010, 2012; Milman et al., 2014)
IGF1R gene mutations associated with longevity (Bonafe et al., 2005; Suh et al., 2008)
*Impaired IGF1R signaling in cells expressing longevity–associated human IGFR1 alleles (Tazearslan et al., 2011)
Delays in aging/age-related disease & increased longevity may result from overall enhanced stress resistance due to decreased
signaling via GH/IGF1 pathways
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Dwarfism - Prop-1 gene mutation
GH, prolactin & TSH deficient
Increased life span (49-68%)
Enhanced insulin sensitivity
Enhanced stress resistance
Growth Hormone Mutant Mice
Overexpresses bovine GH (PEPCK)
Very high plasma [GH]
Decreased life span (50%)
Hyperinsulinemic, insulin resistant
Decreased stress resistance
Ames dwarf GH transgenic
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GH transgenic mice have longer healthspans
• Incidence of cancer is reduced
• Fatal disease develops later in life
• Youthful cognitive function (learning & memory) is maintained
• Immune system aging delayed
• Cataract development delayed
• Kidney GBM thickening delayed
• Joint cartilage & osteoarthrosis delayed
• Reproductive senescence accelerated
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Mechanisms of Cellular Stress Resistance/Defense
Scavenging systems (antioxidative defense)
tissue specific systems
Detoxification (GSTs)
Heat shock proteins
Metal chelators Apoptosis
Repair systems (DNA, protein)
Your ‘pet’mechanism
**GH status impacts many of these systems**
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*Total tissue GSH pool > in Ames dwarf mice*
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One mechanism underlying elevated GSH levels = altered GSH metabolic pathway
Glutathione Metabolism
Cysteine
-Glutamylcysteine
Glutathione
GSSG
Glutamylcysteine ligase
GSH synthase
GPX GR
GGT
exogenous &endogenous cpds
GSH-conjugatedcpds (detoxified)
O2_. ROS (H2O2)
ROH (H2O)
GSH S-transferase
-glutamyl transpeptidase
*GH
Liver GST/4HNE Activity
WT saline dwarf saline dwarf GH0
200
400
600
nm
ol/m
in*m
g
****GSTA1
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Glutathione (GSH)metabolism of toxins/carcinogens, antioxidant,DNA synthesis & repair, protein synthesis
Methionine (MET)Essential amino acid
-GSH synthesis-maintenance of intracellular GSH pool-protein synthesis
S-adenosylmethionine (SAM)-methyl donor
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Why is methionine important in aging?
• Calorie (CR), protein (PR) & methionine restriction (MR) extend lifespan in rodents & other species
• CR & MR are associated with attenuation of age-related disease in mammals
• Dietary reduction in calories or protein consequently reduces MET
• Methyl deficient diets induce liver injury /genetic defects in MET pathway associated with age-related pathologies
• Methionine, homocysteine, folate, choline & betaine –severe deficiencies & overexpression associated with disease
• CR, PR & MR associated with an in resistance to cellular stressors
• MET metabolism is central to cellular methylation & redox buffering processes
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Methionine metabolism is enhanced in GH deficiency
Methionine
SAM
SAH
Homocysteine
Cystathionine
Cysteine
-Glutamylcysteine
Glutathione
GSSG
MAT
GNMT
SAH hydrolase
CBS
CTH
GCL
GSH synthase
GPX GR
GGT
exogenous &endogenous cpds
GSH-conjugatedcpds (detoxified)
GST
MET synthase
(Folate pathway)
Dwarf
+GH
(mRNA, protein, activity)
transsulfuration
transmethylation
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Normally: When MET is abundant – transsulfuration is favoredWhen MET is low – transmethylation is favored
Methyl-moiety & carbon chain are lost much faster in dwarf mice transmethylation &transsulfuration are bothincreased
SAM & SAH are altered in Ames mice
SAM is universal methyl donor-95% of all SAM is used for methylation (wide variety of molecules)
-85% of all transmethylation reactions occur in liver*
Dwarf mouse exhibits atypical methionine metabolism
3H 35S0
10
20
30
40
50
60
dwarf
wild type
pC
i/nm
ol S
AM
***
*p<0.05**p<0.005
Methionine Flux
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3 month 12 month 24 month
0
1
2
3
4
5
Interaction p= 0.0011Genotype p<0.0001Age p<0.0001
****Dwarf
WT
DNM T3a mRNA
Re
lativ
e E
xp
res
sio
n
3 month 12 month 24 month
0.0
0.5
1.0
1.5
2.0
2.5
Interaction p= 0.0350Genotype p<0.0001Age p=0.0002
****DNM T1 mRNA
Dwarf
WT
Re
lativ
e E
xp
res
sio
n
Liver DNA methyltransferase expression & activity
Dnmt1 – maintenanceDnmt3a, 3b - de novo
3 months
0.00
0.05
0.10
0.15
***
DN
MT
1
Me
an
Op
tic
al D
en
sit
y
0.00
0.01
0.02
0.03
0.04
0.05
***
DN
MT
3a
Mea
n O
pti
ca
l D
en
sit
y
12 months
0.00
0.05
0.10
0.15
*
0.00
0.02
0.04
0.06
0.08
0.10
24 months
0.00
0.05
0.10
0.15
0.20
0.25
**
0.00
0.05
0.10
0.15
0.20
*
Protein expression
0.0
0.5
1.0
1.5
12 months
0.0
0.5
1.0
1.5 * DwarfWT
3 months
rela
tiv
e D
NM
T a
cti
vit
y
0.0
0.5
1.0
1.5
*
24 months
DNMT ActivityD
nm
t1D
nm
t3a
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DNMT1
WT saline Dwarf saline Dwarf GH
0
1
2
3
Re
lativ
e E
xp
res
sio
n
**
WT Saline Dwarf Saline Dwarf GH
0.00
0.05
0.10
0.15
** *
Me
an
Op
tic
al D
en
sity
DNMT3a
WT saline Dwarf saline Dwarf GH
0
1
2
3
Re
lativ
e E
xp
res
sio
n
WT Saline Dwarf Saline Dwarf GH
0.00
0.05
0.10
0.15
*
GH treatment Dnmt1 & Dnmt3a protein in dwarf mice
mRNA
protein
GH also treatment impacts Dnmt1 & Dnmt3a protein in vitro.
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0.16% 0.43% 1.3%0.0
0.5
1.0
1.5
2.0
2.5
Rela
tive E
xp
ressio
n
DNMT1
Wild type
Dwarf****
Interaction p=0.0135Diet p=0.0054Genotype p<0.0001
0.16% 0.43% 1.3%0
1
2
3
4
Rela
tive E
xp
ressio
n
DNMT3A
Wild type
Dwarf
Interaction p=0.0436Diet p=0.0582Genotype p<0.0001
*
****
0.16% 0.43% 1.3%0
1
2
3
4
Rela
tive E
xp
ressio
n
DNMT3B
Wild type
Dwarf
Interaction p=0.0567Diet p=0.0651Genotype p<0.0001
**
****
DNA methyltransferase gene expression is elevated in dwarf mice on diets with varying levels of MET
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• Dwarf mice exhibit atypical methionine metabolism & GHappears to regulate enzymes in pathway
• Flux of methionine is 2-3X greater in dwarf compared to wild type mice thus, transmethylation & transsulfurationare increased
• Liver DNA methyltransferases (Dnmt1, 3a) are increased in GH deficiency & modulated by GH (mRNA, protein, activity)
**Based on this evidence, we predicted that the dwarf epigenome may be more stable than wild type mice as they age
Metabolic characteristics that may contributeto altered epigenome in long-living mice
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DNA Methylation in Dwarf Mice
Liver DNA methylome of wild type and Ames dwarf mice
2 month wild type (WTY) 2 month dwarf (DY)22 month wild type (WTO) 22 month dwarf (DO)
4 male replicates; 15x coverage; 1440Gbp sequence
0%
20%
40%
60%
80%
100%
DY DO NY NO
Glo
bal
% m
eth
tyla
ted
Cp
Gs
WTY
WTO
DY
DO
Chr1195Mb
-indicates that there are no largescale changes in the epigenome
Peter Adams
-150
-50
50
150
250
-200 -100 0 100 200
PC
2
PC1
WTY WTO DY DO
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0
10000
20000
30000
40000Total
Hypomethylated
Hypermethylated
Dwarf Normal
Ch
ange
in m
eth
ylat
edC
pG
s w
ith
age
Differentially methylated regions between young and old wild type (>=10%)
DY
DO
WTY
WTO
Liver DNA methylome of Ames dwarf mice is more STABLE compared to wild type mice
Peter Adams
0
1000
2000
3000
4000
-91
%
-71
%
-51
%
-31
%
-11
%
9%
29
%
49
%
69
%
Dwarf
NormalNormal
Dwarf
Nu
mb
er o
f D
MR
s
Difference in methylation (O-Y)
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DY
DO
WTY
WTO
Liver DNA methylome of Ames dwarf mice is BUFFEREDcompared to wild type mice
Peter Adams
DMRs hypomethylated with age in both wild type and Ames mice
30%
40%
50%
60%
70%
80%
Mea
n %
met
h p
er s
amp
le
WTY WTO DY DO
Hypomethylation of aDMRs - genomic features aresimilar between genotypes but WT mice harbor significantly greater numbers of hypomethylated genes & enhancers (little overlap on CpG islands).
Higher level of methylation in young dwarf serves tobuffer against age-associated hypomethylation.
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Ames mice respond differently to altered dietary MET compared to wild type mice (median-log-rank; maximal–Fisher test)
Median and maximal lifespans
0.16% MET Dwarf = WT Lifespan extension in wild type mice
0.43% & 1.3% MET Dwarf > WT
Lifespan Study
Several studies have shown that MET restriction extends lifespan
0 250 500 750 1000 1250 1500
0
20
40
60
80
100
WT 0.16%
Dwarf 0.16%
Days
Pe
rce
nt
su
rviv
al
Median p=.135890th % p=.4982
0 250 500 750 1000 1250 1500
0
20
40
60
80
100
Days
Perc
en
t s
urv
iva
l WT 0.43%
Dwarf 0.43%
Median p<.000190th % p=.0003
0 250 500 750 1000 1250 1500
0
20
40
60
80
100
Days
WT 1.3%
Dwarf 1.3%
Pe
rce
nt
su
rviv
al
Median p<.000190th % p=.0005
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0 250 500 750 1000 1250 1500
0
20
40
60
80
100
Days
Pe
rce
nt s
urv
iva
l
GHRKO 0.16%
GHRKO 0.43%
GHRKO 1.3%
0 250 500 750 1000 1250 1500
0
20
40
60
80
100
Days
Pe
rce
nt
su
rviv
al
GH Tg 0.16%
GH Tg 0.43%
GH Tg 1.3%
Median
0.16 vs 0.43 p<.0001
0.16 vs 1.3 p<.0001
90th %
0.16 vs 0.43 p=.0056
0.16 vs 1.3 p=.0060
0 250 500 750 1000 1250 15000
20
40
60
80
100
Days
Pe
rce
nt s
urv
iva
l
Dwarf WT 0.16%
Dwarf WT 0.43%
Dwarf WT 1.3%
Median0.16 vs 0.43 p<.0001
0.16 vs 1.3 p<.0001
90th %0.16 vs 0.43 p=.0164
0.16 vs 1.3 p=.0012
0 250 500 750 1000 1250 15000
20
40
60
80
100
Days
Pe
rce
nt
su
rviv
al
GHRKO WT 0.16%GHRKO WT 0.43%
GHRKO WT 1.3%
Median0.16 vs 0.43 p<.00010.16 vs 1.3 p<.0001
90th %
0.16 vs 0.43 p=.00120.16 vs 1.3 p=.0013
0 250 500 750 1000 1250 15000
20
40
60
80
100
Days
Pe
rce
nt
su
rviv
al
GH Tg WT 0.16%
GH Tg WT 0.43%
GH Tg WT 1.3%
Median
0.16 vs 0.43 p<.00010.16 vs 1.3 p=.0004
90th %0.16 vs 0.43 p=.0003
0.16 vs 1.3 p=.0295
0 250 500 750 1000 1250 15000
20
40
60
80
100
Days
Pe
rce
nt s
urv
iva
l
Dwarf 0.16%
Dwarf 0.43%
Dwarf 1.3%
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Reduced somatotropic signaling
Enhanced methionine metabolism
methyltransferase activity maintenance of DNA methylation pattern
epigenetic stability
cysteine availability thiol compounds
GSH metallothionein
antioxidative defense, potent antioxidant,maintains GSH for redox selenoprotein R metal chelator,
& enhances detoxification (MsrB) protein repair, **Dnmt1-regulated**recycling of MET
(normal chow, MR, ME)
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Conclusions
• GH status impacts MET metabolism & integrated pathways(regardless of dietary MET intake)
• GH signaling is necessary to discriminate levels of dietary MET
• The DNA methylome of GH-deficient mice appears to be:more STABLE than wild type micebetter BUFFERED against changes than wild type micebetter CONTROLLED (more uniform between mice) than wild type
• GH causes a shift in resources - In presence of GH increased demand for amino acids for growth In absence of GH shift in resources towards defense mechanisms
GH is promoted as an ‘anti-aging’ factor yet it suppresses defense mechanisms, impacts nutrient sensing, alters DNA methylation & accelerates age-related disease processes.
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Thank you!